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Publikationserfassung in EVALuna Biblio

EVALuna Biblio ist ein System zur dezentralen Online-Erfassung von Publikationen. In der Hautklinik verwenden wir dieses System seit 15 Jahren. 

Aktuelle Publikationen der Hautklinik

  • Identifying biomarkers and novel therapeutic targets in uveal melanoma.

    J Dtsch Dermatol Ges. 2024;22(1): 29-32

    Wessely A, Koch EAT, Vera J, Berking C, Heppt MV

    Uveal melanoma (UM) is an orphan cancer despite being the most common eye tumor in adults. Patients often present to skin cancer centers for treatment of metastatic disease although there are significant genetic, biological, and clinical differences from cutaneous melanoma. The treatments most commonly used for metastatic UM are tebentafusp and combined immune checkpoint blockade, both of which yield low response rates and may be accompanied by high treatment costs and significant immune-related toxicities. Thus, it is of paramount importance to identify biomarkers and clinical profiles predictive of treatment response and to find novel therapeutic targets. The use of immune checkpoint blockade showed more favorable outcomes in patients with extrahepatic disease and normal levels of serum lactate dehydrogenase in a panel of retrospective studies, making its use more reasonable in this subgroup. To identify novel drug targets, we will analyze the expression and relevance of neural crest transcription factors in patient bio-specimens using next-generation nanopore sequencing. Computer algorithms and network-based analysis will facilitate the identification of druggable targets which will subsequently be validated in patient-derived short-term cell cultures. This approach will help to find novel and personalized treatments for UM.

    Pubmed
  • Unbiased high-dimensional flow cytometry identified NK and DC immune cell signature in Luminal A-type and triple negative breast cancer.

    Oncoimmunology. 2024;13(1):

    Heger L, Heidkamp GF, Amon L, Nimmerjahn F, Bäuerle T, Maier A, Erber R, Hartmann A, Hack CC, Ruebner M, Huebner H, Fasching P, Beckmann MW, Dudziak D

    Breast cancer is the most common malignancy in women worldwide and a highly heterogeneous disease. Four different subtypes are described that differ in the expression of hormone receptors as well as the growth factor receptor HER2. Treatment modalities and survival rate depend on the subtype of breast cancer. However, it is still not clear which patients benefit from immunotherapeutic approaches such as checkpoint blockade. Thus, we aimed to decipher the immune cell signature of the different breast cancer subtypes based on high-dimensional flow cytometry followed by unbiased approaches. Here, we show that the frequency of NK cells is reduced in Luminal A and B as well as triple negative breast cancer and that the phenotype of residual NK cells is changed toward regulatory CD11b-CD16- NK cells. Further, we found higher frequencies of PD-1+ CD4+ and CD8+ T cells in triple negative breast cancer. Moreover, while Luminal A-type breast cancer was enriched for CD14+ cDC2 (named type 3 DC (DC3)), CD14- cDC2 (named DC2) were more frequent in triple negative breast cancer. In contrast, HER2-enriched breast cancer did not show major alterations in the composition of the immune cell compartment in the tumor microenvironment. These findings suggest that patients with Luminal A- and B-type as well as triple negative breast cancer might benefit from immunotherapeutic approaches targeting NK cells.

    Pubmed
  • Fatal and Near-Fatal Anaphylaxis: Data From the European Anaphylaxis Registry and National Health Statistics.

    J Allergy Clin Immunol Pract. 2024;12(1): 96-105.e8

    Höfer V, Dölle-Bierke S, Francuzik W, Ruëff F, Sabouraud-Leclerc D, Treudler R, Moeser A, Hartmann K, Pföhler C, Wagner N, Ensina LF, Wedi B, Cardona V, Worm M

    BACKGROUND: Anaphylaxis is a serious systemic reaction-data on fatal and near-fatal reactions are limited.

    OBJECTIVE: To better understand clinical patterns and risks factors of severe anaphylaxis by a deep analysis of data from fatal and near-fatal anaphylaxis.

    METHODS: Data from the European Anaphylaxis Registry on fatal/near-fatal anaphylactic reactions and national data on anaphylaxis fatalities were investigated.

    RESULTS: A total of 305 fatal/near-fatal reactions among children and adults including 35 fatalities from the European Anaphylaxis Registry were identified. The most frequent elicitors were drugs, insects, and food. Male patients (66%/60%) were more frequently affected. Male sex, higher age, concomitant mastocytosis, and cardiovascular disease were associated with a more severe outcome. With increasing reaction severity, skin symptoms were less frequently observed (45% of fatal reactions). In parallel, anaphylaxis mortality rates were studied. The data show that anaphylaxis mortality rates increased in Germany from 0.48 (2009) to 0.59 per 1,000,000 population per year (2020). This increase was apparent only in the female population. In this data set, drugs were the most frequent elicitor of anaphylaxis fatalities, and the rate for this increased over time.

    CONCLUSIONS: We identified not only elicitors but also individual factors to be associated with an increased risk of fatal anaphylaxis. Such patients should be recognized and managed with great caution. The increase in drug-induced fatalities points to the need for a better allergological care of patients suffering from drug hypersensitivity.

    Pubmed
  • Clinical characteristics and treatment modalities in uremic and non uremic calciphylaxis - a dermatological single-center experience.

    Ren Fail. 2024;46(1):

    Yousuf S, Busch D, Renner R, Schliep S, Erfurt-Berge C

    Calciphylaxis (CP) is a serious, potentially life-threatening disease that presents with medial calcification of small-sized vessels and painful ischemic ulcerations. Although calciphylaxis is frequently seen in patients with end-stage kidney disease on dialysis (calcific uremic arteriolopathy, CUA), there are reported cases of nonuremic calciphylaxis (NUC), which often remain undiagnosed. We conducted a retrospective chart review at our dermatological hospital and evaluated data concerning the epidemiology, comorbidities, medication, laboratory abnormalities, and therapeutic approaches of 60 patients diagnosed with calciphylaxis between 01/2012 and 12/2022. We identified 21 patients diagnosed with NUC and 39 with kidney disease. The predilection sites of skin lesions were the lower legs in 88% (n = 53), followed by the thigh and gluteal regions in 7% (n = 4). Significant differences were identified in comorbidities, such as atrial fibrillation (p < 0.001) and hyperparathyroidism (p < 0.01) accounting for CUA patients. Medication with vitamin K antagonists (p < 0.001), phosphate binders (p < 0.001), and loop diuretics (p < 0.01) was found to be associated with the onset of calciphylaxis. Hyperphosphatemia (p < 0.001), increased parathyroid hormone (p < 0.01) and triglyceride levels (p < 0.01), hypoalbuminemia (p < 0.01) and decreased hemoglobin values (p < 0.001) in the CUA cohort were significantly different from those in the NUC group. All patients with CUA received systemic medication. In contrast, only 38% (n = 8) of patients with NUC received systemic treatment. Striking discrepancies in the treatment of both cohorts were detected. In particular, NUC remains a disease pattern that is still poorly understood and differs from CUA in several important parameters.

    Pubmed
  • Immune signatures of checkpoint inhibitor-induced autoimmunity-A focus on neurotoxicity.

    Neuro-oncol. 2024;26(2): 279-294

    Müller-Jensen L, Schulz AR, Mei HE, Mohr R, Ulrich C, Knape P, Frost N, Frischbutter S, Kunkel D, Schinke C, Roque LG, Maierhof SK, Nickel FT, Heinzerling L, Endres M, Boehmerle W, Huehnchen P, Knauss S

    BACKGROUND: Neurologic immune-related adverse events (irAE-n) are rare but severe toxicities of immune checkpoint inhibitor (ICI) treatment. To overcome diagnostic and therapeutic challenges, a better mechanistic understanding of irAE-n is paramount.

    METHODS: In this observational cohort study, we collected serum and peripheral blood samples from 34 consecutive cancer patients with irAE-n (during acute illness) and 49 cancer control patients without irAE-n (pre- and on-ICI treatment, n = 44 without high-grade irAEs, n = 5 with high-grade nonneurologic irAEs). Patients received either anti-programmed cell death protein (PD)-1 or anti-PD ligand-1 monotherapy or anti-PD-1/anti-cytotoxic T-lymphocyte-associated protein-4 combination therapy. Most common cancers were melanoma, lung cancer, and hepatocellular carcinoma. Peripheral blood immune profiling was performed using 48-marker single-cell mass cytometry and a multiplex cytokine assay.

    RESULTS: During acute illness, patients with irAE-n presented higher frequencies of cluster of differentiation (CD)8+ effector memory type (EM-)1 and central memory (CM) T cells compared to controls without irAEs. Multiorgan immunotoxicities (neurologic + nonneurologic) were associated with higher CD8+ EM1 T cell counts. While there were no B cell changes in the overall cohort, we detected a marked decrease of IgD- CD11c+ CD21low and IgD- CD24+ CD21high B cells in a subgroup of patients with autoantibody-positive irAE-n. We further identified signatures indicative of enhanced chemotaxis and inflammation in irAE-n patients and discovered C-X-C motif chemokine ligand (CXCL)10 as a promising marker to diagnose high-grade immunotoxicities such as irAE-n.

    CONCLUSIONS: We demonstrate profound and partly subgroup-specific immune cell dysregulation in irAE-n patients, which may guide future biomarker development and targeted treatment approaches.

    Pubmed
  • Federated Learning for Decentralized Artificial Intelligence in Melanoma Diagnostics.

    JAMA Dermatol. 2024;():

    Haggenmüller S, Schmitt M, Krieghoff-Henning E, Hekler A, Maron RC, Wies C, Utikal JS, Meier F, Hobelsberger S, Gellrich FF, Sergon M, Hauschild A, French LE, Heinzerling L, Schlager JG, Ghoreschi K, Schlaak M, Hilke FJ, Poch G, Korsing S, Berking C, Heppt MV, Erdmann M, Haferkamp S, Drexler K, Schadendorf D, Sondermann W, Goebeler M, Schilling B, Kather JN, Fröhling S, Brinker TJ

    IMPORTANCE: The development of artificial intelligence (AI)-based melanoma classifiers typically calls for large, centralized datasets, requiring hospitals to give away their patient data, which raises serious privacy concerns. To address this concern, decentralized federated learning has been proposed, where classifier development is distributed across hospitals.

    OBJECTIVE: To investigate whether a more privacy-preserving federated learning approach can achieve comparable diagnostic performance to a classical centralized (ie, single-model) and ensemble learning approach for AI-based melanoma diagnostics.

    DESIGN, SETTING, AND PARTICIPANTS: This multicentric, single-arm diagnostic study developed a federated model for melanoma-nevus classification using histopathological whole-slide images prospectively acquired at 6 German university hospitals between April 2021 and February 2023 and benchmarked it using both a holdout and an external test dataset. Data analysis was performed from February to April 2023.

    EXPOSURES: All whole-slide images were retrospectively analyzed by an AI-based classifier without influencing routine clinical care.

    MAIN OUTCOMES AND MEASURES: The area under the receiver operating characteristic curve (AUROC) served as the primary end point for evaluating the diagnostic performance. Secondary end points included balanced accuracy, sensitivity, and specificity.

    RESULTS: The study included 1025 whole-slide images of clinically melanoma-suspicious skin lesions from 923 patients, consisting of 388 histopathologically confirmed invasive melanomas and 637 nevi. The median (range) age at diagnosis was 58 (18-95) years for the training set, 57 (18-93) years for the holdout test dataset, and 61 (18-95) years for the external test dataset; the median (range) Breslow thickness was 0.70 (0.10-34.00) mm, 0.70 (0.20-14.40) mm, and 0.80 (0.30-20.00) mm, respectively. The federated approach (0.8579; 95% CI, 0.7693-0.9299) performed significantly worse than the classical centralized approach (0.9024; 95% CI, 0.8379-0.9565) in terms of AUROC on a holdout test dataset (pairwise Wilcoxon signed-rank, P < .001) but performed significantly better (0.9126; 95% CI, 0.8810-0.9412) than the classical centralized approach (0.9045; 95% CI, 0.8701-0.9331) on an external test dataset (pairwise Wilcoxon signed-rank, P < .001). Notably, the federated approach performed significantly worse than the ensemble approach on both the holdout (0.8867; 95% CI, 0.8103-0.9481) and external test dataset (0.9227; 95% CI, 0.8941-0.9479).

    CONCLUSIONS AND RELEVANCE: The findings of this diagnostic study suggest that federated learning is a viable approach for the binary classification of invasive melanomas and nevi on a clinically representative distributed dataset. Federated learning can improve privacy protection in AI-based melanoma diagnostics while simultaneously promoting collaboration across institutions and countries. Moreover, it may have the potential to be extended to other image classification tasks in digital cancer histopathology and beyond.

    Pubmed
  • Dermatologist-like explainable AI enhances trust and confidence in diagnosing melanoma.

    Nat Commun. 2024;15(1):

    Chanda T, Hauser K, Hobelsberger S, Bucher TC, Garcia CN, Wies C, Kittler H, Tschandl P, Navarrete-Dechent C, Podlipnik S, Chousakos E, Crnaric I, Majstorovic J, Alhajwan L, Foreman T, Peternel S, Sarap S, Özdemir İ, Barnhill RL, Llamas-Velasco M, Poch G, Korsing S, Sondermann W, Gellrich FF, Heppt MV, Erdmann M, Haferkamp S, Drexler K, Goebeler M, Schilling B, Utikal JS, Ghoreschi K, Fröhling S, Krieghoff-Henning E, Reader Study Consortium , Brinker TJ, Salava A, Thiem A, Dimitrios A, Ammar AM, Vučemilović AS, Yoshimura AM, Ilieva A, Gesierich A, Reimer-Taschenbrecker A, Kolios AGA, Kalva A, Ferhatosmanoğlu A, Beyens A, Pföhler C, Erdil DI, Jovanovic D, Racz E, Bechara FG, Vaccaro F, Dimitriou F, Rasulova G, Cenk H, Yanatma I, Kolm I, Hoorens I, Sheshova IP, Jocic I, Knuever J, Fleißner J, Thamm JR, Dahlberg J, Lluch-Galcerá JJ, Figueroa JSA, Holzgruber J, Welzel J, Damevska K, Mayer KE, Maul LV, Garzona-Navas L, Bley LI, Schmitt L, Reipen L, Shafik L, Petrovska L, Golle L, Jopen L, Gogilidze M, Burg MR, Morales-Sánchez MA, Sławińska M, Mengoni M, Dragolov M, Iglesias-Pena N, Booken N, Enechukwu NA, Persa OD, Oninla OA, Theofilogiannakou P, Kage P, Neto RRO, Peralta R, Afiouni R, Schuh S, Schnabl-Scheu S, Vural S, Hudson S, Saa SR, Hartmann S, Damevska S, Finck S, Braun SA, Hartmann T, Welponer T, Sotirovski T, Bondare-Ansberga V, Ahlgrimm-Siess V, Frings VG, Simeonovski V, Zafirovik Z, Maul JT, Lehr S, Wobser M, Debus D, Riad H, Pereira MP, Lengyel Z, Balcere A, Tsakiri A, Braun RP

    Artificial intelligence (AI) systems have been shown to help dermatologists diagnose melanoma more accurately, however they lack transparency, hindering user acceptance. Explainable AI (XAI) methods can help to increase transparency, yet often lack precise, domain-specific explanations. Moreover, the impact of XAI methods on dermatologists' decisions has not yet been evaluated. Building upon previous research, we introduce an XAI system that provides precise and domain-specific explanations alongside its differential diagnoses of melanomas and nevi. Through a three-phase study, we assess its impact on dermatologists' diagnostic accuracy, diagnostic confidence, and trust in the XAI-support. Our results show strong alignment between XAI and dermatologist explanations. We also show that dermatologists' confidence in their diagnoses, and their trust in the support system significantly increase with XAI compared to conventional AI. This study highlights dermatologists' willingness to adopt such XAI systems, promoting future use in the clinic.

    Pubmed
  • Epidemiology of 7375 children and adolescents hospitalized with COVID-19 in Germany, reported via a prospective, nationwide surveillance study in 2020-2022.

    Sci Rep. 2024;14(1):

    Doenhardt M, Hufnagel M, Diffloth N, Hübner J, Mauer R, Schneider DT, Simon A, Tenenbaum T, Trotter A, Armann J, Berner R, DGPI COVID-19 working group , Abuleed A, Achenbach M, Adamiak-Brych G, Aderhold M, Akanbi S, Akmeinasi M, Albers N, Ammann-Schnell L, Anders K, Andree T, Anhalt J, Apel N, Arens S, Aring C, Armbruster C, Arnold I, Austgen T, Bachmat I, Balles L, Baltaci A, Baranowski T, Barth S, Barth S, Castrillón MPB, Baumann S, Baumbach L, Becker B, Beer A, Beier G, Bell C, Bellou A, Bentz S, Berens J, Berger E, Berzel S, Bley J, Blumberg H, Blume S, Böckenholt K, Böckmann A, Bode S, Boever J, Böhm L, Böhme H, Bölke C, Borchers MM, Bosse HM, Böswald M, Botschen K, Böttger F, Braun S, Brenner B, Brinkmann F, Bruggmoser B, Brunner J, Bucher FL, Buchtala L, Budde J, Bullmann R, Bungert B, Büsdorf D, Cardellini L, Cattaneo C, Chao CM, Chaparro L, Christians C, Cremer K, Cvetanovic G, Czwienzek A, Daluwatta M, de Sousa G, Degirmenci M, Dejas F, Deutschmann J, Deutz U, Dobrianska I, Döhring K, Donath H, Dresen A, Dreßen S, Drozdek M, Dubenhorst J, Dunker M, Eberhardt H, Ebert F, Echelmeyer H, Ehrentraut K, Ehrsam C, Eichelmann TA, Ellmann H, Endmann M, Endres S, Endres E, Engler M, Engler D, Eppler D, Erbe O, Erdmann M, Esser A, Ewest S, Falderbaum P, Faßbender L, Ferber S, Fiedler A, Fischer M, Fischer D, Fischer-Ging E, Fischer-Schmidt I, Fleischer AS, Flümann S, Focke D, Foth S, Fövényesi R, Frank S, Fremerey C, Frenzke H, Freudenberg P, Freudenhammer M, Fritsch C, Frohn S, Fuhrmann S, Pavlíková VG, Galow L, Gappa M, Gärtner S, Gaspar H, Geerken S, Gehm J, Gehrlein F, Geier N, Geißlreiter B, Geltinger M, Gerlach M, Gerleve H, Germann C, Giesen V, Girrbach A, Glas K, Goetz L, Goj K, Goldhardt C, Gottschalk J, Gottschlich JF, Götz O, Gröger K, Gronwald S, Lordemann AG, Grotheer A, Gruber K, Grüner J, Grünwedel M, Gu L, Gummersbach J, Haag S, Haag S, Hagel Y, Hagemann S, Hainmann I, Halwas N, Hanke C, Härtner J, Haselier C, Haupt A, Heffels MK, Heidtmann S, Heimer AL, Heinrich C, Heinrich A, Hempel L, Hempel C, Hennig S, Herbst C, Herholz L, Hermann M, Hermens JS, Hertel M, Herzog M, Heubner G, Hildebrandt J, Hilker KA, Hillebrand G, Himpel M, Hirschhausen C, Höfer M, Hoffmann L, Hoffmann HG, Höfgen M, Hofknecht N, Hofmann A, Hofmann F, Holtkamp K, Holzinger M, Homburg A, Hoppen T, Horst T, Horváth AA, Hummler M, Hundsdörfer P, Hüseman D, Huster C, Ido N, Ioannou P, Jedwilayties S, Jonas N, Junge C, Junghanns L, Kádár A, Kaddour M, Kahlenberg L, Kaiser L, Kaiser-Labusch P, Kalhoff H, Kaltenhauser C, Kaluza E, Kamin W, Kanann CV, Kania M, Kannan CV, Kanneettukandathil S, Karpinski H, Kassbeger F, Kauertz K, Kavvalou A, Kelzon S, Kern I, Kernen E, Kersten M, Keßner MS, Kever D, Khakzar C, Kim J, Kirner L, Kirschstein M, Kiss N, Kitz R, Kleff C, Klein D, Klingel LB, Kluthe C, Knechtel J, Kneißle M, Knirsch F, Kobbe R, Köbsch A, Kohlen L, Kohlhauser-Vollmuth C, Vasconcelos MK, Königs A, Konrad F, Koop S, Kopka J, Kornherr V, Kortenbusch AL, Kosteczka R, Köster H, Kowski S, Kravets H, Krink E, Krogh M, Kuglin R, Kühl R, Kuhlmann A, Küpper-Tetzel LM, Kuska M, Kwaschnowitz S, Lange M, Lankes F, Laubenbacher J, Lautner G, Le TT, Leykamm V, Libuschewski H, Lichtenstein L, Lienert N, Liese J, Lieser U, Lindl I, Lindner T, Lischetzki G, Lohr M, Lorenz N, Lorenzen N, Löwe M, Lubitz D, Lueg M, Luft L, Luo S, Lwowsky D, Machon K, Magin K, Maiberger T, Mand N, Markowsky A, Maurer W, Mauritz M, Meinhold T, Meister J, Menden M, Messer V, Meyburg J, Meyer U, Meyer M, Meyer J, Meyer-Dobkowitz L, Michel P, Mohorovicic M, Moise LG, Mönch K, Monnheimer M, Morawski Y, Morgenbrod A, Moritz K, Muhmann D, Müksch B, Müller S, Müller C, Müller A, Müller V, Müller Y, Müller G, Müller-Franz K, Naehrlich L, Naghed K, Näther N, Nespor T, Neuhierl T, Neukamm AC, Nguyen N, Nielsen D, Niethammer K, Obernosterer L, Opgen-Rhein B, Östreicher I, Özdemir E, Paduraru-Stoian N, Palm M, Parigger L, Pellmann N, Pelster T, Pengu A, Pentek F, Petrasch M, Pfennigs AM, Pfisterer A, Pfülb A, Piehler L, Pindur U, Pingel M, Pitsikoulis E, Plutowski J, Poot W, Poralla S, Pottiez J, Pötzsch S, Pretzel P, Preuß C, Propson S, Puhachova K, Pütz D, Quadri-Niazi S, Queisser B, Rambow J, Rau G, Rau C, Raum J, Reck H, Rehmann V, Reichert F, Reinhardt T, Remy C, Renk H, Richard A, Richter C, Rieber N, Riedhammer S, Ringe H, Rippberger B, Rohrbach M, Rokonal B, Rötger C, Rothermel A, Rox R, Rühlmann A, Ryckmanns MC, Safarova S, Salem M, Sarial D, Sartor H, Saxe J, Schade H, Schäfer M, Scheffler C, Scheffler LB, Scheiermann M, Schiele S, Schierloh K, Schiller M, Schiller B, Schilling R, Schitke C, Schlabach C, Schlichting T, Schlick C, Schlingschröder C, Schmid F, Schmidt B, Schneider J, Schneider D, Schneider HC, Schnelke A, Schobeß A, Schrod L, Schröder A, Schröder S, Schug T, Schulze C, Schuster K, Schütz K, Schwägerl V, Seidel C, Seidel C, Seidel S, Seidel J, Seringhaus-Förster K, Setzer A, Seul R, Shabanah W, Shamdeen MG, Sigl S, Simon I, Solomou C, Sönmez E, Spath L, Spehl M, Stanjek T, Staude D, Steenblock J, Stehle S, Steidl M, Steif B, Stein D, Stein F, Steindor M, Stemberg F, Stephan S, Stienen A, Stockmann A, Strier U, Ströle H, Szudarek R, Ta VH, Tan K, Telaar R, Telschow A, Teufel L, Thein S, Thiel LG, Thiesing L, Thomas L, Thomas J, Timke C, Toni I, Topuz M, Trau S, Tschiedel E, Tzimou S, Uhlemann F, Uhlig T, Ulla L, Urgatz B, Salis NV, Soldenhoff SV, van Bahlen L, van den Heuvel AI, Vehse K, Veit R, Verleysdonk J, Viechtbauer A, Vieth S, Vogel M, von Blomberg S, von der Decken K, von Schnakenburg C, Wagner J, Wahjudi T, Waldecker K, Walden U, Walther U, Walther M, Wegendt C, Wehl G, Weichert S, Weiland JA, Weiß J, Wendt L, Wentzel V, Wersal C, Wetzel U, Wichmann B, Wickert K, Wieland S, Wiethoff CM, Wietz H, Wild F, Willing R, Windischmann C, Winkeler V, Winkelmann M, Winkler S, Wißlicen L, Wormit-Frenzel I, Wowra T, Wroblewski A, Wulf D, Wurm D, Zaddach M, Zahn J, Zbieranek K, Zehnder LS, Zeller A, Zellerhoff M, Zerlik K, Zimmermann J, Zimolová M, Zügge U

    By means of a nationwide, prospective, multicenter, observational cohort registry collecting data on 7375 patients with laboratory-confirmed SARS-CoV-2 admitted to children's hospitals in Germany, March 2020-November 2022, our study assessed the clinical features of children and adolescents hospitalized due to SARS-CoV-2, evaluated which of these patients might be at highest risk for severe COVID-19, and identified underlying risk factors. Outcomes tracked included: symptomatic infection, case fatality, sequelae at discharge and severe disease. Among reported cases, median age was one year, with 42% being infants. Half were admitted for reasons other than SARS-CoV-2. In 27%, preexisting comorbidities were present, most frequently obesity, neurological/neuromuscular disorders, premature birth, and respiratory, cardiovascular or gastrointestinal diseases. 3.0% of cases were admitted to ICU, but ICU admission rates varied as different SARS-CoV-2 variants gained prevalence. Main risk factors linked to ICU admission due to COVID-19 were: patient age (> 12 and 1-4 years old), obesity, neurological/neuromuscular diseases, Trisomy 21 or other genetic syndromes, and coinfections at time of hospitalization. With Omicron, the group at highest risk shifted to 1-4-year-olds. For both health care providers and the general public, understanding risk factors for severe disease is critical to informing decisions about risk-reduction measures, including vaccination and masking guidelines.

    Pubmed
  • Guidelines for mouse and human DC generation.

    Eur J Immunol. 2023;53(11):

    Lutz MB, Ali S, Audiger C, Autenrieth SE, Berod L, Bigley V, Cyran L, Dalod M, Dörrie J, Dudziak D, Flórez-Grau G, Giusiano L, Godoy GJ, Heuer M, Krug AB, Lehmann CHK, Mayer CT, Naik SH, Scheu S, Schreibelt G, Segura E, Seré K, Sparwasser T, Tel J, Xu H, Zenke M

    This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various non-lymphoid tissues. This article provides protocols with top ticks and pitfalls for preparation and successful generation of mouse and human DC from different cellular sources, such as murine BM and HoxB8 cells, as well as human CD34+ cells from cord blood, BM, and peripheral blood or peripheral blood monocytes. We describe murine cDC1, cDC2, and pDC generation with Flt3L and the generation of BM-derived DC with GM-CSF. Protocols for human DC generation focus on CD34+ cell culture on OP9 cell layers for cDC1, cDC2, cDC3, and pDC subset generation and DC generation from peripheral blood monocytes (MoDC). Additional protocols include enrichment of murine DC subsets, CRISPR/Cas9 editing, and clinical grade human DC generation. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.

    Pubmed
  • One Website to Gather them All: Usability Testing of the New German SKin Cancer INFOrmation (SKINFO) Website-A Mixed-methods Approach.

    J Cancer Educ. 2023;38(4): 1264-1270

    Steeb T, Brütting J, Reinhardt L, Hoffmann J, Weiler N, Heppt MV, Erdmann M, Doppler A, Weber C, Schadendorf D, Meier F, Berking C, German Skin Cancer Council

    Skin cancer patients increasingly search the internet to acquire disease-related information. However, information on the internet may be misleading. Recently, SKINFO has been launched, a website exclusively created for German-speaking skin cancer patients providing information as well as additional resources of verified quality. Here, we describe the results of the first usability test of SKINFO using a mixed-methods approach. Ten adult patients with skin cancer were recruited for usability testing in the skin cancer units of the University Hospitals of Erlangen and Dresden, Germany. Testing consisted of three different scenarios where patients were asked to find specific information on the SKINFO website guided by the think-aloud method. Descriptive analysis and content analyses were performed. All patients would recommend SKINFO and appreciated its content, design, and structure. Think-aloud analysis identified the topics layout, navigation, and content and structure which would benefit from refinement. Major criticism included the navigation through the website, and the desire for more specific information addressing patients' relatives and the latest, up-to-date information. Overall, usability testing showed that the unique web-based information platform has the potential to support patients coping with skin cancer and thus strengthen informed decision-making.

    Pubmed
  • Immune checkpoint inhibition and targeted therapy for melanoma: A patient-oriented cross-sectional comparative multicentre study.

    J Eur Acad Dermatol Venereol. 2023;37(5): 884-893

    Thiem A, Mashhadiakbar P, Cussigh C, Hassel JC, Grimmelmann I, Gutzmer R, Schlaak M, Heppt MV, Dücker P, Hüning S, Schulmeyer L, Schilling B, Haferkamp S, Ziemer M, Moritz RKC, Hagelstein V, Terheyden P, Posch C, Gaiser MR, Kropp P, Emmert S, Müller B, Tietze JK

    BACKGROUND: Choosing the adequate systemic treatment for melanoma is driven by clinical parameters and personal preferences.

    OBJECTIVE: Evaluation of the impact of disease and treatment on the daily life of patients receiving systemic therapy for melanoma.

    METHODS: A German-wide, cross-sectional comparative study was conducted at 13 specialized skin cancer centres from 08/2020 to 03/2021. A questionnaire was distributed to assess patients' perception of disease and symptoms, the impact of their current treatment on quality of life (QOL) and activities, adverse events (AEs), therapeutic visits, as well as believe in and satisfaction with their current systemic melanoma treatment. Patient-reported outcomes (PROs) were rated on a continuous numerical rating scale or selected from a given list.

    RESULTS: Four hundred and fourteen patients with systemic melanoma therapy were included. 359 (87%) received immune checkpoint inhibition (ICI) and 55 (13%) targeted therapy (TT). About 1/3 of patients were adjuvantly treated, the remaining because of unresectable/metastatic melanoma. In subgroup analyses, only in the adjuvant setting, TT patients reported a significant decrease in their treatment associated QOL compared to patients with ICI (p = 0.02). Patients with TT were 1.9 times more likely to report AEs than patients with ICI, a difference being significant just for the adjuvant setting (p = 0.01). ICI treatment intervals differed significantly between adjuvant and unresectable/metastatic setting (p = 0.04), though all patients, regardless of their specific ICI drug, evaluated their treatment frequency as adequate. TT patients with dabrafenib/trametinib (n = 37) or encorafenib/binimetinib (n = 15) did not differ regarding the strain of daily pill intake. Patients older than 63 years rated various PROs better than younger patients.

    CONCLUSIONS: Patients evaluated their treatment mainly positively. ICI might be preferred over TT regarding QOL and patient-reported AEs in the adjuvant setting. Older melanoma patients appeared to be less impacted by their disease and more satisfied with their treatment.

    Pubmed
  • Real-world outcomes using PD-1 antibodies and BRAF + MEK inhibitors for adjuvant melanoma treatment from 39 skin cancer centers in Germany, Austria and Switzerland.

    J Eur Acad Dermatol Venereol. 2023;37(5): 894-906

    Schumann K, Mauch C, Klespe KC, Loquai C, Nikfarjam U, Schlaak M, Akçetin L, Kölblinger P, Hoellwerth M, Meissner M, Mengi G, Braun AD, Mengoni M, Dummer R, Mangana J, Sindrilaru MA, Radmann D, Hafner C, Freund J, Rappersberger K, Weihsengruber F, Meiss F, Reinhardt L, Meier F, Rainer B, Richtig E, Ressler JM, Höller C, Eigentler T, Amaral T, Peitsch WK, Hillen U, Harth W, Ziller F, Schatton K, Gambichler T, Susok L, Maul LV, Läubli H, Debus D, Weishaupt C, Börger S, Sievers K, Haferkamp S, Zenderowski V, Nguyen VA, Wanner M, Gutzmer R, Terheyden P, Kähler K, Emmert S, Thiem A, Sachse M, Gercken-Riedel S, Kaune KM, Thoms KM, Heinzerling L, Heppt MV, Tratzmiller S, Hoetzenecker W, Öllinger A, Steiner A, Peinhaupt T, Podda M, Schmid S, Wollina U, Biedermann T, Posch C

    BACKGROUND: Programmed death-1 (PD-1) antibodies and BRAF + MEK inhibitors are widely used for adjuvant therapy of fully resected high-risk melanoma. Little is known about treatment efficacy outside of phase III trials. This real-world study reports on clinical outcomes of modern adjuvant melanoma treatment in specialized skin cancer centers in Germany, Austria and Switzerland.

    METHODS: Multicenter, retrospective study investigating stage III-IV melanoma patients receiving adjuvant nivolumab (NIV), pembrolizumab (PEM) or dabrafenib + trametinib (D + T) between 1/2017 and 10/2021. The primary endpoint was 12-month recurrence-free survival (RFS). Further analyses included descriptive and correlative statistics, and a multivariate linear-regression machine learning model to assess the risk of early melanoma recurrence.

    RESULTS: In total, 1198 patients from 39 skin cancer centers from Germany, Austria and Switzerland were analysed. The vast majority received anti PD-1 therapies (n = 1003). Twelve-month RFS for anti PD-1 and BRAF + MEK inhibitor-treated patients were 78.1% and 86.5%, respectively (hazard ratio [HR] 1.998 [95% CI 1.335-2.991]; p = 0.001). There was no statistically significant difference in overall survival (OS) in anti PD-1 (95.8%) and BRAF + MEK inhibitor (96.9%) treated patients (p > 0.05) during the median follow-up of 17 months. Data indicates that anti PD-1 treated patients who develop immune-related adverse events (irAEs) have lower recurrence rates compared to patients with no irAEs (HR 0.578 [95% CI 0.443-0.754], p = 0.001). BRAF mutation status did not affect overall efficacy of anti PD-1 treatment (p > 0.05). In both, anti PD-1 and BRAF + MEK inhibitor treated cohorts, data did not show any difference in 12-month RFS and 12-month OS comparing patients receiving total lymph node dissection (TLND) versus sentinel lymph node biopsy only (p > 0.05). The recurrence prediction model reached high specificity but only low sensitivity with an AUC = 0.65. No new safety signals were detected. Overall, recorded numbers and severity of adverse events were lower than reported in pivotal phase III trials.

    CONCLUSIONS: Despite recent advances in adjuvant melanoma treatment, early recurrence remains a significant clinical challenge. This study shows that TLND does not reduce the risk of early melanoma recurrence and should only be considered in selected patients. Data further highlight that variables collected during clinical routine are unlikely to allow for a clinically relevant prediction of individual recurrence risk.

    Pubmed
  • Patch testing shellac in consecutive patients-Data of the Information Network of Departments of Dermatology (IVDK) 2021.

    Contact Dermatitis. 2023;88(1): 77-80

    Schubert S, Worm M, Dickel H, Wagner N, Brans R, Schroder-Kraft C, Bauer A, Koch A, Geier J, IVDK

    Pubmed
  • Update on the management of Bowen disease with a focus on patients' needs.

    Br J Dermatol. 2023;188(2):

    Berking C

    Pubmed
  • Guidelines for DC preparation and flow cytometric analysis of human lymphohematopoietic tissues.

    Eur J Immunol. 2023;53(12):

    Heger L, Dudziak D, Amon L, Hatscher L, Kaszubowski T, Lehmann CHK

    This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various non-lymphoid tissues. Within this article, detailed protocols are presented that allow for the generation of single cell suspensions from human lymphohematopoietic tissues including blood, spleen, thymus, and tonsils with a focus on the subsequent analysis of DC via flow cytometry, as well as flow cytometric cell sorting of primary human DC. Further, prepared single cell suspensions as well as cell sorter-purified DC can be subjected to other applications including cellular enrichment procedures, RNA sequencing, functional assays, and many more. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.

    Pubmed
  • Guidelines for mouse and human DC functional assays.

    Eur J Immunol. 2023;53(12):

    Clausen BE, Amon L, Backer RA, Berod L, Bopp T, Brand A, Burgdorf S, Chen L, Da M, Distler U, Dress RJ, Dudziak D, Dutertre CA, Eich C, Gabele A, Geiger M, Ginhoux F, Giusiano L, Godoy GJ, Hamouda AEI, Hatscher L, Heger L, Heidkamp GF, Hernandez LC, Jacobi L, Kaszubowski T, Kong WT, Lehmann CHK, López-López T, Mahnke K, Nitsche D, Renkawitz J, Reza RA, Sáez PJ, Schlautmann L, Schmitt MT, Seichter A, Sielaff M, Sparwasser T, Stoitzner P, Tchitashvili G, Tenzer S, Tochoedo NR, Vurnek D, Zink F, Hieronymus T

    This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various non-lymphoid tissues. Recent studies have provided evidence for an increasing number of phenotypically distinct conventional DC (cDC) subsets that on one hand exhibit a certain functional plasticity, but on the other hand are characterized by their tissue- and context-dependent functional specialization. Here, we describe a selection of assays for the functional characterization of mouse and human cDC. The first two protocols illustrate analysis of cDC endocytosis and metabolism, followed by guidelines for transcriptomic and proteomic characterization of cDC populations. Then, a larger group of assays describes the characterization of cDC migration in vitro, ex vivo, and in vivo. The final guidelines measure cDC inflammasome and antigen (cross)-presentation activity. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.

    Pubmed
  • Guidelines for DC preparation and flow cytometry analysis of mouse lymphohematopoietic tissues.

    Eur J Immunol. 2023;53(12):

    Amon L, Dudziak D, Backer RA, Clausen BE, Gmeiner C, Heger L, Jacobi L, Lehmann CHK, Probst HC, Seichter A, Tchitashvili G, Tochoedo NR, Trapaidze L, Vurnek D

    This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human DC from lymphoid organs, and various non-lymphoid tissues. Within this chapter, detailed protocols are presented that allow for the generation of single-cell suspensions from mouse lymphohematopoietic tissues including spleen, peripheral lymph nodes, and thymus, with a focus on the subsequent analysis of DC by flow cytometry. However, prepared single-cell suspensions can be subjected to other applications including sorting and cellular enrichment procedures, RNA sequencing, Western blotting, and many more. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.

    Pubmed
  • Guidelines for DC preparation and flow cytometry analysis of mouse nonlymphoid tissues.

    Eur J Immunol. 2023;53(11):

    Probst HC, Stoitzner P, Amon L, Backer RA, Brand A, Chen J, Clausen BE, Dieckmann S, Dudziak D, Heger L, Hodapp K, Hornsteiner F, Hovav AH, Jacobi L, Ji X, Kamenjarin N, Lahl K, Lahmar I, Lakus J, Lehmann CHK, Ortner D, Picard M, Roberti MP, Rossnagel L, Saba Y, Schalla C, Schlitzer A, Schraml BU, Schütze K, Seichter A, Seré K, Seretis A, Sopper S, Strandt H, Sykora MM, Theobald H, Tripp CH, Zitvogel L

    This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various nonlymphoid tissues. DC are sentinels of the immune system present in almost every mammalian organ. Since they represent a rare cell population, DC need to be extracted from organs with protocols that are specifically developed for each tissue. This article provides detailed protocols for the preparation of single-cell suspensions from various mouse nonlymphoid tissues, including skin, intestine, lung, kidney, mammary glands, oral mucosa and transplantable tumors. Furthermore, our guidelines include comprehensive protocols for multiplex flow cytometry analysis of DC subsets and feature top tricks for their proper discrimination from other myeloid cells. With this collection, we provide guidelines for in-depth analysis of DC subsets that will advance our understanding of their respective roles in healthy and diseased tissues. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all coauthors, making it an essential resource for basic and clinical DC immunologists.

    Pubmed
  • [Immune-mediated inflammatory diseases in Germany : A cross-sectional analysis of comorbidities and pharmacotherapy].

    Z Rheumatol. 2023;():

    Leipe J, Schmelz R, Riemekasten G, Thaçi D, Henes J, Schäkel K, Pinter A, Sticherling M, Wegner J, Fusco S, Linke M, Weber V, Manz KC, Bartz H, Roecken M, Schmidt S, Hoyer BF

    BACKGROUND: Immune-mediated inflammatory diseases (IMID) can lead to a substantial disease burden for those affected, in particular by the concomitant occurrence of other IMIDs or in the presence of comorbidities. The care of patients with IMIDs is complex and involves various medical disciplines.

    OBJECTIVE: To describe the burden of disease and the current routine drug treatment of patients with IMID.

    MATERIAL AND METHODS: The retrospective cross-sectional analysis was based on statutory health insurance claims data from the InGef database. Prevalent patients with psoriasis (Pso), psoriatic arthritis (PsA), spondylarthritis (SpA), rheumatoid arthritis (RA), Crohn's disease (MC), ulcerative colitis (CU), or connective tissue disease were identified among 3,988,695 insured patients in 2018. The concomitant occurrence of different IMIDs and the extent to which patients with IMID are affected by other comorbidities compared to a reference population were investigated. The current routine drug treatment was described based on the use of predefined forms of treatment.

    RESULTS: In the database 188,440 patients with IMID (4.7%) were identified. Compared to the reference population the prevalence of comorbidities, such as depressive episodes and cardiovascular risk factors was higher in patients with IMID. For MC, CU, RA, and PsA disease-modifying antirheumatic drugs (DMARD) and classical systemic forms of treatment were used most commonly. In Pso, SpA, and connective tissue disease nonsteroidal anti-inflammatory drugs (NSAID) were the most frequently used treatment often in combination with other drugs.

    CONCLUSION: A considerable number of patients with IMIDs (16.9-27.5%) suffer from different diseases of the IMID group. They are frequently affected by accompanying illnesses and require interdisciplinary medical treatment.

    Pubmed
  • Different phenotypes of drug-induced anaphylaxis-Data from the European Anaphylaxis Registry.

    Allergy. 2023;78(6): 1615-1627

    Hanschmann T, Francuzik W, Dölle-Bierke S, Hofmeier KS, Grabenhenrich L, Ruëff F, Renaudin JM, Pföhler C, Treudler R, Bilò MB, Lang R, Ensina LF, Christoff G, Cardona V, Wagner N, Reider N, Müller S, Dickel H, Worm M

    BACKGROUND: Drugs are a frequent cause of severe anaphylactic reactions. Here, we analyze a large dataset on drug induced anaphylaxis regarding elicitors, risk factors, symptoms, and treatment.

    METHODS: Data from the European Anaphylaxis Registry (2007-2019) with 1815 reported cases of drug-induced anaphylaxis were studied accordingly.

    RESULTS: Drugs are the third most frequent cause of anaphylaxis reported in the Anaphylaxis Registry. Among the eliciting groups of drugs analgesics and antibiotics were far most often reported. Female and senior patients were more frequently affected, while the number of children with DIA was low. DIA patients had symptoms affecting the skin and mucous membranes (n = 1525, 84.02%), the respiratory (n = 1300, 71.63%), the cardiovascular (n = 1251, 68.93%) and the gastrointestinal system (n = 549, 30.25%). Drugs caused significant more severe reactions, occurred more often in medical facilities and led to increased hospitalization rates in comparison to food and insect venom induced anaphylaxis. Adrenaline was used more often in patients with DIA than in anaphylaxis due to other causes. Patients with skin symptoms received more antihistamines and corticosteroids in the acute treatment, while gastrointestinal symptoms led to less adrenaline use.

    CONCLUSION: The study contributes to a better understanding of DIA, with a large number of cases from Europe supporting previous data, e.g., analgesics and antibiotics being the most frequent culprits for DIA. Female gender and higher age are relevant risk factors and despite clear recommendations, the emergency treatment of DIA is not administered according to the guidelines.

    Pubmed
  • A network medicine approach for identifying diagnostic and prognostic biomarkers and exploring drug repurposing in human cancer.

    Comput Struct Biotechnol J. 2023;21(): 34-45

    Zhang L, Fan S, Vera J, Lai X

    Cancer is a heterogeneous disease mainly driven by abnormal gene perturbations in regulatory networks. Therefore, it is appealing to identify the common and specific perturbed genes from multiple cancer networks. We developed an integrative network medicine approach to identify novel biomarkers and investigate drug repurposing across cancer types. We used a network-based method to prioritize genes in cancer-specific networks reconstructed using human transcriptome and interactome data. The prioritized genes show extensive perturbation and strong regulatory interaction with other highly perturbed genes, suggesting their vital contribution to tumorigenesis and tumor progression, and are therefore regarded as cancer genes. The cancer genes detected show remarkable performances in discriminating tumors from normal tissues and predicting survival times of cancer patients. Finally, we developed a network proximity approach to systematically screen drugs and identified dozens of candidates with repurposable potential in several cancer types. Taken together, we demonstrated the power of the network medicine approach to identify novel biomarkers and repurposable drugs in multiple cancer types. We have also made the data and code freely accessible to ensure reproducibility and reusability of the developed computational workflow.

    Pubmed
  • Conventional and three-dimensional photography as a tool to map distribution patterns of in-transit melanoma metastases on the lower extremity.

    Front Med (Lausanne). 2023;10():

    Müller K, Berking C, Voskens C, Heppt MV, Heinzerling L, Koch EAT, Kramer R, Merkel S, Schuler-Thurner B, Schellerer V, Steeb T, Wessely A, Erdmann M

    BACKGROUND: In melanoma, in-transit metastases characteristically occur at the lower extremity along lymphatic vessels.

    OBJECTIVES: The objective of this study was to evaluate conventional or three-dimensional photography as a tool to analyze in-transit metastasis pattern of melanoma of the lower extremity. In addition, we assessed risk factors for the development of in-transit metastases in cutaneous melanoma.

    METHODS: In this retrospective, monocentric study first we compared the clinical data of all evaluable patients with in-transit metastases of melanoma on the lower extremity (n = 94) with melanoma patients without recurrence of disease (n = 288). In addition, based on conventional (n = 24) and three-dimensional photography (n = 22), we defined the specific distribution patterns of the in-transit metastases on the lower extremity.

    RESULTS: Using a multivariate analysis we identified nodular melanoma, tumor thickness, and ulceration as independent risk factors to develop in-transit metastases ITM (n = 94). In patients with melanoma on the lower leg (n = 31), in-transit metastases preferentially developed along anatomically predefined lymphatic pathways. In contrast when analyzing in-transit metastases of melanoma on the foot (n = 15) no clear pattern could be visualized. In addition, no difference in distance between in-transit metastases and primary melanoma on the foot compared to the lower leg was observed using three-dimensional photography (n = 22).

    CONCLUSION: A risk-adapted follow-up of melanoma patients to detect in-transit metastases can be applied by knowledge of the specific lymphatic drainage of the lower extremity. Our current analysis suggests a more complex lymphatic drainage of the foot.

    Pubmed
  • Itching in Atopic Dermatitis: Patient- and Physician-reported Outcomes in the German Atopic Dermatitis Registry TREATgermany.

    Acta Derm Venereol. 2023;103():

    Weisshaar E, Bentz P, Apfelbacher C, Haufe E, Heinrich L, Heratizadeh A, Abraham S, Harder I, Kleinheinz A, Wollenberg A, Schäkel K, Wiemers F, Ertner J, Augustin M, Wildberger J, Von Kiedrowski R, Worm M, Zink A, Effendy I, Asmussen A, Pawlak M, Sticherling M, Hilgers M, Handrick C, Quist S, Schwarz B, Bell M, Staubach-Renz P, Hong-Weldemann SH, Homey B, Brücher JJ, Weidinger S, Werfel T, Schmitt J, TREATgermany study group

    TREATgermany is an investigator-initiated prospective disease registry. It investigates physician- and patient-reported disease severity (Eczema Area and Severity Index (EASI), objective Scoring Atopic Dermatitis (oSCORAD), Investigator Global Assessment, Patient-Oriented Eczema Measure (POEM), Patient Global Assessment (PGA)), patient-reported symptoms (itch, sleep loss, depressive symptoms), therapy courses and dermatological quality of life (DLQI) in moderate-to-severe atopic dermatitis with SCORAD > 20. 1,134 atopic dermatitis patients (mean age 41.0 ± 14.7 years, 42.5% females) were enrolled by 40 German recruiting sites (dermatological clinics and practices) between June 2016 and April 2021. The current analysis focuses on itch scores obtained with a numerical rating scale (NRS)) documented for the previous 3 days prior to baseline visit. The results show that 97.2% (1,090 of 1,121) patients experienced itch. Itch severity correlated moderately with severity of atopic dermatitis oSCORAD (rho = 0.44 (0.39-0.48)) and EASI score (rho = 0.41 (0.36-0.46)). A strong correlation was found with self-reported disease severity as PGA (rho = 0.68 (0.65-0.71)), POEM sum score (rho = 0.66 (0.63-0.69)) and dermatological quality of life impairment DLQI (rho = 0.61 (0.57-0.65)). Itch as a subjective complaint is more closely correlated with patient-reported outcomes than with objective assessments by the physician.

    Pubmed
  • Identification of circulating microRNA patterns in patients in psoriasis and psoriatic arthritis.

    Rheumatology (Oxford). 2023;62(10): 3448-3458

    Haschka J, Simon D, Bayat S, Messner Z, Kampylafka E, Fagni F, Skalicky S, Hackl M, Resch H, Zwerina J, Kleyer A, Cavallaro A, Sticherling M, Schett G, Kocijan R, Rech J

    OBJECTIVE: miRNAs are small non-coding RNAs that control gene expression. Specific intra- and extracellular miRNA signatures have been identified in various diseases. Whether certain miRNA signatures are associated with psoriasis (PsO) and PsA is currently unknown. We aimed to search for circulating miRNA signatures associated with PsO and PsA patients.

    METHODS: Expression of miRNAs was analysed by reverse transcription quantitative real-time PCR (RT-qPCR) in the serum of PsA, PsO patients and healthy controls. Demographic and disease-specific characteristics and imaging data from hand MRI were recorded. In the discovery phase, 192 miRNA assays were analysed in 48 samples (PsA, PsO, controls: each N = 16). For validation, 17 selected miRNAs were measured in the total population.

    RESULTS: A total of 141 patients and controls were analysed (51 PsA, 40 PsO, 50 controls). In the discovery phase 51 miRNAs in PsO and 64 miRNAs in PsA were down- or upregulated compared with controls, with 33 miRNAs being changed in both (adj. P < 0.05). The 17 top candidates from discovery were assessed in the validation phase, 9 of them discriminated PsA and PsO from controls [area under the curve (AUC) ≥0.70, all P < 0.05]. Four miRNAs (miR-19b-3p, miR-21-5p, miR-92a-3p and let-7b-5p) were significantly differently regulated between PsO and PsA. A combination of these miRNAs increased the AUC to 0.92 in multivariate regression model to discriminate PsO and PsA.

    CONCLUSION: miRNA signatures in PsA and PsO patients differ from controls. Nine miRNAs were differentially regulated in PsA and PsO patients, five of them previously reported to be involved in bone and cartilage metabolism, indicating an intimate association of psoriatic inflammation and bone/cartilage changes.

    Pubmed
  • Extensive furuncular myiasis in a travel returnee from Africa.

    J Eur Acad Dermatol Venereol. 2023;37(5): e590-e592

    Rechtien L, Kaufmann M, Sticherling M

    Pubmed
  • VEXAS syndrome mimicking lupus-like disease.

    Rheumatology (Oxford). 2023;62(9): e271-e272

    Valor-Méndez L, Sticherling M, Zeschick M, Atreya R, Schmidt FD, Waldfahrer F, Saake M, Hüffmeier U, Schett G, Rech J

    Pubmed
  • CARs and Drugs: Pharmacological Ways of Boosting CAR-T-Cell Therapy.

    Int J Mol Sci. 2023;24(3):

    Harrer DC, Dörrie J, Schaft N

    The development of chimeric antigen receptor T cells (CAR-T cells) has marked a new era in cancer immunotherapy. Based on a multitude of durable complete remissions in patients with hematological malignancies, FDA and EMA approval was issued to several CAR products targeting lymphoid leukemias and lymphomas. Nevertheless, about 50% of patients treated with these approved CAR products experience relapse or refractory disease necessitating salvage strategies. Moreover, in the vast majority of patients suffering from solid tumors, CAR-T-cell infusions could not induce durable complete remissions so far. Crucial obstacles to CAR-T-cell therapy resulting in a priori CAR-T-cell refractory disease or relapse after initially successful CAR-T-cell therapy encompass antigen shutdown and CAR-T-cell dysfunctionality. Antigen shutdown predominately rationalizes disease relapse in hematological malignancies, and CAR-T-cell dysfunctionality is characterized by insufficient CAR-T-cell proliferation and cytotoxicity frequently observed in patients with solid tumors. Thus, strategies to surmount those obstacles are being developed with high urgency. In this review, we want to highlight different approaches to combine CAR-T cells with drugs, such as small molecules and antibodies, to pharmacologically boost CAR-T-cell therapy. In particular, we discuss how certain drugs may help to counteract antigen shutdown and CAR-T-cell dysfunctionality in both hematological malignancies and solid tumors.

    Pubmed
  • Standardized Computer-Assisted Analysis of PRAME Immunoreactivity in Dysplastic Nevi and Superficial Spreading Melanomas.

    Int J Mol Sci. 2023;24(7):

    Koch EAT, Erdmann M, Berking C, Kiesewetter F, Kramer R, Schliep S, Heppt MV

    PRAME (PReferentially expressed Antigen in MElanoma) is a cancer testis antigen that is frequently expressed in melanoma compared to benign melanocytic proliferations and nevi. However, the interpretation of the intensity and distribution of PRAME immunostaining is not standardized a lot, which makes interpretation difficult. PRAME-stained histological slides of superficial spreading melanomas (SSM) and dysplastic nevi (DN) were digitized and analyzed using the digital pathology and image platform QuPath. t-tests and ROC AUCs were performed with SPSS. A p-value of <0.05 was used for statistical significance, and a ROC AUC score of >0.8 was considered a good result. A cut-off score was defined in an evaluation cohort and subsequently analyzed in an independent validation cohort. In total, 81 PRAME-stained specimens were included. The evaluation cohort included 32 (50%) SSM and 32 (50%) DN, and the mean of PRAME-positive cells/mm2 for the entire lesion was 455.3 (SD 428.2) in SSM and 60.5 (SD 130.1; p < 0.001) in DN. The ROC AUC of PRAME-positive cells of the entire lesion was 0.866, and in the epidermis it was 0.901. The defined cut-off score to distinguish between DN and SSM was 97.67 cells/mm2. In the validation cohort, 16 out of 17 cases (94.1%) were correctly classified by the cut-off score. The computer-aided assessment of PRAME immunostaining is a useful tool in dermatopathology to distinguish between DN and SSM. Lesions with a moderate expression and indifferent morphologic features will remain a challenge for dermatopathologists.

    Pubmed
  • Is tebentafusp superior to combined immune checkpoint blockade and other systemic treatments in metastatic uveal melanoma? A comparative efficacy analysis with population adjustment.

    Cancer Treat Rev. 2023;115():

    Petzold A, Steeb T, Wessely A, Koch EAT, Vera J, Berking C, Heppt MV

    BACKGROUND: Distinct systemic treatments exist for metastatic uveal melanoma. Tebentafusp and combined immune checkpoint blockade (ICB) with ipilimumab plus anti-PD-1 antibodies are the most commonly used treatment options but their comparative efficacy is unclear. The aim of this study is to compare currently available systemic treatments regarding overall survival (OS) and progression-free survival (PFS) with a focus on the comparison of tebentafusp versus combined ICB.

    METHODS: The protocol for this study was defined a priori and registered online in the PROSPERO international prospective register of systematic reviews (CRD42022308356, date of registration: 7.2.2022). We performed a systematic literature search in Medline, Embase, and Central to identify eligible studies reporting Kaplan-Meier curves or individual-level survival data showing OS and PFS for metastatic uveal melanoma patients treated with systemic treatments. Kaplan-Meier curves were digitized using the "WebPlotDigitizer" program. Individual-level survival data were subsequently remodelled and pooled for distinct treatment groups. To compare the OS of tebentafusp versus combined ICB, we used matching-adjusted indirect comparison (MAIC), two-stage MAIC (2SMAIC), and simulated treatment comparison (STC) together with digitized individual-level survival data as population-adjusted models.

    RESULTS: Overall, 55 independent studies were included of which 2,682 patients were evaluable for OS and 2,258 for PFS. Tebentafusp showed the highest median OS (mOS) of 22.4 months (95% confidence interval (CI): 19.9-29.6) compared to combined ICB (mOS: 15.7 months (95% CI: 14.4-17.9)), anti-PD-(L)1 antibody (mOS: 10.9 months (95% CI: 9.8-13.4)), chemotherapy (mOS: 9.95 months (95% CI: 8.9-11.2)), targeted therapies (mOS: 8.86 months (95% CI: 7.5-10.8)), and anti-CTLA-4 antibody (mOS: 7.8 months (95% CI: 6.8-9.3). The median PFS (mPFS) was similar among the treatment groups ranging from 2.7 months to 3.4 months. For the comparison of tebentafusp versus combined ICB, the hazard ratio (HR) was 0.641 (95% CI: 0.449-0.915) in the unadjusted model, whereas the population-adjusted models showed a HR of 0.386 (95% CI: 0.236-0.631) using MAIC, 0.378 (95% CI: 0.234-0.612) applying 2SMAIC and 0.284 (95% CI: 0.184-0.440) using STC.

    CONCLUSIONS: Tebentafusp achieved the best results compared to combined ICB and other systemic treatments, although these results have to be interpreted with caution due to the approximative methodical approach and high heterogeneity of included studies.

    Pubmed
  • Characterization of the impact of immune checkpoint inhibitors on platelet activation and aggregation.

    Immunobiology. 2023;228(1):

    Schlüter J, Cunningham S, Zimmermann R, Achenbach S, Kramer R, Erdmann M, Beckmann M, Heinzerling L, Hackstein H

    Immune checkpoint inhibitors (ICIs) are effective oncological drugs which block cellular check-point receptors typically targeted by tumor immune evasion strategies. Despite their benefits, clinicians have reported treatment-associated thromboembolism during ICI therapy in recent years. Though several theories on this ICI-associated pathogenesis exist, the direct effects of ICIs on platelets remains unknown. We therefore investigated the potential direct and indirect effect of PD-1, PD-L1 and CTLA-4-targeting ICIs on platelet functionality in multifaceted in vitro experiments. Interestingly, we could not observe a clear effect of ICI on platelet aggregation and primary hemostasis in whole blood and platelet concentrate-based assays. Furthermore, the presence of ICIs in toll-like receptor stimulation had no significant impact on platelet surface marker expression. In a second approach, we investigated the indirect immunological impact of ICIs on platelet activation by exposing platelets to supernatants from ICI- and Staphylococcal enterotoxin B-exposed PBMCs. Whereas ICIs affected IL-2 levels in supernatants, we could not detect clear differences in the secretion of pro-thrombogenic factors and platelet responses. The obtained data suggest that the direct influence of ICIs on platelet activation or the influence of altered T cell function on platelet activation cannot be considered a major factor in the development of thrombotic events.

    Pubmed
  • Inter-Rater Agreement in Assessing Risk of Bias in Melanoma Prediction Studies Using the Prediction Model Risk of Bias Assessment Tool (PROBAST): Results from a Controlled Experiment on the Effect of Specific Rater Training.

    J Clin Med. 2023;12(5):

    Kaiser I, Pfahlberg AB, Mathes S, Uter W, Diehl K, Steeb T, Heppt MV, Gefeller O

    Assessing the risk of bias (ROB) of studies is an important part of the conduct of systematic reviews and meta-analyses in clinical medicine. Among the many existing ROB tools, the Prediction Model Risk of Bias Assessment Tool (PROBAST) is a rather new instrument specifically designed to assess the ROB of prediction studies. In our study we analyzed the inter-rater reliability (IRR) of PROBAST and the effect of specialized training on the IRR. Six raters independently assessed the risk of bias (ROB) of all melanoma risk prediction studies published until 2021 (n = 42) using the PROBAST instrument. The raters evaluated the ROB of the first 20 studies without any guidance other than the published PROBAST literature. The remaining 22 studies were assessed after receiving customized training and guidance. Gwet's AC1 was used as the primary measure to quantify the pairwise and multi-rater IRR. Depending on the PROBAST domain, results before training showed a slight to moderate IRR (multi-rater AC1 ranging from 0.071 to 0.535). After training, the multi-rater AC1 ranged from 0.294 to 0.780 with a significant improvement for the overall ROB rating and two of the four domains. The largest net gain was achieved in the overall ROB rating (difference in multi-rater AC1: 0.405, 95%-CI 0.149-0.630). In conclusion, without targeted guidance, the IRR of PROBAST is low, questioning its use as an appropriate ROB instrument for prediction studies. Intensive training and guidance manuals with context-specific decision rules are needed to correctly apply and interpret the PROBAST instrument and to ensure consistency of ROB ratings.

    Pubmed
  • Contact sensitization to benzisothiazolinone: IVDK-data of the years 2002 to 2021.

    Contact Dermatitis. 2023;88(6): 446-455

    Geier J, Brans R, Weisshaar E, Wagner N, Szliska C, Heratizadeh A, Schubert S, IVDK

    BACKGROUND: Benzisothiazolinone (BIT; CAS no. 2634-33-5) is used as a biocide in various products, including water-based paints, metalworking fluids, and household products. In recent years, increasing sensitization rates have been observed in Europe.

    OBJECTIVE: To describe a time trend of sensitization to BIT, analyse concomitant reactions, and identify patients with increased risk of BIT sensitization.

    METHODS: Retrospective analysis of data from 26 739 patients patch tested with BIT, sodium salt, 0.1% petrolatum as part of several special test series within the Information Network of Departments of Dermatology (IVDK), 2002 to 2021.

    RESULTS: Positive reactions to BIT were noted in 771 patients (2.9%). Sensitization frequency varied over time and increased in recent years, peaking at 6.5% in 2020. Painters and metalworkers handling metalworking fluids, but not cleaners, had a significantly increased risk of BIT sensitization. From our data, there is no evidence of immunological cross-reactivity between BIT and other isothiazolinones.

    CONCLUSION: The increasing frequency of sensitization justifies adding BIT to the baseline series. More research on the clinical relevance of positive patch test reactions to BIT and the cause for the rising numbers of BIT sensitization is needed.

    Pubmed
  • S1-guideline cutaneous and subcutaneous leiomyosarcoma.

    J Dtsch Dermatol Ges. 2023;21(5): 555-563

    Helbig D, Dippel E, Erdmann M, Frisman A, Kage P, Leiter U, Mentzel T, Seidel C, Weishaupt C, Ziemer M, Ugurel S

    Superficial leiomyosarcomas (LMS) are rare skin cancers (2-3% of cutaneous sarcomas) that originate from dermally located hair follicle muscles, dartos or areolar muscles (cutaneous/dermal LMS), or from vascular muscle cells of the subcutaneous adipose tissue (subcutaneous LMS). These superficial LMS are distinct from LMS of the deep soft tissues. Leiomyosarcomas are typically localized at the lower extremities, trunk or capillitium, and present as painful, erythematous to brownish nodules. Diagnosis is made by histopathology. The treatment of choice for primary LMS is complete (R0) microscopically controlled excision, with safety margins of 1 cm in dermal LMS, and 2 cm in subcutaneous LMS, if possible. Non-resectable or metastatic LMS require individual treatment decisions. After R0 resection with 1 cm safety margins, the local recurrence rate of dermal LMS is very low, and metastasis is very rare. Subcutaneous LMS, very large, or incompletely excised LMS recur and metastasize more frequently. For this reason, clinical follow-up examinations are recommended every six months for cutaneous LMS, and every three months for subcutaneous LMS within the first two years (in subcutaneous LMS including locoregional lymph node sonography). Imaging such as CT/MRI is indicated only in primary tumors with special features, recurrences, or already metastasized tumors.

    Pubmed
  • Integration of transcriptomics data into agent-based models of solid tumor metastasis.

    Comput Struct Biotechnol J. 2023;21(): 1930-1941

    Retzlaff J, Lai X, Berking C, Vera J

    Recent progress in our understanding of cancer mostly relies on the systematic profiling of patient samples with high-throughput techniques like transcriptomics. With this approach, one can find gene signatures and networks underlying cancer aggressiveness and therapy resistance. However, omics data alone cannot generate insights into the spatiotemporal aspects of tumor progression. Here, multi-level computational modeling is a promising approach that would benefit from protocols to integrate the data generated by the high-throughput profiling of patient samples. We present a computational workflow to integrate transcriptomics data from tumor patients into hybrid, multi-scale cancer models. In the method, we conduct transcriptomics analysis to select key differentially regulated pathways in therapy responders and non-responders and link them to agent-based model parameters. We then determine global and local sensitivity through systematic model simulations that assess the relevance of parameter variations in triggering therapy resistance. We illustrate the methodology with a de novo generated agent-based model accounting for the interplay between tumor and immune cells in a melanoma micrometastasis. The application of the workflow identifies three distinct scenarios of therapy resistance.

    Pubmed
  • [Ein Lues-ähnliches Bild verursacht durch PVL-positive Staphylokokken].

    J Dtsch Dermatol Ges. 2023;21 Suppl 2(): 34-35

    Busch D, Schliep S, Berking C, Bosch-Voskens C

    Pubmed
  • Quality, Understandability and Reliability of YouTube Videos on Skin Cancer Screening.

    J Cancer Educ. 2023;38(5): 1667-1674

    Reinhardt L, Steeb T, Mifka A, Berking C, Meier F, German Skin Cancer Council

    In 2008, a nationwide skin cancer screening (SCS) program was implemented in Germany. However, participation rates remain low. YouTube videos on SCS might educate eligible persons to undergo SCS. Until now, no scientific evaluation of the quality of videos available for German-speaking persons eligible for SCS has been performed. Here, we identified and evaluated videos on SCS provided on YouTube. YouTube was searched in May 2022 for German terms related to SCS. Two authors evaluated the videos of the first three pages that met the predefined eligibility criteria. The quality of the videos´ information was evaluated using DISCERN and the Global Quality Scale (GQS). The understandability and actionability were assessed with the Patient Education Materials Assessment Tool (PEMAT). The reliability was assessed with the Journal of American Medical Association (JAMA) score. Subgroup differences were identified by the Kruskal-Wallis test. Overall, 38 videos were included in the evaluation. Most videos were provided by health professionals (clinics and practices). The average scores (mean (SD)) for the individual tools were as follows: DISCERN 3.1/5 points (± 0.52), GQS 3.72/5 points (± 0.7), understandability 64,27% (± 13.53%), actionability 58.22% (± 15.18%), JAMA 37.17% (± 18.94%). These results indicate a mediocre to good understandability, a mediocre quality and actionability, and a low reliability. Videos that were assessed as useful were of significantly better quality. An improvement of freely available informational videos on SCS, especially with regard to the reliability criteria, is urgently needed.

    Pubmed
  • Opportunities to inform German residents about the possibility of skin cancer screening and to inform stakeholders to take appropriate actions: A qualitative approach.

    Cancer Med. 2023;12(9): 10829-10839

    Steeb T, Wessely A, Heppt MV, Erdmann M, Klug SJ, Berking C

    BACKGROUND: The national skin cancer screening (SCS) was introduced in Germany in 2008. However, public awareness and participation rates remain low. There are no campaigns or target group-specific invitation strategies for SCS yet. Thus, our aim was to derive potential suggestions on how to best inform German residents about the possibility of SCS.

    METHODS: Semi-structured, individual interviews with male and female German residents aged ≥35 years were conducted in Erlangen (Germany) to explore opportunities on raising awareness of SCS. Interviews were audiotaped, transcribed verbatim, and analyzed using qualitative content analysis.

    RESULTS: Overall, 39 persons were interviewed. About 79.5% (31/39) had already undergone at least one SCS. Numerous opportunities to raise awareness of the possibility of SCS were suggested which were categorized into three main topics: the role of public promotion, health-related caregivers, and health insurance. Similar themes were identified for inviting entitled persons to undergo SCS after 2 years. Furthermore, age-dependent communication approaches were proposed, that is, younger persons should be approached electronically, while the older generation should be targeted with traditional media like mail.

    CONCLUSIONS: The results of this project will inform stakeholders to take appropriate actions. The findings may contribute to increase participation rates in SCS and thus lead to earlier detection of skin cancer.

    Pubmed
  • Poor Adherence to Self-Applied Topical Drug Treatment Is a Common Source of Low Lesion Clearance in Patients with Actinic Keratosis-A Cross-Sectional Study.

    J Clin Med. 2023;12(11):

    Koch EAT, Steeb T, Bender-Säbelkampf S, Busch D, Feustel J, Kaufmann MD, Maronna A, Meder C, Ronicke M, Toussaint F, Wellein H, Berking C, Heppt MV

    BACKGROUND: Many treatments for actinic keratosis (AK) have been proven efficient in clinical trials. However, patients with AK may still experience unsatisfactory therapeutic outcomes in clinical practice.

    OBJECTIVES: To investigate patient adherence to self-applied topical interventions for AK and to explore factors associated with adherence in a real-world setting.

    METHODS: A cross-sectional study was conducted. Patients presenting with AK were asked to complete a self-administered questionnaire about their last topical AK treatment.

    RESULTS: A total of 113 patients participated with a median age of 78.5 years (range 58-94). Fifty-four patients (47.8%) received topical diclofenac, ten (8.8%) imiquimod, nine (8%) 5-fluorouracil, nine (8%) 5-fluorouracil plus salicylic acid, and eight (7.1%) photodynamic therapy. The non-adherence rate was 46.9% (n = 53), and only 30.9% (n = 35) used the topical treatments according to the summary of product characteristics (SmPC). These subgroups were compared. Patients of the non-compliant group were significantly less informed about the application time of the specific topical intervention (p = 0.002) and adjusted the timeframe (p < 0.001) and application frequency of the therapy (p = 0.02) independently of their physician. Conversely, patients reporting a sufficient pre-treatment consultation (p = 0.019) generally complied with the SmPC compliance application.

    CONCLUSIONS: A thorough pre-treatment consultation can help to increase treatment adherence and ensure lesion clearance.

    Pubmed
  • Case report: Bullous pemphigoid in HIV-1-positive patients: interplay or coincidence? A case series and review of the literature.

    Front Immunol. 2023;14():

    Foerster Y, Sollfrank L, Rechtien L, Harrer T, Berking C, Sticherling M

    Bullous pemphigoid (BP) is an autoimmune inflammatory skin disease, mostly affecting the elderly population. Therefore, patients often have multiple comorbidities, but there is inconsistent data regarding the relationship between HIV-1 infection and BP, which has been rarely reported in combination. Herein, we describe three patients who presented with BP and concomitant HIV-1 infection that was well controlled with modern combined antiretroviral therapy. All patients received topical and oral corticosteroids. Depending on the individual severity, further add-on therapeutics, such as azathioprine, dapsone, doxycycline and the interleukin 4/13 antibody dupilumab, were added to the therapy regimen. All patients recovered from pruritic skin lesions and blistering. The cases are further discussed in the context of the current study landscape. In conclusion, HIV-1 infection shifts the cytokine profile from T-helper type 1 (TH1) towards T-helper type 2 (TH2), resulting in the excessive secretion of distinct cytokines, such as interleukin 4 (IL-4) and interleukin 10 (IL-10). With IL-4 being a main driver in the pathogenesis of BP, HIV-1-positive patients may benefit greatly from targeting IL-4 with monoclonal antibodies.

    Pubmed
  • [Fertility, teratogenicity, and contraception during therapy with BRAF/MEK inhibitors].

    Dermatologie (Heidelb). 2023;74(7): 496-500

    Livingstone E, Berking C

    BACKGROUND: Targeted mutation-based therapy with BRAF and MEK inhibitors has become an integral part of systemic therapy for metastatic melanoma in the advanced setting and for the adjuvant therapy of melanoma in stage III after complete resection. Due to the increased chances of survival and early use in the adjuvant situation, fertility preservation as well as aspects of teratogenicity and pregnancy are increasingly relevant in patients who are often still young.

    OBJECTIVES: To communicate the published and study-based information on fertility preservation, teratogenicity and pregnancy under therapy with BRAF and MEK inhibitors.

    MATERIALS AND METHODS: Summaries of product characteristics as well as studies and case reports on BRAF and MEK inhibitors published in PubMed were used as sources of information.

    RESULTS: There are no specific preclinical studies or experience in humans on fertility, teratogenicity, and contraception with targeted therapy. Recommendations can only be derived from toxicity studies and individual case reports.

    CONCLUSIONS: Patients should be offered counseling on the options for fertility-protective measures before starting targeted therapy. Due to unclear teratogenicity, adjuvant melanoma therapy with dabrafenib and trametinib should not be initiated in pregnant patients. In the advanced metastatic situation, BRAF and MEK inhibitors should only be given after extensive interdisciplinary education and counselling of the pregnant patient and her partner. Patients should be informed about the need for adequate contraception during targeted therapy.

    Pubmed
  • [Fertility, contraception and teratogenicity with immune checkpoint blockade].

    Dermatologie (Heidelb). 2023;74(7): 501-504

    Hassel JC, Berking C

    BACKGROUND: Immune checkpoint inhibitors (ICI) are now being used in a number of dermato-oncological indications. In particular, the approval for adjuvant therapy of high-risk stage IIB/C and III melanoma means that more patients of fertile age receive ICI.

    OBJECTIVES: This raises the question of how ICIs affect male and female fertility and whether they are teratogenic.

    MATERIALS AND METHODS: Compilation of current data from the summary of product characteristics (SmPCs) and by literature search (PubMed).

    RESULTS: Immune-related adverse events of ICI can impair fertility in the acute stage, and especially in the case of endocrine side effects, also in the long term. These include hypothyroidism, as well as adrenal and pituitary insufficiency. However, fertility can usually be restored with hormone replacement. Direct autoimmune effects on the reproductive organs are probably very rare, although immune-related orchitis has been described. Reliable contraception should be used in women of childbearing age. Pregnant women should only receive ICI in urgent exceptional cases, because the miscarriage rate is probably significantly increased.

    CONCLUSIONS: Unfortunately, the current data on patient counselling is still very sparse. Scientific studies on the influence of ICI on fertility and teratogenicity are urgently needed.

    Pubmed
  • DeepNAPSI multi-reader nail psoriasis prediction using deep learning.

    Sci Rep. 2023;13(1):

    Folle L, Fenzl P, Fagni F, Thies M, Christlein V, Meder C, Simon D, Minopoulou I, Sticherling M, Schett G, Maier A, Kleyer A

    Nail psoriasis occurs in about every second psoriasis patient. Both, finger and toe nails can be affected and also severely destroyed. Furthermore, nail psoriasis is associated with a more severe course of the disease and the development of psoriatic arthritis. User independent quantification of nail psoriasis, however, is challenging due to the heterogeneous involvement of matrix and nail bed. For this purpose, the nail psoriasis severity index (NAPSI) has been developed. Experts grade pathological changes of each nail of the patient leading to a maximum score of 80 for all nails of the hands. Application in clinical practice, however, is not feasible due to the time-intensive manual grading process especially if more nails are involved. In this work we aimed to automatically quantify the modified NAPSI (mNAPSI) of patients using neuronal networks retrospectively. First, we performed photographs of the hands of patients with psoriasis, psoriatic arthritis, and rheumatoid arthritis. In a second step, we collected and annotated the mNAPSI scores of 1154 nail photos. Followingly, we extracted each nail automatically using an automatic key-point-detection system. The agreement among the three readers with a Cronbach's alpha of 94% was very high. With the nail images individually available, we trained a transformer-based neural network (BEiT) to predict the mNAPSI score. The network reached a good performance with an area-under-receiver-operator-curve of 88% and an area-under precision-recall-curve (PR-AUC) of 63%. We could compare the results with the human annotations and achieved a very high positive Pearson correlation of 90% by aggregating the predictions of the network on the test set to the patient-level. Lastly, we provided open access to the whole system enabling the use of the mNAPSI in clinical practice.

    Pubmed
  • Bispecific antibodies redirect synthetic agonistic receptor modified T cells against melanoma.

    J Immunother Cancer. 2023;11(5):

    Märkl F, Benmebarek MR, Keyl J, Cadilha BL, Geiger M, Karches C, Obeck H, Schwerdtfeger M, Michaelides S, Briukhovetska D, Stock S, Jobst J, Müller PJ, Majed L, Seifert M, Klüver AK, Lorenzini T, Grünmeier R, Thomas M, Gottschlich A, Klaus R, Marr C, von Bergwelt-Baildon M, Rothenfusser S, Levesque MP, Heppt MV, Endres S, Klein C, Kobold S

    BACKGROUND: Melanoma is an immune sensitive disease, as demonstrated by the activity of immune check point blockade (ICB), but many patients will either not respond or relapse. More recently, tumor infiltrating lymphocyte (TIL) therapy has shown promising efficacy in melanoma treatment after ICB failure, indicating the potential of cellular therapies. However, TIL treatment comes with manufacturing limitations, product heterogeneity, as well as toxicity problems, due to the transfer of a large number of phenotypically diverse T cells. To overcome said limitations, we propose a controlled adoptive cell therapy approach, where T cells are armed with synthetic agonistic receptors (SAR) that are selectively activated by bispecific antibodies (BiAb) targeting SAR and melanoma-associated antigens.

    METHODS: Human as well as murine SAR constructs were generated and transduced into primary T cells. The approach was validated in murine, human and patient-derived cancer models expressing the melanoma-associated target antigens tyrosinase-related protein 1 (TYRP1) and melanoma-associated chondroitin sulfate proteoglycan (MCSP) (CSPG4). SAR T cells were functionally characterized by assessing their specific stimulation and proliferation, as well as their tumor-directed cytotoxicity, in vitro and in vivo.

    RESULTS: MCSP and TYRP1 expression was conserved in samples of patients with treated as well as untreated melanoma, supporting their use as melanoma-target antigens. The presence of target cells and anti-TYRP1 × anti-SAR or anti-MCSP × anti-SAR BiAb induced conditional antigen-dependent activation, proliferation of SAR T cells and targeted tumor cell lysis in all tested models. In vivo, antitumoral activity and long-term survival was mediated by the co-administration of SAR T cells and BiAb in a syngeneic tumor model and was further validated in several xenograft models, including a patient-derived xenograft model.

    CONCLUSION: The SAR T cell-BiAb approach delivers specific and conditional T cell activation as well as targeted tumor cell lysis in melanoma models. Modularity is a key feature for targeting melanoma and is fundamental towards personalized immunotherapies encompassing cancer heterogeneity. Because antigen expression may vary in primary melanoma tissues, we propose that a dual approach targeting two tumor-associated antigens, either simultaneously or sequentially, could avoid issues of antigen heterogeneity and deliver therapeutic benefit to patients.

    Pubmed
  • Dupilumab but not cyclosporine treatment shifts the microbiome toward a healthy skin flora in patients with moderate-to-severe atopic dermatitis.

    Allergy. 2023;78(8): 2290-2300

    Hartmann J, Moitinho-Silva L, Sander N, Harder I, Häsler R, Rodriguez E, Haufe E, Kleinheinz A, Abraham S, Heratizadeh A, Weisshaar E, Schäkel K, Handrick C, Augustin M, Wollenberg A, Staubach-Renz P, Ertner K, Sticherling M, Schwarz B, Quist S, Wiemers F, Schenck F, Wildberger J, Tittmann L, Lieb W, Schmitt J, Werfel T, Weidinger S, TREATgermany Study Group

    BACKGROUND: Atopic dermatitis (AD) patients display an altered skin microbiome which may not only be an indicator but also a driver of inflammation. We aimed to investigate associations among AD patients' skin microbiome, clinical data, and response to systemic therapy in patients of the TREATgermany registry.

    METHODS: Skin swabs of 157 patients were profiled with 16S rRNA gene amplicon sequencing before and after 3 months of treatment with dupilumab or cyclosporine. For comparison, 16s microbiome data from 258 population-based healthy controls were used. Disease severity was assessed using established instruments such as the Eczema Area and Severity Index (EASI).

    RESULTS: We confirmed the previously shown correlation of Staphylococcus aureus abundance and bacterial alpha diversity with AD severity as measured by EASI. Therapy with Dupilumab shifted the bacterial community toward the pattern seen in healthy controls. The relative abundance of Staphylococci and in particular S. aureus significantly decreased on both lesional and non-lesional skin, whereas the abundance of Staphylococcus hominis increased. These changes were largely independent from the degree of clinical improvement and were not observed for cyclosporine.

    CONCLUSIONS: Systemic treatment with dupilumab but not cyclosporine tends to restore a healthy skin microbiome largely independent of the clinical response indicating potential effects of IL-4RA blockade on the microbiome.

    Pubmed
  • Itching and treatments in atopic dermatitis (AD): results from the German AD registry TREATgermany.

    Br J Dermatol. 2023;188(3): 430-432

    Weisshaar E, Bentz P, Haufe E, Heinrich L, Apfelbacher C, Heratizadeh A, Abraham S, Harder I, Kleinheinz A, Wollenberg A, Schäkel K, Wiemers F, Ertner K, Augustin M, Wildberger J, von Kiedrowski R, Worm M, Zink A, Effendy I, Asmussen A, Pawlak M, Sticherling M, Hilgers M, Handrick C, Quist S, Schwarz B, Bell M, Staubach-Renz P, Hong-Weldemann SH, Homey B, Bruecher J, Weidinger S, Werfel T, Schmitt J, TREATgermany study group

    Pubmed
  • Skin lesions may be misleading for final diagnosis - a case of delayed diagnosis and therapy.

    J Dtsch Dermatol Ges. 2023;21(9): 1046-1048

    Meder C, Sticherling M

    Pubmed
  • Secukinumab in Pediatric Patients with Plaque Psoriasis: Pooled Safety Analysis from Two Phase 3 Randomized Clinical Trials.

    Am J Clin Dermatol. 2023;24(5): 821-835

    Sticherling M, Nikkels AF, Hamza AM, Kwong P, Szepietowski JC, El Sayed M, Ghislain PD, Khotko AA, Patekar M, Ortmann CE, Forrer P, Papanastasiou P, Keefe D

    BACKGROUND: Plaque psoriasis affects ~ 1% of the pediatric population, negatively impacting quality of life. The efficacy and safety of secukinumab in pediatric patients with moderate to severe or severe chronic plaque psoriasis have been established in two pivotal phase 3 trials (open-label, NCT03668613; double-blind, NCT02471144).

    OBJECTIVES: The aims were to report the pooled safety of secukinumab up to 52 weeks from two studies in subgroups of pediatric patients stratified by age and bodyweight, and to present, alongside the pediatric data, the pooled safety data from four pivotal adult secukinumab trials.

    METHODS: The safety of secukinumab was evaluated in subgroups of pediatric patients defined by age (6 to < 12 and 12 to < 18 years) and bodyweight (< 25 kg, 25 to < 50 kg, and ≥ 50 kg) in the pooled population. Patients received secukinumab low dose (LD; 75/75/150 mg), secukinumab high dose (HD; 75/150/300 mg), placebo, or etanercept (0.8 mg/kg). For safety analyses, data were pooled from the pediatric studies NCT03668613 and NCT02471144, and presented alongside the pooled data from four adult pivotal studies (NCT01365455, NCT01636687, NCT01358578, NCT01555125).

    RESULTS: A total of 198 pediatric patients (overall exposure: 184.6 patient-years [PY]) and 1989 adult patients (1749.5 PY) receiving secukinumab up to week 52 were included in this analysis. At week 52, the incidence of adverse events (AEs) was lower in the lower age and bodyweight subgroups. The AEs reported within these subgroups were consistent with the overall AEs reported in this analysis. Overall, exposure-adjusted incidence rates for treatment-emergent AEs were lower in the secukinumab-treated pediatric pool (198.8/100 PY) compared with the etanercept (266.3/100 PY) and adult pools (256.1/100 PY). Up to 52 weeks, the incidence rates of the AEs in the secukinumab-treated patients in the 6 to < 12 years subgroup and 12 to < 18 years subgroup were 167.7/100 PY and 214.7/100 PY, respectively. Similarly, incidence rates of the AEs in the secukinumab-treated patients in the < 25 kg, 25 kg to < 50 kg, and ≥ 50 kg subgroups were 177.3/100 PY, 192.5/100 PY, and 206.8/100 PY, respectively. Nasopharyngitis was the most frequently reported AE in secukinumab-treated pediatric patients across age (< 12 years: 11.8/100 PY; ≥ 12 years: 42.4/100 PY) and bodyweight (< 25 kg: 22.8/100 PY; 25 kg to < 50 kg: 19.0/100 PY; ≥ 50 kg: 43.0/100 PY). Of the 198 secukinumab-treated pediatric patients, one reported nail Candida, one reported skin Candida, and two reported vulvovaginal Candida. Transient and mostly mild events of neutropenia were observed with secukinumab, none leading to study treatment discontinuation. No incidence of treatment-emergent anti-drug antibodies was reported in pediatric patients treated with secukinumab.

    CONCLUSIONS: Secukinumab was well tolerated in pediatric patients with moderate to severe and severe plaque psoriasis across age and bodyweight subgroups. The overall safety profile of secukinumab in pediatric patients was consistent with that of adult patients.

    GOV IDENTIFIER: NCT03668613 (Novartis Study Code CAIN457A2311, referred to as A2311), actual study start date: August 29, 2018; actual primary completion date: September 19, 2019; estimated study completion date: September 14, 2023. NCT02471144 (Novartis Study Code CAIN457A2310, referred to as A2310), study start date: September 29, 2015; primary completion date: December 13, 2018; estimated study completion date: March 31, 2023.

    Pubmed
  • Mobility range, level of pain and sleep quality of patients with venous leg ulcers.

    Int Wound J. 2023;20(8): 3177-3184

    Siegling M, Renner R, Erfurt-Berge C

    This study aimed to compare mobility range, level of pain and sleep quality in patients with venous leg ulcers to age- and gender-matched controls without ulcers. Twenty patients with venous leg ulceration and 20 matched controls each answered a questionnaire, completed the short-physical performance battery, filled in a subject diary and wore a smartwatch for 1 week. The median daily step counts of the ulcer group (3622 steps/day) and the control group (5133 steps/day) were significantly different (P = .017). Significant correlations between total step count and age, duration of physical outdoor activities and scores in the short-physical performance battery were observed in the ulcer group. The scores in the short-physical performance battery were significantly different in both groups (P = .005), indicating weaker physical performance in the ulcer group. The greatest difference in the self-reported level of pain between the two groups was stated during movement. On average, the ulcer group slept shorter by 1 h 38 min (P = .002) and had 0.7 wake phases per night (P = .019) more than the control group. Assessing mobility in patients with venous leg ulcers can be used to develop preventive and interventional concepts to improve and individualise physical therapies.

    Pubmed
  • Patient-reported Outcomes and Burden of Disease in Paediatric Patients with Psoriasis: Real-world Data from EU5 and US.

    Acta Derm Venereol. 2023;103():

    Seyger MMB, Paller A, Sticherling M, Bachhuber T, Thomas N, Hetherington J, Lucas J, Richardson C, Augustin M

    Pubmed
  • Cutaneous squamous cell carcinoma: state of the art, perspectives and unmet needs.

    J Dtsch Dermatol Ges. 2023;21(4): 421-424

    Heppt MV, Leiter U

    Squamous cell carcinoma of the skin (cSCC) is one of the most common cancers of the Caucasian population and accounts for 20% of all cutaneous tumors. An S3 guideline from the German Guideline Program in Oncology has been available since 2019 and was updated in 2022. The diagnosis of cSCC is based on clinical examination. Excision and histological confirmation are required for clinically suspicious lesions to allow for prognostic assessment and correct treatment. The treatment of first choice is excision with complete histological assessment of the surgical margins. Adjuvant radiation therapy may be considered if there is a high risk of recurrence. The immune checkpoint inhibitor cemiplimab is approved and recommended as the treatment of first choice for locally advanced or metastatic cSCC in Europe. If contraindications are present, chemotherapy, EGFR inhibitors, or palliative radiation therapy may be used. Surveillance should be performed in a risk-stratified manner and includes a dermatological control supplemented by sonography examinations in high-risk patients. Much research is still needed for solid organ transplant patients, concomitant hematologic diseases, and cSCC showing primary or acquired resistance to immunotherapies. Current developments include new drug combinations, intralesional therapies alone or in combination with immune checkpoint inhibitors, and neoadjuvant approaches.

    Pubmed
  • Label-free discrimination of extracellular vesicles from large lipoproteins.

    J Extracell Vesicles. 2023;12(8):

    Kashkanova AD, Blessing M, Reischke M, Baur JO, Baur AS, Sandoghdar V, Van Deun J

    Extracellular vesicles (EVs) are increasingly gaining interest as biomarkers and therapeutics. Accurate sizing and quantification of EVs remain problematic, given their nanometre size range and small scattering cross-sections. This is compounded by the fact that common EV isolation methods result in co-isolation of particles with comparable features. Especially in blood plasma, similarly-sized lipoproteins outnumber EVs to a great extent. Recently, interferometric nanoparticle tracking analysis (iNTA) was introduced as a particle analysis method that enables determining the size and refractive index of nanoparticles with high sensitivity and precision. In this work, we apply iNTA to differentiate between EVs and lipoproteins, and compare its performance to conventional nanoparticle tracking analysis (NTA). We show that iNTA can accurately quantify EVs in artificial EV-lipoprotein mixtures and in plasma-derived EV samples of varying complexity. Conventional NTA could not report on EV numbers, as it was not able to distinguish EVs from lipoproteins. iNTA has the potential to become a new standard for label-free EV characterization in suspension.

    Pubmed
  • Liver-directed treatment is associated with improved survival and increased response to immune checkpoint blockade in metastatic uveal melanoma: results from a retrospective multicenter trial.

    Front Med. 2023;17(5): 878-888

    Koch EAT, Petzold A, Wessely A, Dippel E, Eckstein M, Gesierich A, Gutzmer R, Hassel JC, Knorr H, Kreuzberg N, Leiter U, Loquai C, Meier F, Meissner M, Mohr P, Pföhler C, Rahimi F, Schadendorf D, Schlaak M, Thoms KM, Ugurel S, Utikal J, Weichenthal M, Schuler-Thurner B, Berking C, Heppt MV

    Metastases of uveal melanoma (UM) spread predominantly to the liver. Due to low response rates to systemic therapies, liver-directed therapies (LDT) are commonly used for tumor control. The impact of LDT on the response to systemic treatment is unknown. A total of 182 patients with metastatic UM treated with immune checkpoint blockade (ICB) were included in this analysis. Patients were recruited from prospective skin cancer centers and the German national skin cancer registry (ADOReg) of the German Dermatologic Cooperative Oncology Group (DeCOG). Two cohorts were compared: patients with LDT (cohort A, n = 78) versus those without LDT (cohort B, n = 104). Data were analyzed for response to treatment, progression-free survival (PFS), and overall survival (OS). The median OS was significantly longer in cohort A than in cohort B (20.1 vs. 13.8 months; P = 0.0016) and a trend towards improved PFS was observed for cohort A (3.0 vs. 2.5 months; P = 0.054). The objective response rate to any ICB (16.7% vs. 3.8%, P = 0.0073) and combined ICB (14.1% vs. 4.5%, P = 0.017) was more favorable in cohort A. Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM.

    Pubmed
  • eImmunonkologie: Development and Launch of a Virtual Education Platform for the Immunotherapy of Cutaneous Neoplasms.

    Med. Sci. Educ.. 2023;33(1): 7-9

    Kaufmann MD, Steeb T, Wessely A, Meyerolbersleben M, French LE, Berking C, Heppt MV

    The use of immunotherapies in clinical practice has significantly expanded treatment options and improved the prognosis of patients with advanced cancers over the past decade. We have developed a virtual teaching module entitled "eImmunonkologie" which is the first interdisciplinary virtual course on immuno-oncology for medical students in German-speaking countries.

    Pubmed
  • Tebentafusp in Patients with Metastatic Uveal Melanoma: A Real-Life Retrospective Multicenter Study.

    Cancers (Basel). 2023;15(13):

    Tomsitz D, Ruf T, Heppt M, Staeger R, Ramelyte E, Dummer R, Garzarolli M, Meier F, Meier E, Richly H, Gromke T, Siveke JT, Franklin C, Klespe KC, Mauch C, Kilian T, Seegräber M, Schilling B, French LE, Berking C, Heinzerling L

    BACKGROUND: Tebentafusp has recently been approved for the treatment of metastatic uveal melanoma (mUM) after proving to have survival benefits in a first-line setting.

    PATIENTS AND METHODS: This retrospective, multicenter study analyzed the outcomes and safety of tebentafusp therapy in 78 patients with mUM.

    RESULTS: Patients treated with tebentafusp had a median PFS of 3 months (95% CI 2.7 to 3.3) and a median OS of 22 months (95% CI 10.6 to 33.4). In contrast to a published Phase 3 study, our cohort had a higher rate of patients with elevated LDH (65.4% vs. 35.7%) and included patients with prior systemic and local ablative therapies. In patients treated with tebentafusp following ICI, there was a trend for a longer median OS (28 months, 95% CI 26.9 to 29.1) compared to the inverse treatment sequence (24 months, 95% CI 13.0 to 35.0, p = 0.257). The most common treatment-related adverse events were cytokine release syndrome in 71.2% and skin toxicity in 53.8% of patients. Tumor lysis syndrome occurred in one patient.

    CONCLUSIONS: Data from this real-life cohort showed a median PFS/OS similar to published Phase 3 trial data. Treatment with ICI followed by tebentafusp may result in longer PFS/OS compared to the inverse treatment sequence.

    Pubmed
  • Adjuvant treatment and outcome of stage III melanoma patients: Results of a multicenter real-world German Dermatologic Cooperative Oncology Group (DeCOG) study.

    Eur J Cancer. 2023;191():

    Lodde GC, Hassel J, Wulfken LM, Meier F, Mohr P, Kähler K, Hauschild A, Schilling B, Loquai C, Berking C, Hüning S, Eckardt J, Gutzmer R, Reinhardt L, Glutsch V, Nikfarjam U, Erdmann M, Beckmann CL, Stang A, Kowall B, Galetzka W, Roesch A, Ugurel S, Zimmer L, Schadendorf D, Forschner A, Livingstone E

    PURPOSE: Clinical trials demonstrated significantly improved recurrence-free survival (RFS) of melanoma patients receiving adjuvant treatment. As data from controlled trials are based on selected populations, we investigated adjuvantly treated stage III melanoma patients under real-world conditions.

    PATIENTS AND METHODS: In a prior multicenter cohort study, stage III-IV melanoma patients were analysed for their choice of adjuvant therapy. In this follow-up study, we examined RFS, overall and melanoma-specific survival (MSS) and response to the subsequent treatment of 589 stage III patients (232 BRAF-mutated) receiving adjuvant PD-1 inhibitors (PD1; n = 479) or targeted therapy (TT; n = 110).

    RESULTS: The median follow-up of the total cohort was 25.7 months. The main reason for premature discontinuation of adjuvant therapy was disease progression in PD1- (28.8%, n = 138/479) and adverse events in TT-treated patients (28.2%, n = 31/110). Among BRAF-mutated patients, RFS at 24 months was 49% (95% CI 40.6-59.0%) for PD1- and 67% (95% CI 58-77%) for TT-treated patients. The risk of recurrence was higher for BRAF-mutated PD1 than TT (hazard ratio 1.99; 95% CI 1.34-2.96; hazard ratio adjusted for age, sex and tumour stage, 2.21; 95% CI 1.48-3.30). Twenty-four months MSS was 87% (95% CI 81.0-94.1) for PD1 and 92% (95% CI 86.6-97.0) for TT. Response to subsequent systemic treatment for unresectable disease was 22% for all PD1- and 16% for TT-treated patients.

    CONCLUSIONS: PD1-treated patients had more and earlier recurrences than TT patients. In BRAF-mutated patients, adjuvant TT might prevent early recurrences more effectively than PD1 treatment. Management of recurrence despite adjuvant treatment is challenging, with low response to current therapeutic options.

    Pubmed
  • Increased Motility and Suppression of Ex Vivo-Expanded Regulatory T Cells Designed for Adoptive Transfer Therapy in Ulcerative Colitis.

    Cell Mol Gastroenterol Hepatol. 2023;16(1): 183-187.e2

    Müller TM, Liu LJ, Czerwinski T, Wiesinger M, Dedden M, Paap EM, Ullrich KA, Atreya I, Siegmund B, Atreya R, Fabry B, Berking C, Neurath MF, Zundler S, Voskens CJ

    Pubmed
  • [Fertility preservation in patients with melanoma-a huge relief for those affected].

    Dermatologie (Heidelb). 2023;74(7): 479-480

    Berking C, Hassel JC, Livingstone E

    Pubmed
  • Adjuvant immunotherapy with nivolumab versus observation in completely resected Merkel cell carcinoma (ADMEC-O): disease-free survival results from a randomised, open-label, phase 2 trial.

    Lancet. 2023;402(10404): 798-808

    Becker JC, Ugurel S, Leiter U, Meier F, Gutzmer R, Haferkamp S, Zimmer L, Livingstone E, Eigentler TK, Hauschild A, Kiecker F, Hassel JC, Mohr P, Fluck M, Thomas I, Garzarolli M, Grimmelmann I, Drexler K, Spillner AN, Eckhardt S, Schadendorf D, DeCOG , van Akkoi A, van Houdt W, Wilhelm T, Farmer K, Ulrich C, Gambichler T, Bluhm L, Schinagl H, Kellner I, Herbst R, Meiß F, Rafei-Shamsabadi D, Sell S, Kaatz M, Wulfken L, Hartmann M, Kähler K, Ziemer M, Simon J, Terheyden P, Thaci D, Loquai C, Mitzel-Rink H, Grabbe S, Stege H, Gaiser M, Utikal J, Berking C, Heinzerling L, Schlaak M, Tomsitz D, Dyballa J, Magnolo N, Weishaupt C, Berneburg M, Garbe C, Flatz L, Gesierich A, Schilling B

    BACKGROUND: Merkel cell carcinoma (MCC) is an immunogenic but aggressive skin cancer. Even after complete resection and radiation, relapse rates are high. PD-1 and PD-L1 checkpoint inhibitors showed clinical benefit in advanced MCC. We aimed to assess efficacy and safety of adjuvant immune checkpoint inhibition in completely resected MCC (ie, a setting without an established systemic standard-of-care treatment).

    METHODS: In this multicentre phase 2 trial, patients (any stage, Eastern Cooperative Oncology Group performance status 0-1) at 20 academic medical centres in Germany and the Netherlands with completely resected MCC lesions were randomly assigned 2:1 to receive nivolumab 480 mg every 4 weeks for 1 year, or observation, stratified by stage (American Joint Committee on Cancer stages 1-2 vs stages 3-4), age (<65 vs ≥65 years), and sex. Landmark disease-free survival (DFS) at 12 and 24 months was the primary endpoint, assessed in the intention-to-treat populations. Overall survival and safety were secondary endpoints. This planned interim analysis was triggered when the last-patient-in was followed up for more than 1 year. This study is registered with ClinicalTrials.gov (NCT02196961) and with the EU Clinical Trials Register (2013-000043-78).

    FINDINGS: Between Oct 1, 2014, and Aug 31, 2020, 179 patients were enrolled (116 [65%] stage 3-4, 122 [68%] ≥65 years, 111 [62%] male). Stratification factors (stage, age, sex) were balanced across the nivolumab (n=118) and internal control group (observation, n=61); adjuvant radiotherapy was more common in the control group. At a median follow-up of 24·3 months (IQR 19·2-33·4), median DFS was not reached (between-groups hazard ratio 0·58, 95% CI 0·30-1·12); DFS rates in the nivolumab group were 85% at 12 months and 84% at 24 months, and in the observation group were 77% at 12 months and 73% at 24 months. Overall survival results were not yet mature. Grade 3-4 adverse events occurred in 48 [42%] of 115 patients who received at least one dose of nivolumab and seven [11%] of 61 patients in the observation group. No treatment-related deaths were reported.

    INTERPRETATION: Adjuvant therapy with nivolumab resulted in an absolute risk reduction of 9% (1-year DFS) and 10% (2-year DFS). The present interim analysis of ADMEC-O might suggest clinical use of nivolumab in this area of unmet medical need. However, overall survival events rates, with ten events in the active treatment group and six events in the half-the-size observation group, are not mature enough to draw conclusions. The explorative data of our trial support the continuation of ongoing, randomised trials in this area. ADMEC-O suggests that adjuvant immunotherapy is clinically feasible in this area of unmet medical need.

    FUNDING: Bristol Myers Squibb.

    Pubmed
  • Author Correction: DeepNAPSI multi-reader nail psoriasis prediction using deep learning.

    Sci Rep. 2023;13(1):

    Folle L, Fenzl P, Fagni F, Thies M, Christlein V, Meder C, Simon D, Minopoulou I, Sticherling M, Schett G, Maier A, Kleyer A

    Pubmed
  • Itch, sleep loss, depressive symptoms, fatigue, and productivity loss in patients with moderate-to-severe atopic dermatitis: Analyses of TREATgermany registry data.

    J Dtsch Dermatol Ges. 2023;21(10): 1157-1168

    Birkner T, Siegels D, Heinrich L, Haufe E, Abraham S, Heratizadeh A, Harder I, Bell M, Fell I, Worm M, Handrick C, Effendy I, Asmussen A, Kleinheinz A, Homey B, Sticherling M, Hong-Weldemann SH, Augustin M, Weisshaar E, Schäkel K, Schaefer T, Schwarz B, Wiemers F, Brücher JJ, Quist S, Wollenberg A, Biedermann T, Ertner K, von Kiedrowski R, Werfel T, Weidinger S, Schmitt J, and the TREATgermany Study Group

    BACKGROUND: TREATgermany is a multicenter registry including patients with moderate-to-severe atopic dermatitis (AD) from currently 74 study centers (university clinics, hospitals and practices) in Germany. As of August 31, 2021, 1,230 adult patients were enrolled.

    METHODS: In TREATgermany, patients and physicians fill in questionnaires pertaining to symptoms, disease severity, quality of life, depressiveness, and fatigue. In particular, limitations in work performance are assessed using the Work Limitations Questionnaire (WLQ). To assess associations between occupational performance/work limitations and symptoms, correlations and regression models were calculated.

    RESULTS: The examined sample of 228 employed patients reported an average of 6% at-work productivity loss within the past two weeks prior to enrolment in the registry. The WLQ productivity loss score was moderately associated with itch (r = 0.32) and sleep loss (r = 0.39) and strongly associated with depressive symptoms (r = 0.68) and fatigue (r = 0.60).

    CONCLUSIONS: The analyses of the registry data show that moderate-to-severe atopic dermatitis has a negative impact on the work productivity of the patients. The analyses further point out the relevant associations between work productivity, depressive symptoms, and fatigue highlighting the disease burden caused by the psychological components of AD.

    Pubmed
  • Effect of abrocitinib in a patient with extensive necrobiosis lipoidica.

    J Eur Acad Dermatol Venereol. 2023;37(10): e1208-e1210

    Arnet L, Erfurt-Berge C

    Pubmed
  • [The term mixed leg ulcer should no longer be used today].

    Dermatologie (Heidelb). 2023;74(7): 555-559

    Dissemond J, Bültemann A, Gerber V, Motzkus M, Rembe JD, Erfurt-Berge C

    A wound on the lower legs of patients with chronic venous insufficiency (CVI) and peripheral arterial disease (PAD) is today usually referred to as a mixed leg ulcer. This does not take into account the different stages of the diseases and, thus, their pathophysiological relevance. In everyday clinical practice, this often leads, among other things, to these patients not receiving compression therapy. The multidisciplinary professional association Initiative Chronische Wunden (ICW) e. V., therefore, recommends that this undifferentiated and misleading term should no longer be used. Instead, a leg ulcer with advanced CVI and concomitant PAD in stage I-IIb according to Fontaine or Rutherford category 0-3 should be classified as a venous leg ulcer, while a leg ulcer with advanced PAD in stage III or IV according to Fontaine or Rutherford category 4-6 and advanced CVI is termed an arteriovenous leg ulcer. A leg ulcer in advanced PAD stage IV according to Fontaine or Rutherford category 5 or 6 without advanced CVI is called an arterial leg ulcer. Other relevant comorbidities with an influence on wound healing should also be described separately.

    Pubmed
  • Tirbanibulin 1% Ointment Significantly Reduces the Actinic Keratosis Area and Severity Index in Patients with Actinic Keratosis: Results from a Real-World Study.

    J Clin Med. 2023;12(14):

    Kirchberger MC, Gfesser M, Erdmann M, Schliep S, Berking C, Heppt MV

    BACKGROUND: Actinic keratosis (AK) is a cutaneous lesion resulting from the proliferation of atypical epidermal keratinocytes caused by long-term exposure to ultraviolet radiation. AK may progress to cutaneous squamous cell carcinoma (cSCC) and therefore is often treated with topical agents such as 5-fluorouracil, diclofenac, imiquimod, and photodynamic therapy. Tirbanibulin has been approved based on two phase III trials in the USA. However, real-world evidence for tirbanibulin is absent.

    METHODS: This was a single-centre study of adult patients with clinically typical, visible AK on the face or scalp treated with tirbanibulin 1% ointment. Treatment was administered as per label once daily for 5 consecutive days on the same lesions or field. Treatment outcomes were assessed 4 weeks after treatment, with additional optional assessments conducted at later time points. Efficacy was measured using the actinic keratosis area and severity index (AKASI) and digital dermoscopy.

    RESULTS: A total of 33 patients were treated of whom 30 were analysed. The median AKASI score was 5.6 (1.4-11) pre-treatment and 1.2 (0-7.4) post-treatment (p < 0.0001). Complete clearance as defined by AKASI scores less than 1 was achieved in 47% (n = 14) and 57% (n = 13) at the first and second follow-up, respectively. All local reactions resolved spontaneously and without sequelae. The most common local reactions were erythema (80%, n = 26) and flaking or scaling (43%, n = 13).

    CONCLUSIONS: Tirbanibulin 1% ointment significantly and rapidly reduced the AKASI score in a real-world setting. The complete clearance rates were in line with those observed in the two pivotal trials.

    Pubmed
  • Autologous regulatory T cell transfer in patients with refractory ulcerative colitis: Interim report of a phase 1, dose-escalation trial

    J Crohns Colitis. 2023;17 Suppl 1(): 899-900

    Voskens C, Stoica D, Rosenberg M, Weidinger C, Vitali F, Zundler S, Ganslmayer M, Wiesinger M, Wunder J, Kummer M, Siegmund B, Schnoy E, Rath T, Hartmann A, Hackstein H, Schuler-Thurner B, Berking C, Schuler G, Atreya R, Neurath MF

    Pubmed
  • [Individualized precision medicine].

    Urologie. 2023;62(9): 879-888

    Wullich B, Taubert H, Goebell PJ, Kuwert T, Beck M, Schott C, Baur AS, Eckstein M, Wach S

    Spectacular advances have been made in personalized medicine , which has rapidly revolutionized our traditional understanding of disease diagnosis and treatment. Molecular testing of tissue and liquid samples using next generation sequencing has developed into a key technology in this scenario. It can be used for both the determination of biomarkers for diagnostic, prognostic and predictive purposes, as well as the possible improvement of treatment outcome through the use of targeted therapies and the avoidance of therapies in the event of special resistance situations. In addition to drugs that have already been approved, which among other things intervene in cellular DNA repair, many new drugs have been developed and are in clinical testing. Furthermore, new possibilities in molecular imaging have dramatically expanded our understanding of tumor spread and created new approaches for targeted therapies.

    Pubmed
  • Circumventing pyroptosis via hyperactivation shapes superior immune responses of human type 2 dendritic cells compared to type 3 dendritic cells.

    Eur J Immunol. 2023;53(9):

    Hatscher L, Kaszubowski T, Amon L, Dudziak D, Heger L

    Exploiting inflammasome activation in dendritic cells (DCs) is a promising approach to fight cancer and to augment adjuvant-induced immune responses. As inflammasome formation is typically accompanied by pyroptosis, hyperactivation-defined as inflammasome activation in the absence of pyroptosis-represents a mechanism of circumventing cell death of DCs while simultaneously benefitting from inflammasome signaling. We previously demonstrated a unique specialization for inflammasome responses and hyperactivation of human cDC2 among all human DC subsets. As recent investigations revealed heterogeneity among the human cDC2 population, we aimed to analyze whether the two recently identified cDC2 subpopulations DC2 and DC3 harbor similar or different inflammasome characteristics. Here, we report that both DC2 and DC3 are inflammasome competent. We show that DC3 generally induce stronger inflammasome responses, which are associated with higher levels of cell death. Although DC2 release lower levels of inflammasome-dependent IL-1β, they induce stronger CD4+ T cell responses than DC3, which are predominantly skewed toward a TH 1/TH 17 phenotype. Thus, mainly DC2 seem to be able to enter a state of hyperactivation, resulting in enhanced T cell stimulatory capacity.

    Pubmed
  • Immunoglobulin G-dependent inhibition of inflammatory bone remodeling requires pattern recognition receptor Dectin-1.

    Immunity. 2023;56(5): 1046-1063.e7

    Seeling M, Pöhnl M, Kara S, Horstmann N, Riemer C, Wöhner M, Liang C, Brückner C, Eiring P, Werner A, Biburger M, Altmann L, Schneider M, Amon L, Lehmann CHK, Lee S, Kunz M, Dudziak D, Schett G, Bäuerle T, Lux A, Tuckermann J, Vögtle T, Nieswandt B, Sauer M, Böckmann RA, Nimmerjahn F

    Immunoglobulin G (IgG) antibodies are major drivers of inflammation during infectious and autoimmune diseases. In pooled serum IgG (IVIg), however, antibodies have a potent immunomodulatory and anti-inflammatory activity, but how this is mediated is unclear. We studied IgG-dependent initiation of resolution of inflammation in cytokine- and autoantibody-driven models of rheumatoid arthritis and found IVIg sialylation inhibited joint inflammation, whereas inhibition of osteoclastogenesis was sialic acid independent. Instead, IVIg-dependent inhibition of osteoclastogenesis was abrogated in mice lacking receptors Dectin-1 or FcγRIIb. Atomistic molecular dynamics simulations and super-resolution microscopy revealed that Dectin-1 promoted FcγRIIb membrane conformations that allowed productive IgG binding and enhanced interactions with mouse and human IgG subclasses. IVIg reprogrammed monocytes via FcγRIIb-dependent signaling that required Dectin-1. Our data identify a pathogen-independent function of Dectin-1 as a co-inhibitory checkpoint for IgG-dependent inhibition of mouse and human osteoclastogenesis. These findings may have implications for therapeutic targeting of autoantibody and cytokine-driven inflammation.

    Pubmed
  • Purified complement C3b triggers phagocytosis and activation of human neutrophils via complement receptor 1.

    Sci Rep. 2023;13(1):

    Boero E, Gorham RD, Francis EA, Brand J, Teng LH, Doorduijn DJ, Ruyken M, Muts RM, Lehmann C, Verschoor A, van Kessel KPM, Heinrich V, Rooijakkers SHM

    The complement system provides vital immune protection against infectious agents by labeling them with complement fragments that enhance phagocytosis by immune cells. Many details of complement-mediated phagocytosis remain elusive, partly because it is difficult to study the role of individual complement proteins on target surfaces. Here, we employ serum-free methods to couple purified complement C3b onto E. coli bacteria and beads and then expose human neutrophils to these C3b-coated targets. We examine the neutrophil response using a combination of flow cytometry, confocal microscopy, luminometry, single-live-cell/single-target manipulation, and dynamic analysis of neutrophil spreading on opsonin-coated surfaces. We show that purified C3b can potently trigger phagocytosis and killing of bacterial cells via Complement receptor 1. Comparison of neutrophil phagocytosis of C3b- versus antibody-coated beads with single-bead/single-target analysis exposes a similar cell morphology during engulfment. However, bulk phagocytosis assays of C3b-beads combined with DNA-based quenching reveal that these are poorly internalized compared to their IgG1 counterparts. Similarly, neutrophils spread slower on C3b-coated compared to IgG-coated surfaces. These observations support the requirement of multiple stimulations for efficient C3b-mediated uptake. Together, our results establish the existence of a direct pathway of phagocytic uptake of C3b-coated targets and present methodologies to study this process.

    Pubmed
  • Breaking primary checkpoint inhibitor resistance: Interim analysis of a multicenter phase II study by intermittent application of an alkylating agent among patients with metastatic melanoma

    J Clin Oncol. 2023;41 Suppl S(16):

    Heinzerling L, Haferkamp S, Schilling B, Berking C, Geissler E, Zeman F

    Pubmed
  • NOTOS: A pivotal study of navtemadlin, a first-in-class mouse double minute 2 inhibitor (MDM2i), in patients (pts) with TP53 wild-type (TP53(WT)) Merkel cell carcinoma (MCC) for whom anti PD-1/L1 therapy has failed.

    J Clin Oncol. 2023;41 Suppl S(16):

    Wong MKK, Burgess MA, Chandra S, Fecher LA, Gaudy-Marqueste C, Silk AW, Hanna GJ, Lebbe C, Quereux G, Rabinowits G, Schadendorf D, Dutriaux C, Berking C, Liberal JM, Ascierto PA, Houlihan E, Steinmann K, Chan T, Rothbaum WP, Kelly CM

    Pubmed
  • Anti-PD1 plus BRAF/MEK inhibitors (triplet therapy) after failure of standard therapy in patients (pts) with advanced melanoma.

    J Clin Oncol. 2023;41 Suppl S(16):

    Zimmer L, Dimitriou F, Grover P, Hassel JC, Erdmann M, Forschner A, Johnson DB, Livingstone E, Roesch A, Ugurel S, Schulz C, Berking C, Menzies AM, Long GV, Dummer R, Schadendorf D, Albrecht LJ

    Pubmed
  • Uveal melanoma

    Onkologie (Heidelberg, Germany). 2023;29(8): 705-710

    Hassel JC, Heppt MV

    Uveal melanoma is rare and constitutes 5% of all melanomas. They develop mainly from pigment cells of the choroidea, less commonly from the ciliary body or the iris of the eye. The treatment of primary uveal melanoma includes surgery and radiation therapy. Especially large tumors and those with extraocular extension are enucleated. Smaller tumors can be irradiated with plaque brachytherapy or protons. Follow-up, which consists of ophthalmologic examinations, liver ultrasound, and may include assessment of the transaminases in the peripheral blood, is ideally based on the risk profile of the primary tumor and performed every 3-6 months. According to the genetic risk profile, 50% of patients develop distant metastasis, mainly in the liver. Therefore, in addition to systemic therapy, local liver-directed therapies such as chemoperfusion/chemosaturation, transarterial chemoembolization (TACE), and selective internal radiotherapy (SIRT) can be administered. To date, however, there is no definitive evidence that these treatments not only inhibit progression in the liver but improve overall survival. Treatment of choice in patients with metastases is the newly approved immunotherapy with tebentafusp, a bispecific protein consisting of a gp100-TCR (T cell receptor) fused to a CD3 antibody leading to activation of T cells in the microenvironment of the uveal melanoma. It is the first drug proven to lead to a significant survival benefit for patients with metastasized uveal melanoma compared with other systemic therapies such as immune checkpoint inhibitors and chemotherapy. Interestingly, patients with progressing metastases also have a survival benefit. However, treatment can only be given to patients with the human leukocyte antigen (HLA)-A0201 phenotype to which the TCR was designed and which is present in approximately 50% of patients. Further promising new drugs are under development.

    Pubmed
  • Predilection sites of pyoderma gangrenosum: Retrospective study of 170 clearly diagnosed patients.

    Int Wound J. 2023;20(10): 4227-4234

    Moelleken M, Erfurt-Berge C, Ronicke M, Busch D, Hübner UH, Hüsers J, Przysucha M, Dissemond J

    Pyoderma gangrenosum (PG) is a non-infectious, neutrophilic dermatosis that was difficult to diagnose in clinical practice. Today, the PARACELSUS score is a validated tool for diagnostics. Based on this score, patients with clearly diagnosed PG were examined with regard to predilection sites. In this retrospective study, the data of patients from the University Hospitals of Essen and Erlangen were analysed in whom the diagnosis of PG could be clearly confirmed using the PARACELSUS score. A total of 170 patients, 49 men (29%) and 121 women (71%) with an average age at first manifestation of 55.5 years, could be included in the analysis. The predilection sites were identified as the lower legs in 80.6% of the patients and the extensor sides in 75.2%. Other localisations of PG were the thighs in 14.1%, mammae and abdomen in 10.0% each, back and gluteal in 7.1% each, feet in 5.9%, arms in 4.7%, genital in 3.5% and head in 2.9%. This retrospective study is the first to identify a collective of PG patients with the highest data quality using the PARACELSUS score. It could be shown that PG can basically occur on the entire integument. However, the predilection sites of PG, which have now been reliably identified for the first time, are the lower legs and in particular the extensor sides.

    Pubmed
  • Human T cells loaded with superparamagnetic iron oxide nanoparticles retain antigen-specific TCR functionality.

    Front Immunol. 2023;14():

    Pfister F, Dörrie J, Schaft N, Buchele V, Unterweger H, Carnell LR, Schreier P, Stein R, Kubánková M, Guck J, Hackstein H, Alexiou C, Janko C

    BACKGROUND: Immunotherapy of cancer is an emerging field with the potential to improve long-term survival. Thus far, adoptive transfer of tumor-specific T cells represents an effective treatment option for tumors of the hematological system such as lymphoma, leukemia or myeloma. However, in solid tumors, treatment efficacy is low owing to the immunosuppressive microenvironment, on-target/off-tumor toxicity, limited extravasation out of the blood vessel, or ineffective trafficking of T cells into the tumor region. Superparamagnetic iron oxide nanoparticles (SPIONs) can make cells magnetically controllable for the site-specific enrichment.

    METHODS: In this study, we investigated the influence of SPION-loading on primary human T cells for the magnetically targeted adoptive T cell therapy. For this, we analyzed cellular mechanics and the T cell response after stimulation via an exogenous T cell receptor (TCR) specific for the melanoma antigen MelanA or the endogenous TCR specific for the cytomegalovirus antigen pp65 and compared them to T cells that had not received SPIONs.

    RESULTS: SPION-loading of human T cells showed no influence on cellular mechanics, therefore retaining their ability to deform to external pressure. Additionally, SPION-loading did not impair the T cell proliferation, expression of activation markers, cytokine secretion, and tumor cell killing after antigen-specific activation mediated by the TCR.

    CONCLUSION: In summary, we demonstrated that SPION-loading of T cells did not affect cellular mechanics or the functionality of the endogenous or an exogenous TCR, which allows future approaches using SPIONs for the magnetically enrichment of T cells in solid tumors.

    Pubmed
  • Systematic symptom screening in patients with advanced cancer treated in certified oncology centers: results of the prospective multicenter German KeSBa project.

    J Cancer Res Clin Oncol. 2023;149(11): 8829-8842

    Braulke F, Para S, Alt-Epping B, Tewes M, Bäumer M, Haberland B, Mayer-Steinacker R, Hopprich A, de Wit M, Grabe M, Bender-Säbelkampf S, Weßling C, Aulmann C, Gerlach C, Regincos P, Fischer F, Haarmann S, Huys T, Drygas S, Rambau A, Kiani A, Schnabel A, Buhl C, Seipke S, Hiemer S, Polata S, Meßmann M, Hansmeier A, Anastasiadou L, Letsch A, Wecht D, Hellberg-Naegele M, Krug U, Wedding U, van Oorschot B

    PURPOSE: Guidelines recommend a structured symptom screening (SC) for especially advanced cancer patients (CPs). The aim of this multicenter German prospective quality assurance project KeSBa (Kennzahl Symptom- und Belastungserfassung) was to gain knowledge on SC procedures in Oncology Centers (OCs) for advanced cancer patients and a first impression on the consequences of SC.

    METHODS: The KeSBa project consisted of three phases: pilot, 3 months screening and feedback phase. Participating OCs decided to use either the Minimal Documentation System (MIDOS) or the Integrated Palliative care Outcome Scale (IPOS) and defined the cutoff values for positive screening results.

    RESULTS: Out of 172 certified German OCs, 40 (23%) participated in the KeSBa pilot phase, 29 (16.8%) in the 3 months screening phase using MIDOS (n = 18, 58.6%) or IPOS (n = 11, 41.3%) and in the feedback round. 25/29 performed paper-based screening (86.2%). 2.963 CPs were screened. Results were documented for 1255 (42.2%, SC +) positive and 874 (29.5%, SC-) negative screenings depending on the center´s schedules: 452 SC + CPs (28.4%) and 42 SC- CPs (2.6%) had contact to specialized palliative care or other supportive specialist teams afterwards, 458 SC + CPs (28.8%) and 605 SC- CPs (38.1%) remained in standard oncology care. In the feedback round missing resources (personal and IT) and improved communication were mentioned most often.

    CONCLUSION: Routine SC is feasible in advanced CPs treated in OCs but associated with considerable workload. In 42.2% of CPs SC was classified as positive, indicating the need of further diagnostics or professional judgment. SC requires staff and IT resources.

    Pubmed
  • Cellular and humoral immune responses to SARS-CoV-2 vaccination in patients after CD19.CAR T-cell therapy.

    Blood Adv. 2023;7(10): 2066-2069

    Reimann H, Kremer AN, Blumenberg V, Schmidt KG, Aigner M, Jacobs B, Eisenhauer N, Kämpf A, Roesler W, Kharboutli S, Mougiakakos D, Lang V, Lischer C, Irrgang P, Leppkes M, Gonzalez JV, Krönke G, Kremer AE, Tenbusch M, Bruns H, Harrer T, Müller F, Schett G, Mackensen A, Subklewe M, Völkl S

    Pubmed
  • Treatment management for BRAF-mutant melanoma patients with tumor recurrence on adjuvant therapy: a multicenter study from the prospective skin cancer registry ADOREG.

    J Immunother Cancer. 2023;11(9):

    Haist M, Stege H, Rogall F, Tan Y, von Wasielewski I, Klespe KC, Meier F, Mohr P, Kähler KC, Weichenthal M, Hauschild A, Schadendorf D, Ugurel S, Lodde G, Zimmer L, Gutzmer R, Debus D, Schilling B, Kreuter A, Ulrich J, Meiss F, Herbst R, Forschner A, Leiter U, Pfoehler C, Kaatz M, Ziller F, Hassel JC, Tronnier M, Sachse M, Dippel E, Terheyden P, Berking C, Heppt MV, Kiecker F, Haferkamp S, Gebhardt C, Simon JC, Grabbe S, Loquai C

    BACKGROUND: Adjuvant therapy with immune-checkpoint inhibitors (CPI) or BRAF/MEK-directed targeted therapy (TT) improves recurrence-free survival (RFS) for patients with advanced, BRAFV600-mutant (BRAFmut) resected melanoma. However, 40% of these patients will develop distant metastases (DM) within 5 years, which require systemic therapy. Little data exist to guide the choice of upfront adjuvant therapy or treatment management upon DM. This study evaluated the efficacy of subsequent treatments following tumor recurrence upon upfront adjuvant therapy.

    METHODS: For this multicenter cohort study, we identified 515 BRAFmut patients with resected stage III melanoma who were treated with PD-1 inhibitors (anti-PD1) or TT in the adjuvant setting. Disease characteristics, treatment regimens, details on tumor recurrence, subsequent treatment management, and survival outcomes were collected within the prospective, real-world skin cancer registry ADOReg. Primary endpoints included progression-free survival (PFS) following DM and best tumor response to first-line (1L) treatments.

    RESULTS: Among 515 eligible patients, 273 patients received adjuvant anti-PD1 and 242 adjuvant TT. At a median follow-up of 21 months, 54.6% of anti-PD1 patients and 36.4% of TT patients recurred, while 39.6% (anti-PD1) and 29.3% (TT) developed DM. Risk of recurrence was significantly reduced in patients treated with TT compared with anti-PD1 (adjusted HR 0.52; 95% CI 0.40 to 0.68, p<0.001). Likewise, median RFS was significantly longer in TT-treated patients (31 vs 17 months, p<0.001). Patients who received TT as second adjuvant treatment upon locoregional recurrence had a longer RFS2 as compared with adjuvant CPI (41 vs 6 months, p=0.009). Patients who recurred at distant sites following adjuvant TT showed favorable response rates (42.9%) after switching to 1L ipilimumab+nivolumab (ipi+nivo). Patients with DM during adjuvant anti-PD1 achieved response rates of 58.7% after switching to 1L TT and 35.3% for 1L ipi+nivo. Overall, median PFS was significantly longer in patients who switched treatments for stage IV disease (median PFS 9 vs 5 months, p=0.004).

    CONCLUSIONS: BRAFmut melanoma patients who developed DM upon upfront adjuvant therapy achieve favorable tumor control and prolonged PFS after switching treatment modalities in the first-line setting of stage IV disease. Patients with locoregional recurrence benefit from complete resection of recurrence followed by a second adjuvant treatment with TT.

    Pubmed
  • Practical guidelines for the management of adverse events of the T cell engager bispecific tebentafusp.

    Eur J Cancer. 2023;191():

    Hassel JC, Berking C, Forschner A, Gebhardt C, Heinzerling L, Meier F, Ochsenreither S, Siveke J, Hauschild A, Schadendorf D

    Tebentafusp is a new T cell receptor bispecific fusion protein and the first approved treatment option for human leucocyte antigen-A*02:01 (HLA-A*02:01) metastatic uveal melanoma, with a proven benefit in overall survival versus the investigator's choice. As a first-in-class therapeutic option, this Immune mobilising monoclonal T cell receptor Against Cancer (ImmTAC) is associated with a new adverse event (AE) profile. Based on clinical experience, a national expert group discussed recommendations for tebentafusp treatment, focusing on AE management. Further topics included prerequisites for initiating tebentafusp treatment, appropriate treatment setting, and patient selection criteria. To provide guidance for treating physicians, the resulting recommendations are summarised including a model standard operating procedure for AE management. Patients in good clinical condition and with a low tumour burden are good candidates for tebentafusp treatment, particularly if treated as early as possible after the diagnosis of metastatic disease. The safety profile of tebentafusp is manageable and includes two major pathologies: cytokine release syndrome (CRS) and skin-related events. Postdose monitoring should thus focus on pyrexia and hypotension as the first symptoms of cytokine release. To minimise the risk of hypotension associated with CRS, patients should receive intravenous fluids before starting treatment. The monitoring of liver values is crucial, as patients may experience an increase in transaminases, which can even manifest as tumour lysis syndrome.

    Pubmed
  • COMBI-r: A Prospective, Non-Interventional Study of Dabrafenib Plus Trametinib in Unselected Patients with Unresectable or Metastatic BRAF V600-Mutant Melanoma.

    Cancers (Basel). 2023;15(18):

    Berking C, Livingstone E, Debus D, Loquai C, Weichenthal M, Leiter U, Kiecker F, Mohr P, Eigentler TK, Remy J, Schober K, Heppt MV, von Wasielewski I, Schadendorf D, Gutzmer R

    Combined BRAF/MEK-inhibition constitutes a relevant treatment option for BRAF-mutated advanced melanoma. The prospective, non-interventional COMBI-r study assessed the effectiveness and tolerability of the BRAF-inhibitor dabrafenib combined with the MEK-inhibitor trametinib in patients with advanced melanoma under routine clinical conditions. Progression-free survival (PFS) was the primary objective, and secondary objectives included overall survival (OS), disease control rate, duration of therapy, and the frequency and severity of adverse events. This study enrolled 472 patients at 55 German sites. The median PFS was 8.3 months (95%CI 7.1-9.3) and the median OS was 18.3 months (14.9-21.3), both tending to be longer in pre-treated patients. In the 147 patients with CNS metastases, PFS was similar in those requiring corticosteroids (probably representing symptomatic patients, 5.6 months (3.9-7.2)) compared with those not requiring corticosteroids (5.9 months (4.8-6.9)); however, OS was shorter in patients with brain metastases who received corticosteroids (7.8 (6.3-11.6)) compared to those who did not (11.9 months (9.6-19.5)). The integrated subjective assessment of tumor growth dynamics proved helpful to predict outcome: investigators' upfront categorization correlated well with time-to-event outcomes. Taken together, COMBI-r mirrored PFS outcomes from other prospective, observational studies and confirmed efficacy and safety findings from the pivotal phase III COMBI-d/-v and COMBI-mb trials.

    Pubmed
  • Case Report: The many faces of bullous pemphigoid.

    Front Immunol. 2023;14():

    Rechtien L, Sollfrank L, Foerster Y, Berking C, Sticherling M

    The pemphigoid group comprises a number of bullous skin diseases with autoantibodies against different constituents of the basement membrane zone that result in subepidermal detachment and clinically characteristic tense blisters, erosions, urticarial erythema, and itching. Apart from the most frequent type of bullous pemphigoid with antibodies against BP180, which is found predominantly in elderly patients, the disease may present at other ages and different pathogenic conditions. Here, four cases are presented of young age (3 months and 25, 34, and 46 years) and in association with vaccination, pregnancy, or metastatic cancer. Though anti-BP180 was found in all cases, a different pathogenic background may be found in any of them, resulting in characteristic clinical manifestation, yet demanding specifically adapted therapeutic approaches.

    Pubmed
  • Impact of novel melanoma therapeutics on female fertility - a pilot study

    J Dtsch Dermatol Ges. 2023;21 Suppl 1(): 164-164

    Hornung-Eichler A, Antoniadis S, Erdmann M, Berking C, Heppt MV

    Pubmed
  • A syphilis-like picture caused by PVL-positive staphylococci

    J Dtsch Dermatol Ges. 2023;21 Suppl 1(): 7-8

    Busch D, Schliep S, Berking C, Bosch-Voskens C

    Pubmed
  • Transcriptomes of MPO-deficient patients with generalized pustular psoriasis reveals expansion of CD4+cytotoxic T cells and an involvement of the complement system

    Eur J Hum Genet. 2023;31 Suppl 1(): 439-440

    Haskamp S, Frey B, Becker I, Atreya I, Berking C, Moessner R, Wilsmann-Theis D, Uebe S, Kirchner P, Hueffmeier U

    Pubmed
  • Blistering Autoimmune Diseases - Importance in Middle Franconia

    J Dtsch Dermatol Ges. 2023;21 Suppl 1(): 107-107

    Schoenfelder V, Sticherling M

    Pubmed
  • Real-world Data of the new JAK Inhibitors Baricitinib, Upadacitinib, and Abrocitinib in Patients with Atopic Dermatitis

    J Dtsch Dermatol Ges. 2023;21 Suppl 1(): 111-112

    Sollfrank L, Rechtien L, Sticherling M

    Pubmed
  • Severe furunculoid Myiasis after a Tour of Africa

    J Dtsch Dermatol Ges. 2023;21 Suppl 1(): 1-1

    Rechtien L, Kaufmann M, Sticherling M

    Pubmed
  • Maximal Variants of Psoriasis unguium - A Case Series

    J Dtsch Dermatol Ges. 2023;21 Suppl 1(): 153-154

    Rechtien L, Sollfrank L, Sticherling M

    Pubmed
  • Alopecia areata - Epidemiology and Treatment Response with a Focus on Diphenylcyclopropenone Therapy

    J Dtsch Dermatol Ges. 2023;21 Suppl 1(): 129-129

    Busch D, Sticherling M

    Pubmed
  • Use of JAK Inhibitors in Patients with Alopecia areata at the Dermatology Clinic of the University Hospital in Erlange, Germany

    J Dtsch Dermatol Ges. 2023;21 Suppl 1(): 132-132

    Busch D, Sticherling M

    Pubmed
  • Psoriasis - Status and Care in the university Environment

    J Dtsch Dermatol Ges. 2023;21 Suppl 1(): 114-114

    Morcos C, Sticherling M

    Pubmed
  • Patch testing hydroperoxides of limonene and linalool in consecutive patients-Results of the IVDK 2018-2020.

    Contact Dermatitis. 2023;89(2): 85-94

    Schubert S, Geier J, Brans R, Heratizadeh A, Kränke B, Schnuch A, Bauer A, Dickel H, Buhl T, Vieluf D, Wagner N, Worm M, IVDK

    BACKGROUND: Hydroperoxides of limonene (Lim-OOHs) and linalool (Lin-OOHs) are potent contact sensitizers.

    OBJECTIVES: To investigate the prevalence of positive patch test (PT) reactions to Lim-OOHs and Lin-OOHs in consecutive patients, their demographic factors and concomitant reactions.

    METHODS: Between 7/2018 and 12/2020, Lim-OOHs 0.3% pet. and Lin-OOHs 1% pet. were patch tested in 5511 consecutive patients. We assessed PT reactivity and analysed data from patients with either positive or negative PTs to Lim-OOHs and Lin-OOHs.

    RESULTS: Positive PT results to Lim-OOHs (n = 170, 3.1%) and Lin-OOHs (n = 483, 8.8%) were frequent. Most of the positive reactions were weak (LimOOHs n = 134/LinOOHs n = 429), and even more frequently, doubtful (n = 252/n = 578) or irritant reactions (n = 81/n = 178) were documented. PT reactivity to Lim-OOHs and Lin-OOHs was increased in patients with irritant reactions to sodium lauryl sulphate (SLS). The proportion of leg dermatitis and concomitant positive reactions to fragrances and essential oils was increased in patients with reactivity to these hydroperoxides.

    CONCLUSION: The observed reaction pattern suggests that both test preparations display an irritant potential with an increased risk of false positive reactions. Preparations should be chemically monitored in order to reduce irritancy. Mindful interpretation of PT results and aimed patch testing of lower concentrations is recommended.

    Pubmed
  • Food-Induced Anaphylaxis: Data From the European Anaphylaxis Registry.

    J Allergy Clin Immunol Pract. 2023;11(7): 2069-2079.e7

    Dölle-Bierke S, Höfer V, Francuzik W, Näher AF, Bilo MB, Cichocka-Jarosz E, Lopes de Oliveira LC, Fernandez-Rivas M, García BE, Hartmann K, Jappe U, Köhli A, Lange L, Maris I, Mustakov TB, Nemat K, Ott H, Papadopoulos NG, Pföhler C, Ruëff F, Sabouraud-Leclerc D, Spindler T, Stock P, Treudler R, Vogelberg C, Wagner N, Worm M

    BACKGROUND: Food is one of the most common elicitors of anaphylaxis, with an increasing incidence over recent years.

    OBJECTIVES: To characterize elicitor-specific phenotypes and identify factors enhancing the risk or severity of food-induced anaphylaxis (FIA).

    METHODS: We analyzed data from the European Anaphylaxis Registry applying an age- and sex-matched analysis of associations (Cramer's V) for single food triggers and calculated odds ratios (ORs) for severe FIA.

    RESULTS: We identified 3,427 cases of confirmed FIA showing an age-dependent elicitor ranking (for children: peanut, cow's milk, cashew, and hen's egg; and for adults: wheat flour, shellfish, hazelnut, and soy). The age- and sex-matched analysis revealed defined symptom patterns for wheat and cashew. Wheat-induced anaphylaxis was more frequently associated with cardiovascular symptoms (75.7%; Cramer's V = 0.28) and cashew-induced anaphylaxis with gastrointestinal symptoms (73.9%; Cramer's V = 0.20). Furthermore, concomitant atopic dermatitis was slightly associated with anaphylaxis to hen's egg (Cramer's V = 0.19) and exercise was strongly associated with anaphylaxis to wheat (Cramer's V = 0.56). Additional factors influencing the severity were alcohol intake in wheat anaphylaxis (OR = 3.23; CI, 1.31-8.83) and exercise in peanut anaphylaxis (OR = 1.78; CI, 1.09-2.95).

    CONCLUSIONS: Our data show that FIA is age-dependent. In adults, the range of elicitors inducing FIA is broader. For some elicitors, the severity of FIA seems to be related to the elicitor. These data require confirmation in future studies considering a clear differentiation between augmentation and risk factors in FIA.

    Pubmed
  • Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors.

    Med (N Y). 2023;4(2): 113-129.e7

    Nuñez NG, Berner F, Friebel E, Unger S, Wyss N, Gomez JM, Purde MT, Niederer R, Porsch M, Lichtensteiger C, Kramer R, Erdmann M, Schmitt C, Heinzerling L, Abdou MT, Karbach J, Schadendorf D, Zimmer L, Ugurel S, Klümper N, Hölzel M, Power L, Kreutmair S, Capone M, Madonna G, Cevhertas L, Heider A, Amaral T, Hasan Ali O, Bomze D, Dimitriou F, Diem S, Ascierto PA, Dummer R, Jäger E, Driessen C, Levesque MP, van de Veen W, Joerger M, Früh M, Becher B, Flatz L

    BACKGROUND: Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs.

    METHODS: In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs.

    FINDINGS: When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs.

    CONCLUSIONS: We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs.

    FUNDING: This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen.

    Pubmed
  • Quantification of skin findings using 3D whole-body images and artificial swarm intelligence using vitiligo as an example

    J Dtsch Dermatol Ges. 2023;21 Suppl 1(): 57-57

    Sitaru S, Erdmann M, Schnetz S, Becker M, Buettner M, Piraud M, Kofler F, Vivar G, Biedermann T, Zink A

    Pubmed
  • Monitoring of enzymatic biomarkers from plasma extracellular vesicles in patients with metastatic uveal melanoma treated with tebentafusp

    J Dtsch Dermatol Ges. 2023;21 Suppl 4(): 19-20

    Karimi B, Berking C, VanDeun J, Eberhardt M, Vera J, Heppt M, Bosch-Voskens CJ, Baur A, Erdmann M

    Pubmed
  • Resistance of metastatic uveal melanoma might be overcome by the combined use of ex-vivo expanded NK cells and PD-L1 checkpoint inhibitors

    J Dtsch Dermatol Ges. 2023;21 Suppl 4(): 83-83

    Azodanlou D, Maerz J, Wiesinger M, Heppt M, Berking C, Erdmann M, Bosch-Voskens CJ

    Pubmed
  • Optimized management of immune checkpoint-associated side effects through interdisciplinary discussion as part of an immunotox board

    J Dtsch Dermatol Ges. 2023;21 Suppl 4(): 29-30

    Kramer R, Bosch-Voskens CJ, Dietrich P, Fischer S, Fuchs F, Heppt M, Knitza J, Manger B, Meidenbauer N, Neufert C, Nickel FT, Pavel M, Toussaint F, Yovcheva V, Berking C, Heinzerling L, Erdmann M

    Pubmed
  • Editorial: Multiomics and multiparametric analyses to characterize myeloid cell subsets.

    Front Immunol. 2023;14():

    Vu Manh TP, Dalod M, Dudziak D

    Pubmed
  • XCR1 expression distinguishes human conventional dendritic cell type 1 with full effector functions from their immediate precursors.

    Proc Natl Acad Sci U S A. 2023;120(33):

    Heger L, Hatscher L, Liang C, Lehmann CHK, Amon L, Lühr JJ, Kaszubowski T, Nzirorera R, Schaft N, Dörrie J, Irrgang P, Tenbusch M, Kunz M, Socher E, Autenrieth SE, Purbojo A, Sirbu H, Hartmann A, Alexiou C, Cesnjevar R, Dudziak D

    Dendritic cells (DCs) are major regulators of innate and adaptive immune responses. DCs can be classified into plasmacytoid DCs and conventional DCs (cDCs) type 1 and 2. Murine and human cDC1 share the mRNA expression of XCR1. Murine studies indicated a specific role of the XCR1-XCL1 axis in the induction of immune responses. Here, we describe that human cDC1 can be distinguished into XCR1- and XCR1+ cDC1 in lymphoid as well as nonlymphoid tissues. Steady-state XCR1+ cDC1 display a preactivated phenotype compared to XCR1- cDC1. Upon stimulation, XCR1+ cDC1, but not XCR1- cDC1, secreted high levels of inflammatory cytokines as well as chemokines. This was associated with enhanced activation of NK cells mediated by XCR1+ cDC1. Moreover, XCR1+ cDC1 excelled in inhibiting replication of Influenza A virus. Further, under DC differentiation conditions, XCR1- cDC1 developed into XCR1+ cDC1. After acquisition of XCR1 expression, XCR1- cDC1 secreted comparable level of inflammatory cytokines. Thus, XCR1 is a marker of terminally differentiated cDC1 that licenses the antiviral effector functions of human cDC1, while XCR1- cDC1 seem to represent a late immediate precursor of cDC1.

    Pubmed
  • Morphology as indicator of adaptive changes of model tissues in osmotically and chemically changing environments.

    Biomater. Adv.. 2023;154():

    Höllring K, Vurnek D, Gehrer S, Dudziak D, Hubert M, Smith AS

    We investigate the formation and maintenance of the homeostatic state in the case of 2D epithelial tissues following an induction of hyperosmotic conditions, using media enriched with 80 to 320 mOsm of mannitol, NaCl, and urea. We characterise the changes in the tissue immediately after the osmotic shock, and follow it until the new homeostatic state is formed. We characterise changes in cooperative motility and proliferation pressure in the tissue upon treatment with the help of a theoretical model based on the delayed Fisher-Kolmogorov formalism, where the delay in density evolution is induced by the the finite time of the cell division. Finally we explore the adaptation of the homeostatic tissue to highly elevated osmotic conditions by evaluating the morphology and topology of cells after 20 days in incubation. We find that hyperosmotic environments together with changes in the extracellular matrix induce different mechanical states in viable tissues, where only some remain functional. The perspective is a relation between tissue topology and function, which could be explored beyond the scope of this manuscript. Experimental investigation of morphological effect of change of osmotic conditions on long-term tissue morphology and topology Effect of osmotic changes on transient tissue growth behaviour Analysis of recovery process of tissues post-osmotic-shock Toxicity limits of osmolytes in mid- to long-term tissue evolution Tissue adaptation to physiological changes in environment Long-term tissue stabilisation under altered osmotic conditions.

    Pubmed
  • Standardized Computer-Assisted Analysis of 5-hmC Immunoreactivity in Dysplastic Nevi and Superficial Spreading Melanomas.

    Int J Mol Sci. 2023;24(19):

    Koch EAT, Berking C, Erber R, Erdmann M, Kiesewetter F, Schliep S, Heppt MV

    5-Hydroxymethylcytosine (5-hmC) is an important intermediate of DNA demethylation. Hypomethylation of DNA is frequent in cancer, resulting in deregulation of 5-hmC levels in melanoma. However, the interpretation of the intensity and distribution of 5-hmC immunoreactivity is not very standardized, which makes its interpretation difficult. In this study, 5-hmC-stained histological slides of superficial spreading melanomas (SSM) and dysplastic compound nevi (DN) were digitized and analyzed using the digital pathology and image platform QuPath. Receiver operating characteristic/area under the curve (ROCAUC) and t-tests were performed. A p-value of <0.05 was used for statistical significance, and a ROCAUC score of >0.8 was considered a "good" result. In total, 92 5-hmC-stained specimens were analyzed, including 42 SSM (45.7%) and 50 DN (54.3%). The mean of 5-hmC-positive cells/mm2 for the epidermis and dermo-epidermal junction and the entire lesion differed significantly between DN and SSM (p = 0.002 and p = 0.006, respectively) and showed a trend towards higher immunoreactivity in the dermal component (p = 0.069). The ROCAUC of 5-hmC-positive cells of the epidermis and dermo-epidermal junction was 0.79, for the dermis 0.74, and for the entire lesion 0.76. These results show that the assessment of the epidermal with junctional expression of 5-hmC is slightly superior to dermal immunoreactivity in distinguishing between DN and SSM.

    Pubmed
  • Identifying novel therapeutic targets in uveal melanoma by SOX10-based drug repurposing

    J Dtsch Dermatol Ges. 2023;21 Suppl 4(): 83-84

    Wessely A, Lischer C, Weich A, Vera J, Berking C, Heppt M

    Pubmed
  • HDAC2 is involved in the regulation of Brn3a in melanocytes and melanoma

    Exp Dermatol. 2023;32(4): E20-E20

    Heppt MV, Wessely A, Hornig E, Kammerbauer C, Graf S, Besch R, French LE, Kuphal S, Kappelmann-Fenzl M, Bosserhoff AK, Berking C

    Pubmed
  • Inhibiting the neural crest transcription factor SOX10 leads to cell cycle arrest and apoptosis in uveal melanoma cells

    Exp Dermatol. 2023;32(4): E117-E117

    Wessely A, Kammerbauer C, Berking C, Heppt MV

    Pubmed
  • Guselkumab demonstrates long-term efficacy and maintenance of treatment response post-withdrawal in systemic-treatment naïve patients and non-responders to fumaric acid esters: Results from parts II and III of a randomised, active-comparator-controlled phase IIIb trial (POLARIS).

    Br J Dermatol. 2023;():

    Thaҫi D, Pinter A, Sebastian M, Termeer C, Sticherling M, Gerdes S, Schäkel K, Wegner S, Krampe S, Bartz H, Rausch C, Taut F, Eyerich K

    BACKGROUND: The anti-interleukin-23 antibody guselkumab demonstrated favourable Week 24 efficacy and safety over fumaric acid esters (FAE) in systemic-treatment naïve patients with moderate-to-severe plaque psoriasis (study part I).

    OBJECTIVES: Part II: compare a) sustainability of treatment responses (Weeks 24-32) in guselkumab- and FAE-treated patients and b) treatment responses (Weeks 32-56) in patients treated with guselkumab, FAE, and FAE non-responders switching to guselkumab. Part III: investigate the maintenance of response through Week 100 in patients withdrawn from guselkumab at Week 56.

    METHODS: At Week 0, systemic-treatment naïve patients were randomised 1:1 to guselkumab (GUS) or FAE as per label. At Week 32, patients with PASI75 response (r) continued assigned treatment (GUSr-GUS; FAEr-FAE), whereas non-responders (nr) received guselkumab (FAEnr-GUS; GUSnr-GUS). Guselkumab-treated patients with Week 56 PASI90 response were withdrawn (w) and followed until loss of response or Week 100.

    RESULTS: At Week 32, 98.2% (54/55) of guselkumab- and 41.2% (14/34) of FAE-treated patients were PASI75 responders. At Week 56, 90.7%, 50.0% and 80.0% of GUSr-GUS, FAEr-FAE and FAEnr-GUS patients, respectively, achieved a PASI90 response; 72.2%, 28.6% and 45.0%, respectively, achieved a DLQI score 0/1. At Week 100, 44 weeks post-withdrawal, 47.2% (17/36) and 25.0% (3/12) of GUS-GUSw and FAE-GUSw patients, respectively, maintained PASI score ≤5. Overall, the adverse event and discontinuation rates were lower for guselkumab than FAE.

    CONCLUSIONS: In these exploratory analyses, guselkumab, as a first-line systemic treatment or second-line systemic treatment in FAE non-responders, was associated with long-term clinical efficacy up to Week 100, including a withdrawal period.

    Pubmed
  • Threshold Optimization for Tumor Markers S100b and MIA in Uveal Melanoma - A Single Center Analysis.

    Anticancer Res. 2023;43(10): 4525-4532

    Glaser N, Petzold A, Wessely A, Kaufmann MD, Koch EAT, Knorr H, Voskens C, Heppt MV, Berking C, Erdmann M

    BACKGROUND/AIM: Uveal melanoma (UM) is the most common malignant tumor of the eye in adults. Metastases develop in 50% of the patients, predominantly in the liver. In UM, the cut-off concentrations of the blood-based tumor markers S100b and MIA are inconclusive.

    PATIENTS AND METHODS: In this retrospective monocenter study, we statistically evaluated 1,878 S100b and 1,768 MIA measurements in 244 patients with UM from 2011-2020. Threshold optimization was performed using receiver operating characteristic (ROC) curves.

    RESULTS: A total of 171 patients with non-metastatic UM (nmUM) and 73 patients with metastatic UM (mUM) showed no differences in sex, age at diagnosis or the affected eye. In mUM, 80% of the patients developed metastases to the liver at a median of 46 months after initial diagnosis. The sensitivity and specificity of S100b was 16.10% and 94.52%, and that of MIA was 31.86% and 81.42%, respectively. ROC curves revealed poor values for the area under the curve of 0.57 for S100b and 0.55 for MIA. The optimal cut-off concentration to detect metastases was 0.14 μg/l for S100b and 17.4 ng/ml for MIA. With at least one tumor marker elevated, optimized sensitivity was 20.40% and specificity 96.76%.

    CONCLUSION: Current thresholds for S100b and MIA in UM are not able to detect early metastatic disease and require additional diagnostics to clarify false positive results. Threshold optimization considering both S100b and MIA results in a better diagnostic validity with an acceptable specificity and a poor sensitivity. Highly sensitive blood-based and imaging methods to detect metastases early in UM are urgently needed.

    Pubmed
  • S3 guideline "actinic keratosis and cutaneous squamous cell carcinoma" - update 2023, part 2: epidemiology and etiology, diagnostics, surgical and systemic treatment of cutaneous squamous cell carcinoma (cSCC), surveillance and prevention.

    J Dtsch Dermatol Ges. 2023;21(11): 1422-1433

    Leiter U, Heppt MV, Steeb T, Alter M, Amaral T, Bauer A, Bechara FG, Becker JC, Breitbart EW, Breuninger H, Diepgen T, Dirschka T, Eigentler T, ElGammal AKS, Felcht M, Flaig MJ, Follmann M, Fritz K, Grabbe S, Greinert R, Gutzmer R, Hauschild A, Hillen U, Ihrler S, John SM, Kofler L, Koelbl O, Krause-Bergmann A, Kraywinkel K, Krohn S, Langer T, Loquai C, Löser CR, Mohr P, Nashan D, Nothacker M, Pfannenberg C, Salavastru C, Schmitz L, Stockfleth E, Szeimies RM, Ulrich C, Voelter-Mahlknecht S, Vordermark D, Weichenthal M, Welzel J, Wermker K, Wiegand S, Garbe C, Berking C

    Actinic keratosis (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline "actinic keratosis and cutaneous squamous cell carcinoma" was updated and expanded by the topics cutaneous squamous cell carcinoma in situ (Bowen's disease) and actinic cheilitis. The guideline is aimed at dermatologists, general practitioners, ear nose and throat specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings, as well as other medical specialties, policy makers and insurance funds involved in the diagnosis and treatment of patients with AK and cSCC. A separate guideline exists for patients and their relatives. In this part, we will address aspects relating to epidemiology and etiology, diagnostics, surgical and systemic treatment of cutaneous squamous cell carcinoma (cSCC), surveillance and prevention.

    Pubmed
  • S3 guideline "actinic keratosis and cutaneous squamous cell carcinoma"- update 2023, part 1: treatment of actinic keratosis, actinic cheilitis, cutaneous squamous cell carcinoma in situ (Bowen's disease), occupational disease and structures of care.

    J Dtsch Dermatol Ges. 2023;21(10): 1249-1262

    Heppt MV, Leiter U, Steeb T, Alter M, Amaral T, Bauer A, Bechara FG, Becker JC, Breitbart EW, Breuninger H, Diepgen T, Dirschka T, Eigentler T, El Gammal AKS, Felcht M, Flaig MJ, Follmann M, Fritz K, Grabbe S, Greinert R, Gutzmer R, Hauschild A, Hillen U, Ihrler S, John SM, Kofler L, Koelbl O, Krause-Bergmann A, Kraywinkel K, Krohn S, Langer T, Loquai C, Löser CR, Mohr P, Nashan D, Nothacker M, Pfannenberg C, Salavastru C, Schmitz L, Stockfleth E, Szeimies RM, Ulrich C, Voelter-Mahlknecht S, Vordermark D, Weichenthal M, Welzel J, Wermker K, Wiegand S, Garbe C, Berking C

    Pubmed
  • BCL2 Inhibition Reveals a Dendritic Cell-Specific Immune Checkpoint That Controls Tumor Immunosurveillance.

    Cancer Discov. 2023;13(11): 2448-2469

    Zhao L, Liu P, Mao M, Zhang S, Bigenwald C, Dutertre CA, Lehmann CHK, Pan H, Paulhan N, Amon L, Buqué A, Yamazaki T, Galluzzi L, Kloeckner B, Silvin A, Pan Y, Chen H, Tian AL, Ly P, Dudziak D, Zitvogel L, Kepp O, Kroemer G

    UNLABELLED: We developed a phenotypic screening platform for the functional exploration of dendritic cells (DC). Here, we report a genome-wide CRISPR screen that revealed BCL2 as an endogenous inhibitor of DC function. Knockout of BCL2 enhanced DC antigen presentation and activation as well as the capacity of DCs to control tumors and to synergize with PD-1 blockade. The pharmacologic BCL2 inhibitors venetoclax and navitoclax phenocopied these effects and caused a cDC1-dependent regression of orthotopic lung cancers and fibrosarcomas. Thus, solid tumors failed to respond to BCL2 inhibition in mice constitutively devoid of cDC1, and this was reversed by the infusion of DCs. Moreover, cDC1 depletion reduced the therapeutic efficacy of BCL2 inhibitors alone or in combination with PD-1 blockade and treatment with venetoclax caused cDC1 activation, both in mice and in patients. In conclusion, genetic and pharmacologic BCL2 inhibition unveils a DC-specific immune checkpoint that restrains tumor immunosurveillance.

    SIGNIFICANCE: BCL2 inhibition improves the capacity of DCs to stimulate anticancer immunity and restrain cancer growth in an immunocompetent context but not in mice lacking cDC1 or mature T cells. This study indicates that BCL2 blockade can be used to sensitize solid cancers to PD-1/PD-L1-targeting immunotherapy. This article is featured in Selected Articles from This Issue, p. 2293.

    Pubmed
  • Evaluating the Efficacy and Safety of 4% 5-Fluorouracil Cream in Patients with Actinic Keratosis: An Expert Opinion.

    Acta Derm Venereol. 2023;103():

    Stockfleth E, Heppt MV, Bégeault N, Delarue A

    Actinic keratosis is a lesion that develops in sun-exposed areas of the skin and is considered to be a precancerous condition or an early in situ squamous cell carcinoma. Treatment of actinic keratosis is important for reducing skin cancer risk, with treatment choice based on patient-, lesion- and treatment-related considerations. Of the topical treatments used for field-directed therapy, those containing 5-fluorouracil are among the most effective and widely prescribed. The most recently developed topical 5-fluorouracil preparation (Tolak®; Pierre Fabre, France) contains 4% 5-fluorouracil in an aqueous cream. This narrative review discusses data on 4% 5-fluorouracil cream to treat actinic keratosis, and provides the authors' expert opinion on issues associated with it use. The effect of the cream has been evaluated in phase 2 and 3 trials of adult patients with actinic keratosis on the face, ears or scalp. These trials included patients with severe baseline disease, defined by high lesion counts and large-size treatment fields, which possibly affected the proportion of patients who were able to achieve complete clearance. Other efficacy parameters (e.g. percentage change in lesion count, ≥ 75% clearance of lesions or clinically significant changes in validated severity scales) should also be assessed to fully evaluate 4% 5-fluorouracil treatment efficacy in these patients. Nevertheless, 4% 5-fluorouracil is associated with high efficacy, a low level of recurrence and a satisfactory safety profile.

    Pubmed
  • Acral Fibrokeratoma in the Form of a Victory Sign

    J Dtsch Dermatol Ges. 2023;21 Suppl 1(): 169-170

    Lorz A, Heppt F, Krahl D

    Pubmed
  • 67. Arbeitssitzung (Frühjahrssymposium) der Deutschen Kontaktallergie-Gruppe (DKG).

    J Dtsch Dermatol Ges. 2023;21(8): 937-938

    Brans R, Wagner N

    Pubmed
  • Tolerability of BRAF and MEK Inhibitors for Metastasized Melanoma after Intra-Class Switch: A Multicenter, Retrospective Study.

    Cancers (Basel). 2023;15(5):

    Salzmann M, Wald A, Stege H, Loquai C, Zimmer L, Hayani KM, Heinzerling L, Gutzmer R, Enk AH, Hassel JC

    Targeted therapy with BRAF and MEK inhibitors (BRAFi, MEKi) is one of the mainstays of melanoma treatment. When dose-limiting toxicity (DLT) is observed, an option represents the intra-class switch to a different BRAFi+MEKi combination. Currently, there is scarce evidence for this procedure. This is a multicenter, retrospective analysis from six German skin cancer centers of patients who received two different combinations of BRAFi and MEKi. In total, 94 patients were included: 38 patients (40%) were re-exposed with a different combination because of previous unacceptable toxicity, 51 (54%) were re-exposed after progression, and 5 (5%) were included for other reasons. Of the 44 patients with a DLT during their first BRAFi+MEKi combination, only five (11%) experienced the same DLT during their second combination. A new DLT was experienced by 13 patients (30%). Six patients (14%) had to discontinue the second BRAFi treatment due to its toxicity. Compound-specific adverse events were avoided in the majority of patients by switching to a different combination. Efficacy data were similar to historical cohorts of BRAFi+MEKi rechallenge, with an overall response rate of 31% for patients who had previously progressed to treatment. We conclude that switching to a different BRAFi+MEKi combination if dose-limiting toxicity occurs is a feasible and rational approach in patients with metastatic melanoma.

    Pubmed
  • TIGIT+ NK cells in combination with specific gut microbiota features predict response to checkpoint inhibitor therapy in melanoma patients.

    BMC Cancer. 2023;23(1):

    Tsakmaklis A, Farowski F, Zenner R, Lesker TR, Strowig T, Schlößer H, Lehmann J, von Bergwelt-Baildon M, Mauch C, Schlaak M, Knuever J, Schweinsberg V, Heinzerling LM, Vehreschild MJGT

    BACKGROUND: Composition of the intestinal microbiota has been correlated to therapeutic efficacy of immune checkpoint inhibitors (ICI) in various cancer entities including melanoma. Prediction of the outcome of such therapy, however, is still unavailable. This prospective, non-interventional study was conducted in order to achieve an integrated assessment of the connection between a specific intestinal microbiota profile and antitumor immune response to immune checkpoint inhibitor therapy (anti-PD-1 and/or anti-CTLA-4) in melanoma patients.

    METHODS: We assessed blood and stool samples of 29 cutaneous melanoma patients who received immune checkpoint inhibitor therapy. For functional and phenotypical immune analysis, 12-color flow cytometry and FluoroSpot assays were conducted. Gut microbiome was analyzed with shotgun metagenomics sequencing. To combine clinical, microbiome and immune variables, we applied the Random Forest algorithm.

    RESULTS: A total of 29 patients was analyzed in this study, among whom 51.7% (n = 15) reached a durable clinical benefit. The Immune receptor TIGIT is significantly upregulated in T cells (p = 0.0139) and CD56high NK cells (p = 0.0037) of responders. Several bacterial taxa were associated with response (e.g. Ruminococcus torques) or failure (e.g. Barnesiella intestinihominis) to immune therapy. A combination of two microbiome features (Barnesiella intestinihominis and the Enterobacteriaceae family) and one immune feature (TIGIT+ CD56high NK cells) was able to predict response to ICI already at baseline (AUC = 0.85; 95% CI: 0.841-0.853).

    CONCLUSIONS: Our results reconfirm a link between intestinal microbiota and response to ICI therapy in melanoma patients and furthermore point to TIGIT as a promising target for future immunotherapies.

    Pubmed
  • Immune checkpoint inhibition in patients with NRAS mutated and NRAS wild type melanoma: a multicenter Dermatologic Cooperative Oncology Group study on 637 patients from the prospective skin cancer registry ADOREG.

    Eur J Cancer. 2023;188(): 140-151

    Zaremba A, Mohr P, Gutzmer R, Meier F, Pföhler C, Weichenthal M, Terheyden P, Forschner A, Leiter U, Ulrich J, Utikal J, Welzel J, Kaatz M, Gebhardt C, Herbst R, Sindrilaru A, Dippel E, Sachse M, Meiss F, Heinzerling L, Haferkamp S, Weishaupt C, Löffler H, Kreft S, Griewank K, Livingstone E, Schadendorf D, Ugurel S, Zimmer L

    BACKGROUND: Melanomas frequently harbour somatic mutations in BRAF (40%) or NRAS (20%). Impact of NRAS mutations on the therapeutic outcome of immune checkpoint inhibitors (ICI) remains controversial. Potential correlation of the NRAS mutational status and programmed cell death ligand-1 (PD-L1) expression in melanoma is unknown.

    PATIENTS AND METHODS: Advanced, non-resectable melanoma patients with known NRAS mutation status treated with first-line ICI between 06/2014 and 05/2020 in the prospective multicenter skin cancer registry ADOREG were included. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) according to NRAS status were analysed. A multivariate Cox model was used to analyse factors associated with PFS and OS; survival was analysed using the Kaplan-Meier approach.

    RESULTS: Among 637 BRAF wild-type patients, 310 (49%) had an NRAS mutation with Q61R (41%) and Q61K (32%). NRAS-mutated (NRASmut) melanomas were significantly more often located on the lower extremities and trunk (p = 0.001); nodular melanoma was the most common subtype (p < 0.0001). No significant differences were found for PFS and OS for anti-PD1 monotherapy (2-year PFS 39%, [95% confidence interval (CI), 33-47] in NRASmut patients and 41% [95% CI, 35-48] in NRAS-wild type (NRASwt) patients; 2-year OS was 54% [95% CI, 48-61] in NRASmut patients and 57% [95% CI, 50-64] in NRASwt patients) and anti-PD1 plus anti-CTLA4 therapy between both cohorts (2-year PFS was 54% [95% CI, 44-66] in NRASmut patients and 53% [95% CI, 41-67] in NRASwt patients; 2-year OS was 58% [95% CI, 49-70] in NRASmut patients and 62% [95% CI, 51-75] in NRASwt patients). The ORR to anti-PD1 was 35% for NRASwt patients and 26% for NRASmut patients and 34% compared to 32% for combinational therapy. Data on PD-L1 expression was available in 82 patients (13%). PD-L1 expression (>5%) was not correlated to NRAS mutational status. In multivariate analysis, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group performance status ≥ 1, and brain metastases were significantly associated with a higher risk of death in all patients.

    CONCLUSIONS: The PFS and OS were not affected by NRAS mutational status in patients treated with anti-PD1-based ICI. Similar ORR was seen in NRASwt and NRASmut patients. Tumour PD-L1 expression did not correlate with NRAS mutational status.

    Pubmed
  • Clinical risk factors for checkpoint pneumonitis vs. other pneumonitis in lung cancer patients treated with checkpoint inhibitors

    Eur Respir J. 2023;62 Suppl 67():

    Wehlte L, Daisenberger L, Walter J, Heinzerling L, Pfluger T, Tufman A

    Pubmed
  • Stereotactic radiosurgery and combined immune checkpoint therapy with ipilimumab and nivolumab in patients with melanoma brain metastases: A retrospective monocentric toxicity analysis.

    Clin Transl Radiat Oncol. 2023;39():

    Bodensohn R, Werner S, Reis J, Pazos Escudero M, Kaempfel AL, Hadi I, Forbrig R, Manapov F, Corradini S, Belka C, Theurich S, Heinzerling L, Schlaak M, Niyazi M

    PURPOSE AND OBJECTIVE: Adding stereotactic radiosurgery (SRS) to combined immune checkpoint therapy with ipilimumab and nivolumab (IPI + NIVO) has led to promising results for patients with melanoma brain metastases (MBM). This study retrospectively analyzes the toxicity profile depending on the timing of SRS with regard to IPI + NIVO.

    MATERIALS AND METHODS: For this study, the clinical database was searched for all patients with MBM who were treated with SRS and IPI + NIVO. The patients were separated into three groups: group A completed IPI + NIVO (usually up to four cycles) >14 days before SRS, in group B IPI + NIVO was initiated>14 days after SRS, and group C received SRS concurrently to IPI + NIVO. Treatment related toxicity was obtained from clinical and neuroradiological records. Analyses were performed using the Fisher-Yates-test.

    RESULTS: 31 patients were assessed including six (19.4 %), seven (22.6 %) and 18 (58.1 %) patients, in groups A, B and C, respectively. Baseline prognostic markers between groups were balanced. In total, five (16.1 %) patients experienced neurological grade 3 toxicities related to SRS. All of these five patients were in group C, which was near-significantly correlated with a risk for grade 3 toxicities (p = 0.058). Post-hoc analyses showed that a maximum time period of seven days between SRS and IPI + NIVO was significantly correlated with grade 3 toxicity (p = 0.048).

    CONCLUSION: Application of SRS to IPI + NIVO within a seven-day span was related to higher toxicity rates in this retrospective analysis. After previous studies focused on immune checkpoint monotherapies with SRS and declared it as safe, this study indicates that concomitant application of IPI + NIVO and SRS might increase side effects. Prospective validation is warranted to corroborate these findings.

    Pubmed
  • Anti-PD1 plus BRAF/MEK inhibitors (triplet therapy) after failure of standard therapy in patients (pts) with advanced melanoma

    J Dtsch Dermatol Ges. 2023;21 Suppl 4(): 44-44

    Albrecht LJ, Dimitriou F, Grover P, Hassel JC, Erdmann M, Forschner A, Johnson D, Livingstone E, Roesch A, Ugurel S, Schulz C, Berking C, Menzies AM, Long GV, Dummer R, Schadendorf D, Zimmer L

    Pubmed
  • Autologous regulatory T-cell transfer in refractory ulcerative colitis with concomitant primary sclerosing cholangitis.

    Gut. 2023;72(1): 49-53

    Voskens C, Stoica D, Rosenberg M, Vitali F, Zundler S, Ganslmayer M, Knott H, Wiesinger M, Wunder J, Kummer M, Siegmund B, Schnoy E, Rath T, Hartmann A, Hackstein H, Schuler-Thurner B, Berking C, Schuler G, Atreya R, Neurath MF

    OBJECTIVE: Ulcerative colitis (UC) is a chronic, debilitating immune-mediated disease driven by disturbed mucosal homeostasis, with an excess of intestinal effector T cells and an insufficient expansion of mucosal regulatory T cells (Tregs). We here report on the successful adoptive transfer of autologous, ex vivo expanded Tregs in a patient with refractory UC and associated primary sclerosing cholangitis (PSC), for which effective therapy is currently not available.

    DESIGN: The patient received a single infusion of 1×106 autologous, ex vivo expanded, polyclonal Tregs per kilogram of body weight, and the clinical, biochemical, endoscopic and histological responses were assessed 4 and 12 weeks after adoptive Treg transfer.

    RESULTS: The patient showed clinical, biochemical, endoscopic and histological signs of response until week 12 after adoptive Treg transfer, which was associated with an enrichment of intestinal CD3+/FoxP3+ and CD3+/IL-10+ T cells and increased mucosal transforming growth factor beta and amphiregulin levels. Moreover, there was marked improvement of PSC with reduction of liver enzymes. This pronounced effect lasted for 4 weeks before values started to increase again.

    CONCLUSION: These findings suggest that adoptive Treg therapy might be effective in refractory UC and might open new avenues for clinical trials in PSC.

    TRIAL REGISTRATION NUMBER: NCT04691232.

    Pubmed
  • Clinical Manifestation of Cutaneous Leishmaniasis Following a Mechanical Trauma.

    Int J Low Extrem Wounds. 2023;22(1): 146-148

    Busch D, Bogdan C, Erfurt-Berge C

    Unusual skin ulcers frequently represent a diagnostic challenge. When the most common disease entities such as arterial, venous or diabetic ulcers have been excluded, the question of further differential diagnoses and procedures arises. Other possible causes include chronic inflammatory diseases, neoplasia, self-inflicted wounds, primary infectious diseases and physical/chemical damage to the skin. To narrow down the differential diagnoses, a detailed history of the patient is essential, which also needs to include events further back in time.

    Pubmed
  • Association of Structural Entheseal Lesions With an Increased Risk of Progression From Psoriasis to Psoriatic Arthritis.

    Arthritis Rheumatol. 2022;74(2): 253-262

    Simon D, Tascilar K, Kleyer A, Bayat S, Kampylafka E, Sokolova M, Zekovic A, Hueber AJ, Rech J, Schuster L, Engel K, Sticherling M, Schett G

    OBJECTIVE: To test whether the presence of structural entheseal lesions in psoriasis patients influences the risk of progression to psoriatic arthritis (PsA).

    METHODS: We conducted a prospective cohort study of psoriasis patients without clinical evidence of musculoskeletal involvement who underwent baseline assessment of structural entheseal lesions and volumetric bone mineral density (vBMD) at entheseal and intraarticular sites by high-resolution peripheral quantitative computed tomography. Adjusted relative risks of developing PsA associated with baseline vBMD and the presence of structural entheseal lesions were calculated using multivariable Cox regression models.

    RESULTS: The cohort included 114 psoriasis patients (72 men and 42 women) with a mean ± SD follow-up duration of 28.2 ± 17.7 months, during which 24 patients developed PsA (9.7 per 100 patient-years [95% confidence interval (95% CI) 6.2-14.5]). Patients with structural entheseal lesions were at higher risk of developing PsA compared to patients without such lesions (21.4 per 100 patient-years [95% CI 12.5-34.3]; hazard ratio [HR] 5.10 [95% CI 1.53-16.99], P = 0.008). With respect to vBMD, a 1-SD increase in entheseal, but not intraarticular, vBMD was associated with an ~30% reduced risk of progression to PsA. Especially, higher cortical vBMD at entheseal segments was associated with a lower risk of developing PsA (HR 0.32 per 1 SD [95% CI 0.14-0.71]), and the association remained robust after multiple imputation of missing data (HR 0.64 [95% CI 0.42-0.98]).

    CONCLUSION: The presence of structural entheseal lesions as well as low cortical vBMD at entheseal segments are associated with an increased risk of developing PsA in patients with psoriasis.

    Pubmed
  • Biologics and small molecules in patients with scalp psoriasis: a systematic review.

    J Dermatolog Treat. 2022;33(1): 473-482

    Alsenaid A, Ezmerli M, Srour J, Heppt M, Illigens BM, Prinz JC

    BACKGROUND: Scalp psoriasis is common in psoriasis patients, difficult to treat and manifests a significant burden on quality of life.

    OBJECTIVE: Efficacy assessment of biologics and small molecules in scalp psoriasis with reported safety and quality of life.

    METHODS: Biological therapies and small molecules licensed for treatment of plaque psoriasis are assessed. Fourteen studies reporting results from RCTs are included. Efficacy assessment is measured through improvement of Psoriasis Scalp Severity Index (PSSI), Scalp Physician Global Assessment (ScPGA) and/or Scalp-Specific Investigator's Global Assessment (ss-IGA).

    RESULTS: Among biologics measured by PSSI, brodalumab, secukinumab and in a subgroup ixekizumab showed high efficacy in moderate to severe scalp psoriasis. Both brodalumab and ixekizumab demonstrated rapid response within 2 weeks. Guselkumab was superior to adalimumab and ixekizumab was superior to etanercept. Apremilast showed long-term efficacy. Only few studies reported quality of life in treatment of scalp involvement which showed improvement. All treatments demonstrated acceptable safety profile.

    CONCLUSION: Effective treatment of scalp psoriasis is essential for improving the quality of life of psoriasis patients. Both Biologics and small molecules proved efficacy. This review may help choosing the appropriate treatment in cases where scalp psoriasis is the main complaint. A unified measurement tool for scalp psoriasis severity is needed to facilitate comparisons.

    Pubmed
  • Transcriptomes of MPO-Deficient Patients with Generalized Pustular Psoriasis Reveals Expansion of CD4+ Cytotoxic T Cells and an Involvement of the Complement System.

    J Invest Dermatol. 2022;142(8): 2149-2158.e10

    Haskamp S, Frey B, Becker I, Schulz-Kuhnt A, Atreya I, Berking C, Pauli D, Ekici AB, Berges J, Mößner R, Wilsmann-Theis D, Sticherling M, Uebe S, Kirchner P, Hüffmeier U

    Generalized pustular psoriasis is a severe psoriatic subtype characterized by epidermal neutrophil infiltration. Although variants in IL36RN and MPO have been shown to affect immune cells, a systematic analysis of neutrophils and PBMC subsets and their differential gene expression dependent on MPO genotypes was not performed yet. We assessed the transcriptomes of MPO-deficient patients using single-cell RNA sequencing of PBMCs and RNA sequencing of neutrophils in a stable disease state. Cell-type annotation by multimodal reference mapping of single-cell RNA-sequencing data was verified by flow cytometry of surface and intracellular markers; the proportions of CD4+ cytotoxic T lymphocytes and other CD4+ effector cells were increased in generalized pustular psoriasis, whereas the frequencies of naïve CD4+ T cells were significantly lower. The expression of FGFBP2 marking CD4+ cytotoxic T lymphocytes and CD8+ effector memory T cells was elevated in patients with generalized pustular psoriasis with disease-contributing variants compared with that in noncarriers (P = 0.0015). In neutrophils, differentially expressed genes were significantly enriched in genes of the classical complement activation pathway. Future studies assessing affected cell types and pathways will show their contribution to generalized pustular psoriasis's pathogenesis and indicate whether findings can be transferred to the acute epidermal situation and whether depletion or inactivation of CD4+ cytotoxic T lymphocytes may be a reasonable therapeutic approach.

    Pubmed
  • Comparative efficacy analysis identifies immune checkpoint blockade as a new survival benchmark in advanced cutaneous squamous cell carcinoma.

    Eur J Cancer. 2022;170(): 42-53

    Petzold A, Steeb T, Wessely A, Schatton T, Berking C, Heppt MV

    BACKGROUND: Cutaneous squamous cell carcinoma is a common type of skin cancer that may progress to locally advanced or metastatic disease. Both disease stages are managed by a variety of treatment options, including immune checkpoint blockade (ICB), targeted therapy to epidermal growth factor, chemotherapy or treatment combinations. However, the comparative efficacy of such treatments is unclear.

    METHODS: We performed a systematic literature search of Medline, Embase and Central to identify eligible studies reporting Kaplan-Meier curves or individual patient data for overall survival (OS) or progression-free survival (PFS). Kaplan-Meier curves were digitised using the "'WebPlotDigitizer" program. Individual patient data was subsequently remodelled and pooled for distinct treatment groups.

    RESULTS: Overall, 22 independent studies were included of which n = 927 patients were evaluable for PFS and n = 1054 for OS. ICB showed the highest median PFS (mPFS 9.9 months (95% CI: 8.1-19.9)) and median OS (mOS not reached (95% CI: 31.5 months-not reached)) compared to chemotherapy (mPFS 3.0 months (95% CI: 2.2-4.8), mOS 12.6 months (95% CI: 9.6-15.8)), targeted therapy to epidermal growth factor (mPFS 4.9 months (95% CI: 4.4-5.6), mOS 12.7 months (95% CI: 11.9-14.9)) and combination therapies without ICB (mPFS 9.1 months (95% CI: 8.0-12.1), mOS 18.1 months (95% CI: 16.3-22.8)). The survival benchmark with ICB after 26 months for metastatic squamous cell carcinoma was 70.8% (95% CI: 61.5%-81.5%) versus 37.9% (95% CI: 29.5%-48.8%) for the combination group and 17.1% (95% CI: 9.5%-30.8%) for chemotherapy.

    CONCLUSION: ICB is superior to other systemic treatments and sets a novel survival benchmark for advanced cutaneous squamous cell carcinoma.

    Pubmed
  • Artificial intelligence in cancer target identification and drug discovery.

    Signal Transduct Target Ther. 2022;7(1):

    You Y, Lai X, Pan Y, Zheng H, Vera J, Liu S, Deng S, Zhang L

    Artificial intelligence is an advanced method to identify novel anticancer targets and discover novel drugs from biology networks because the networks can effectively preserve and quantify the interaction between components of cell systems underlying human diseases such as cancer. Here, we review and discuss how to employ artificial intelligence approaches to identify novel anticancer targets and discover drugs. First, we describe the scope of artificial intelligence biology analysis for novel anticancer target investigations. Second, we review and discuss the basic principles and theory of commonly used network-based and machine learning-based artificial intelligence algorithms. Finally, we showcase the applications of artificial intelligence approaches in cancer target identification and drug discovery. Taken together, the artificial intelligence models have provided us with a quantitative framework to study the relationship between network characteristics and cancer, thereby leading to the identification of potential anticancer targets and the discovery of novel drug candidates.

    Pubmed
  • Intravascular Large B-Cell Lymphoma: A Review with a Focus on the Prognostic Value of Skin Involvement.

    Curr Oncol. 2022;29(5): 2909-2919

    Breakell T, Waibel H, Schliep S, Ferstl B, Erdmann M, Berking C, Heppt MV

    Intravascular large B-cell lymphoma (IVLBCL) is an aggressive Non-Hodgkin lymphoma (NHL) characterised by the presence of neoplastic lymphoid cells within small- and medium-sized blood vessels. According to the clinical presentation, the current WHO classification distinguishes the 'classic' (formerly 'Western') from a hemophagocytic syndrome-associated (formerly 'Asian') variant. A third 'cutaneous' variant has been proposed, characterised by a good prognosis and unique clinical features. While laboratory findings can hint at diagnosis, symptoms are rather nonspecific, and deep skin biopsy supported by further measures such as bone marrow aspiration and positron emission tomography-computed tomography scanning is needed to make a definite diagnosis. Treatment is comprised of anthracycline-based chemotherapy supplemented with rituximab and central nervous system prophylaxis. While there are various prognostic models for NHL, only one is specific to IVLBCL, which does not sufficiently represent some patient groups, especially regarding the lack of differentiation within the patient collective with skin involvement. This underlines the necessity for the establishment of further prognostic models in particular for IVLBCL patients with cutaneous manifestations.

    Pubmed
  • An Image Based Object Recognition System for Wound Detection and Classification of Diabetic Foot and Venous Leg Ulcers.

    Stud Health Technol Inform. 2022;294(): 63-67

    Hüsers J, Moelleken M, Richter ML, Przysucha M, Malihi L, Busch D, Götz NA, Heggemann J, Hafer G, Wiemeyer S, Babitsch B, Heidemann G, Dissemond J, Erfurt-Berge C, Hübner U

    Venous leg ulcers and diabetic foot ulcers are the most common chronic wounds. Their prevalence has been increasing significantly over the last years, consuming scarce care resources. This study aimed to explore the performance of detection and classification algorithms for these types of wounds in images. To this end, algorithms of the YoloV5 family of pre-trained models were applied to 885 images containing at least one of the two wound types. The YoloV5m6 model provided the highest precision (0.942) and a high recall value (0.837). Its mAP_0.5:0.95 was 0.642. While the latter value is comparable to the ones reported in the literature, precision and recall were considerably higher. In conclusion, our results on good wound detection and classification may reveal a path towards (semi-) automated entry of wound information in patient records. To strengthen the trust of clinicians, we are currently incorporating a dashboard where clinicians can check the validity of the predictions against their expertise.

    Pubmed
  • Blood Eosinophils Are Associated with Efficacy of Targeted Therapy in Patients with Advanced Melanoma.

    Cancers (Basel). 2022;14(9):

    Wendlinger S, Wohlfarth J, Kreft S, Siedel C, Kilian T, Dischinger U, Heppt MV, Wistuba-Hamprecht K, Meier F, Goebeler M, Schadendorf D, Gesierich A, Kosnopfel C, Schilling B

    BACKGROUND: Eosinophils appear to contribute to the efficacy of immunotherapy and their frequency was suggested as a predictive biomarker. Whether this observation could be transferred to patients treated with targeted therapy remains unknown.

    METHODS: Blood and serum samples of healthy controls and 216 patients with advanced melanoma were prospectively and retrospectively collected. Freshly isolated eosinophils were phenotypically characterized by flow cytometry and co-cultured in vitro with melanoma cells to assess cytotoxicity. Soluble serum markers and peripheral blood counts were used for correlative studies.

    RESULTS: Eosinophil-mediated cytotoxicity towards melanoma cells, as well as phenotypic characteristics, were similar when comparing healthy donors and patients. However, high relative pre-treatment eosinophil counts were significantly associated with response to MAPKi (p = 0.013). Eosinophil-mediated cytotoxicity towards melanoma cells is dose-dependent and requires proximity of eosinophils and their target in vitro. Treatment with targeted therapy in the presence of eosinophils results in an additive tumoricidal effect. Additionally, melanoma cells affected eosinophil phenotype upon co-culture.

    CONCLUSION: High pre-treatment eosinophil counts in advanced melanoma patients were associated with a significantly improved response to MAPKi. Functionally, eosinophils show potent cytotoxicity towards melanoma cells, which can be reinforced by MAPKi. Further studies are needed to unravel the molecular mechanisms of our observations.

    Pubmed
  • Diverse molecular causes of unsolved autosomal dominant tubulointerstitial kidney diseases.

    Kidney Int. 2022;102(2): 405-420

    Wopperer FJ, Knaup KX, Stanzick KJ, Schneider K, Jobst-Schwan T, Ekici AB, Uebe S, Wenzel A, Schliep S, Schürfeld C, Seitz R, Bernhardt W, Gödel M, Wiesener A, Popp B, Stark KJ, Gröne HJ, Friedrich B, Weiß M, Basic-Jukic N, Schiffer M, Schröppel B, Huettel B, Beck BB, Genomics England Research Consortium , Sayer JA, Ziegler C, Büttner-Herold M, Amann K, Heid IM, Reis A, Pasutto F, Wiesener MS

    Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) is caused by mutations in one of at least five genes and leads to kidney failure usually in mid adulthood. Throughout the literature, variable numbers of families have been reported, where no mutation can be found and therefore termed ADTKD-not otherwise specified. Here, we aim to clarify the genetic cause of their diseases in our ADTKD registry. Sequencing for all known ADTKD genes was performed, followed by SNaPshot minisequencing for the dupC (an additional cytosine within a stretch of seven cytosines) mutation of MUC1. A virtual panel containing 560 genes reported in the context of kidney disease (nephrome) and exome sequencing were then analyzed sequentially. Variants were validated and tested for segregation. In 29 of the 45 registry families, mutations in known ADTKD genes were found, mostly in MUC1. Sixteen families could then be termed ADTKD-not otherwise specified, of which nine showed diagnostic variants in the nephrome (four in COL4A5, two in INF2 and one each in COL4A4, PAX2, SALL1 and PKD2). In the other seven families, exome sequencing analysis yielded potential disease associated variants in novel candidate genes for ADTKD; evaluated by database analyses and genome-wide association studies. For the great majority of our ADTKD registry we were able to reach a molecular genetic diagnosis. However, a small number of families are indeed affected by diseases classically described as a glomerular entity. Thus, incomplete clinical phenotyping and atypical clinical presentation may have led to the classification of ADTKD. The identified novel candidate genes by exome sequencing will require further functional validation.

    Pubmed
  • Generalisierte pustulöse Psoriasis: Überblick zum Status quo und Ergebnisse einer Diskussionsrunde.

    J Dtsch Dermatol Ges. 2022;20(6): 753-772

    Reich K, Augustin M, Gerdes S, Ghoreschi K, Kokolakis G, Mößner R, Mrowietz U, Navarini AA, Pinter A, Schäkel K, Staubach P, Sticherling M, Thaçi D, Wilsmann-Theis D

    Pubmed
  • Patch test results with the European baseline series, 2019/20-Joint European results of the ESSCA and the EBS working groups of the ESCD, and the GEIDAC.

    Contact Dermatitis. 2022;87(4): 343-355

    Uter W, Wilkinson SM, Aerts O, Bauer A, Borrego L, Brans R, Buhl T, Dickel H, Dugonik A, Larese Filon F, Mercader Garcìa P, Giménez Arnau A, Patruno C, Pesonen M, Pónyai G, Rustemeyer T, Schubert S, Schuttelaar MA, Simon D, Stingeni L, Valiukevičienė S, Weisshaar E, Werfel T, Gonçalo M, ESSCAA and EBSB ESCD working groups, and the GEIDACC , Kränke B, Hofreiter KS, Navarini A, Grabbe J, Spring P, Beiteke U, Dietrich C, Schliemann S, Becker D, John SM, Wagner N, Napolitano M, Gallo R, Pandurovic MK, Kmecl T, Vok M, Godnič MS, Kecelj N, Cooper SM, Cousen P, Dendooven E, Mercader-García P, Salvador JFS, Pérez JS, Redondo VF, Miquel FJM, de Frutos FJO, Ortega MEG, Carrascosa JM, Arnau AMG, Ninet VZ, Pérez RG, Sánchez TS, Nieto MAP, Baldrich ES, Guijarro SC, Mendaza FH, González IR, Serna MR, Garcés MH, Borrego L

    BACKGROUND: Continual analyses of patch test results with the European baseline series (EBS) serve both contact allergy surveillance and auditing the value of included allergens.

    OBJECTIVES: To present results of current EBS patch testing, obtained in 53 departments in 13 European countries during 2019 and 2020.

    METHODS: Anonymised or pseudonymised individual data and partly aggregated data on demographic/clinical characteristics and patch test rest results with the EBS were prospectively collected and centrally pooled and analysed.

    RESULTS: In 2019 and 2020, 22 581 patients were patch tested with the EBS. Sensitization to nickel remained most common (19.8 [19.2-20.4]% positivity [95% confidence interval]). Fragrance mix I and Myroxylon pereirae yielded very similar results with 6.80 (6.43-7.19)% and 6.62 (6.25-7.00)% positivity, respectively. Formaldehyde at 2% aq. yielded almost one percentage point more positive reactions than 1% concentration (2.49 [2.16-2.85]% vs. 1.59 [1.33-1.88]); methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) and MI alone up to around 5% positives. Among the new additions, propolis was most commonly positive (3.48 [3.16-3.82]%), followed by 2-hydroxyethyl methacrylate (2.32 [2.0-2.68]%).

    CONCLUSION: Ongoing surveillance on the prevalence of contact sensitization contributes to an up-to-date baseline series containing the most frequent and/or relevant contact sensitizers for routine patch testing in Europe.

    Pubmed
  • Breaking Entry-and Species Barriers: LentiBOOST® Plus Polybrene Enhances Transduction Efficacy of Dendritic Cells and Monocytes by Adenovirus 5.

    Viruses. 2022;14(1):

    Strack A, Deinzer A, Thirion C, Schrödel S, Dörrie J, Sauerer T, Steinkasserer A, Knippertz I

    Due to their ability to trigger strong immune responses, adenoviruses (HAdVs) in general and the serotype5 (HAdV-5) in particular are amongst the most popular viral vectors in research and clinical application. However, efficient transduction using HAdV-5 is predominantly achieved in coxsackie and adenovirus receptor (CAR)-positive cells. In the present study, we used the transduction enhancer LentiBOOST® comprising the polycationic Polybrene to overcome these limitations. Using LentiBOOST®/Polybrene, we yielded transduction rates higher than 50% in murine bone marrow-derived dendritic cells (BMDCs), while maintaining their cytokine expression profile and their capability to induce T-cell proliferation. In human dendritic cells (DCs), we increased the transduction rate from 22% in immature (i)DCs or 43% in mature (m)DCs to more than 80%, without inducing cytotoxicity. While expression of specific maturation markers was slightly upregulated using LentiBOOST®/Polybrene on iDCs, no effect on mDC phenotype or function was observed. Moreover, we achieved efficient HAdV5 transduction also in human monocytes and were able to subsequently differentiate them into proper iDCs and functional mDCs. In summary, we introduce LentiBOOST® comprising Polybrene as a highly potent adenoviral transduction agent for new in-vitro applications in a set of different immune cells in both mice and humans.

    Pubmed
  • Using the Prediction Model Risk of Bias Assessment Tool (PROBAST) to Evaluate Melanoma Prediction Studies.

    Cancers (Basel). 2022;14(12):

    Kaiser I, Mathes S, Pfahlberg AB, Uter W, Berking C, Heppt MV, Steeb T, Diehl K, Gefeller O

    Rising incidences of cutaneous melanoma have fueled the development of statistical models that predict individual melanoma risk. Our aim was to assess the validity of published prediction models for incident cutaneous melanoma using a standardized procedure based on PROBAST (Prediction model Risk Of Bias ASsessment Tool). We included studies that were identified by a recent systematic review and updated the literature search to ensure that our PROBAST rating included all relevant studies. Six reviewers assessed the risk of bias (ROB) for each study using the published "PROBAST Assessment Form" that consists of four domains and an overall ROB rating. We further examined a temporal effect regarding changes in overall and domain-specific ROB rating distributions. Altogether, 42 studies were assessed, of which the vast majority (n = 34; 81%) was rated as having high ROB. Only one study was judged as having low ROB. The main reasons for high ROB ratings were the use of hospital controls in case-control studies and the omission of any validation of prediction models. However, our temporal analysis results showed a significant reduction in the number of studies with high ROB for the domain "analysis". Nevertheless, the evidence base of high-quality studies that can be used to draw conclusions on the prediction of incident cutaneous melanoma is currently much weaker than the high number of studies on this topic would suggest.

    Pubmed
  • Patient Characteristics and Treatment Patterns in European Pediatric Patients with Psoriasis: A Real-World, Cross-Sectional Study.

    Dermatol Ther (Heidelb). 2022;12(8): 1793-1808

    Sticherling M, McPherson T, de Lucas Laguna R, Costanzo A, Reed C, Artime E, Robert C, Lucas J, Schuster C, Mahé E

    INTRODUCTION: This study evaluated patient characteristics and treatment patterns according to weight in pediatric patients with psoriasis in a real-world setting.

    METHODS: Primary care and specialist physicians treating pediatric patients with psoriasis aged 6-17 years in five European countries were surveyed in the 2019-2020 Adelphi Real World Pediatric Psoriasis Disease Specific Programme. At least two patients with current or previous biologic use were included per physician. Patient characteristics and treatment patterns were analyzed overall and for patients weighing 25-50 kg or more than 50 kg.

    RESULTS: Data from 772 patients weighing 25-50 kg and 1147 weighing more than 50 kg were analyzed. Median age at diagnosis was significantly less in lighter than heavier patients (10.0 vs. 14.0 years; p < 0.001), as was median disease duration (2.2 vs. 3.0 years; p < 0.001). Topical treatments were prescribed in 59.0% of patients overall (70.3% of lighter and 51.4% of heavier patients; p < 0.001), and were used to treat mild rather than moderate-to-severe psoriasis. Conventional systemic use was low (10.8% of patients overall) and predominantly for moderate-to-severe psoriasis. In this biologic-enriched sample, most biologics (78.2%) were prescribed in older (> 13 years) patients. Biologic use increased with line of therapy (6.6% of first-line, 18.0% of second-line, 33.7% of third-line, 44.7% of fourth-line treatments).

    CONCLUSION: Biologics are predominantly prescribed in older (> 13 years) and heavier (> 50 kg) patients, with little first- or second-line use. The low use of biologics in European pediatric patients with psoriasis may represent an unmet treatment need, as topical or conventional systemic agents remain the main treatment option for moderate or severe psoriasis in these patients through the treatment pathway.

    Pubmed
  • Prognosis of Patients With Primary Melanoma Stage I and II According to American Joint Committee on Cancer Version 8 Validated in Two Independent Cohorts: Implications for Adjuvant Treatment.

    J Clin Oncol. 2022;40(32): 3741-3749

    Garbe C, Keim U, Amaral T, Berking C, Eigentler TK, Flatz L, Gesierich A, Leiter U, Stadler R, Sunderkötter C, Tüting T, Utikal J, Wollina U, Zimmer L, Zouboulis CC, Ascierto PA, Eggermont AMM, Grob JJ, Hauschild A, Sekulovic LK, Long GV, Luke JJ, Michielin O, Peris K, Schadendorf D, Kirkwood JM, Lorigan PC

    PURPOSE: The first randomized trial of adjuvant treatment with checkpoint inhibitor in stage II melanoma reported a significant reduction in risk of tumor recurrence. This study evaluates two independent data sets to further document survival probabilities for patients with primary stage I and II melanoma.

    PATIENTS AND METHODS: The Central Malignant Melanoma Registry (CMMR) in Germany evaluated 17,544 patients with a primary diagnosis of stage I and II melanoma from 2000 to 2015. The exploratory cohort consisted of 6,725 patients from the Center for Dermato-Oncology at the University of Tübingen, and the confirmatory cohort consisted of 10,819 patients from 11 other German centers. Survival outcomes were compared with published American Joint Committee on Cancer version 8 (AJCCv8) stage I and II survival data.

    RESULTS: For the two CMMR cohorts in stage IA compared with the AJCCv8 cohort, melanoma-specific survival rates at 10 years were 95.1%-95.6% versus 98%; 89.7%-90.9% versus 94% in stage IB; 80.7%-83.1% versus 88% in stage IIA; 72.0%-79.9% versus 82% in stage IIB; and 57.6%-64.7% versus 75% in stage IIC, respectively. Recurrence rates were approximately twice as high as melanoma-specific mortality rates in stages IA-IIA.

    CONCLUSION: The melanoma-specific survival rates in the two CMMR cohorts across stages I and II are less favorable than published in AJCCv8. This has important implications for the consideration of adjuvant treatment in this population.

    Pubmed
  • Monocytes Elicit a Neutrophil-Independent Th1/Th17 Response Upon Immunization With a Mincle-Dependent Glycolipid Adjuvant.

    Front Immunol. 2022;13():

    Desel C, Murray PJ, Lehmann CHK, Heger L, Christensen D, Andersen P, Mack M, Dudziak D, Lang R

    Successful subunit vaccination with recombinant proteins requires adjuvants. The glycolipid trehalose-dibehenate (TDB), a synthetic analog of the mycobacterial cord factor, potently induces Th1 and Th17 immune responses and is a candidate adjuvant for human immunization. TDB binds to the C-type lectin receptor Mincle and triggers Syk-Card9-dependent APC activation. In addition, interleukin (IL)-1 receptor/MyD88-dependent signaling is required for TDB adjuvanticity. The role of different innate immune cell types in adjuvant-stimulated Th1/Th17 responses is not well characterized. We investigated cell recruitment to the site of injection (SOI) and to the draining lymph nodes (dLNs) after immunization with the TDB containing adjuvant CAF01 in a protein-based vaccine. Recruitment of monocytes and neutrophils to the SOI and the dramatic increase in lymph node cellularity was partially dependent on both Mincle and MyD88. Despite their large numbers at the SOI, neutrophils were dispensable for the induction of Th1/Th17 responses. In contrast, CCR2-dependent monocyte recruitment was essential for the induction of Th1/Th17 cells. Transport of adjuvant to the dLN did not require Mincle, MyD88, or CCR2. Together, adjuvanticity conferred by monocytes can be separated at the cellular level from potential tissue damage by neutrophils.

    Pubmed
  • The Effect of Hyperthermia and Radiotherapy Sequence on Cancer Cell Death and the Immune Phenotype of Breast Cancer Cells.

    Cancers (Basel). 2022;14(9):

    Sengedorj A, Hader M, Heger L, Frey B, Dudziak D, Fietkau R, Ott OJ, Scheidegger S, Barba SM, Gaipl US, Rückert M

    Hyperthermia (HT) is an accepted treatment for recurrent breast cancer which locally heats the tumor to 39-44 °C, and it is a very potent sensitizer for radiotherapy (RT) and chemotherapy. However, currently little is known about how HT with a distinct temperature, and particularly, how the sequence of HT and RT changes the immune phenotype of breast cancer cells. Therefore, human MDA-MB-231 and MCF-7 breast cancer cells were treated with HT of different temperatures (39, 41 and 44 °C), alone and in combination with RT (2 × 5 Gy) in different sequences, with either RT or HT first, followed by the other. Tumor cell death forms and the expression of immune checkpoint molecules (ICMs) were analyzed by multicolor flow cytometry. Human monocyte-derived dendritic cells (moDCs) were differentiated and co-cultured with the treated cancer cells. In both cell lines, RT was the main stressor for cell death induction, with apoptosis being the prominent cell death form in MCF-7 cells and both apoptosis and necrosis in MDA-MB-231 cells. Here, the sequence of the combined treatments, either RT or HT, did not have a significant impact on the final outcome. The expression of all of the three examined immune suppressive ICMs, namely PD-L1, PD-L2 and HVEM, was significantly increased on MCF-7 cells 120 h after the treatment of RT with HT of any temperature. Of special interest for MDA-MB-231 cells is that only combinations of RT with HT of both 41 and 44 °C induced a significantly increased expression of PD-L2 at all examined time points (24, 48, 72, and 120 h). Generally, high dynamics of ICM expression can be observed after combined RT and HT treatments. There was no significant difference between the different sequences of treatments (either HT + RT or RT + HT) in case of the upregulation of ICMs. Furthermore, the co-culture of moDCs with tumor cells of any treatment had no impact on the expression of activation markers. We conclude that the sequence of HT and RT does not strongly affect the immune phenotype of breast cancer cells. However, when HT is combined with RT, it results in an increased expression of distinct immune suppressive ICMs that should be considered by including immune checkpoint inhibitors in multimodal tumor treatments with RT and HT. Further, combined RT and HT affects the immune system in the effector phase rather than in the priming phase.

    Pubmed
  • The soluble CD83 molecule accelerates wound closure and improves wound healing quality

    Wound Repair Regen. 2022;30(5): A24-A24

    Royzman D, Peckert-Maier K, Stich L, Wild AB, Ostalecki C, Seyferth S, Eming SA, Fuchs M, Kunz M, Sturmer EK, Peters EMJ, Berking C, Zinser E, Steinkasserer A

    Pubmed
  • Intensity and longevity of SARS-CoV-2 vaccination response in patients with immune-mediated inflammatory disease: a prospective cohort study.

    Lancet Rheumatol.. 2022;4(9): e614-e625

    Simon D, Tascilar K, Fagni F, Kleyer A, Krönke G, Meder C, Dietrich P, Orlemann T, Mößner J, Taubmann J, Mutlu MY, Knitza J, Kemenes S, Liphardt AM, Schönau V, Bohr D, Schuster L, Hartmann F, Minopoulou I, Leppkes M, Ramming A, Pachowsky M, Schuch F, Ronneberger M, Kleinert S, Hueber AJ, Manger K, Manger B, Atreya R, Berking C, Sticherling M, Neurath MF, Schett G

    BACKGROUND: Concerns have been raised about the reduced immunogenicity of vaccines against SARS-CoV-2 in patients with immune-mediated inflammatory diseases and the higher risk of breakthrough infections. The objective of our study was to investigate the intensity and longevity of SARS-CoV-2 vaccination responses in patients with immune-mediated inflammatory diseases, and to assess the effects of diagnosis, treatment, and adapted vaccination schedules.

    METHODS: SARS-CoV-2 IgG antibody response after SARS-CoV-2 vaccination was measured over time in a large prospective cohort of healthy controls and participants with immune-mediated inflammatory diseases (attending or admitted to affiliated centres) between Dec 15, 2020, and Dec 1, 2021. Cohort participants with immune-mediated inflammatory diseases and control participants with no diagnosis of immune-mediated inflammatory diseases, were eligible for this analysis. Demographic data and disease-specific data were collected using a questionnaire. Humoral response was compared across treatment and disease groups, and with respect to the receipt of additional vaccinations. SARS-CoV-2 antibody response was measured by ELISA using optical density ratio units and modelled over time with age and sex adjustment using mixed-effects models. Using these models, marginal mean antibody titres and marginal risks of a poor response (optical density ratio <1·1) were calculated for each week starting from week 8 after the first vaccination to week 40.

    FINDINGS: Among 5076 individuals registered, 2535 participants with immune-mediated inflammatory diseases (mean age 55·0 [15·2] years; 1494 [58·9%] women and 1041 [41·1%] men) and 1198 healthy controls (mean age 40·7 [13·5] years; 554 [46·2%] women and 644 [53·8%] men) were included in this analysis. Mean antibody titres were higher in healthy controls compared with people with immune-mediated inflammatory diseases at all timepoints, with a peak antibody response in healthy controls (mean optical density ratio 12·48; 95% CI 11·50-13·53) of more than twice that in participants with immune-mediated inflammatory diseases (5·50; 5·23-5·77; mean difference 6·98; 5·92-8·04). A poor response to vaccination was observed in participants with immune-mediated inflammatory diseases who were taking B-cell inhibitors (peak mean difference from healthy controls 11·68; 10·07-13·29) and T-cell inhibitors (peakmean difference from healthy controls 10·43; 8·33-12·53). Mean differences in antibody responses between different immune-mediated inflammatory diseases were small. Participants with immune-mediated inflammatory diseases who were given a third vaccine dose had higher mean antibody titres than did healthy controls vaccinated with two vaccine doses at 40 weeks after the initial vaccination (mean difference 1·34; 0·01-2·69).

    INTERPRETATION: People with immune-mediated inflammatory diseases show a lower and less durable SARS-CoV-2 vaccination response and are at risk of losing humoral immune protection. Adjusted vaccination schedules with earlier booster doses or more frequent re-doses, or both, could better protect people with immune-mediated inflammatory diseases.

    FUNDING: Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, European Research Council, Innovative Medicine Initiative, Friedrich-Alexander-Universität Erlangen-Nürnberg, Else Kröner-Memorial Foundation.

    Pubmed
  • Model soups improve performance of dermoscopic skin cancer classifiers.

    Eur J Cancer. 2022;173(): 307-316

    Maron RC, Hekler A, Haggenmüller S, von Kalle C, Utikal JS, Müller V, Gaiser M, Meier F, Hobelsberger S, Gellrich FF, Sergon M, Hauschild A, French LE, Heinzerling L, Schlager JG, Ghoreschi K, Schlaak M, Hilke FJ, Poch G, Korsing S, Berking C, Heppt MV, Erdmann M, Haferkamp S, Schadendorf D, Sondermann W, Goebeler M, Schilling B, Kather JN, Fröhling S, Lipka DB, Krieghoff-Henning E, Brinker TJ

    BACKGROUND: Image-based cancer classifiers suffer from a variety of problems which negatively affect their performance. For example, variation in image brightness or different cameras can already suffice to diminish performance. Ensemble solutions, where multiple model predictions are combined into one, can improve these problems. However, ensembles are computationally intensive and less transparent to practitioners than single model solutions. Constructing model soups, by averaging the weights of multiple models into a single model, could circumvent these limitations while still improving performance.

    OBJECTIVE: To investigate the performance of model soups for a dermoscopic melanoma-nevus skin cancer classification task with respect to (1) generalisation to images from other clinics, (2) robustness against small image changes and (3) calibration such that the confidences correspond closely to the actual predictive uncertainties.

    METHODS: We construct model soups by fine-tuning pre-trained models on seven different image resolutions and subsequently averaging their weights. Performance is evaluated on a multi-source dataset including holdout and external components.

    RESULTS: We find that model soups improve generalisation and calibration on the external component while maintaining performance on the holdout component. For robustness, we observe performance improvements for pertubated test images, while the performance on corrupted test images remains on par.

    CONCLUSIONS: Overall, souping for skin cancer classifiers has a positive effect on generalisation, robustness and calibration. It is easy for practitioners to implement and by combining multiple models into a single model, complexity is reduced. This could be an important factor in achieving clinical applicability, as less complexity generally means more transparency.

    Pubmed
  • Adjuvant nivolumab plus ipilimumab or nivolumab alone versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): final results of a randomised, double-blind, phase 2 trial.

    Lancet. 2022;400(10358): 1117-1129

    Livingstone E, Zimmer L, Hassel JC, Fluck M, Eigentler TK, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kiecker F, Dippel E, Roesch A, Ziemer M, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D, Dermatologic Cooperative Oncology Group , Livingstone E, Zimmer L, Hassel JC, Fluck M, Eigentler TK, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kiecker F, Dippel E, Roesch A, Ziemer M, Conrad B, Körner S, Simon JC, Herbst RA, Berking C, Utikal J, Sell S, Martens UM, Terheyden P, Stadler R, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D

    BACKGROUND: The IMMUNED trial previously showed significant improvements in recurrence-free survival for adjuvant nivolumab plus ipilimumab as well as for adjuvant nivolumab alone in patients with stage IV melanoma with no evidence of disease after resection or radiotherapy. Here, we report the final analysis, including overall survival data.

    METHODS: IMMUNED was an investigator-sponsored, double-blind, placebo-controlled, three-arm, phase 2 trial conducted in 20 academic medical centres in Germany. Eligible patients were aged 18-80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Patients were randomly assigned (1:1:1) to either nivolumab plus ipilimumab (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab 3 mg/kg every 2 weeks), nivolumab monotherapy (nivolumab 3 mg/kg every 2 weeks), or matching placebo, for up to 1 year. The primary endpoint was recurrence-free survival in the intention-to-treat population. Secondary endpoints were time-to-recurrence, overall survival, progression-free survival or recurrence-free survival 2 (in patients in the placebo group who crossed over to nivolumab monotherapy after experiencing disease recurrence), and safety endpoints. This trial is registered on ClinicalTrials.gov (NCT02523313), and is complete.

    FINDINGS: Between Sept 2, 2015, and Nov 20, 2018, 175 patients were enrolled in the study, and 167 were randomly assigned to receive either nivolumab plus ipilimumab (n=56), nivolumab plus ipilimumab-matching placebo (n=59), or double placebo control (n=52). At a median follow-up of 49·2 months (IQR 34·9-58·1), 4-year recurrence-free survival was 64·2% (95% CI 49·2-75·9) in the nivolumab plus ipilimumab group, 31·4% (19·7-43·8) in the nivolumab alone group, and 15·0% (6·7-26·6) in the placebo group. The hazard ratio (HR) for recurrence for the nivolumab plus ipilimumab group versus placebo was 0·25 (97·5% CI 0·13-0·48; p<0·0001), and for the nivolumab group versus placebo was 0·60 (0·36-1·00; p=0·024). Median overall survival was not reached in any treatment group. The HR for overall survival was significantly in favour of the nivolumab plus ipilimumab group versus placebo (HR 0·41; 95% CI 0·17-0·99; p=0·040), but not for the nivolumab group versus placebo (HR 0·75; 0·36-1·56; p=0·44). 4-year overall survival was 83·8% (95% CI 68·8-91·9) in the nivolumab plus ipilimumab group, 72·6% (57·4-83·2) in the nivolumab alone group, and 63·1% (46·9-75·6) in the placebo group. The median progression-free survival or recurrence-free survival 2 of patients in the placebo group who crossed over to nivolumab monotherapy after experiencing disease recurrence was not reached (95% CI 21·2 months to not reached). Rates of grade 3-4 treatment-related adverse events remained largely unchanged compared with our previous report, occurring in 71% (95% CI 57-82) of the nivolumab plus ipilimumab group, and 29% (95% CI 17-42) of patients receiving nivolumab alone. There were no treatment-related deaths.

    INTERPRETATION: Both active regimens continued to show significantly improved recurrence-free survival compared with placebo in patients with stage IV melanoma with no evidence of disease who were at high risk of recurrence. Overall survival was significantly improved for patients receiving nivolumab plus ipilimumab compared with placebo. Use of subsequent anti-PD-1-based therapy was high in patients in the placebo group after recurrence and most likely impacted the overall survival comparison of nivolumab alone versus placebo. The recurrence-free and overall survival benefit of nivolumab plus ipilimumab over placebo reinforces the change of practice already initiated for the treatment of patients with stage IV melanoma with no evidence of disease.

    FUNDING: Bristol-Myers Squibb.

    Pubmed
  • Real-world data on the effectiveness, safety and drug survival of dupilumab: an analysis from the TREATgermany registry.

    Br J Dermatol. 2022;187(6): 1022-1024

    Stölzl D, Sander N, Heratizadeh A, Haufe E, Harder I, Abraham S, Heinrich L, Kleinheinz A, Wollenberg A, Weisshaar E, Schäkel K, Ertner K, Wiemers F, Wildberger J, Worm M, von Kiedrowski R, Effendy I, Asmussen A, Augustin M, Pawlak M, Sticherling M, Zink A, Hilgers M, Handrick C, Quist S, Schwarz B, Staubach-Renz P, Bell M, Hong-Weldemann SH, Homey B, Brücher JJ, Schmitt J, Werfel T, Weidinger S, TREATgermany study group

    This interim analysis from the atopic dermatitis registry TREATgermany shows robust long-term efficacy, favourable safety and high persistence of dupilumab under real life conditions.

    Pubmed
  • Differences in Stakeholders' Perception of the Impact of COVID-19 on Clinical Care and Decision-Making.

    Cancers (Basel). 2022;14(17):

    Haier J, Beller J, Adorjan K, Bleich S, de Greck M, Griesinger F, Heppt MV, Hurlemann R, Mees ST, Philipsen A, Rohde G, Schilling G, Trautmann K, Combs SE, Geyer S, Schaefers J

    BACKGROUND: Pandemics are related to changes in clinical management. Factors that are associated with individual perceptions of related risks and decision-making processes focused on prevention and vaccination, but perceptions of other healthcare consequences are less investigated. Different perceptions of patients, nurses, and physicians on consequences regarding clinical management, decisional criteria, and burden were compared.

    STUDY DESIGN: Cross-sectional OnCoVID questionnaire studies.

    METHODS: Data that involved 1231 patients, physicians, and nurses from 11 German institutions that were actively involved in clinical treatment or decision-making in oncology or psychiatry were collected. Multivariate statistical approaches were used to analyze the stakeholder comparisons.

    RESULTS: A total of 29.2% of professionals reported extensive changes in workload. Professionals in psychiatry returned severe impact of pandemic on all major aspects of their clinical care, but less changes were reported in oncology (p &lt; 0.001). Both patient groups reported much lower recognition of treatment modifications and consequences for their own care. Decisional and pandemic burden was intensively attributed from professionals towards patients, but less in the opposite direction.

    CONCLUSIONS: All of the groups share concerns about the impact of the COVID-19 pandemic on healthcare management and clinical processes, but to very different extent. The perception of changes is dissociated in projection towards other stakeholders. Specific awareness should avoid the dissociated impact perception between patients and professionals potentially resulting in impaired shared decision-making.

    Pubmed
  • Distinct antibody clones detect PD-1 checkpoint expression and block PD-L1 interactions on live murine melanoma cells.

    Sci Rep. 2022;12(1):

    Martins C, Silva M, Rasbach E, Singh P, Itoh Y, Williams JB, Statham E, Meurer A, Martinez DV, Brandenburg A, Heppt MV, Barthel SR, Schatton T

    Monoclonal antibodies (abs) targeting the programmed cell death 1 (PD-1) immune checkpoint pathway have revolutionized tumor therapy. Because T-cell-directed PD-1 blockade boosts tumor immunity, anti-PD-1 abs have been developed for examining T-cell-PD-1 functions. More recently, PD-1 expression has also been reported directly on cancer cells of various etiology, including in melanoma. Nevertheless, there is a paucity of studies validating anti-PD-1 ab clone utility in specific assay types for characterizing tumor cell-intrinsic PD-1. Here, we demonstrate reactivity of several anti-murine PD-1 ab clones and recombinant PD-L1 with live B16-F10 melanoma cells and YUMM lines using multiple independent methodologies, positive and negative PD-1-specific controls, including PD-1-overexpressing and PD-1 knockout cells. Flow cytometric analyses with two separate anti-PD-1 ab clones, 29F.1A12 and RMP1-30, revealed PD-1 surface protein expression on live murine melanoma cells, which was corroborated by marked enrichment in PD-1 gene (Pdcd1) expression. Immunoblotting, immunoprecipitation, and mass spectrometric sequencing confirmed PD-1 protein expression by B16-F10 cells. Recombinant PD-L1 also recognized melanoma cell-expressed PD-1, the blockade of which by 29F.1A12 fully abrogated PD-1:PD-L1 binding. Together, our data provides multiple lines of evidence establishing PD-1 expression by live murine melanoma cells and validates ab clones and assay systems for tumor cell-directed PD-1 pathway investigations.

    Pubmed
  • [Pigmented lesions of the mucosa].

    Dermatologie (Heidelb). 2022;73(9): 682-691

    Heppt MV, Heinzerling L

    BACKGROUND: Pigmented lesions of the mucosa are a common reason to consult a dermatologist. They have heterogeneous etiologies and comprise a wide range of differential diagnoses. Both practitioners and patients are often uncertain about the malignancy of the lesions.

    MATERIALS AND METHODS: Review and demonstration of the most common pigmentation disorders of the mucous membranes, including discussion of clinical findings and underlying causes.

    RESULTS: Pigmented mucosal lesions can be classified as either focal or multifocal-diffuse. Focal hyperpigmentation encompasses melanotic macules, nevi, deposition of exogenous materials or pigments, and oral melanoacanthoma. They are mostly benign but must be discerned from mucosal melanoma with an aggressive course and poor prognosis. Multifocal or diffuse hyperpigmentation may be drug-induced or indicative of an underlying medical condition. Importantly, as part of hereditary syndromes further diagnostic work-up is required.

    CONCLUSION: Specific knowledge of the distribution and causes of pigmented mucosal lesions helps in clinical assessment between benign findings and those requiring further work-up and histologic clarification.

    Pubmed
  • Automatic Wound Type Classification with Convolutional Neural Networks.

    Stud Health Technol Inform. 2022;295(): 281-284

    Malihi L, Hüsers J, Richter ML, Moelleken M, Przysucha M, Busch D, Heggemann J, Hafer G, Wiemeyer S, Heidemann G, Dissemond J, Erfurt-Berge C, Hübner U

    Chronic wounds are ulcerations of the skin that fail to heal because of an underlying condition such as diabetes mellitus or venous insufficiency. The timely identification of this condition is crucial for healing. However, this identification requires expert knowledge unavailable in some care situations. Here, artificial intelligence technology may support clinicians. In this study, we explore the performance of a deep convolutional neural network to classify diabetic foot and venous leg ulcers using wound images. We trained a convolutional neural network on 863 cropped wound images. Using a hold-out test set with 80 images, the model yielded an F1-score of 0.85 on the cropped and 0.70 on the full images. This study shows promising results. However, the model must be extended in terms of wound images and wound types for application in clinical practice.

    Pubmed
  • Atypical Mycobacteriosis During TNF Blockade.

    Dtsch Arztebl Int. 2022;119(21):

    Kaufmann MD, Erfurt-Berge C, Wörl P

    Pubmed
  • [Local therapeutic procedure for blisters of the skin: a position paper of the Initiative Chronic Wounds (ICW)].

    Dermatologie (Heidelb). 2022;73(10): 795-800

    Dissemond J, Bültemann A, Gerber V, Motzkus M, Münter C, Erfurt-Berge C

    Blisters of the skin can be caused by very different diseases. Therefore, it is an interdisciplinary and interprofessionally relevant challenge. In the clinical routine different local therapeutic procedures are currently practiced. Either the blister is left in place or the blister is punctured and the blister roof is left in place; alternatively, the complete blister roof is ablated. Each of these approaches has potential advantages and disadvantages. A review of the current literature and consensus by the experts of the Initiative Chronische Wunde (ICW) e.V. was performed. The following approaches are recommended: uncomplicated blisters without pressure pain: leave blisters in place; pressure painful and palmar and plantar localized blisters: puncture blister and leave roof; ruptured blisters without clinical signs of infection: leave remnants of bladder roof; ruptured bladders with clinical signs of infection: remove remnants of the blister roof; blisters in burns of grade 2a or higher or in cases of unclear burn depth or chemical burn: remove blister roof. This is followed in each case by the application of a sterile wound dressing. There is no single correct local therapeutic procedure for blisters on the skin. When planning a therapeutic concept, the genesis of the blisters should be clarified and, if necessary, causal treatment should be given. Local therapy is then based on various individual factors. Thus, the approach chosen together with the patient can vary between individuals.

    Pubmed
  • Comment on the article "Epidermotropism of inflammatory cells differentiates pyoderma gangrenosum from venous ulcers" Reply

    J Dtsch Dermatol Ges. 2022;20(7): 1030-1031

    Ronicke M, Baur A, Kirr M, Erdmann M, Erfurt-Berge C, Ostalecki C

    Pubmed
  • A Modified Surgical Technique for Kidney Transplantation in Mice.

    J Vis Exp. 2022;(185):

    Yin D, Fu J, Chen R, Shushakova N, Allabauer I, Wei XY, Schiffer M, Dudziak D, Rong S, Hoerning A

    Kidney transplantation in mice is a complicated and challenging surgery procedure. There are very few publications demonstrating the key steps of this operation. Therefore, this article introduces the technique and points out the surgical caveats associated with this operation. In addition, important modifications in comparison to the conventional procedure are demonstrated. Firstly, a patch of the abdominal aorta is cut and prepared so that the proximal bifurcations of the renal artery, including the ureteral artery are transected together with the donor kidney en bloc. This reduces the risk of a ureter necrosis and avoids the development of a urinary tract occlusion. Secondly, a new method of the vascular anastomosis is demonstrated that allows the operator to flexibly increase or decrease the size of the anastomosis after renal transplant reperfusion has already been initiated. This avoids the development of vessel strictures and intraabdominal bleeding. Thirdly, a technique that enables the anastomosis of the delicate donor ureter and the recipient bladder that does not cause a trauma is shown. Adopting this protocol can shorten the operation time and reduces the damage to the recipient's bladder, thereby significantly increasing the operation success rate for the recipient mice.

    Pubmed
  • Inhibition of Melanoma Cell-Intrinsic Tim-3 Stimulates MAPK-Dependent Tumorigenesis.

    Cancer Res. 2022;82(20): 3774-3784

    Schatton T, Itoh Y, Martins C, Rasbach E, Singh P, Silva M, Mucciarone KN, Heppt MV, Geddes-Sweeney J, Stewart K, Brandenburg A, Liang J, Dimitroff CJ, Mihm MC, Landsberg J, Schlapbach C, Lian CG, Murphy GF, Kupper TS, Ramsey MR, Barthel SR

    T-cell immunoglobulin mucin family member 3 (Tim-3) is an immune checkpoint receptor that dampens effector functions and causes terminal exhaustion of cytotoxic T cells. Tim-3 inhibitors are under investigation in immuno-oncology (IO) trials, because blockade of T-cell-Tim-3 enhances antitumor immunity. Here, we identify an additional role for Tim-3 as a growth-suppressive receptor intrinsic to melanoma cells. Inhibition of melanoma cell-Tim-3 promoted tumor growth in both immunocompetent and immunocompromised mice, while melanoma-specific Tim-3 overexpression attenuated tumorigenesis. Ab-mediated Tim-3 blockade inhibited growth of immunogenic murine melanomas in T-cell-competent hosts, consistent with established antitumor effects of T-cell-Tim-3 inhibition. In contrast, Tim-3 Ab administration stimulated tumorigenesis of both highly and lesser immunogenic murine and human melanomas in T-cell-deficient mice, confirming growth-promoting effects of melanoma-Tim-3 antagonism. Melanoma-Tim-3 activation suppressed, while its blockade enhanced, phosphorylation of pro-proliferative downstream MAPK signaling mediators. Finally, pharmacologic MAPK inhibition reversed unwanted Tim-3 Ab-mediated tumorigenesis in T-cell-deficient mice and enhanced desired antitumor activity of Tim-3 interference in T-cell-competent hosts. These results identify melanoma-Tim-3 blockade as a mechanism that antagonizes T-cell-Tim-3-directed IO therapeutic efficacy. They further reveal MAPK targeting as a combination strategy for circumventing adverse consequences of unintended melanoma-Tim-3 inhibition.

    SIGNIFICANCE: Tim-3 is a growth-suppressive receptor intrinsic to melanoma cells, the blockade of which promotes MAPK-dependent tumorigenesis and thus counteracts antitumor activity of T-cell-directed Tim-3 inhibition.

    Pubmed
  • Beyond Cancer: Regulation and Function of PD-L1 in Health and Immune-Related Diseases.

    Int J Mol Sci. 2022;23(15):

    Beenen AC, Sauerer T, Schaft N, Dörrie J

    Programmed Cell Death 1 Ligand 1 (PD-L1, CD274, B7-H1) is a transmembrane protein which is strongly involved in immune modulation, serving as checkpoint regulator. Interaction with its receptor, Programmed Cell Death Protein 1 (PD-1), induces an immune-suppressive signal, which modulates the activity of T cells and other effector cells. This mediates peripheral tolerance and contributes to tumor immune escape. PD-L1 became famous due to its deployment in cancer therapy, where blockage of PD-L1 with the help of therapeutic antagonistic antibodies achieved impressive clinical responses by reactivating effector cell functions against tumor cells. Therefore, in the past, the focus has been placed on PD-L1 expression and its function in various malignant cells, whereas its role in healthy tissue and diseases apart from cancer remained largely neglected. In this review, we summarize the function of PD-L1 in non-cancerous cells, outlining its discovery and origin, as well as its involvement in different cellular and immune-related processes. We provide an overview of transcriptional and translational regulation, and expression patterns of PD-L1 in different cells and organs, and illuminate the involvement of PD-L1 in different autoimmune diseases as well as in the context of transplantation and pregnancy.

    Pubmed
  • Modulation of urelumab glycosylation separates immune stimulatory activity from organ toxicity.

    Front Immunol. 2022;13():

    Reitinger C, Ipsen-Escobedo A, Hornung C, Heger L, Dudziak D, Lux A, Nimmerjahn F

    Checkpoint control and immunomodulatory antibodies have become important tools for modulating tumor or self-reactive immune responses. A major issue preventing to make full use of the potential of these immunomodulatory antibodies are the severe side-effects, ranging from systemic cytokine release syndrome to organ-specific toxicities. The IgG Fc-portion has been demonstrated to contribute to both, the desired as well as the undesired antibody activities of checkpoint control and immunomodulatory antibodies via binding to cellular Fcγ-receptors (FcγR). Thus, choosing IgG subclasses, such as human IgG4, with a low ability to interact with FcγRs has been identified as a potential strategy to limit FcγR or complement pathway dependent side-effects. However, even immunomodulatory antibodies on the human IgG4 background may interact with cellular FcγRs and show dose limiting toxicities. By using a humanized mouse model allowing to study the immunomodulatory activity of human checkpoint control antibodies in vivo, we demonstrate that deglycosylation of the CD137-specific IgG4 antibody urelumab results in an amelioration of liver toxicity, while maintaining T cell stimulatory activity. In addition, our results emphasize that antibody dosing impacts the separation of side-effects of urelumab from its therapeutic activity via IgG deglycosylation. Thus, glycoengineering of human IgG4 antibodies may be a possible approach to limit collateral damage by immunomodulatory antibodies and allow for a greater therapeutic window of opportunity.

    Pubmed
  • Assessment of the Genetic Spectrum of Uncombable Hair Syndrome in a Cohort of 107 Individuals.

    JAMA Dermatol. 2022;158(11): 1245-1253

    Basmanav FB, Cesarato N, Kumar S, Borisov O, Kokordelis P, Ralser DJ, Wehner M, Axt D, Xiong X, Thiele H, Dolgin V, Gossmann Y, Fricker N, Dewenter MK, Weller K, Suri M, Reichenbach H, Oji V, Addor MC, Ramirez K, Stewart H, Garcia Bartels N, Weibel L, Wagner N, George S, Kilic A, Tantcheva-Poor I, Stewart A, Dikow N, Blaumeiser B, Medvecz M, Blume-Peytavi U, Farrant P, Grimalt R, Bertok S, Bradley L, Eskin-Schwartz M, Birk OS, Bygum A, Simon M, Krawitz P, Fischer C, Hamm H, Fritz G, Betz RC

    IMPORTANCE: Uncombable hair syndrome (UHS) is a rare hair shaft anomaly that manifests during infancy and is characterized by dry, frizzy, and wiry hair that cannot be combed flat. Only about 100 known cases have been reported so far.

    OBJECTIVE: To elucidate the genetic spectrum of UHS.

    DESIGN, SETTING, AND PARTICIPANTS: This cohort study includes 107 unrelated index patients with a suspected diagnosis of UHS and family members who were recruited worldwide from January 2013 to December 2021. Participants of all ages, races, and ethnicities were recruited at referral centers or were enrolled on their own initiative following personal contact with the authors. Genetic analyses were conducted in Germany from January 2014 to December 2021.

    MAIN OUTCOMES AND MEASURES: Clinical photographs, Sanger or whole-exome sequencing and array-based genotyping of DNA extracted from blood or saliva samples, and 3-dimensional protein modeling. Descriptive statistics, such as frequency counts, were used to describe the distribution of identified pathogenic variants and genotypes.

    RESULTS: The genetic characteristics of patients with UHS were established in 80 of 107 (74.8%) index patients (82 [76.6%] female) who carried biallelic pathogenic variants in PADI3, TGM3, or TCHH (ie, genes that encode functionally related hair shaft proteins). Molecular genetic findings from 11 of these 80 individuals were previously published. In 76 (71.0%) individuals, the UHS phenotype were associated with pathogenic variants in PADI3. The 2 most commonly observed PADI3 variants account for 73 (48.0%) and 57 (37.5%) of the 152 variant PADI3 alleles in total, respectively. Two individuals carried pathogenic variants in TGM3, and 2 others carried pathogenic variants in TCHH. Haplotype analyses suggested a founder effect for the 4 most commonly observed pathogenic variants in the PADI3 gene.

    CONCLUSIONS AND RELEVANCE: This cohort study extends and gives an overview of the genetic variant spectrum of UHS based on molecular genetic analyses of the largest worldwide collective of affected individuals, to our knowledge. Formerly, a diagnosis of UHS could only be made by physical examination of the patient and confirmed by microscopical examination of the hair shaft. The discovery of pathogenic variants in PADI3, TCHH, and TGM3 may open a new avenue for clinicians and affected individuals by introducing molecular diagnostics for UHS.

    Pubmed
  • Decitabine-Mediated Upregulation of CSPG4 in Ovarian Carcinoma Cells Enables Targeting by CSPG4-Specific CAR-T Cells.

    Cancers (Basel). 2022;14(20):

    Harrer DC, Schenkel C, Berking C, Herr W, Abken H, Dörrie J, Schaft N

    The addition of CAR-T cells to the armamentarium of immunotherapy revigorated the field of oncology by inducing long-lasting remissions in patients with relapsing/refractory hematological malignancies. Nevertheless, in the lion's share of patients diagnosed with solid tumors, CAR-T-cell therapy so far failed to demonstrate satisfactory anti-tumor activity. A crucial cause of resistance against the antigen-specific attack of CAR-T cells is predicated on the primary or secondary absence of suitable target antigens. Thus, the necessity to create a broad repertoire of different target antigens is vital. We aimed to evaluate the potential of the well-established melanoma antigen chondroitin sulfate proteoglycan 4 (CSPG4) as an inducible antigen in ovarian cancer cells, using CSPG4-negative SKOV-3 ovarian cancer cells as a model. Based on the hypomethylating activity of the FDA-approved drug decitabine, we refined a protocol to upregulate CSPG4 in the majority of decitabine-treated SKOV-3 cells. CSPG4-specific CAR-T cells generated by mRNA-electroporation showed CSPG4-directed cytokine secretion and cytotoxicity towards decitabine-treated SKOV-3. Another ovarian cancer cell line (Caov-3) and the neoplastic cell line 293T behaved similar. In aggregate, we generated proof-of-concept data paving the way for the further exploration of CSPG4 as an inducible antigen for CAR-T cells in ovarian cancer.

    Pubmed
  • Long-Term Management of Advanced Basal Cell Carcinoma: Current Challenges and Future Perspectives.

    Cancers (Basel). 2022;14(19):

    Heppt MV, Gebhardt C, Hassel JC, Alter M, Gutzmer R, Leiter U, Berking C

    The first-line therapy for locally advanced basal cell carcinoma (laBCC) is Hedgehog pathway inhibitors (HHIs), as they achieve good efficacy and duration of response. However, toxicity in the course of long-term treatment may lead to a decrease in the quality of life, and consequently to interruption or even discontinuation of therapy. As HHI therapy is a balancing act between effectiveness, adverse events, quality of life, and adherence, numerous successful treatment strategies have evolved, such as dose reduction and dose interruptions with on-off treatment schedules or interruptions with re-challenge after progression. As a small percentage of patients show primary or acquired resistance to HHIs, the inhibition of programmed cell death protein 1 (PD-1) has been approved as a second-line therapy, which may also be accompanied by immune-related toxicities and non-response. Thus, optimization of current treatment schedules, novel agents, and combination strategies are urgently needed for laBCC. Here, we narratively model the treatment sequence for patients with laBCC and summarize the current state of approved treatment regimens and therapeutic strategies to optimize the long-term management of laBCC.

    Pubmed
  • Melanoma 2.0. Skin cancer as a paradigm for emerging diagnostic technologies, computational modelling and artificial intelligence.

    Brief Bioinform. 2022;23(6):

    Vera J, Lai X, Baur A, Erdmann M, Gupta S, Guttà C, Heinzerling L, Heppt MV, Kazmierczak PM, Kunz M, Lischer C, Pützer BM, Rehm M, Ostalecki C, Retzlaff J, Witt S, Wolkenhauer O, Berking C

    We live in an unprecedented time in oncology. We have accumulated samples and cases in cohorts larger and more complex than ever before. New technologies are available for quantifying solid or liquid samples at the molecular level. At the same time, we are now equipped with the computational power necessary to handle this enormous amount of quantitative data. Computational models are widely used helping us to substantiate and interpret data. Under the label of systems and precision medicine, we are putting all these developments together to improve and personalize the therapy of cancer. In this review, we use melanoma as a paradigm to present the successful application of these technologies but also to discuss possible future developments in patient care linked to them. Melanoma is a paradigmatic case for disruptive improvements in therapies, with a considerable number of metastatic melanoma patients benefiting from novel therapies. Nevertheless, a large proportion of patients does not respond to therapy or suffers from adverse events. Melanoma is an ideal case study to deploy advanced technologies not only due to the medical need but also to some intrinsic features of melanoma as a disease and the skin as an organ. From the perspective of data acquisition, the skin is the ideal organ due to its accessibility and suitability for many kinds of advanced imaging techniques. We put special emphasis on the necessity of computational strategies to integrate multiple sources of quantitative data describing the tumour at different scales and levels.

    Pubmed
  • Soluble CD83 improves and accelerates wound healing by the induction of pro-resolving macrophages.

    Front Immunol. 2022;13():

    Royzman D, Peckert-Maier K, Stich L, König C, Wild AB, Tauchi M, Ostalecki C, Kiesewetter F, Seyferth S, Lee G, Eming SA, Fuchs M, Kunz M, Stürmer EK, Peters EMJ, Berking C, Zinser E, Steinkasserer A

    To facilitate the recovery process of chronic and hard-to-heal wounds novel pro-resolving treatment options are urgently needed. We investigated the pro-regenerative properties of soluble CD83 (sCD83) on cutaneous wound healing, where sCD83 accelerated wound healing not only after systemic but also after topical application, which is of high therapeutic interest. Cytokine profile analyses revealed an initial upregulation of inflammatory mediators such as TNFα and IL-1β, followed by a switch towards pro-resolving factors, including YM-1 and IL-10, both expressed by tissue repair macrophages. These cells are known to mediate resolution of inflammation and stimulate wound healing processes by secretion of growth factors such as epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), which promote vascularization as well as fibroblast and keratinocyte differentiation. In conclusion, we have found strong wound healing capacities of sCD83 beyond the previously described role in transplantation and autoimmunity. This makes sCD83 a promising candidate for the treatment of chronic- and hard-to-heal wounds.

    Pubmed
  • Multicenter real-world data of adjuvant treatment and disease outcome of patients with melanoma with high-risk of recurrence.

    J Clin Oncol. 2022;40 Suppl S(16):

    Livingstone E, Forschner A, Hassel JC, Wulfken LM, Meier FE, Mohr P, Kaehler KC, Schilling B, Loquai C, Berking C, Huening S, Eckardt J, Gutzmer R, Reinhardt L, Kowall B, Galetzka W, Hauschild A, Zimmer L, Schadendorf D, Lodde G

    Pubmed
  • Response to First-Line Treatment with Immune-Checkpoint Inhibitors in Patients with Advanced Cutaneous Squamous Cell Carcinoma: A Multicenter, Retrospective Analysis from the German ADOReg Registry.

    Cancers (Basel). 2022;14(22):

    Haist M, Stege H, Lang BM, Tsochataridou A, Salzmann M, Mohr P, Schadendorf D, Ugurel S, Placke JM, Weichenthal M, Gutzmer R, Leiter U, Kaatz M, Haferkamp S, Berking C, Heppt M, Tschechne B, Schummer P, Gebhardt C, Grabbe S, Loquai C

    Cutaneous squamous cell carcinoma (cSCC) is a common malignancy of the skin and has an overall favorable outcome, except for patients with an advanced stage of the disease. The efficacy of checkpoint inhibitors (CPI) for advanced cSCC has been demonstrated in recent clinical studies, but data from real-world cohorts and trial-ineligible cSCC patients are limited. We retrospectively investigated patients with advanced cSCC who have been treated with CPI in a first-line setting at eight German skin cancer centers registered within the multicenter registry ADOReg. Clinical outcome parameters including response, progression-free (PFS) and overall survival (OS), time-to-next-treatment (TTNT), and toxicity were analyzed and have been stratified by the individual immune status. Among 39 evaluable patients, the tumor response rate (rwTRR) was 48.6%, the median PFS was 29.0 months, and the median OS was not reached. In addition, 9 patients showed an impaired immune status due to immunosuppressive medication or hematological diseases. Our data demonstrated that CPI also evoked tumor responses among immunocompromised patients (rwTRR: 48.1 vs. 50.0%), although these responses less often resulted in durable remissions. In line with this, the median PFS (11 vs. 40 months, p = 0.059), TTNT (12 months vs. NR, p = 0.016), and OS (29 months vs. NR, p &lt; 0.001) were significantly shorter for this patient cohort. CPI therapy was well tolerated in both subcohorts with 15% discontinuing therapy due to toxicity. Our real-world data show that first-line CPI therapy produced strong and durable responses among patients with advanced cSCC. Immunocompromised patients were less likely to achieve long-term benefit from anti-PD1 treatment, despite similar tumor response rates.

    Pubmed
  • Are YouTube videos on cutaneous squamous cell carcinoma a useful and reliable source for patients?

    J Dtsch Dermatol Ges. 2022;20(12): 1641-1644

    Reinhardt L, Steeb T, Harlaß M, Brütting J, Meier F, Berking C

    Pubmed
  • S2k Guideline for the diagnosis and treatment of mucous membrane pemphigoid.

    J Dtsch Dermatol Ges. 2022;20(11): 1530-1550

    Hofmann SC, Günther C, Böckle BC, Didona D, Ehrchen J, Gaskins M, Geerling G, Gläser R, Hadaschik E, Hampl M, Haßkamp P, Jackowski J, Kiritsi D, Nast A, Pleyer U, Reichel C, Roth M, Schumann M, Sticherling M, Worm M, Zillikens D, Goebeler M, Schmidt E

    Mucous membrane pemphigoid (MMP) is a pemphigoid disease with predominant mucous membrane involvement. It mainly affects the mucous membranes of the mouth, eyes, nose and pharynx, but also the larynx, trachea, esophagus, genital and perianal regions. The manifestation of the disease covers a wide spectrum from gingival erythema and single oral lesions to severe tracheal strictures that obstruct breathing and conjunctival scarring with marked visual impairment and, not infrequently, blindness. In addition to a clinical picture of predominant mucosal involvement, diagnosis is based on direct immunofluorescence of a peri-lesional biopsy and serology. The main target antigen is BP180 (collagen XVII), and reactivity with laminin 332 is associated with malignancy in approximately 25 % of MMP patients. The treatment of MMP is challenging. On the one hand, due to the involvement of different mucous membranes, good interdisciplinary cooperation is required; on the other hand, due to the rarity of the disease, no randomized controlled clinical trials are available. The aim of this guideline is to present the clinical picture, including severity and scoring systems, and to give guidance for diagnosing and treating this complex disease. In MMP, interdisciplinary cooperation plays an essential role as well as the prompt diagnosis and initiation of adequate therapy in order to avoid irreversible damage to the mucous membranes with serious complications.

    Pubmed
  • Introducing SKINFO - the new and unique web-based information platform for German-speaking skin cancer patients

    Oncology Research and Treatment. 2022;45 Suppl 3(SUPPL 3): 216-217

    Steeb T, Hoffmann J, Meier F, Weber C, Bergmann M, Mueller-Schuchardt A, Weiler N, Doppler A, Berking C, Schadendorf D

    Pubmed
  • [Digital and innovative teaching in dermatology : Practically oriented teaching online].

    Dermatologie (Heidelb). 2022;73(11): 829-837

    Wittbecker LM, Pham C, Wohlgemuth LK, Hoang MA, Bandholz TC, Schuh S, Gihl J, Erfurt-Berge C, Gläser R, Welzel J

    BACKGROUND: Due to the corona pandemic and also to the new competence-oriented catalogue of learning objectives in medicine and the master plan for medical studies 2020, the development of digital and practical teaching concepts has experienced a great increase in importance.

    AIM OF THE WORK: As a result of this development, it was an important task to establish this combination and incorporate it into the curricular teaching process.

    MATERIAL AND METHODS: The "Toolkit dermatology" was established, which was sent to a total of more than 650 students at German university dermatology clinics. Using educational films, the students were able to practice their skills. In a further development, the toolkit was combined with classroom lectures and the students were asked to evaluate the toolkit online.

    RESULTS: The vast majority of students (95-100%) clearly stated that the toolkit helped them to develop their practical skills. Some of them were in fact motivated to complete a clinical traineeship/practical tertial year in dermatology (21-88%). The combination of toolkit and subsequent classroom teaching was also rated very positively (82.2%), as this hybrid mode of teaching provided a better understanding.

    DISCUSSION: Digital teaching formats as part of the concept of blended learning, i.e. the combination of virtual and analogue teaching formats, are becoming increasingly more important. Solutions for the disadvantages, such as the lack of real interaction and suitable examination formats, still remain to be found; however, the toolkit project demonstrates that hands-on and digital teaching can lead to high student motivation as well as a high educational standard.

    Pubmed
  • Clinical Experience Using a Monofilament Fiber Cleansing and Debriding Technology for Various Skin Conditions.

    J Drugs Dermatol. 2022;21(11): 1173-1180

    Andriessen A, Wiegand C, Eberlein T, Erfurt-Berge C, Roes C

    BACKGROUND: Gentle skin cleansing and exfoliation and the use of moisturizers as an adjunct to medical treatment should be part of the prevention, treatment, and maintenance of cutaneous conditions such as acne vulgaris (acne) psoriasis, and xerosis. A monofilament fiber debriding technology (MFDT) is used for effective, safe, and rapid skin cleansing and exfoliation and debris, slough, and biofilm removal. The current review addresses the clinical experience using MFDT for various cutaneous conditions that require cleansing or exfoliation or both and how to combine it with medical treatment.

    METHODS: A literature review explored clinical insights into the role of skin cleansing and exfoliation for patients with various dermatological conditions. The searches yielded 29 publications, 7 guidelines/algorithms, 13 reviews, 8 clinical studies, and one in vitro study.

    RESULTS: Mechanical cleansing using a device can be helpful; however, avoid injury of the skin as it may result in thickening of the epidermis leading to hyperkeratosis and disruption of the skin barrier. Clinical experience with MFDT for acne, psoriasis, atopic dermatitis, and xerosis is discussed. Additionally, MFDT was used to exfoliate hyperkeratosis, actinic keratosis, and traumatic skin tattoos.

    CONCLUSIONS: Mechanical cleansing using MFDT was shown to be safe and beneficial for skin cleansing and exfoliation of various cutaneous conditions; however, only anecdotal evidence or small studies are available to support its use for these conditions. J Drugs Dermatol. 2022;21(11):1173-1180. doi:10.36849/JDD.6261.

    Pubmed
  • The GERMELATOX-A (Dermatologic Cooperative Oncology Group): Study attitude of German melanoma patients towards toxicity during adjuvant treatment.

    J Clin Oncol. 2022;40 Suppl S(16):

    Kahler KC, Huning SH, Nashan D, Meiss F, Rafei-Shamsabadi DA, Rissmann H, Colapietro C, Livingstone E, Maul LV, Heppt MV, Hassel JC, Gutzmer R, Loquai C, Heinzerling L, Sachse MM, Bohne AS, Moysig L, Peters W, Rusch J, Blome C

    Pubmed
  • Case report: Patient specific combination of surgery and immunotherapy in advanced squamous cell carcinoma of the head and neck - a case series and review of literature.

    Front Immunol. 2022;13():

    Olmos M, Lutz R, Büntemeyer TO, Glajzer J, Nobis CP, Ries J, Möst T, Eckstein M, Hecht M, Gostian AO, Erdmann M, Foerster Y, Kesting M, Weber M

    BACKGROUND: Prognosis of patients with recurrent or metastatic head and neck cancer is generally poor. Adjuvant immunotherapy (IT) featuring immune checkpoint inhibition (ICI) is standard of care in advanced stage head and neck squamous cell carcinoma (HNSCC) and cutaneous squamous cell carcinoma (CSCC). ICI response rates in CSCC are described as higher than in HNSCC. IT is constantly shifting into earlier disease stages which confronts the surgeon with immunotherapeutically pre-treated patients. It is therefore becoming increasingly difficult to assess which patients with symptomatic tumor disease and a lack of curative surgical option might benefit from salvage surgery.

    CASE PRESENTATIONS: The following 6 cases describe therapeutic decision-making regarding ICI and (salvage) surgery in patients with advanced stage HNSCC or CSCC. Cases A and B focus on neoadjuvant ICI followed by salvage surgery. In Cases C and D salvage surgery was performed after short-term stabilization with partial response to ICI. The last two cases (Cases E and F) address the surgical approach after failure of ICI. All cases are discussed in the context of the current study landscape and with focus on individual decision-making. For better understanding, a timetable of the clinical course is given for each case.

    CONCLUSIONS: ICI is rapidly expanding its frontiers into the neoadjuvant setting, frequently confronting the surgeon with heavily pretreated patients. Salvage surgery is a viable therapeutic concept despite the rise of systemic treatment options. Decision-making on surgical intervention in case of a salvage surgery remains an individual choice. For neoadjuvant ICI monitoring regarding pathological tumor response or tumor necrosis rate, we suggest correlation between the initial biopsy and the definite tumor resectate in order to increase its significance as a surrogate marker. Scheduling of neoadjuvant ICI should be further investigated, as recent studies indicate better outcomes with shorter time frames.

    Pubmed
  • A Mixed Methods Assessment of the Management Role of Physicians.

    Adv. Med. Educ. Pract.. 2022;13(): 1003-1017

    Rechtien L, Gradel M, Fischer MR, Graupe T, Dimitriadis K

    Introduction: Physicians are increasingly confronted with new requirements in their daily job, which go beyond the mere treatment of patients. The aim of this Mixed-Method-Study is to better understand management as it relates to physicians' daily work, to clarify the physicians' perception of their management role and to examine physician's self-assessed competence in these functions.

    Methods: We used three different instruments: Semi-structured interviews, a self-assessment survey and direct observations to evaluate managerial activities performed by residents. Both latter were based on instruments established for management research.

    Results: Interviewed residents were familiar with the term "Management" but had difficulties in defining it. Concerning managerial functions in context of their daily work, we identified three main categories: Self-management, Patient-management and Management of the ward. In this context, physicians named numerous examples of management tasks and for which they felt ill prepared. Eighty-eight residents participated in the self-assessment survey and rated the majority of the management tasks as necessary for the residents' work. Although physicians estimated the proportion of managerial work to comprise only 40.6%, a much higher number of mere management tasks could be identified through direct observations (n = 12). Activities related to management were more often observed than genuine physician tasks.

    Discussion: This study illustrates the prominent role of management activities in context of the residents' work, while at the same time showing that residents do not feel sufficiently educated, prepared nor competent in management tasks.

    Pubmed
  • Neural Networks for Distinguishing Rheumatoid Arthritis from Psoriatic Arthritis by Using Magnetic Resonance Imaging

    Arthritis Rheumatol. 2022;74 Suppl 9(): 457-459

    Folle L, Bayat S, Kleyer A, Fagni F, Kapsner L, Schlereth M, Meinderink T, Breininger K, Tascilar K, Kroenke G, Uder M, Sticherling M, Bickelhaupt S, Schett G, Maier A, Roemer F, Simon D

    Pubmed
  • A single-center, retrospective Analysis for the Detection of Distant Metastases in Patients with regionally metastatic Melanoma in the Era of effective adjuvant Therapies

    J Dtsch Dermatol Ges. 2022;20 Suppl 3(): 79-79

    Toussaint F, Kramer R, Bender-Saebelkampf S, Hornung-Eichler A, Karimi B, Heppt M, Bosch-Voskens CJ, Berking C, Erdmann M

    Pubmed
  • In vitro assessment of checkpoint-induced cytokine levels as new tool in the therapeutic decision-making process after checkpoint-induced cytokine release syndrome in metastatic melanoma

    J Dtsch Dermatol Ges. 2022;20 Suppl 3(): 78-78

    Kramer R, Bender-Saebelkampf S, Berking C, Heppt M, Erdmann M, Bosch-Voskens CJ

    Pubmed
  • Primary cutaneous manifestation of systemically aggressive diffuse large B-cell lymphoma

    J Dtsch Dermatol Ges. 2022;20 Suppl 3(): 114-114

    Bender-Saebelkampf S, Spriewald B, Berking C, Erdmann M, Wagner N

    Pubmed
  • Effects of the German organ transplant scandal 2012 on the tissue donation project of the Institute of Legal Medicine Munich A retrospective evaluation of informed consent for tissue donation given by the next of kin

    Rechtsmedizin. 2022;32(6): 452-457

    Bender-Saebelkampf S, Troschuetz S, Graw M, Braun C

    Background The German organ donation scandal in 2012 led to a dramatic drop in consent rates. With 51 musculoskeletal, 145 corneal and 38 heart valve donations in 2013-2015, the Institute of Legal Medicine Munich procured a sizeable quantity of donated tissues performed in southern Germany. Objective The main goal of this study was to identify any traceable decrease in donations and the role the interview with the next of kin of tissue donors played in this context. Material and methods We retrospectively analyzed our donor database from July 2012 to December 2015 concerning discussions about and/or a stated effect of the scandal on the decision to consent to donation. We also contacted the next of kin within 1 year after the donation for a retrospective evaluation using a questionnaire consisting of 9 items. Results For a total of 388 potential donors consent was given in 54.9%. In 40 cases, the scandal was a topic of discussion and in 15 cases resulted in refusal. Among these, 6 persons destroyed their donor card in light of the scandal. After a thorough discussion, a tissue donation was finally allowed in 4 of these 6 cases. A total of 142 consenting next of kin retrospectively evaluated the primary contact as positive and meaningful. The decisions were stable in 100% of the cases. Conclusion With overall positive results in the retrospective interview evaluating the donation contact, we conclude that the relatively minor impact of the scandal on tissue donation relies on comprehensive information given by an empathetic, trained tissue coordinator. Active information and transparency about donation processes are key factors to gain the necessary trust of the public.

    Pubmed
  • Nectin-1 determines the susceptibility of malignant melanoma to oncolytic herpes simplex virus in vitro and in vivo

    Exp Dermatol. 2022;31(2): E25-E25

    Schwertner B, Lindner G, Stauner CT, Klapproth E, Magnus C, Rohrhofer A, Gross S, Schuler-Thurner B, Oettl V, Feichtgruber N, Drexler K, Evert K, Krahn M, Berneburg M, Schmidt B, Schuster P, Haferkamp S

    Pubmed
  • Bin-based visualization of cytokine-co-expression patterns of IL-10-producing CD4 T cell subsets.

    Eur J Immunol. 2022;52(10): 1684-1687

    Mohr E, Hinnenthal T, Gryzik S, Hoang Y, Lischke T, Retzlaff J, Mekonnen A, Paul F, Valleriani A, Radbruch A, Vera J, Baumgrass R

    Pubmed
  • SOX10-based drug repurposing identifies novel therapeutic targets in uveal melanoma

    J Dtsch Dermatol Ges. 2022;20 Suppl 3(): 82-82

    Wessely A, Kammerbauer C, Lischer C, Weich A, Vera J, Berking C, Heppt M

    Pubmed
  • PRI: Re-Analysis of a Public Mass Cytometry Dataset Reveals Patterns of Effective Tumor Treatments.

    Front Immunol. 2022;13():

    Hoang Y, Gryzik S, Hoppe I, Rybak A, Schädlich M, Kadner I, Walther D, Vera J, Radbruch A, Groth D, Baumgart S, Baumgrass R

    Recently, mass cytometry has enabled quantification of up to 50 parameters for millions of cells per sample. It remains a challenge to analyze such high-dimensional data to exploit the richness of the inherent information, even though many valuable new analysis tools have already been developed. We propose a novel algorithm "pattern recognition of immune cells (PRI)" to tackle these high-dimensional protein combinations in the data. PRI is a tool for the analysis and visualization of cytometry data based on a three or more-parametric binning approach, feature engineering of bin properties of multivariate cell data, and a pseudo-multiparametric visualization. Using a publicly available mass cytometry dataset, we proved that reproducible feature engineering and intuitive understanding of the generated bin plots are helpful hallmarks for re-analysis with PRI. In the CD4+T cell population analyzed, PRI revealed two bin-plot patterns (CD90/CD44/CD86 and CD90/CD44/CD27) and 20 bin plot features for threshold-independent classification of mice concerning ineffective and effective tumor treatment. In addition, PRI mapped cell subsets regarding co-expression of the proliferation marker Ki67 with two major transcription factors and further delineated a specific Th1 cell subset. All these results demonstrate the added insights that can be obtained using the non-cluster-based tool PRI for re-analyses of high-dimensional cytometric data.

    Pubmed
  • Decision Conflicts in Clinical Care during COVID-19: A Multi-Perspective Inquiry.

    Healthcare (Basel). 2022;10(10):

    Haier J, Beller J, Adorjan K, Bleich S, de Greck M, Griesinger F, Heppt M, Hurlemann R, Mees ST, Philipsen A, Rohde G, Schilling G, Trautmann K, Combs SE, Geyer S, Schaefers J

    Background: The early COVID-19-pandemic was characterized by changes in decision making, decision-relevant value systems and the related perception of decisional uncertainties and conflicts resulting in decisional burden and stress. The vulnerability of clinical care professionals to these decisional dilemmas has not been characterized yet. Methods: A cross-sectional questionnaire study (540 patients, 322 physicians and 369 nurses in 11 institutions throughout Germany) was carried out. The inclusion criterion was active involvement in clinical treatment or decision making in oncology or psychiatry during the first year of COVID-19. The questionnaires covered five decision dimensions (conflicts and uncertainty, resources, risk perception, perception of consequences for clinical processes, and the perception of consequences for patients). Data analysis was performed using ANOVA, Pearson rank correlations, and the Chi²-test, and for inferential analysis, nominal logistic regression and tree classification were conducted. Results: Professionals reported changes in clinical management (27.5%) and a higher workload (29.2%), resulting in decisional uncertainty (19.2%) and decisional conflicts (22.7%), with significant differences between professional groups (p < 0.005), including anxiety, depression, loneliness and stress in professional subgroups (p < 0.001). Nominal regression analysis targeting “Decisional Uncertainty” provided a highly significant prediction model (LQ p < 0.001) containing eight variables, and the analysis for “Decisional Conflicts” included six items. The classification rates were 64.4% and 92.7%, respectively. Tree analysis confirmed three levels of determinants. Conclusions: Decisional uncertainty and conflicts during the COVID-19 pandemic were independent of the actual pandemic load. Vulnerable professional groups for the perception of a high number of decisional dilemmas were characterized by individual perception and the psychological framework. Coping and management strategies should target vulnerability, enable the handling of the individual perception of decisional dilemmas and ensure information availability and specific support for younger professionals.

    Pubmed
  • Noninvasive monitoring system for Tenebrio molitor larvae based on image processing with a watershed algorithm and a neural net approach

    J. Insects Food Feed. 2022;8(8): 913-920

    Baur A, Koch D, Gatternig B, Delgado A

    Due to the increase of the human world population, modern-day research is looking for new methods of protein exploitation. Therefore the authors conducted a joint research project with the goal to automate the breeding of Tenebrio molitor as a novel protein source. An important task is to monitor the size of larvae in order to control the rearing process. In this work, a suitable algorithm is presented to measure the size distribution of the population. It is a combination of classical image processing functions and a neural net to enhance the dataset for a more reliable result. The output can be used to determine the most efficient time for harvesting. First, a grayscale picture of the insects in one box is taken and binarised by a threshold algorithm. The connected objects in this image are separated by an irregular watershed algorithm that delivers separate segments of larvae. Not all single segments can be used for measuring the size distribution; therefore, an artificial neural network is used for a classification. In the end, the algorithm separates the segments given by the watershed and categorises them into four categories: good segments, medium segments, bad segments, and artefacts. The good segments have a recall rate of 91.4%. In the end, the identified segments can be used to establish a method for determining the size distribution and, thus, to document the growth of the larvae.

    Pubmed
  • Mapping bone marrow metastasis in neuroblastoma by deep multiplex imaging and transcriptomics

    Cancer Res. 2022;82 Suppl S(12):

    Lazic D, Kromp F, Rifatbegovic F, Repiscak P, Mivalt F, Halbritter F, Bernkopf M, Bileck A, Ussowicz M, Ambros IM, Ambros PF, Gerner C, Ladenstein R, Ostalecki C, Taschner-Mandl S

    Pubmed
  • INTRATUMORALLY ADMINISTERED CV8102 IN PATIENTS WITH ADVANCED SOLID TUMORS: PRELIMINARY RESULTS FROM ONGOING EXPANSION PART IN STUDY 008

    J Immunother Cancer. 2022;10 Suppl 2(): A818-A818

    Eigentler T, Samoylenko I, Ochsenreither S, Richtig E, Thomas I, Erdmann M, Lebbe C, Soto-Castillo JJ, Terheyden P, Poltoratskiy A, Sekacheva M, Semiletova Y, Henze J, Schmitt-Bormann B, Codo P, Falk M, Gnad-Vogt U

    Pubmed
  • IMMUNE PROFILING OF PATIENTS WITH ADVANCED MELANOMA INTRATUMORALLY TREATED WITH CV8102 AS A SINGLE-AGENT OR IN COMBINATION WITH ANTIPD-1 ANTIBODIES - RESULTS OF A PHASE I TRIAL EXPANSION

    J Immunother Cancer. 2022;10 Suppl 2(): A816-A816

    Gonzalez M, Wengenmayer P, Samoylenko I, Ochsenreither S, Richtig E, Thomas I, Erdmann M, Lebbe C, Martin-Liberal J, Terheyden P, Poltoratskiy A, Sekacheva M, Semiletova Y, Eigentler T, Schmitt-Bormann B, Vahrenhorst D, Kays SK, Seibel T, Quintini G, Scheel B, Falk M, Gnad-Vogt U, Codo P

    Pubmed
  • Dupilumab-induced erythema nodosum in a patient with atopic hand eczema

    Allergologie. 2022;45(8): 629-630

    Ronicke M, Sticherling M, Wagner N

    Pubmed
  • Dissecting the IFN gamma-mediated transcriptomic alterations in Merkel cell carcinoma cell lines using Nanopore sequencing

    Exp Dermatol. 2022;31(2): E94-E94

    Sauerer T, Lischer C, Berking C, Vera-Gonzalez J, Doerrie J

    Pubmed
  • Reinvigoration of innate and adaptive immunity via therapeutic cellular vaccine for patients with AML

    Mol Ther Oncolytics. 2022;27(): 315-332

    Fujii SI, Kawamata T, Shimizu K, Nakabayashi J, Yamasaki S, Iyoda T, Shinga J, Nakazato H, Sanpei A, Kawamura M, Ueda S, Dorrie J, Mojsov S, Dhodapkar MV, Hidaka M, Nojima M, Nagamura F, Yoshida S, Goto T, Tojo A

    Strategies integrating activation of innate and adaptive immu-nity against cancer are desired. We established a novel plat-form, Wilms' tumor antigen 1 (WT1)-expressing artificial adjuvant vector cells (aAVC-WT1), linking invariant natural killer T (iNKT)-mediated dendritic cell activation to T cell im-munity. Here, we report the first-in-human application of aAVC-WT1 in nine patients with relapsed and refractory acute myelogenous leukemia. No dose-limiting toxicities were observed, whereas activation of iNKT and/or NK cells was observed in all patients. Five patients experienced objective leukemic regression, which correlated with WT1-specific T cell responses. Paired single-cell RNA and T cell receptor (TCR) sequencing demonstrated effector CD8+ T cell clones in the bone marrow. Some bone marrow CD8+ T cells under-went transition from pre-existing precursor exhausted T cells to functional T cells or emerged as newly activated T cells, some of which were maintained long term. These demonstrate the feasibility and safety of aAVC-WT1 therapy and the capac-ity of this platform to activate both innate and adaptive immu-nity in humans.

    Pubmed
  • Editorial: Macrophage immunity and metabolism in cancer: Novel diagnostic and therapeutic strategies.

    Front Immunol. 2022;13():

    Leavenworth JW, Lai X, Miao H, Wang D, Zhao H, Li Y

    Pubmed
  • Soluble CD83 promotes cutaneous wound healing in an IDO-and beta-catenindependent manner

    Exp Dermatol. 2022;31(2): E55-E56

    Royzman D, Peckert-Maier K, Stich L, Wild A, Ostalecki C, Kiesewetter F, Seyferth S, Lee G, Eming SA, Berking C, Zinser E, Steinkasserer A

    Pubmed
  • The quality of national skin cancer screening from the perspective of general practitioners: A questionnaire-based comparison between Saxony and Bavaria (SaBaScreen)

    J Dtsch Dermatol Ges. 2022;20 Suppl 3(): 113-113

    Strasser C, Reinhardt L, Steeb T, Wessely A, Schelling J, Petzold A, Heppt M, Meier F, Berking C

    Pubmed
  • The need for regular training in skin cancer screening: a cross-sectional study among general practitioners in Germany.

    J Eur Acad Dermatol Venereol. 2022;36(11): e913-e915

    Steeb T, Reinhardt L, Strasser C, Wessely A, Schelling J, Petzold A, Heppt MV, Meier F, Berking C

    Pubmed
  • LONG-TERM HUMORAL RESPONSE TO SARS-COV-2 VACCINATION IN PATIENTS WITH IMMUNE-MEDIATED INFLAMMATORY DISEASE

    Ann Rheum Dis. 2022;81 Suppl 1(): 371-372

    Tascilar K, Simon D, Kleyer A, Fagni F, Kroenke G, Meder C, Dietrich P, Orlemann T, Kliem T, Moessner J, Liphardt AM, Schoenau V, Bohr D, Schuster L, Hartmann F, Taubmann J, Leppkes M, Ramming A, Pachowsky M, Schuch F, Ronneberger M, Kleinert S, Hueber A, Manger K, Manger B, Atreya R, Berking C, Sticherling M, Neurath MF, Schett G

    Pubmed
  • Therapy Management of the first Recurrence after adjuvant Therapy in Stage III: multicenter real-world Data

    J Dtsch Dermatol Ges. 2022;20 Suppl 3(): 3-3

    Lodde G, Forschner A, Hassel JC, Wulfken LM, Meier F, Mohr P, Kaehler K, Schilling B, Loquai C, Berking C, Huening S, Eckardt J, Gutzmer R, Reinhardt L, Glutsch V, Nikfarjam U, Erdmann M, Kowall B, Galetzka W, Roesch A, Ugurel S, Zimmer L, Schadendorf D, Livingstone E

    Pubmed
  • Site-specific tumor response and survival in patients with metastatic melanoma receiving immune checkpoint inhibition or targeted therapy: implications for treatment choice

    J Dtsch Dermatol Ges. 2022;20 Suppl 3(): 3-4

    Wagner N, Lenders MM, Kuehl K, Reinhardt L, Fuchss M, Ring N, Richtig G, Ebel C, Andre F, Staeger R, Zellweger C, Stuermer SH, Lang R, Paar M, Gussek P, Kimeswenger S, Oellinger A, Amaral T, Forschner A, Leiter-Stoeppke U, Weide B, Gassenmaier M, Schraag A, Klumpp B, Hoetzenecker W, Ziemer M, Berking C, Mangana J, Nguyen VA, Terheyden P, Richtig E, Loquai C, Diem S, Cozzio A, Roecken M, Garbe C, Gebhardt C, Meier F, Eigentler T, Flatz L

    Pubmed
  • Predictors of long-term survival of stage IV melanoma patients: a multicenter DeCOG study on 539 patients from the prospective skin cancer registry ADOREG

    J Dtsch Dermatol Ges. 2022;20 Suppl 3(): 16-17

    Placke JM, Mohr P, Bluhm L, Kahler K, Weichenthal M, Meier F, Garzarolli M, Gutzmer R, Grimmelmann I, Utikal JS, Pfohler C, Herbst R, Ulrich J, Terheyden P, Forschner A, Leiter-Stoppke U, Kreuter A, Heinzerling L, Heppt M, Berking C, Weishaupt C, Gambichler T, Engel DR, Franklin C, Zaremba A, Krefting F, Lodde G, Zimmer L, Livingstone E, Becker JC, Tasdogan A, Rosch A, Schadendorf D, Ugurel S

    Pubmed
  • Real-world clinical outcomes of pembrolizumab for advanced melanoma in the German ADOREG skin cancer registry

    J Dtsch Dermatol Ges. 2022;20 Suppl 3(): 18-18

    Mohr P, Scherrer E, Alar V, Assaf C, Beissert S, Berking C, Eigentler T, Grimmelmann I, Gutzmer R, Haferkamp S, Hassel JC, Hauschild A, Herbst R, Jiang R, Kaatz M, Kahler K, Krepler C, Kreuter A, Leiter-Stoppke U, Loquai C, Meier F, Pfohler C, Rudolph A, Schadendorf D, Schiavone M, Schley G, Terheyden P, Ugurel S, Ulrich J, Utikal JS, Weishaupt C, Welzel J, Weichenthal M

    Pubmed
  • Which patients should receive adjuvant treatment - an analysis of stage IIA-IIIA patients of the CMMR

    J Dtsch Dermatol Ges. 2022;20 Suppl 3(): 19-19

    Leiter-Stoppke U, Keim U, Amaral T, Forschner A, Berking C, Gesierich A, Gutzmer R, Sunderkotter C, Utikal JS, Zimmer L, Flatz L, Garbe C

    Pubmed
  • Interdisciplinary Approach to the Diagnosis and Treatment of Leg Ulcers

    Phlebologie. 2022;51(5): 259-268

    Erfurt-Berge C, Renner R

    Pubmed
  • How does Nutrition Affect Wound Healing?

    Phlebologie. 2022;51(03): 148-152

    Renner R, Erfurt-Berge C

    Interference during the complex wound healing process might lead to a delayed or absence of wound closure. One possible disruptive factor can be wrong nutrition. It is necessary to differentiate between quantitative and qualitative malnutrition. Preferential obese patients suffer from a qualitative malnutrition and sarkopenia.

    Specific diseases require a specific nutritional recommendation. For example, patients with dialysis, decubitus, or leg ulcers often have a lack of proteins. In addition, other nutrient deficiencies with vitamin C, zinc, folate, vitamin D or trace elements might have a negative impact on wound healing.

    Prospective studies should clarify if substitution of those nutrient deficiencies might improve wound healing. It seems to be reasonable to strive for an improvement in the consumption of vitamins, trace elements and proteins adopted to a balanced alimentation and adjusted to individual dietary habits.

    Pubmed
  • Blockade of tumor cell-intrinsic PD-1 inhibits Merkel cell carcinoma growth

    J Invest Dermatol. 2022;142 Suppl S(12): S258-S258

    Heppt MV, Martins C, Rasbach E, Kleffel S, Mucciarone K, Brandenburg A, Thakuria M, Rahbari N, Murphy G, Ramsey MR, Barthel SR, Posch C, Schatton TF

    Pubmed
  • Distinct antibody clones detect PD-1 checkpoint expression and block PD-L1 interactions on live murine melanoma cells

    J Invest Dermatol. 2022;142 Suppl S(12): S265-S265

    Martins C, Silva M, Itoh Y, Rasbach E, Heppt MV, Meurer A, Brandenburg A, Barthel SR, Schatton TF

    Pubmed
  • Tim-3 is a growth-suppressive immune checkpoint receptor intrinsic to melanoma cells

    J Invest Dermatol. 2022;142 Suppl S(12): S261-S261

    Martins C, Itoh Y, Silva M, Rasbach E, Singh P, Heppt MV, Schlapbach C, Ramsey MR, Barthel SR, Schatton TF

    Pubmed
  • Cost-effectiveness of Response-Adapted De-escalation of Immunotherapy in Advanced Melanoma.

    JAMA Dermatol. 2022;158(12): 1387-1393

    Cartun Z, Kunz WG, Heinzerling L, Tomsitz D, Guertler A, Westphalen CB, Ricke J, Weir W, Unterrainer M, Mehrens D

    IMPORTANCE: Combination immunotherapy with nivolumab and ipilimumab has markedly improved outcomes for patients with advanced melanoma. However, these therapies pose a considerable financial burden to both patients and the health care system. The ADAPT-IT trial demonstrated comparable progression-free and overall survival for patients with response-adapted ipilimumab discontinuation compared with standard of care (SOC).

    OBJECTIVE: To determine the cost-effectiveness of ipilimumab discontinuation for patients with interim imaging-confirmed tumor response in the treatment of advanced melanoma.

    DESIGN, SETTING, AND PARTICIPANTS: This cost-effectiveness analysis was performed using data from the ADAPT-IT (follow-up of 33 months) and CheckMate 067 (follow-up of 6.5 years) trials, as well as published literature over the ADAPT-IT trial duration of 33 months. The analysis was performed in a US setting from a US-payer perspective, and the willingness-to-pay (WTP) threshold was set at $100 000/quality-adjusted life-year (QALY). A total of 355 patients with previously untreated melanoma (unresectable stage III or IV metastatic melanoma) were included.

    EXPOSURE: Response-adapted ipilimumab discontinuation compared with SOC therapy.

    MAIN OUTCOMES AND MEASURES: The primary outcomes of the CheckMate trial were overall survival and progression-free survival, while that of ADAPT-IT was objective response. This informed a decision model to estimate lifetime costs and QALYs associated with both strategies. Incremental cost, effectiveness, and cost-effectiveness ratio were assessed. Sensitivity and scenario analyses were performed to account for variability in trials and input parameters.

    RESULTS: Of the 355 patients included in the analysis, 41 patients were from the ADAPT-IT trial (median age, 65 years; 28 [68%] male) and 314 patients from the CheckMate 067 trial (median age, 61 years; 206 [66%] male). Response-adapted treatment was the cost-effective option in 94.0% of scenarios based on Monte Carlo simulations, with a dominant incremental cost-effectiveness ratio and an incremental net monetary benefit of $28 849 compared with SOC therapy. Cost savings were estimated at $19 891 per patient compared with SOC. In scenario analyses, current SOC was only considered as a cost-effective option under best survival assumptions and if the willingness-to-pay threshold exceeded $630 000/QALY.

    CONCLUSIONS AND RELEVANCE: This economic evaluation demonstrated that response-adapted treatment de-escalation in patients with advanced melanoma may lead to considerable savings in health care costs and could represent the most cost-effective strategy across various resource settings. Future trials should aim to provide further evidence on noninferiority.

    Pubmed
  • Global Circumferential and Radial Strain Among Patients With Immune Checkpoint Inhibitor Myocarditis.

    JACC Cardiovasc Imaging. 2022;15(11): 1883-1896

    Quinaglia T, Gongora C, Awadalla M, Hassan MZO, Zafar A, Drobni ZD, Mahmood SS, Zhang L, Coelho-Filho OR, Suero-Abreu GA, Rizvi MA, Sahni G, Mandawat A, Zatarain-Nicolás E, Mahmoudi M, Sullivan R, Ganatra S, Heinzerling LM, Thuny F, Ederhy S, Gilman HK, Sama S, Nikolaidou S, Mansilla AG, Calles A, Cabral M, Fernández-Avilés F, Gavira JJ, González NS, García de Yébenes Castro M, Barac A, Afilalo J, Zlotoff DA, Zubiri L, Reynolds KL, Devereux R, Hung J, Picard MH, Yang EH, Gupta D, Michel C, Lyon AR, Chen CL, Nohria A, Fradley MG, Thavendiranathan P, Neilan TG

    BACKGROUND: Global circumferential strain (GCS) and global radial strain (GRS) are reduced with cytotoxic chemotherapy. There are limited data on the effect of immune checkpoint inhibitor (ICI) myocarditis on GCS and GRS.

    OBJECTIVES: This study aimed to detail the role of GCS and GRS in ICI myocarditis.

    METHODS: In this retrospective study, GCS and GRS from 75 cases of patients with ICI myocarditis and 50 ICI-treated patients without myocarditis (controls) were compared. Pre-ICI GCS and GRS were available for 12 cases and 50 controls. Measurements were performed in a core laboratory blinded to group and time. Major adverse cardiovascular events (MACEs) were defined as a composite of cardiogenic shock, cardiac arrest, complete heart block, and cardiac death.

    RESULTS: Cases and controls were similar in age (66 ± 15 years vs 63 ± 12 years; P = 0.20), sex (male: 73% vs 61%; P = 0.20) and cancer type (P = 0.08). Pre-ICI GCS and GRS were also similar (GCS: 22.6% ± 3.4% vs 23.5% ± 3.8%; P = 0.14; GRS: 45.5% ± 6.2% vs 43.6% ± 8.8%; P = 0.24). Overall, 56% (n = 42) of patients with myocarditis presented with preserved left ventricular ejection fraction (LVEF). GCS and GRS were lower in myocarditis compared with on-ICI controls (GCS: 17.5% ± 4.2% vs 23.6% ± 3.0%; P < 0.001; GRS: 28.6% ± 6.7% vs 47.0% ± 7.4%; P < 0.001). Over a median follow-up of 30 days, 28 cardiovascular events occurred. A GCS (HR: 4.9 [95% CI: 1.6-15.0]; P = 0.005) and GRS (HR: 3.9 [95% CI: 1.4-10.8]; P = 0.008) below the median was associated with an increased event rate. In receiver-operating characteristic (ROC) curves, GCS (AUC: 0.80 [95% CI: 0.70-0.91]) and GRS (AUC: 0.76 [95% CI: 0.64-0.88]) showed better performance than cardiac troponin T (cTnT) (AUC: 0.70 [95% CI: 0.58-0.82]), LVEF (AUC: 0.69 [95% CI: 0.56-0.81]), and age (AUC: 0.54 [95% CI: 0.40-0.68]). Net reclassification index and integrated discrimination improvement demonstrated incremental prognostic utility of GRS over LVEF (P = 0.04) and GCS over cTnT (P = 0.002).

    CONCLUSIONS: GCS and GRS are lower in ICI myocarditis, and the magnitude of reduction has prognostic significance.

    Pubmed
  • Persistent immune-related adverse events after cessation of checkpoint inhibitor therapy: Prevalence and impact on patients' health-related quality of life.

    Eur J Cancer. 2022;176(): 88-99

    Schulz TU, Zierold S, Sachse MM, Pesch G, Tomsitz D, Schilbach K, Kähler KC, French LE, Heinzerling L

    BACKGROUND: Immune checkpoint inhibitors (ICIs) may induce persistent immune-related adverse events (irAEs). We investigated persistent irAEs and implications on patients' lives compared to non-ICI-induced autoimmune diseases (AIs).

    METHODS: The multicentre, cross-sectional study comprised 200 patients with cancer ≥12 weeks after ICI cessation (ICI-patients) and 2705 patients with AIs (AI-patients), recruited in German outpatient clinics and support groups. The prevalence of persistent irAEs subdivided in long-term (12 weeks to <12 months) and chronic irAEs (≥12 months) since ICI discontinuation, health-related quality of life (HRQoL) using the EuroQol 5D-5L (EQ-Index/VAS score), and burden of autoimmune symptoms and respective therapies were assessed.

    RESULTS: Long-term/chronic irAEs occurred in 51.9%/35.5% of outpatient ICI-patients, including arthralgia (16.7%/16.1%), myalgia (13.0%/14.0%), hypothyroidism (11.1%/10.8%), xerostomia (7.4%/8.6%), vitiligo (13.0%/7.5%) and hypophysitis (9.3%/7.5%). ICI-patients with long-term/chronic irAEs reported clinically significantly reduced HRQoL compared to ICI-patients without long-term/chronic irAEs (EQ-Index score: 0.767/0.752 versus 0.920/0.923, p < 0.001/0.001; EQ-VAS score: 52.2/52.0 versus 63.6/74.7, p =/< 0.040/0.001). Multiple linear regression analyses confirmed clinically significant reductions in HRQoL scores by chronic irAEs (EQ-Index/VAS score: -0.163/-23.4, p < 0.001/0.001). HRQoL, burden of autoimmune symptoms and burden of respective therapies in ICI-patients with chronic irAEs were similar to AI-patients with non-exacerbated AIs. Patients with chronic irAEs felt inadequately informed about side-effects compared to patients without chronic irAEs (p < 0.001).

    CONCLUSION: Persistent irAEs impose a significant burden on patients after ICI cessation. Especially in early tumour stages, risk-benefit ratios must be carefully evaluated, and patients need to be informed about potential long-term sequelae.

    Pubmed
  • Dataset of a retrospective multicenter cohort study on characteristics of immune checkpoint inhibitor-induced encephalitis and comparison with HSV-1 and anti-LGI1 encephalitis.

    Data Brief. 2022;45():

    Müller-Jensen L, Zierold S, Versluis JM, Boehmerle W, Huehnchen P, Endres M, Mohr R, Compter A, Blank CU, Hagenacker T, Meier F, Reinhardt L, Gesierich A, Salzmann M, Hassel JC, Ugurel S, Zimmer L, Banks P, Spain L, Soon JA, Enokida T, Tahara M, Kähler KC, Seggewiss-Bernhardt R, Harvey C, Long GV, Schöberl F, von Baumgarten L, Hundsberger T, Schlaak M, French LE, Knauss S, Heinzerling LM

    Over the past decade, cancer immunotherapy with immune checkpoint inhibitors (ICIs) has significantly improved the outcome of many malignancies. However, with the broad use of ICIs, neurological immune related adverse events (irAE) are increasingly recognized. ICI-induced encephalitis (ICI-iE) is a particularly severe irAE, often leading to treatment termination, long-term sequalae or death. Despite its high morbidity and mortality, data on clinical features and diagnostic criteria are limited. We aimed to define clinical, radiologic and laboratory characteristics of ICI-iE and identify factors that discriminate it from anti-leucine-rich glioma-inactivated (anti-LGI)-1 encephalitis and herpes simplex virus (HSV)-1 encephalitis - two alternative causes of encephalitis - to increase the awareness of ICI-iE and improve its diagnosis and management. To that end, we retrospectively collected 30 cases of ICI-iE that were reported to the Side Effect Registry Immuno-Oncology (SERIO) and 46 cases of anti-LGI1 encephalitis or herpes simplex virus (HSV)-1 encephalitis that presented to a large German neurological referral center (Charité Universitätsmedizin Berlin) between January 2015 and September 2021. Signs and symptoms, imaging and electroencephalogram features, laboratory findings and outcome measures were assessed using standardized case report forms as well as patients' medical records and compared between the groups. The data reported here represents the largest primary cohort of patients with ICI-iE to date and the first comparison with other types of encephalitis. As all three disorders - ICI-iE, HSV-1 encephalitis and anti-LGI1 encephalitis - are rare neurological entities, this dataset can be used as a reference in future clinical studies on ICI-induced neurotoxicity, neurological autoimmune disorders, and central nervous system infections.

    Pubmed
  • Development of Lymphopenia during Therapy with Immune Checkpoint Inhibitors Is Associated with Poor Outcome in Metastatic Cutaneous Melanoma.

    Cancers (Basel). 2022;14(13):

    Tomsitz D, Schlaak M, Zierold S, Pesch G, Schulz TU, Müller G, Zecha C, French LE, Heinzerling L

    Predictive markers for immune checkpoint inhibitor (ICI) therapy are needed. Thus, baseline blood counts have been investigated as biomarkers, showing that lymphopenia at the start of therapy with (ICI) is associated with a worse outcome in metastatic melanoma. We investigated the relationship between the occurrence of lymphopenia under ICI and disease outcome. Patients with metastatic melanoma who had undergone therapy with ICI were identified in our database. Only patients with a normal lymphocyte count at baseline were included in this retrospective study. Progression-free survival (PFS) and overall survival (OS) were compared between patients in which lymphopenia occurred during ICI therapy and those who did not develop lymphopenia. In total, 116 patients were analyzed. Lymphopenia occurred in 42.2% of patients, with a mean onset after 17 weeks (range 1-180 weeks). The occurrence of lymphopenia during immunotherapy was significantly associated with a shorter PFS and OS. Patients who developed lymphopenia (n = 49) had a mean PFS of 13.3 months (range 1-67 months) compared to 16.9 months (range 1-73 months) for patients who did not develop lymphopenia (n = 67; p = 0.025). Similarly, patients with lymphopenia had a significantly shorter OS of 28.1 months (range 2-70 months) compared with 36.8 months (range 4-106 months) in patients who did not develop lymphopenia (p = 0.01). Patients with metastatic melanoma who develop lymphopenia during ICI therapy have a worse prognosis with significantly shorter PFS and OS compared with patients who do not develop lymphopenia.

    Pubmed
  • Health-related quality of life (EuroQol 5D-5L) in patients with autoimmunity in the context of immunotherapy: A large dataset comprising cancer patients after cessation of checkpoint inhibitor therapy and patients with autoimmune diseases.

    Data Brief. 2022;45():

    Schulz TU, Zierold S, Sachse MM, Pesch G, Tomsitz D, Schilbach K, Kähler KC, French LE, Heinzerling L

    This dataset contains demographic, clinical, and health-related quality of life (HRQoL) data from 2905 patients including 200 cancer patients after immune checkpoint inhibitor (ICI) cessation and 2705 patients with a wide variety of autoimmune diseases. Within this multicenter, cross-sectional survey study data were collected questionnaire-based in cancer patients (ICI-patients) ≥ 18 years of age who had received at least one dose of ICI with ≥ 12 weeks since ICI discontinuation. Patients with autoimmune diseases (AI-patients) were ≥ 18 years, had at least one autoimmune disease and had never received ICI. ICI-patients were recruited in three skin cancer centers and via support groups. AI-patients were recruited in an outpatient clinic for internal medicine and via support groups. Specific questionnaires for ICI-patients/AI-patients were provided paper-based for patients from outpatient clinics and online for patients from support groups. Both questionnaires contained sections with demographic information, clinical data, and the standardized patient-reported outcome measure EuroQol 5D-5L (EQ-5D-5L) to assess HRQoL. Clinical data focused on autoimmunity and therapy of autoimmunity in (1) ICI-patients referring to particularly persistent immune-related adverse events (persistent irAEs) and in (2) AI-patients referring to respective autoimmune diseases. Additionally, specific items on cancer and cancer therapy were included in ICI-patients, and AI-patients were asked about the presence of acute exacerbations of autoimmune diseases. This dataset contains the raw data for ICI-patients and AI-patients, analyzed data on patient demographics, clinical characteristics and HRQoL scores among ICI-patients with/without persistent irAEs and among AI-patients. The data provide a basis for further investigations within the cohort of ICI-patients after ICI cessation and/or for AI-patients with different autoimmune diseases with regard to HRQoL, autoimmunity and therapy of autoimmunity.

    Pubmed
  • Characteristics of immune checkpoint inhibitor-induced encephalitis and comparison with HSV-1 and anti-LGI1 encephalitis: A retrospective multicentre cohort study.

    Eur J Cancer. 2022;175(): 224-235

    Müller-Jensen L, Zierold S, Versluis JM, Boehmerle W, Huehnchen P, Endres M, Mohr R, Compter A, Blank CU, Hagenacker T, Meier F, Reinhardt L, Gesierich A, Salzmann M, Hassel JC, Ugurel S, Zimmer L, Banks P, Spain L, Soon JA, Enokida T, Tahara M, Kähler KC, Seggewiss-Bernhardt R, Harvey C, Long GV, Schöberl F, von Baumgarten L, Hundsberger T, Schlaak M, French LE, Knauss S, Heinzerling LM

    AIM: Immune checkpoint inhibitor-induced encephalitis (ICI-iE) is a rare but life-threatening toxicity of immune checkpoint inhibitor treatment. We aim to identify the characteristics of ICI-iE and describe factors that discriminate it from herpes simplex virus (HSV)-1 encephalitis and anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis, as two alternative entities of encephalitis.

    METHODS: In this retrospective multicentre cohort study, we collected patients with ICI-iE reported to the Side Effect Registry Immuno-Oncology from January 2015 to September 2021 and compared their clinical features and outcome with 46 consecutive patients with HSV-1 or anti-LGI1 encephalitis who were treated at a German neurological referral centre.

    RESULTS: Thirty cases of ICI-iE, 25 cases of HSV-1 encephalitis and 21 cases of anti-LGI1 encephalitis were included. Clinical presentation of ICI-iE was highly variable and resembled that of HSV-1 encephalitis, while impairment of consciousness (66% vs. 5%, p = .007), confusion (83% vs. 43%; p = .02), disorientation (83% vs. 29%; p = .007) and aphasia (43% vs. 0%; p = .007) were more common in ICI-iE than in anti-LGI1 encephalitis. Antineuronal antibodies (17/18, 94%) and MRI (18/30, 60%) were mostly negative in ICI-iE, but cerebrospinal fluid (CSF) showed pleocytosis and/or elevated protein levels in almost all patients (28/29, 97%). Three patients (10%) died of ICI-iE. Early immunosuppressive treatment was associated with better outcome (r = 0.43).

    CONCLUSIONS: ICI-iE is a heterogeneous entity without specific clinical features. CSF analysis has the highest diagnostic value, as it reveals inflammatory changes in most patients and enables the exclusion of infection. Early treatment of ICI-iE is essential to prevent sequelae and death.

    Pubmed
  • NanoString technology distinguishes anti-TIF-1γ+ from anti-Mi-2+ dermatomyositis patients (vol 31, e12957, 2021)

    Brain Pathol. 2022;32(2):

    Heinzerling L

    Pubmed
  • Molecular dynamics simulations of the delta and omicron SARS-CoV-2 spike - ACE2 complexes reveal distinct changes between both variants.

    Comput Struct Biotechnol J. 2022;20(): 1168-1176

    Socher E, Heger L, Paulsen F, Zunke F, Arnold P

    SARS-CoV-2, the virus causing the COVID-19 pandemic, changes frequently through the appearance of mutations constantly leading to new variants. However, only few variants evolve as dominating and will be considered as "Variants of Concern" (VOCs) by the world health organization (WHO). At the end of 2020 the alpha (B.1.1.7) variant appeared in the United Kingdom and dominated the pandemic situation until mid of 2021 when it was substituted by the delta variant (B.1.617.2) that first appeared in India as predominant. At the end of 2021, SARS-CoV-2 omicron (B.1.1.529) evolved as the dominating variant. Here, we use in silico modeling and molecular dynamics (MD) simulations of the receptor-binding domain of the viral spike protein and the host cell surface receptor ACE2 to analyze and compare the interaction pattern between the wild type, delta and omicron variants. We identified residue 493 in delta (glutamine) and omicron (arginine) with altered binding properties towards ACE2.

    Pubmed
  • Effectiveness and safety of dabrafenib and trametinib in patients with BRAFV600 mutated metastatic melanoma in the real-world setting: Final results of the non-interventional COMBI-r study

    Ann Oncol. 2022;33 Suppl 7(7): S927-S927

    Berking C, Livingstone E, Weichenthal M, Leiter-Stoppke U, Remy J, Eigentler T, Mohr P, Kiecker F, Loquai C, Debus D, Gutzmer R

    Pubmed
  • Effectiveness and Safety of Dabrafenib and Trametinib in Patients with BRAFV600 Mutated Metastatic Melanoma in the Real-World Setting - Final Results of the Non-Interventional COMBI-r Study

    J Dtsch Dermatol Ges. 2022;20 Suppl 3(): 4-4

    Berking C, Livingstone E, Weichenthal M, Leiter-Stoeppke U, Remy J, Eigentler T, Mohr P, Kiecker F, Loquai C, Debus D, Gutzmer R

    Pubmed
  • First interims analysis of a two cohort registry study for patients with advanced cutaneous squamous cell carcinoma (CSCC) treated with cemiplimab or other approaches

    J Dtsch Dermatol Ges. 2022;20 Suppl 3(): 44-44

    Gutzmer R, Geusau A, Heppt M, Leiter-Stoeppke U, GunTinas-Lichius O, Duecker P, Utikal JS, Loquai C, Grabbe S, Terheyden P, Ziller F, Tschechne B, Gschnell M, Mohr P, Heinzerling M, Grimmelmann J, Dippel MO, Hassel J, Kaatz M, Simon J, Zahn MO, Ulrich J, Gambichler T, Welzel J, Ramelyte E, Weichenthal M

    Pubmed
  • ASSESSING SIMILARITY OF STUDIES FOR NETWORK META-ANALYSIS: THE USE OF FEASIBILITY ASSESSMENT AND SENSITIVITY ANALYSES TO ESTIMATE THE EFFICACY OF TIRBANIBULIN, A NEW DRUG FOR ACTINIC KERATOSIS

    Value Health. 2022;25 Suppl S(12): S367-S368

    Heppt M, Dykukha I, Chapman-Rounds M, Graziadio S, Edwards M

    Pubmed
  • CHALLENGES OF NETWORK META-ANALYSIS FOR SAFETY OUTCOMES: THE ANALYSIS OF TIRBANIBULIN AGAINST COMMON TREATMENTS IN EUROPE FOR ACTINIC KERATOSIS

    Value Health. 2022;25 Suppl S(12): S351-S351

    Heppt M, Dykukha I, Chapman-Rounds M, Graziadio S, Edwards M

    Pubmed
  • Glaucoma-TrEl: A web-based interactive database to build evidence-based hypotheses on the role of trace elements in glaucoma.

    BMC Res Notes. 2022;15(1):

    Choudhari JK, Eberhardt M, Chatterjee T, Hohberger B, Vera J

    OBJECTIVE: Glaucoma is a chronic neurological disease that is associated with high intraocular pressure (IOP), causes gradual damage to retinal ganglion cells, and often culminates in vision loss. Recent research suggests that glaucoma is a complex multifactorial disease in which multiple interlinked genes and pathways play a role during onset and development. Also, differential availability of trace elements seems to play a role in glaucoma pathophysiology, although their mechanism of action is unknown. The aim of this work is to disseminate a web-based repository on interactions between trace elements and protein-coding genes linked to glaucoma pathophysiology.

    RESULTS: In this study, we present Glaucoma-TrEl, a web database containing information about interactions between trace elements and protein-coding genes that are linked to glaucoma. In the database, we include interactions between 437 unique genes and eight trace elements. Our analysis found a large number of interactions between trace elements and protein-coding genes mutated or linked to the pathophysiology of glaucoma. We associated genes interacting with multiple trace elements to pathways known to play a role in glaucoma. The web-based platform provides an easy-to-use and interactive tool, which serves as an information hub facilitating future research work on trace elements in glaucoma.

    Pubmed
  • Select hyperactivating NLRP3 ligands enhance the TH1-and TH17-inducing potential of human type 2 conventional dendritic cells

    Eur J Immunol. 2022;52 Suppl 1(): 178-179

    Heger L, Hatscher L, Lehmann CHK, Purbojo A, Onderka C, Liang C, Hartmann A, Cesnjevar R, Bruns H, Gross O, Nimmerjahn F, Ivanovic-Burmazovic I, Kunz M, Dudziak D

    Pubmed
  • A cross-tissue protein profiling atlas reveals distinct cDC2 subpopulations within the murine conventional dendritic cell network

    Eur J Immunol. 2022;52 Suppl 1(): 38-38

    Amon L, Lehmann CHK, Seichter A, Heger L, Dudziak D

    Pubmed
  • Eine uberma ss ige Phagozytose von Myelomzellen induziert Pyroptose in Myelom-assoziierten Makrophagen und beeintrachtigt die Wirksamkeit therapeutischer Antikorper.

    Oncology Research and Treatment. 2022;45 Suppl 2(SUPPL 2): 281-281

    Flamann C, Biedermann A, Mougiakakos D, Bitterer K, Karg K, Bittenbring J, Buttner-Herold M, Liebisch G, Leffler M, Lischer C, Eberhardt M, Vera-Gonzales J, Zeiser R, A. A, H. H

    Pubmed
  • BISPECIFIC ANTIBODIES ENABLE SYNTHETIC AGONISTIC RECEPTOR T CELL THERAPY IN MELANOMA

    J Immunother Cancer. 2022;10 Suppl 1(): A4-A5

    Benmebarek M, Maerkl F, Keyl J, Cadilha B, Geiger M, Karches C, Obeck H, Schwerdtfeger M, Briukhovetska D, Jobst J, Mueller P, Seifert M, Grunmeier R, Thomas M, Marr C, Levesque M, Heppt M, Endres S, Klein C, Kobold S

    Pubmed
  • Adrenaline autoinjector is under-prescribed in typical cold urticaria patients living in tropical climate countries.

    Qatar Med J. 2022;2022(2):

    Bizjak M, Košnik M, Dinevski D, Francis Thomsen S, Fomina D, Borzova E, Kulthanan K, Meshkova R, Aarestrup F, Melina Ahsan D, Al-Ahmad M, Altrichter S, Bauer A, Brockstädt M, Costa C, Demir S, Fachini Criado R, Felipe Ensina L, Gelincik A, Giménez-Arnau AM, Gonçalo M, Gotua M, Grønlund Holm J, Inomata N, Kasperska-Zajac A, Khoshkhui M, Klyucharova A, Kocatürk E, Lu R, Makris M, Maltseva N, Pasali M, Paulino M, Pesqué D, Peter J, Dario Ramón G, Ritchie C, Oliveira Rodrigues Valle S, Rudenko M, Sikora A, Wagner N, Xepapadaki P, Xue X, Zhao Z, Terhorst-Molawi D, Maurer M

    Background: The diagnosis of typical cold urticaria (ColdU) relies on whealing in response to local cold stimulation testing (CST). It can also manifest with cold-induced anaphylaxis (ColdA). Till date, it is largely unclear how often patients with ColdU receive adrenaline treatment and are provided with an adrenaline autoinjector (AAI). Methods: An international, cross-sectional study, COLD-CE (i.e., comprehensive evaluation of ColdU and other cold-induced reactions), was carried out at 32 UCAREs. Detailed histories were taken and CST with an ice cube and/or TempTest® performed. ColdA was defined as an acute cold-induced (i.e., by cold water, air, or surfaces) involvement of the skin and/or visible mucosal tissue and at least one of the symptoms (cardiovascular manifestations, difficulty breathing, or gastrointestinal symptoms). Results: Of the 551 ColdU patients, 75% (n = 412) had a positive CST. Of them, concomitant chronic spontaneous urticaria was diagnosed in 10%. Of 372 patients with stand-alone ColdU, 69% were women and 91% adults. Their median age was 36 (IQR 26 - 48) years. Patients were also categorized into residents of countries with a tropical (n = 33), temperate (n = 264), or cold (n = 75) climate (Table 1: R13C1, R17C1, R21C1). AAI was more often prescribed to residents of temperate than tropical countries (30% vs. 12%, p = .038; Table 1: R31C1), although the frequency of ColdA did not significantly differ between these countries (44% vs. 42%, p = 1.000; R29C2). Residents of tropical countries had a higher frequency of ColdA induced by cold air than residents of temperate (36% vs. 12%, p = .001; R29C4) or cold (36% vs. 12%, p = .007; R25C4) countries. Cardiovascular manifestations induced by cold air were diagnosed in 33% (n = 11) of residents of tropical countries, but only 18% (n = 2) and 36% (n = 4) of them had received adrenaline and AAI, respectively (R13 - 15C7). Furthermore, hypotension and/or loss of consciousness induced by cold air occurred in 18% (n = 6) of patients, but only 17% (n = 1) received adrenaline (R13 - 14C10). ColdA was induced by complete cold water immersion in 9% (n = 3) of patients, and none of them received adrenaline treatment nor AAI (R13 - 15C3). Conclusion: Our findings suggest that ColdA is undertreated and call for changes in ColdU management.

    Pubmed
  • Detection and Analysis of Critical Dynamic Properties of Oligodendrocyte Differentiation

    Mathematics. 2022;10(16):

    Nikolov SG, Wolkenhauer O, Nenov M, Vera J

    In this paper, we derive a four-dimensional ordinary differential equation (ODE) model representing the main interactions between Sox9, Sox10, Olig2 and several miRNAs, which drive the process of (olygodendrocyte) differentiation. We utilize the Lyapunov-Andronov theory to analyze its dynamical properties. Our results indicated that the strength of external signaling (morphogenic gradients shh and bmp), and the transcription rate of mOlig2 explain the existence of stable and unstable (sustained oscillations) behavior in the system. Possible biological implications are discussed.

    Pubmed
  • The Role of MicroRNAs in Cancer Biology and Therapy from a Systems Biology Perspective.

    Adv Exp Med Biol. 2022;1385(): 1-22

    Lai X, Schmitz U, Vera J

    Since the discovery of microRNAs (miRNAs) in Caenorhabditis elegans, our understanding of their cellular function has progressed continuously. Today, we have a good understanding of miRNA-mediated gene regulation, miRNA-mediated cross talk between genes including competing endogenous RNAs, and miRNA-mediated signaling transduction both in normal human physiology and in diseases.Besides, these noncoding RNAs have shown their value for clinical applications, especially in an oncological context. They can be used as reliable biomarkers for cancer diagnosis and prognosis and attract increasing attention as potential therapeutic targets. Many achievements made in the miRNA field are based on joint efforts from computational and molecular biologists. Systems biology approaches, which integrate computational and experimental methods, have played a fundamental role in uncovering the cellular functions of miRNAs.In this chapter, we review and discuss the role of miRNAs in oncology from a system biology perspective. We first describe biological facts about miRNA genetics and function. Next, we discuss the role of miRNAs in cancer progression and review the application of miRNAs in cancer diagnostics and therapy. Finally, we elaborate on the role that miRNAs play in cancer gene regulatory networks. Taken together, we emphasize the importance of systems biology approaches in our continued efforts to study miRNA cancer regulation.

    Pubmed
  • Impact of off-label use regulations on patient care in dermatology - a prospective study of cost-coverage applications filed by tertiary dermatology clinics throughout Germany.

    J Eur Acad Dermatol Venereol. 2022;36(11): 2241-2249

    Werner RN, Pennitz A, Eisert L, Schmidle P, Zink A, Abraham S, Schäkel K, Wolff I, Goebeler M, Plange J, Sollfrank L, Zielbauer S, Koll P, Amschler K, Müller V, Nast A

    BACKGROUND: In dermatology, a medical speciality with a relatively high number of rare diseases, physicians often have to resort to off-label treatment options. To avoid claims, physicians in Germany can file a cost-coverage request (off-label application, OL-A).

    OBJECTIVES: Our aim was to investigate the extent to which the current regulations affect patient care.

    MATERIAL AND METHODS: Prospective cohort study among tertiary dermatology clinics throughout Germany, consecutively including OL-As (05/2019-09/2020) and assessing the follow-up correspondence. We modelled regressions to assess factors associated with cost-coverage decisions and the time needed by health insurers to process the OL-As.

    RESULTS: Thirteen clinics provided data on 121 OL-As, two of which applied for on-label treatments. Of the remaining 119 OL-As, 70 (58.8%) were immediately approved and 44 (37.0%) rejected. Including cases with one or more appeals, 87 of 119 OL-As (73.1%) were finally approved and 26 (21.9%) rejected. There was an association of the final approval rate with (1) the class of medication/treatment, with approval rates being significantly lower for JAK inhibitors than for biologics (OR 0.16, 95%-CI: 0.03-0.82); (2) German state, with approval rates being lower in eastern than in western states (OR 0.30, 95%-CI 0.12-0.76); and (3) cost of the intervention (no linear trend). However, none of these predictors was significant in our multiple logistic regression models. The median health insurer's processing time (first response) was 29 days (IQR 22-38). Our analyses showed no evidence of an association with the predictors we assessed. In cases approved, the median time from the decision to file an OL-A to the actual initiation of the treatment was 65.5 days (IQR 51-92).

    CONCLUSIONS: Our study points to substantial delays and inequalities in the provision of timely health care for dermatological patients with rare diseases, often involving treatments for which there is no adequate approved therapy.

    Pubmed
  • Long-term recurrence rates of actinic keratosis: A systematic review and pooled analysis of randomized controlled trials.

    J Am Acad Dermatol. 2022;86(5): 1116-1119

    Steeb T, Wessely A, Petzold A, Brinker TJ, Schmitz L, Schöffski O, Berking C, Heppt MV

    Pubmed
  • Assessment of sorafenib induced changes in tumor perfusion of uveal melanoma metastases with dynamic contrast-enhanced ultrasound (DCE-US).

    J Cancer Res Clin Oncol. 2022;148(4): 955-965

    Wildner D, Heinzerling L, Scheulen ME, Kaempgen E, Schuler G, Strobel D, Janka R, Neurath MF, Sturm J, Knieling F

    PURPOSE: Dynamic contrast-enhanced ultrasound (DCE-US) was used to monitor early response to sorafenib therapy in patients with liver metastases from uveal melanoma.

    METHODS: In total, 21 patients with liver metastases were recruited within a prospective trial and underwent daily sorafenib therapy. DCE-US of a target lesion was performed before initiation of treatment, on day 15 and 56. Two independent blinded investigators performed software analysis for DCE-US parameters and inter-observer-correlation was calculated. Response to treatment was evaluated on day 56. DCE-US parameters were correlated with clinical response and RECIST1.1 criteria.

    RESULTS: Inter-observer-correlation (r) of DCE-US parameters [time-to-peak (TTP), mean-transit-time (MTT), peak intensity (PI), regional blood volume (RBV), regional blood flow (RBF)] at baseline, day 15, and day 56 was highly significant (r-range 0.73-0.97, all p < 0.001). Out of 17 evaluable patients, 12 patients survived day 56 (clinical responders, cRE), whereas, five patients died before day 56 and were classified as non-responders (cNR). TTP values significantly increased in the cRE group 15 days after initiation of treatment for investigator 1 (p = 0.034) and at day 56 for both investigators (p = 0.028/0.028). MTT had increased significantly in the cRE group on day 56 (p = 0.037/0.022). In the cNR group changes for TTP and MTT remained insignificant. Thus, increase of the DCE-US parameters TTP and MTT are associated with response to treatment and prognosis.

    CONCLUSION: An increase of TTP and MTT at frequent intervals could serve as a surrogate marker for early response evaluation to anti-angiogenic treatment of metastatic uveal melanoma.

    Pubmed
  • Comorbidity and Therapeutic Approaches in Patients with Necrobiosis Lipoidica.

    Dermatology. 2022;238(1): 148-155

    Erfurt-Berge C, Heusinger V, Reinboldt-Jockenhöfer F, Dissemond J, Renner R

    BACKGROUND: Necrobiosis lipoidica (NL) is a rare granulomatous disorder of unknown aetiology. Randomized controlled studies are not available due to it being an orphan disease.

    OBJECTIVES: We evaluated patients in 2 dermatological centres to cluster data about epidemiology, the therapeutic approaches for NL, and their efficacy.

    MATERIALS AND METHODS: Comorbidity and the efficacy of the applied treatment was assessed for 98 patients.

    RESULTS: We identified 54% of patients with concomitant diabetes and 19% with thyroidal disorders. Topical steroids (85.7%) were predominantly used followed by calcineurin inhibitors (31%) and phototherapy (41.8%). Systemically, fumaric acid esters were more frequently applied (26.8%) than steroids (24.4%) and dapsone (24.4%). Steroids, compression therapy, calcineurin inhibitors, phototherapy, fumaric acid esters, and dapsone showed remarkable efficacy.

    CONCLUSION: Therapeutic options were chosen individually in accordance with the severity of NL and presence of ulceration. Topical calcineurin inhibitors, systemic application of fumaric acid esters, and dapsone represent effective alternatives to the use of steroids.

    Pubmed
  • A disease network-based deep learning approach for characterizing melanoma.

    Int J Cancer. 2022;150(6): 1029-1044

    Lai X, Zhou J, Wessely A, Heppt M, Maier A, Berking C, Vera J, Zhang L

    Multiple types of genomic variations are present in cutaneous melanoma and some of the genomic features may have an impact on the prognosis of the disease. The access to genomics data via public repositories such as The Cancer Genome Atlas (TCGA) allows for a better understanding of melanoma at the molecular level, therefore making characterization of substantial heterogeneity in melanoma patients possible. Here, we proposed an approach that integrates genomics data, a disease network, and a deep learning model to classify melanoma patients for prognosis, assess the impact of genomic features on the classification and provide interpretation to the impactful features. We integrated genomics data into a melanoma network and applied an autoencoder model to identify subgroups in TCGA melanoma patients. The model utilizes communities identified in the network to effectively reduce the dimensionality of genomics data into a patient score profile. Based on the score profile, we identified three patient subtypes that show different survival times. Furthermore, we quantified and ranked the impact of genomic features on the patient score profile using a machine-learning technique. Follow-up analysis of the top-ranking features provided us with the biological interpretation of them at both pathway and molecular levels, such as their mutation and interactome profiles in melanoma and their involvement in pathways associated with signaling transduction, immune system and cell cycle. Taken together, we demonstrated the ability of the approach to identify disease subgroups using a deep learning model that captures the most relevant information of genomics data in the melanoma network.

    Pubmed
  • Clinical determinants of long-term survival in metastatic uveal melanoma.

    Cancer Immunol Immunother. 2022;71(6): 1467-1477

    Koch EAT, Petzold A, Wessely A, Dippel E, Erdmann M, Heinzerling L, Hohberger B, Knorr H, Leiter U, Meier F, Mohr P, Rahimi F, Schell B, Schlaak M, Terheyden P, Schuler-Thurner B, Ugurel S, Utikal J, Vera J, Weichenthal M, Ziller F, Berking C, Heppt MV

    This study aimed to identify prognostic factors in patients with metastatic uveal melanoma (UM) that were associated with long-term survival in a real-world setting. A total of 94 patients with metastatic UM were included from German skin cancer centers and the German national skin cancer registry (ADOReg). Data were analyzed for the response to treatment, progression-free survival, and overall survival (OS). Prognostic factors were explored with univariate Cox regression, log-rank, and χ2-tests. Identified factors were subsequently validated after the population was divided into two cohorts of short-term survival (< 2 years OS, cohort A, n = 50) and long-term survival (> 2 years OS, cohort B, n = 44). A poor ECOG performance status (hazard ratio [HR] 2.0, 95% confidence interval [CI] 1.0-3.9) and elevated serum LDH (HR 2.0, 95% CI 1.0-3.8) were associated with a poor OS, whereas a good response to immune checkpoint blockade (ICB, p < 0.001), radiation therapy (p < 0.001), or liver-directed treatments (p = 0.01) were associated with a prolonged OS. Long-term survivors (cohort B) showed a higher median number of organs affected by metastasis (p < 0.001), while patients with liver metastases only were more common in cohort A (40% vs. 9%; p = 0.002). A partial response to ICB was observed in 16% (12/73), being 21% (8/38) for combined ICB, 17% (1/6) for single CTLA4 inhibition, and 10% (3/29) for single PD1 inhibition. One complete response occurred in cohort B with combined ICB. We conclude that the response to ICB and the presence of extrahepatic disease were favorable prognostic factors for long-term survival.

    Pubmed
  • Three generations of suffering: cryopyrin-associated periodic syndrome with NLRP3 mutation in a family.

    J Dtsch Dermatol Ges. 2022;20(1): 110-112

    Wagner N, Manger B, Kittler J, Rech J, Sticherling M, Berking C, Kirchberger MC

    Pubmed
  • Very late reactions in the patch test with fragrance mix I and oak moss absolute (Evernia prunastri, INCI): Data of the Information Network of Departments of Dermatology (IVDK).

    Contact Dermatitis. 2022;86(1): 54-57

    Schubert S, Schnuch A, Bauer A, Wagner N, Schröder-Kraft C, Dickel H, Weisshaar E, Effendy I, Becker D, Buhl T, Simon D, Koch A, Kreft B, Vieluf D, Löffler H, Geier J

    Pubmed
  • Impact of Cytokine Inhibitor Therapy on the Prevalence, Seroconversion Rate, and Longevity of the Humoral Immune Response Against SARS-CoV-2 in an Unvaccinated Cohort.

    Arthritis Rheumatol. 2022;74(5): 783-790

    Simon D, Tascilar K, Kleyer A, Fagni F, Krönke G, Meder C, Dietrich P, Orlemann T, Kliem T, Mößner J, Liphardt AM, Schönau V, Bohr D, Schuster L, Hartmann F, Leppkes M, Ramming A, Pachowsky M, Schuch F, Ronneberger M, Kleinert S, Hueber AJ, Manger K, Manger B, Atreya R, Berking C, Sticherling M, Neurath MF, Schett G

    OBJECTIVE: To investigate the impact of biologic disease-modifying antirheumatic drug (bDMARD) treatment on the prevalence, seroconversion rate, and longevity of the humoral immune response against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs).

    METHODS: Anti-SARS-CoV-2 IgG antibodies were measured in a prospective cohort of health care professional controls and non-health care controls and IMID patients receiving no treatment or receiving treatment with conventional or biologic DMARDs during the first and second COVID-19 waves. Regression models adjusting for age, sex, sampling time, and exposure risk behavior were used to calculate relative risks (RRs) of seropositivity. Seroconversion rates were assessed in participants with polymerase chain reaction (PCR)-positive SARS-CoV-2 infection. Antibody response longevity was evaluated by reassessing participants who tested positive during the first wave.

    RESULTS: In this study, 4,508 participants (2,869 IMID patients and 1,639 controls) were analyzed. The unadjusted RR (0.44 [95% confidence interval (95% CI) 0.31-0.62]) and adjusted RR (0.50 [95% CI 0.34-0.73]) for SARS-CoV-2 IgG antibodies were significantly lower in IMID patients treated with bDMARDs compared to non-health care controls (P < 0.001), primarily driven by treatment with tumor necrosis factor inhibitors, interleukin-17 (IL-17) inhibitors, and IL-23 inhibitors. Adjusted RRs for untreated IMID patients (1.12 [95% CI 0.75-1.67]) and IMID patients receiving conventional synthetic DMARDs (0.70 [95% CI 0.45-1.08]) were not significantly different from non-health care controls. Lack of seroconversion in PCR-positive participants was more common among bDMARD-treated patients (38.7%) than in non-health care controls (16%). Overall, 44% of positive participants lost SARS-CoV-2 antibodies by follow-up, with higher rates in IMID patients treated with bDMARDs (RR 2.86 [95% CI 1.43-5.74]).

    CONCLUSION: IMID patients treated with bDMARDs have a lower prevalence of SARS-CoV-2 antibodies, seroconvert less frequently after SARS-CoV-2 infection, and may exhibit a reduced longevity of their humoral immune response.

    Pubmed
  • Perception of the coronavirus pandemic by patients with atopic dermatitis - Results from the TREATgermany registry.

    J Dtsch Dermatol Ges. 2022;20(1): 45-57

    Helmert C, Siegels D, Haufe E, Abraham S, Heratizadeh A, Kleinheinz A, Harder I, Schäkel K, Effendy I, Wollenberg A, Sticherling M, Stahl M, Worm M, Schwichtenberg U, Schwarz B, Rossbacher J, Buck PM, Schenck F, Werfel T, Weidinger S, Schmitt J, TREATgermany Study Team

    BACKGROUND: TREATgermany, a registry for patients with moderate to severe atopic dermatitis (AD), established an additional questionnaire in spring 2020 to investigate the effects of the coronavirus pandemic on the daily life of patients with AD.

    MATERIAL AND METHODS: A questionnaire was used to analyze general information regarding a patient's experience of the coronavirus pandemic and, using the Inventory of Life-Changing Events, the resulting personal burden. To analyze possible associations between disease severity (EASI score, oSCORAD, IGA, PGA, POEM), quality of life (DLQI) and personal burden, t-tests, analyses of variance and correlations were evaluated, controlled for sex and age.

    RESULTS: 58 % (n = 233) of the included 400 registry patients reported high burden scores caused by the coronavirus pandemic, regardless of an actual infection. Men showed significantly higher burden scores than women, and younger than older respondents (both P = 0.03). There were no differences in burden scores related to the physician's assessment of disease severity. However, patients with higher quality of life impairments and higher disease severity perceived the burden of the coronavirus pandemic as less severe (DLQI P = 0.019, PGA P = 0.044).

    CONCLUSIONS: Our data show that registry patients considered the coronavirus pandemic as a life-changing event and perceived the burden differently. This should be taken into account in the treatment of patients with moderate to severe AD as well as in further studies.

    Pubmed
  • SCLE manifestation after mRNA COVID-19 vaccination.

    J Eur Acad Dermatol Venereol. 2022;36(4): e261-e263

    Rechtien L, Erfurt-Berge C, Sticherling M

    Pubmed
  • Patient-reported outcomes and burden of disease in paediatric patients with psoriasis: real-world data from the EU5 and USA

    Br J Dermatol. 2022;186(1): E28-E29

    Seyger M, Paller A, Sticherling M, Bachhuber T, Fang J, Hetherington J, Lucas J, Meakin S, Richardson C, Augustin M

    Pubmed
  • Pooled safety analysis from two phase III studies of secukinumab in paediatric patients with moderate-to-severe plaque psoriasis up to week 52

    Br J Dermatol. 2022;186(1): E39-E40

    Sticherling M, Nikkels AF, Hamza AM, Kwong P, Ortmann CE, Papanastasiou P, Forrer P, Keefe D

    Pubmed
  • Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Re-Induction following Resistance or Toxicity.

    Cancers (Basel). 2022;14(3):

    Koch EAT, Petzold A, Wessely A, Dippel E, Gesierich A, Gutzmer R, Hassel JC, Haferkamp S, Kähler KC, Knorr H, Kreuzberg N, Leiter U, Loquai C, Meier F, Meissner M, Mohr P, Pföhler C, Rahimi F, Schadendorf D, Schell B, Schlaak M, Terheyden P, Thoms KM, Schuler-Thurner B, Ugurel S, Ulrich J, Utikal J, Weichenthal M, Ziller F, Berking C, Heppt MV

    Re-induction with immune checkpoint blockade (ICB) needs to be considered in many patients with uveal melanoma (UM) due to limited systemic treatment options. Here, we provide hitherto the first analysis of ICB re-induction in UM. A total of 177 patients with metastatic UM treated with ICB were included from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of ICB re-induction, two cohorts were compared: patients who received at least one ICB re-induction (cohort A, n = 52) versus those who received only one treatment line of ICB (cohort B, n = 125). In cohort A, a transient benefit of overall survival (OS) was observed at 6 and 12 months after the treatment start of ICB. There was no significant difference in OS between both groups (p = 0.1) with a median OS of 16.2 months (cohort A, 95% CI: 11.1-23.8) versus 9.4 months (cohort B, 95% CI: 6.1-14.9). Patients receiving re-induction of ICB (cohort A) had similar response rates compared to those receiving ICB once. Re-induction of ICB may yield a clinical benefit for a small subgroup of patients even after resistance or development of toxicities.

    Pubmed
  • HDAC2 Is Involved in the Regulation of BRN3A in Melanocytes and Melanoma.

    Int J Mol Sci. 2022;23(2):

    Heppt MV, Wessely A, Hornig E, Kammerbauer C, Graf SA, Besch R, French LE, Matthies A, Kuphal S, Kappelmann-Fenzl M, Bosserhoff AK, Berking C

    The neural crest transcription factor BRN3A is essential for the proliferation and survival of melanoma cells. It is frequently expressed in melanoma but not in normal melanocytes or benign nevi. The mechanisms underlying the aberrant expression of BRN3A are unknown. Here, we investigated the epigenetic regulation of BRN3A in melanocytes and melanoma cell lines treated with DNA methyltransferase (DNMT), histone acetyltransferase (HAT), and histone deacetylase (HDAC) inhibitors. DNMT and HAT inhibition did not significantly alter BRN3A expression levels, whereas panHDAC inhibition by trichostatin A led to increased expression. Treatment with the isoform-specific HDAC inhibitor mocetinostat, but not with PCI-34051, also increased BRN3A expression levels, suggesting that class I HDACs HDAC1, HDAC2, and HDAC3, and class IV HDAC11, were involved in the regulation of BRN3A expression. Transient silencing of HDACs 1, 2, 3, and 11 by siRNAs revealed that, specifically, HDAC2 inhibition was able to increase BRN3A expression. ChIP-Seq analysis uncovered that HDAC2 inhibition specifically increased H3K27ac levels at a distal enhancer region of the BRN3A gene. Altogether, our data suggest that HDAC2 is a key epigenetic regulator of BRN3A in melanocytes and melanoma cells. These results highlight the importance of epigenetic mechanisms in regulating melanoma oncogenes.

    Pubmed
  • A One-Armed Phase I Dose Escalation Trial Design: Personalized Vaccination with IKKβ-Matured, RNA-Loaded Dendritic Cells for Metastatic Uveal Melanoma.

    Front Immunol. 2022;13():

    Koch EAT, Schaft N, Kummer M, Berking C, Schuler G, Hasumi K, Dörrie J, Schuler-Thurner B

    Uveal melanoma (UM) is an orphan disease with a mortality of 80% within one year upon the development of metastatic disease. UM does hardly respond to chemotherapy and kinase inhibitors and is largely resistant to checkpoint inhibition. Hence, further therapy approaches are urgently needed. To improve clinical outcome, we designed a trial employing the 3rd generation personalized IKKβ-matured RNA-transfected dendritic cell (DC) vaccine which primes T cells and in addition activates NK cells. This ongoing phase I trial [NCT04335890 (www.clinicaltrials.gov), Eudract: 2018-004390-28 (www.clinicaltrialsregister.eu)] investigates patients with treatment-naive metastatic UM. Monocytes are isolated by leukapheresis, differentiated to immature DCs, matured with a cytokine cocktail, and activated via the NF-κB pathway by electroporation with RNA encoding a constitutively active mutant of IKKβ. Three types of antigen-RNA are co-electroporated: i) amplified mRNA of the tumor representing the whole transcriptome, ii) RNA encoding driver mutations identified by exome sequencing, and iii) overexpressed non-mutated tumor antigens detected by transcriptome sequencing. This highly personalized DC vaccine is applied by 9 intravenous infusions in a staggered schedule over one year. Parallel to the vaccination, standard therapy, usually an immune checkpoint blockade (ICB) as mono (anti-PD-1) or combined (anti-CTLA4 and anti-PD-1) regimen is initiated. The coordinated vaccine-induced immune response encompassing tumor-specific T cells and innate NK cells should synergize with ICB, perhaps resulting in measurable clinical responses in this resistant tumor entity. Primary outcome measures of this trial are safety, tolerability and toxicity; secondary outcome measures comprise overall survival and induction of antigen-specific T cells.

    Pubmed
  • Multi-Level Computational Modeling of Anti-Cancer Dendritic Cell Vaccination Utilized to Select Molecular Targets for Therapy Optimization.

    Front Cell Dev Biol. 2022;9():

    Lai X, Keller C, Santos G, Schaft N, Dörrie J, Vera J

    Dendritic cells (DCs) can be used for therapeutic vaccination against cancer. The success of this therapy depends on efficient tumor-antigen presentation to cytotoxic T lymphocytes (CTLs) and the induction of durable CTL responses by the DCs. Therefore, simulation of such a biological system by computational modeling is appealing because it can improve our understanding of the molecular mechanisms underlying CTL induction by DCs and help identify new strategies to improve therapeutic DC vaccination for cancer. Here, we developed a multi-level model accounting for the life cycle of DCs during anti-cancer immunotherapy. Specifically, the model is composed of three parts representing different stages of DC immunotherapy - the spreading and bio-distribution of intravenously injected DCs in human organs, the biochemical reactions regulating the DCs' maturation and activation, and DC-mediated activation of CTLs. We calibrated the model using quantitative experimental data that account for the activation of key molecular circuits within DCs, the bio-distribution of DCs in the body, and the interaction between DCs and T cells. We showed how such a data-driven model can be exploited in combination with sensitivity analysis and model simulations to identify targets for enhancing anti-cancer DC vaccination. Since other previous works show how modeling improves therapy schedules and DC dosage, we here focused on the molecular optimization of the therapy. In line with this, we simulated the effect in DC vaccination of the concerted modulation of combined intracellular regulatory processes and proposed several possibilities that can enhance DC-mediated immunogenicity. Taken together, we present a comprehensive time-resolved multi-level model for studying DC vaccination in melanoma. Although the model is not intended for personalized patient therapy, it could be used as a tool for identifying molecular targets for optimizing DC-based therapy for cancer, which ultimately should be tested in in vitro and in vivo experiments.

    Pubmed
  • European patch test results with audit allergens as candidates for inclusion in the European Baseline Series, 2019/20: Joint results of the ESSCAA and the EBSB working groups of the ESCD, and the GEIDACC.

    Contact Dermatitis. 2022;86(5): 379-389

    Uter W, Wilkinson SM, Aerts O, Bauer A, Borrego L, Buhl T, Cooper SM, Dickel H, Gallo R, Giménez-Arnau AM, John SM, Navarini AA, Pesonen M, Pónyai G, Rustemeyer T, Schliemann S, Schubert S, Schuttelaar MA, Valiukevičienė S, Wagner N, Weisshaar E, Gonçalo M, ESSCA and EBS ESCD working groups, and the GEIDAC

    BACKGROUND: In 2019, a number of allergens (haptens), henceforth, "the audit allergens," were considered as potential additions to the European Baseline Series (EBS), namely, sodium metabisulfite, 2-bromo-2-nitropropane-1,3-diol, diazolidinyl urea, imidazolidinyl urea, Compositae mix II (2.5% or 5% pet), linalool hydroperoxides (lin-OOH), limonene hydroperoxides (lim-OOH), benzisothiazolinone (BIT), octylisothiazolinone (OIT), decyl glucoside, and lauryl glucoside; Evernia furfuracea (tree moss), was additionally tested by some departments as well.

    OBJECTIVES: To collect further data on patch test reactivity and clinical relevance of the audit allergens in consecutive patients across Europe.

    METHODS: Patch test data covering the audit allergens in 2019 and 2020 were collected by those departments of the European Surveillance System on Contact Allergies testing these, as well as further collaborators from the EBS working group of the European Society of Contact Dermatitis (ESCD), and the Spanish Grupo Español de Investigación en Dermatitis de Contacto y Alergia Cutánea. As patch test outcome, reactions between day (D) 3 and D5 were considered.

    RESULTS: Altogether n = 12 403 patients were tested with any of the audit allergen. Positive reactions were most common to lin-OOH 1% pet. (8.74% [95%CI: 8.14-9.37%]), followed by lin-OOH 0.5% pet., and lim-OOH 0.3% pet (5.41% [95% CI: 4.95-5.89%]). Beyond these terpene hydroperoxides, BIT 0.1% pet. was the second most common allergen with 4.72% (95% CI: 4.2-5.28%), followed by sodium metabisulfite 1% pet. (3.75% [95%CI: 3.32-4.23%]) and Compositae mix 5% pet. (2.31% [95% CI: 1.84-2.87%]). For some allergens, clinical relevance was frequently difficult to ascertain.

    CONCLUSIONS: Despite many positive patch test reactions, it remains controversial whether lin- and lim-OOH should be tested routinely, while at least the two preservatives BIT and sodium metabisulfite appear suitable. The present results are a basis for further discussion and ultimately decision on their implementation into routine testing among the ESCD members.

    Pubmed
  • Risk factors for systemic reactions in typical cold urticaria: Results from the COLD-CE study.

    Allergy. 2022;77(7): 2185-2199

    Bizjak M, Košnik M, Dinevski D, Thomsen SF, Fomina D, Borzova E, Kulthanan K, Meshkova R, Ahsan DM, Al-Ahmad M, Altrichter S, Bauer A, Brockstädt M, Costa C, Demir S, Fachini Criado R, Ensina LF, Gelincik A, Giménez-Arnau AM, Gonçalo M, Gotua M, Holm JG, Inomata N, Kasperska-Zajac A, Khoshkhui M, Klyucharova A, Kocatürk E, Lu R, Makris M, Maltseva N, Miljković J, Pasali M, Paulino M, Pesqué D, Peter J, Ramón GD, Ritchie C, Rodrigues Valle SO, Rudenko M, Sikora A, de Souza Lima EM, Wagner N, Xepapadaki P, Xue X, Zhao Z, Terhorst-Molawi D, Maurer M

    BACKGROUND: Cold urticaria (ColdU), that is, the occurrence of wheals or angioedema in response to cold exposure, is classified into typical and atypical forms. The diagnosis of typical ColdU relies on whealing in response to local cold stimulation testing (CST). It can also manifest with cold-induced anaphylaxis (ColdA). We aimed to determine risk factors for ColdA in typical ColdU.

    METHODS: An international, cross-sectional study COLD-CE was carried out at 32 urticaria centers of reference and excellence (UCAREs). Detailed history was taken and CST with an ice cube and/or TempTest® performed. ColdA was defined as an acute cold-induced involvement of the skin and/or visible mucosal tissue and at least one of: cardiovascular manifestations, difficulty breathing, or gastrointestinal symptoms.

    RESULTS: Of 551 ColdU patients, 75% (n = 412) had a positive CST and ColdA occurred in 37% (n = 151) of the latter. Cold-induced generalized wheals, angioedema, acral swelling, oropharyngeal/laryngeal symptoms, and itch of earlobes were identified as signs/symptoms of severe disease. ColdA was most commonly provoked by complete cold water immersion and ColdA caused by cold air was more common in countries with a warmer climate. Ten percent (n = 40) of typical ColdU patients had a concomitant chronic spontaneous urticaria (CSU). They had a lower frequency of ColdA than those without CSU (4% vs. 39%, p = .003). We identified the following risk factors for cardiovascular manifestations: previous systemic reaction to a Hymenoptera sting, angioedema, oropharyngeal/laryngeal symptoms, and itchy earlobes.

    CONCLUSION: ColdA is common in typical ColdU. High-risk patients require education about their condition and how to use an adrenaline autoinjector.

    Pubmed
  • Phase Ib/II Trial of Ribociclib in Combination with Binimetinib in Patients with NRAS-mutant Melanoma.

    Clin Cancer Res. 2022;28(14): 3002-3010

    Schuler M, Zimmer L, Kim KB, Sosman JA, Ascierto PA, Postow MA, De Vos F, van Herpen CML, Carlino MS, Johnson DB, Berking C, Reddy MB, Harney AS, Berlin JD, Amaria RN

    PURPOSE: Enhanced MAPK pathway signaling and cell-cycle checkpoint dysregulation are frequent in NRAS-mutant melanoma and, as such, the regimen of the MEK inhibitor binimetinib and the selective CDK4/6 inhibitor ribociclib is a rational combination.

    PATIENTS AND METHODS: This is a phase Ib/II, open-label study of ribociclib + binimetinib in patients with NRAS-mutant melanoma (NCT01781572). Primary objectives were to estimate the MTD/recommended phase II dose (RP2D) of the combination (phase Ib) and to characterize combination antitumor activity at the RP2D (phase II). Tumor genomic characterization and pharmacokinetics/pharmacodynamics were also evaluated.

    RESULTS: Ten patients (16.4%) experienced dose-limiting toxicities in cycle 1 of phase Ib. Overall response rate in the phase II cohort (n = 41) for the selected RP2D (binimetinib 45 mg twice daily + ribociclib 200 mg once daily, 21 days on/7 days off) was 19.5% [8/41; 95% confidence interval (CI), 8.8-34.9]. The response rate was 32.5% (13/40; 95% CI, 20.1-48.0) in patients with NRAS mutation with concurrent alterations of CDKN2A, CDK4, or CCND1. Median progression-free survival was 3.7 months (95% CI, 3.5-5.6) and median overall survival was 11.3 months (95% CI, 9.3-14.2) for all patients. Common treatment-related toxicities included creatine phosphokinase elevation, rash, edema, anemia, nausea, diarrhea, and fatigue. Pharmacokinetics and safety were consistent with single-agent data, supporting a lack of drug-drug interaction.

    CONCLUSIONS: Ribociclib + binimetinib can be safely administered and is clinically active in patients with NRAS-mutant melanoma. Co-mutations of cell-cycle genes may define a population with greater likelihood of treatment benefit. See related commentary by Moschos, p. 2977.

    Pubmed
  • [Wound treatment without curative intention: position paper of the Initiative Chronische Wunden (ICW) e. V.]

    Dermatologie (Heidelb). 2022;73(7): 550-555

    Dissemond J, Protz K, Erfurt-Berge C, Kröger K, Kottner J

    Today, patients with chronic wounds are treated in many different fields of medicine. Despite this great interdisciplinary and interprofessional importance, there is still a lack of uniformly accepted definitions and classifications. Therefore, a group of experts from the professional society Initiative Chronische Wunden (ICW) e. V. translated and adapted the classification of chronic wounds into healable, maintenance and nonhealable wounds on the basis of the internationally published literature into German. This classification results in the aim of curative, limited respectively non-curative or palliative wound care, which are very important for everyday clinical practice. It thus becomes clear that complete wound closure is not always the central intention of wound treatment. For many patients with chronic wounds, other aspects such as the best possible quality of life and the promotion of health-related self-management as well as the avoidance of complications are important for treatment concepts. These therapy intentions should be differentiated and individually discussed with patients in order to facilitate shared decision making.

    Pubmed
  • [Position paper of the Initiative Chronische Wunde (ICW) e. V. on the nomenclature of debridement in chronic wounds].

    Dermatologie (Heidelb). 2022;73(5): 369-375

    Dissemond J, Bültemann A, Gerber V, Motzkus M, Münter KC, Erfurt-Berge C

    The nomenclature used today in wound treatment varies widely across different disciplines and professions. Therefore, it is a mission of the professional association Initiative Chronische Wunde (ICW) e. V. to exactly and comprehensibly describe terms that were previously unclear. Therefore, the experts of the ICW defined in a consensus procedure debridement of chronic wounds as the removal of adherent, dead tissue, scabs or foreign bodies from wounds. There are various therapy options for this, which can be differentiated into autolytic, biosurgical, mechanical, osmotic, proteolytic/enzymatic and technical debridement. In the case of surgical debridement, a distinction is also made between sharp debridements that can usually be performed on an outpatient basis, such as minor surgical procedures, and surgical debridements with adequate anaesthesia in an operating theatre. Wound irrigation is defined by the ICW as the removal of non-adherent components on wounds with sterile solutions. Debridement and/or wound irrigation are often the first step in phase-appropriate modern wound treatment. Several methods are suitable for use in a combined or successive therapy. When deciding which therapeutic option to use, a number of individually different factors should be taken into account, depending on the patients to be treated but also on the therapists. The final individual decision for a method should be made together with the patient in each case and then adequately documented.

    Pubmed
  • "Toolkit Dermatology for minor surgical Procedures" - Options of Use at various University Locations during the Corona Pandemic

    J Dtsch Dermatol Ges. 2022;20 Suppl 1(): 39-40

    Wittbecker L, Pham C, Bandholz TC, Schuh S, Welzel J, Busse L, Hornung T, Gihl J, Erfurt-Berge C, Glaeser R

    Pubmed
  • Real-World Therapy with Pembrolizumab: Outcomes and Surrogate Endpoints for Predicting Survival in Advanced Melanoma Patients in Germany.

    Cancers (Basel). 2022;14(7):

    Mohr P, Scherrer E, Assaf C, Bender M, Berking C, Chandwani S, Eigentler T, Grimmelmann I, Gutzmer R, Haferkamp S, Hassel JC, Hauschild A, Herbst R, Jiang R, Kähler KC, Krepler C, Kreuter A, Leiter U, Loquai C, Meier F, Pföhler C, Rudolph A, Schadendorf D, Schiavone M, Schley G, Terheyden P, Ugurel S, Ulrich J, Utikal J, Weishaupt C, Welzel J, Weichenthal M

    Knowledge on the real-world characteristics and outcomes of pembrolizumab-treated advanced melanoma patients in Germany and on the value of different real-world endpoints as surrogates for overall survival (OS) is limited. A sample of 664 pembrolizumab-treated patients with advanced melanoma from the German registry ADOReg was used. We examined OS, real-world progression-free survival (rwPFS), real-world time to next treatment (rwTtNT), and real-world time on treatment (rwToT). Spearman's rank and iterative multiple imputation (IMI)-based correlation coefficients were computed between the OS and the rwPFS, rwTtNT, and rwToT and reported for the first line of therapy and the overall sample. The median OS was 30.5 (95%CI 25.0-35.4) months, the rwPFS was 3.9 months (95%CI 3.5-4.9), the rwTtNT was 10.7 months (95%CI 9.0-12.9), and the rwToT was 6.2 months (95%CI 5.1-6.8). The rwTtNT showed the highest correlation with the OS based on the IMI (rIMI = 0.83), Spearman rank correlations (rs = 0.74), followed by the rwToT (rIMI = 0.74 and rs = 0.65) and rwPFS (rIMI = 0.69 and rs = 0.56). The estimates for the outcomes and correlations were similar for the overall sample and those in first-line therapy. The median OS was higher compared to recent real-world studies, supporting the effectiveness of pembrolizumab in regular clinical practice. The rwTtNT may be a valuable OS surrogate, considering the highest correlation was observed with the OS among the investigated real-world endpoints.

    Pubmed
  • Comparative Efficacy and Safety of Tirbanibulin for Actinic Keratosis of the Face and Scalp in Europe: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

    J Clin Med. 2022;11(6):

    Heppt MV, Dykukha I, Graziadio S, Salido-Vallejo R, Chapman-Rounds M, Edwards M

    Actinic keratosis (AK) is a chronic skin condition that may progress to cutaneous squamous cell carcinoma. We conducted a systematic review of efficacy and safety for key treatments for AK of the face and scalp, including the novel 5-day tirbanibulin 1% ointment. MEDLINE, PubMed, Embase, Cochrane Library, clinical trial registries and regulatory body websites were searched. The review included 46 studies, of which 35 studies included interventions commonly used in Europe and were sufficiently homogenous to inform a Bayesian network meta-analysis of complete clearance against topical placebo or vehicle. The network meta-analysis revealed the following odds ratios and 95% credible intervals: cryosurgery 13.4 (6.2-30.3); diclofenac 3% 2.9 (1.9-4.3); fluorouracil 0.5% + salicylic acid 7.6 (4.6-13.5); fluorouracil 4% 30.3 (9.1-144.7); fluorouracil 5% 35.0 (10.2-164.4); imiquimod 3.75% 8.5 (3.5-22.4); imiquimod 5% 17.9 (9.1-36.6); ingenol mebutate 0.015% 12.5 (8.1-19.9); photodynamic therapy with aminolevulinic acid 24.1 (10.9-52.8); photodynamic therapy with methyl aminolevulinate 11.7 (6.0-21.9); tirbanibulin 1% 11.1 (6.2-20.9). Four sensitivity analyses, from studies assessing efficacy after one treatment cycle only, for ≤25 cm2 treatment area, after 8 weeks post-treatment, and with single placebo/vehicle node confirmed the findings from the base case. Safety outcomes were assessed qualitatively. These results suggest that tirbanibulin 1% offers a novel treatment for AK, with a single short treatment period, favourable safety profile and efficacy, in line with existing topical treatments available in Europe.

    Pubmed
  • S1-guideline atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS).

    J Dtsch Dermatol Ges. 2022;20(2): 235-243

    Helbig D, Ziemer M, Dippel E, Erdmann M, Hillen U, Leiter U, Mentzel T, Osterhoff G, Ugurel S, Utikal J, von Bubnoff D, Weishaupt C, Grabbe S

    Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are rare cutaneous neoplasms representing histomorphological, genetic as well as epigenetic variants of a disease spectrum. Both tumors typically manifest as nonspecific, often ulcerated, skin- to flesh-colored nodules in chronically sun-damaged skin of elderly male patients. AFX is a rather well demarcated, often rapidly growing tumor. PDS tumors are poorly circumscribed and are characterized by aggressive infiltrative growth. Fast as well as slow growth behavior has been reported for both tumors. Histologically, both are composed of spindle-shaped and epithelioid tumor cells with pleomorphic nuclei as well as atypical multinucleated giant cells. Atypical mitoses are common. In contrast to AFX, PDS involves relevant parts of the subcutis and shows areas of tumor necrosis and/or perineural infiltration. Due to the poorly differentiated nature of AFX/PDS (Grade 3), histopathologically similar cutaneous sarcomas, undifferentiated carcinomas, melanomas and other diseases have to be excluded by immunohistochemical analysis. The treatment of choice is micrographically controlled surgery. In cases of AFX, a cure can be assumed after complete excision. Local recurrence rates are low as long as PDS tumors are surgically removed with a safety margin of 2 cm. Metastasis is rare and mostly associated with very thick or incompletely excised tumors; it mainly affects the skin and lymph nodes. Distant metastasis is even more rare. No approved and effective systemic therapy has been established.

    Pubmed
  • [3D whole body scans in dermatology-a new era in clinical practice and research?]

    Dermatologie (Heidelb). 2022;73(7): 575-579

    Sitaru S, Kaczmarczyk R, Erdmann M, Biedermann T, Zink A

    Pubmed
  • Meeting Report: 47th Annual Meeting of the "Arbeitsgemeinschaft Dermatologische Forschung".

    Exp Dermatol. 2022;31(10): 1641-1651

    Stary G, Fabri M, Gebhardt C, Eming R, Matthias J, Vorobyev A, Effern M, Strobl J, Günther C, Zielinski C, Dudziak D, Géraud C, Raker V, Butze M, Zhao F, Wang Y, Gerloff D, Bertschi NL, Gaffal E, Buhl T

    Pubmed
  • Assessment of the Quality, Understandability, and Reliability of YouTube Videos as a Source of Information on Basal Cell Carcinoma: Web-Based Analysis.

    JMIR Cancer. 2022;8(1):

    Steeb T, Reinhardt L, Harlaß M, Heppt MV, Meier F, Berking C

    BACKGROUND: Patients with skin cancer increasingly watch online videos to acquire disease-related information. Until now, no scientific evaluation of the quality of videos available for German-speaking patients with basal cell carcinoma (BCC) has been performed.

    OBJECTIVE: In this study, we aimed to identify and evaluate videos about BCC provided on YouTube.

    METHODS: A video search on YouTube was conducted in July 2020, using German BCC-related keywords (eg, "Basalzellkarzinom," "Basaliom," "weißer hautkrebs," and "heller hautkrebs"). The first three pages (ie, 60 videos) were searched by two independent researchers for each keyword. Two authors evaluated videos that met the predefined eligibility criteria. The quality of the information of the videos was evaluated using the DISCERN tool and the Global Quality Scale (GQS). The understandability and actionability were assessed with the Patient Education Materials Assessment Tool for Audiovisual Materials (PEMAT-A/V). The reliability was assessed with the JAMA (Journal of the American Medical Association) criteria score. Subgroup differences were identified using the Kruskal-Wallis test.

    RESULTS: A total of 41 videos were included in the evaluation. The mean assessment scores were as follows: DISCERN, 3.3 (SD 0.80); GQS, 3.8 (SD 1.1); JAMA, 27.74% (SD 22.1%); understandability, 70.8% (SD 13.3%); and actionability, 45.9% (SD 43.7%). These values indicated that the videos were of medium to good quality and had good understandability, low actionability, and poor reliability. The quality of videos provided by health professionals was significantly higher than that of videos provided by laypersons.

    CONCLUSIONS: Optimization of health-related videos about BCC is desirable. In particular, adaptation to reliability criteria is necessary to support patient education and increase transparency.

    Pubmed
  • Spontaneous regression rates of actinic keratosis: a systematic review and pooled analysis of randomized controlled trials.

    Sci Rep. 2022;12(1):

    Steeb T, Petzold A, Hornung A, Wessely A, Berking C, Heppt MV

    Actinic keratosis (AK) are precancerous lesions of the skin which may progress to invasive squamous cell carcinoma. However, single lesions may also persist or even regress and heal spontaneously. Until now, evidence on the natural course of AK including spontaneous regression is limited. We aimed to synthesize regression rates of AK. We performed a systematic literature research in Medline, Embase, and CENTRAL for eligible trials until 3rd March 2020. Spontaneous regression rates were pooled using a random-effects model to calculate pooled proportions of participant-specific and lesion-specific complete clearance rates reported for the placebo arms of randomized controlled trials. Subgroup analyses were performed to dissect differences according to the type of placebo, immunocompetence of the participants, and localization of the lesions. Data from 38 records was included. The pooled participant-specific clearance rate was 8% (95% CI 6-10%, I2 = 71%) while the lesion-specific clearance rate was 23% (95% CI 16-31%, I2 = 97%). The highest participant- and lesion-specific clearance rates were achieved 12 weeks after the end of treatment (12% and 33%, respectively). Subgroup analysis revealed participant- as well as lesion-specific clearance rates of 0% for organ transplant recipients (OTR). We conclude that only a few participants achieve complete regression of their AK without any active treatment. Besides, the results underline that lesion clearance without active treatment is unlikely in OTR. Thus, early and consequent treatment of AK is recommended. Special attention should be paid when treating AK of OTR.

    Pubmed
  • Explainable artificial intelligence in skin cancer recognition: A systematic review.

    Eur J Cancer. 2022;167(): 54-69

    Hauser K, Kurz A, Haggenmüller S, Maron RC, von Kalle C, Utikal JS, Meier F, Hobelsberger S, Gellrich FF, Sergon M, Hauschild A, French LE, Heinzerling L, Schlager JG, Ghoreschi K, Schlaak M, Hilke FJ, Poch G, Kutzner H, Berking C, Heppt MV, Erdmann M, Haferkamp S, Schadendorf D, Sondermann W, Goebeler M, Schilling B, Kather JN, Fröhling S, Lipka DB, Hekler A, Krieghoff-Henning E, Brinker TJ

    BACKGROUND: Due to their ability to solve complex problems, deep neural networks (DNNs) are becoming increasingly popular in medical applications. However, decision-making by such algorithms is essentially a black-box process that renders it difficult for physicians to judge whether the decisions are reliable. The use of explainable artificial intelligence (XAI) is often suggested as a solution to this problem. We investigate how XAI is used for skin cancer detection: how is it used during the development of new DNNs? What kinds of visualisations are commonly used? Are there systematic evaluations of XAI with dermatologists or dermatopathologists?

    METHODS: Google Scholar, PubMed, IEEE Explore, Science Direct and Scopus were searched for peer-reviewed studies published between January 2017 and October 2021 applying XAI to dermatological images: the search terms histopathological image, whole-slide image, clinical image, dermoscopic image, skin, dermatology, explainable, interpretable and XAI were used in various combinations. Only studies concerned with skin cancer were included.

    RESULTS: 37 publications fulfilled our inclusion criteria. Most studies (19/37) simply applied existing XAI methods to their classifier to interpret its decision-making. Some studies (4/37) proposed new XAI methods or improved upon existing techniques. 14/37 studies addressed specific questions such as bias detection and impact of XAI on man-machine-interactions. However, only three of them evaluated the performance and confidence of humans using CAD systems with XAI.

    CONCLUSION: XAI is commonly applied during the development of DNNs for skin cancer detection. However, a systematic and rigorous evaluation of its usefulness in this scenario is lacking.

    Pubmed
  • Tebentafusp als neuartige Immuntherapie zeigt einen Überlebensvorteil beim metastasierten Uveamelanom und wird bereits in Deutschland eingesetzt.

    J Dtsch Dermatol Ges. 2022;20(3): 381-383

    Hassel JC, Berking C

    Pubmed
  • [The UV Protection Alliance in Germany-Purpose and goals].

    Ophthalmologie. 2022;119(3): 223-233

    Baldermann C, UV-Schutz-Bündnis , Berking C, Ulrich C, Breitbart E, Bunde H, Volkmer B, Janßen W, Baldermann C, Weiskopf D, Grimm F, Keller B, Kakkassery V, von Kiedrowski R, Stavermann T, Schlette S, Kessel TM, Berneburg M, Höger P, Fartasch M, Strehl C, Engelmayr E, Mons U, Schadendorf D, Helbig U, Heindl LM, Laschewski G, Stockfleth E, Greinert R, Hübner J, Katalinic A, Mohr P, Pieper B, Brose M, Panter W, Schlager H, Schäfermeyer D

    Despite the serious health consequences of UV radiation, protection against UV radiation is even now still not a matter of course. The population has a largely realistic view of UV radiation-related health risks but this does not seem to instigate a change in personal risk assessments and towards an adequate UV protection behavior. This is not least due to the partly contradictory statements and recommendations regarding the positive and negative health effects, also from the scientific community. A harmonization as well as a collation of the statements and activities of individual players in UV protection related to the prevention of UV-related diseases gives the key messages the necessary strength to make UV protection a matter of course in society. To this end, the UV Protection Alliance was initiated by the Federal Office for Radiation Protection (BfS). This article reports on the UV Protection Alliance, presents the partners in the Alliance, the goals of the UV Protection Alliance, previous results of work by the Alliance and actions and interventions of the Alliance partners. The public impact of the UV Protection Alliance is explained and an outlook is given on future tasks of the Alliance.

    Pubmed
  • [The UV Protection Alliance in Germany -Timeline of the development of the contents].

    Ophthalmologie. 2022;119(3): 248-249

    Baldermann C, UV-Schutz-Bündnis , Berking C, Ulrich C, Breitbart E, Bunde H, Volkmer B, Janßen W, Baldermann C, Weiskopf D, Grimm F, Keller B, Kakkassery V, von Kiedrowski R, Stavermann T, Schlette S, Kessel TM, Berneburg M, Höger P, Fartasch M, Strehl C, Engelmayr E, Mons U, Schadendorf D, Helbig U, Heindl LM, Laschewski G, Stockfleth E, Greinert R, Hübner J, Katalinic A, Mohr P, Pieper B, Brose M, Panter W, Schlager H, Schäfermeyer D

    Pubmed
  • Advanced neural networks for classification of MRI in psoriatic arthritis, seronegative, and seropositive rheumatoid arthritis.

    Rheumatology (Oxford). 2022;61(12): 4945-4951

    Folle L, Bayat S, Kleyer A, Fagni F, Kapsner LA, Schlereth M, Meinderink T, Breininger K, Tacilar K, Krönke G, Uder M, Sticherling M, Bickelhaupt S, Schett G, Maier A, Roemer F, Simon D

    OBJECTIVES: To evaluate whether neural networks can distinguish between seropositive RA, seronegative RA, and PsA based on inflammatory patterns from hand MRIs and to test how psoriasis patients with subclinical inflammation fit into such patterns.

    METHODS: ResNet neural networks were utilized to compare seropositive RA vs PsA, seronegative RA vs PsA, and seropositive vs seronegative RA with respect to hand MRI data. Results from T1 coronal, T2 coronal, T1 coronal and axial fat-suppressed contrast-enhanced (CE), and T2 fat-suppressed axial sequences were used. The performance of such trained networks was analysed by the area under the receiver operating characteristics curve (AUROC) with and without presentation of demographic and clinical parameters. Additionally, the trained networks were applied to psoriasis patients without clinical arthritis.

    RESULTS: MRI scans from 649 patients (135 seronegative RA, 190 seropositive RA, 177 PsA, 147 psoriasis) were fed into ResNet neural networks. The AUROC was 75% for seropositive RA vs PsA, 74% for seronegative RA vs PsA, and 67% for seropositive vs seronegative RA. All MRI sequences were relevant for classification, however, when deleting contrast agent-based sequences the loss of performance was only marginal. The addition of demographic and clinical data to the networks did not provide significant improvements for classification. Psoriasis patients were mostly assigned to PsA by the neural networks, suggesting that a PsA-like MRI pattern may be present early in the course of psoriatic disease.

    CONCLUSION: Neural networks can be successfully trained to distinguish MRI inflammation related to seropositive RA, seronegative RA, and PsA.

    Pubmed
  • Paradoxical Reactions to Biologicals in Chronic Inflammatory Systemic Diseases.

    Dtsch Arztebl Int. 2022;119(6): 88-95

    Kremenevski I, Sander O, Sticherling M, Raithel M, LastName FM

    BACKGROUND: Biological agents that contain substances affecting the immune system are increasingly being used to treat chronic inflammatory systemic diseases. Aside from the expected adverse effects, they can also induce unexpected paradoxical reactions (PR). A reaction is called paradoxical when a substance that is generally therapeutically effective induces the opposite of what is intended, with the new appearance or exacerbation of inflammatory changes in the skin and other organs.

    METHODS: The paradoxical reactions that have been described since 1997 are presented here on the basis of the available literature on the main types of chronic inflammatory systemic disease, which was retrieved by a selective search in the PubMed and Google Scholar databases.

    RESULTS: Many studies and registers to date contain no mention of paradoxical reactions. Anti-TNF-alpha treatment for patients with ankylosing spondylitis leads to paradoxical reactions in 19 per 1000 patient years, compared to 11 per 1000 patient years with conventional treatment; the corresponding frequency for paradoxical psoriasis in patients with other chronic inflammatory systemic diseases are 1.04-3.68 versus 1.45 per 1000 patient years. Paradoxical reactions tend to be more common with anti-TNF-alpha treatment than, for example, with the administration of ustekinumab, vedolizumab, and other agents. It is unclear whether some drugs have been noted to cause PR more commonly than others because of varying times since their approval, differences in immunogenicity, and differences between their target structures.

    CONCLUSION: Paradoxical reactions induced by biological agents are a problem confronting physicians in multiple specialties. They need to be distinguished from infectious and neoplastic diseases and from autoimmune conditions of other types. The treatment options for paradoxical reactions include local treatment, symptomatic therapy, prednisolone administration, and the discontinuation or switching of the biological agent, although some patients will react with a further paradoxical reaction to a different biological agent that is used instead.

    Pubmed
  • Physician-reported Clinical Unmet Needs, Burden and Treatment Patterns of Paediatric Psoriasis Patients: A US and EU Real-world Evidence Study.

    Acta Derm Venereol. 2022;102():

    Seyger MMB, Augustin M, Sticherling M, Bachhuber T, Fang J, Hetherington J, Lucas J, Meakin S, Richardson C, Paller AS

    This study is a retrospective analysis using data collected from the Adelphi Paediatric Psoriasis Disease-Specific Programme cross-sectional survey. Despite being treated for their psoriasis, a substantial proportion of paediatric patients presented with moderate (18.3%) or severe (1.3%) disease at sampling; 42.9% and 92.0% had a body surface area (BSA) of >10%, and 38.8% and 100.0% had a Psoriasis Area Severity Index (PASI) score >10, respectively. Overall, 69.9% of patients had only ever been treated with a topical therapy for their psoriasis. For patients with moderate or severe disease at sampling, 16.3% and 14.4% were currently receiving conventional systemics or biologic therapy, respectively. There is a clinical unmet need in this paediatric population; a considerable percentage of patients still experienced moderate or severe disease and persistent psoriasis symptoms, with numerous body areas affected. A significant proportion of patients were undertreated, which may explain the high burden of disease observed.

    Pubmed
  • Reporting Quality of Studies Developing and Validating Melanoma Prediction Models: An Assessment Based on the TRIPOD Statement.

    Healthcare (Basel). 2022;10(2):

    Kaiser I, Diehl K, Heppt MV, Mathes S, Pfahlberg AB, Steeb T, Uter W, Gefeller O

    Transparent and accurate reporting is essential to evaluate the validity and applicability of risk prediction models. Our aim was to evaluate the reporting quality of studies developing and validating risk prediction models for melanoma according to the TRIPOD (Transparent Reporting of a multivariate prediction model for Individual Prognosis Or Diagnosis) checklist. We included studies that were identified by a recent systematic review and updated the literature search to ensure that our TRIPOD rating included all relevant studies. Six reviewers assessed compliance with all 37 TRIPOD components for each study using the published "TRIPOD Adherence Assessment Form". We further examined a potential temporal effect of the reporting quality. Altogether 42 studies were assessed including 35 studies reporting the development of a prediction model and seven studies reporting both development and validation. The median adherence to TRIPOD was 57% (range 29% to 78%). Study components that were least likely to be fully reported were related to model specification, title and abstract. Although the reporting quality has slightly increased over the past 35 years, there is still much room for improvement. Adherence to reporting guidelines such as TRIPOD in the publication of study results must be adopted as a matter of course to achieve a sufficient level of reporting quality necessary to foster the use of the prediction models in applications.

    Pubmed
  • Long-term Efficacy and Safety of Up to 108 Weeks of Ixekizumab in Pediatric Patients With Moderate to Severe Plaque Psoriasis: The IXORA-PEDS Randomized Clinical Trial.

    JAMA Dermatol. 2022;158(5): 533-541

    Paller AS, Seyger MMB, Magariños GA, Pinter A, Cather JC, Rodriguez-Capriles C, Zhu D, Somani N, Garrelts A, Papp KA, IXORA-PEDS Investigators , Magariños GA, Galimberti R, Viola D, Luna P, Lynde C, Marcoux D, Prajapati V, Cy A, Arenberger P, Polaskova S, Buckova H, Bartonova J, Cetkovska P, Hercogova J, Lacour JP, Phan A, Sticherling M, Staubach-Renz P, Simon M, Pinter A, Magnolo N, Dosa P, Noll J, Remenyik E, Kemeny L, Bakos N, Bernabe Del Rio C, Toledo-Bahena M, Gomez Flores M, Barragan Estudillo Z, Seyger M, Weglowska J, Szymanska E, Kaszuba A, Murashkin N, Vicente Villa A, Laguna RL, Rivera Diaz R, Bagel J, Browning J, Bukhalo M, Cather J, Cruz Santana A, Elewski B, Forman S, Gonzalez-Chavez J, Gottlieb S, Hake Harris H, Kaffenberger J, Kwong P, Leitenberger S, Lugo-Somolinos A, Kirkorian A, Martin K, Paller A, Pariser D, Rich P, Rosenblatt A, Seminario-Vidal L, Siegfried E, Travers J, Vendrell-Benito P, Weisman J, Wine Lee L, Zook M, Sanches-Rivera S, Laquer V

    Importance: About 1% of children and adolescents worldwide are affected by plaque psoriasis.

    Objective: To evaluate the long-term efficacy and safety of ixekizumab for pediatric patients with moderate to severe psoriasis.

    Design, Setting, and Participants: This multicenter randomized clinical trial (IXORA-PEDS) evaluated pediatric patients with plaque psoriasis. Participants were aged 6 years to younger than 18 years; had moderate to severe psoriasis, which was defined as Psoriasis Area and Severity Index (PASI) of 12 or higher, static Physician's Global Assessment (sPGA) score of 3 or higher, and psoriasis-affected body surface area of 10% or greater at screening and baseline; were candidates for phototherapy or systemic therapy; or had psoriasis that was not adequately controlled by topical therapies. Data analysis, which followed the intention-to-treat principle, was conducted from May to October 2021.

    Interventions: Pediatric patients were randomized 2:1 to receive either a weight-based dose of ixekizumab every 4 weeks or placebo. After a 12-week placebo-controlled period, patients entered a 48-week, open-label ixekizumab maintenance period (weeks 12-60), followed by an extension period that lasted through 108 weeks. A substudy evaluated the randomized withdrawal of ixekizumab after week 60.

    Main Outcomes and Measures: Efficacy outcomes at week 108 included the percentage of patients achieving 75% (PASI 75), 90% (PASI 90), or 100% (PASI 100) improvement from baseline; an sPGA score of 0 or 1 or score of 0; and improvement of 4 points or higher from baseline in the Itch Numeric Rating Scale. Safety outcomes included assessments of adverse events (AEs), including treatment-emergent AEs, serious AEs, and AEs of special interest, as well as improvement from baseline in a range of challenging body areas. Missing data for categorical outcomes were imputed using modified nonresponder imputation.

    Results: A total of 171 patients (mean [SD] age, 13.5 [3.04] years; 99 female children [57.9%]) were randomized to either ixekizumab (n = 115) or placebo (n = 56). Of 166 patients who entered the maintenance period, 139 (83.7%) completed week 108 of the trial. Primary and gated secondary end points were sustained through week 108, with patients achieving PASI 75 (91.7% [n = 86]), PASI 90 (79.0% [n = 74]), PASI 100 (55.1% [n = 52]), sPGA 0 or 1 (78.3% [n = 74]), and sPGA 0 (52.4% [n = 49]). Fifty-five patients (78.5%) reported an Itch Numeric Rating Scale improvement of 4 points or higher. In patients who received ixekizumab, at week 108, clearance of nail psoriasis was reported in 68.1% (n = 28), clearance of palmoplantar psoriasis was reported in 90.0% (n = 10), clearance of scalp psoriasis was reported in 76.2% (n = 83), and clearance of genital psoriasis was reported in 87.5% (n = 24). There were no new safety findings during weeks 48 to 108 of the trial, including no new cases of inflammatory bowel disease or candida infection.

    Conclusions and Relevance: Results of this study showed improvements across patient-reported outcomes and objective measures of complete skin clearance of psoriasis among pediatric patients who received ixekizumab, and these response rates were sustained through week 108 of the trial. Safety of ixekizumab was consistent with previously reported findings in this population and the known safety profile of this treatment.

    Trial Registration: ClinicalTrials.gov Identifier: NCT03073200.

    Pubmed
  • Genetic characterization of advanced conjunctival melanoma and response to systemic treatment.

    Eur J Cancer. 2022;166(): 60-72

    Lodde GC, Jansen P, Möller I, Sucker A, Hassel JC, Forschner A, Eckardt J, Meier F, Reinhardt L, Kähler KC, Ziemer M, Schlaak M, Rahimi F, Schatton K, Meiss F, Gutzmer R, Pföhler C, Terheyden P, Schilling B, Sachse M, Heppt MV, Sindrilaru A, Leiter U, Zaremba A, Thielmann CM, Ugurel S, Zimmer L, Hadaschik E, Bechrakis NE, Schadendorf D, Westekemper H, Livingstone E, Griewank KG, German Dermatologic Cooperative Oncology Group (DeCOG, committee ocular melanoma)

    BACKGROUND: Conjunctival melanoma is a rare type of ocular melanoma, which is prone to local recurrence and metastasis and can lead to patient death. Novel therapeutic strategies have revolutionized cutaneous melanoma management. The efficacy of these therapies in conjunctival melanoma, however, has not been evaluated in larger patient cohorts.

    METHODS: In this multi-center retrospective cohort study with additional screening of the ADOREG database, data were collected from 34 patients with metastatic conjunctival melanoma who received targeted therapy (TT) (BRAF ± MEK inhibitors) or immune checkpoint inhibitors (ICI) (anti-PD-1 ± anti-CTLA4). In 15 cases, tissue was available for targeted next-generation-sequencing (611 genes) and RNA sequencing. Driver mutations, tumor mutational burden, copy number variations and inflammatory/IFNγ gene expression signatures were determined.

    RESULTS: Genetic characterization identified frequent BRAF (46.7%, 7/15), NRAS (26.7%, 4/15), NF1 (20%, 3/15), and TERT promoter (46.7%, 7/15) mutations. UV associated C>T and CC>TT mutations were common. Median follow-up time after start of first TT or ICI therapy was 13.2 months. In 26 patients receiving first-line ICI, estimated one-year progression-free survival (PFS) rate was 42.0%, PFS and overall survival (OS) 6.2 and 18.0 months, respectively. First-line TT was given to 8 patients, estimated one-year PFS rate was 54.7%, median PFS and OS 12.6 and 29.1 months, respectively.

    CONCLUSIONS: Our findings support the role of UV irradiation in conjunctival melanoma and the genetic similarity with cutaneous melanoma. Conjunctival melanoma patients with advanced disease benefit from both targeted therapies (BRAF ± MEK inhibitors) and immune checkpoint inhibitors.

    Pubmed
  • Allogeneic ABCB5+ mesenchymal stem cells for treatment-refractory chronic venous ulcers: a phase I/IIa clinical trial.

    JID Innov. 2022;2(1):

    Kerstan A, Dieter K, Niebergall-Roth E, Dachtler AK, Kraft K, Stücker M, Daeschlein G, Jünger M, Görge T, Meyer-Pannwitt U, Erfurt-Berge C, von Engelhardt C, Klare A, Pfeiffer C, Esterlechner J, Schröder HM, Gasser M, Waaga-Gasser AM, Goebeler M, Ballikaya S, Sadeghi S, Murphy GF, Orgill DP, Frank NY, Ganss C, Scharffetter-Kochanek K, Frank MH, Kluth MA

    A significant number of chronic venous ulcers (CVUs) fail to heal despite of guideline-conform standard of care. Skin-derived ABCB5+ mesenchymal stem cells (MSCs) can dampen the sustained IL-1β-driven inflammation present in chronic wounds. Based on their wound healing-facilitating effects in a mouse CVU model and an autologous first-in-human study, ABCB5+ MSCs have emerged as a potential candidate for cell-based advanced therapy of non-healing CVUs. In the present interventional, multicenter, single-arm, phase I/IIa clinical trial, subjects whose CVU had emerged as standard therapy-resistant received one or two topical applications of 1×106 allogeneic ABCB5+ MSCs/cm2 wound area in addition to standard treatment. Out of 83 treatment-emergent adverse events, only three were judged related to the cell product; they were mild or moderate and recovered without sequelae. Wound size markedly decreased from baseline to week 12, resulting in a median wound size reduction of 76% (full analysis set, N=31), 78% (per-protocol set, N=27) and 87% (subset of responders; n=21). In conclusion, the study treatment was well tolerated and safe. The treatment elicited a profound wound size reduction within 12 weeks, identifying ABCB5+ MSCs as a potential candidate for adjunctive therapy of otherwise incurable CVUs. These results justify the conduct of a larger, randomized, controlled trial to confirm clinical efficacy.

    Pubmed
  • Automatic Classification of Diabetic Foot Ulcer Images - A Transfer-Learning Approach to Detect Wound Maceration.

    Stud Health Technol Inform. 2022;289(): 301-304

    Hüsers J, Hafer G, Heggemann J, Wiemeyer S, Przysucha M, Dissemond J, Moelleken M, Erfurt-Berge C, Hübner U

    Diabetic foot ulcer (DFU) is a chronic wound and a common diabetic complication as 2% - 6% of diabetic patients witness the onset thereof. The DFU can lead to severe health threats such as infection and lower leg amputations, Coordination of interdisciplinary wound care requires well-written but time-consuming wound documentation. Artificial intelligence (AI) systems lend themselves to be tested to extract information from wound images, e.g. maceration, to fill the wound documentation. A convolutional neural network was therefore trained on 326 augmented DFU images to distinguish macerated from unmacerated wounds. The system was validated on 108 unaugmented images. The classification system achieved a recall of 0.69 and a precision of 0.67. The overall accuracy was 0.69. The results show that AI systems can classify DFU images for macerations and that those systems could support clinicians with data entry. However, the validation statistics should be further improved for use in real clinical settings. In summary, this paper can contribute to the development of methods to automatic wound documentation.

    Pubmed
  • Is benzyl alcohol a significant contact sensitizer?

    J Eur Acad Dermatol Venereol. 2022;36(6): 866-872

    Geier J, Ballmer-Weber B, Buhl T, Rieker-Schwienbacher J, Mahler V, Dickel H, Schubert S, IVDK , Baron JM, Grabbe J, Siedlecki K, Strom K, Hartmann K, Worm M, Simon D, Effendy I, Dickel H, Fartasch M, Vieluf D, Beiteke U, Bauer A, Koch A, Wagner N, Dissemond J, Gina M, Szliska C, Grunwald-Delitz H, Kränke B, Jünger M, Buhl T, Kreft B, Witte J, Schröder C, Werfel T, Schäkel K, Weisshaar E, Löffler H, Pföhler C, Schliemann S, Spring P, Treudler R, Angelova-Fischer I, Nestoris S, Recke A, Becker D, Nicolay J, Pfützner W, Stadler R, Rueff F, Coras-Stepanek B, Brockow K, Brehler R, Baur V, Raap U, Skudlik C

    BACKGROUND: Benzyl alcohol is a widely used preservative, solvent and fragrance material. According to published data, it is a rare sensitizer in humans.

    OBJECTIVES: To identify characteristics and sensitization patterns of patients with positive patch test reactions to benzyl alcohol and to check the reliability of the patch test preparation benzyl alcohol 1% pet.

    PATIENTS AND METHODS: Retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK), 2010-2019.

    RESULTS: Of 70 867 patients patch tested with benzyl alcohol 1% pet., 146 (0.21%) showed a positive reaction, most of them (89%) only weakly positive. The number of doubtful and irritant reactions significantly exceeded the number of positive reactions. Reproducibility of positive test reactions was low. Among benzyl alcohol-positive patients, compared to benzyl alcohol-negative patients, there were significantly more patients with leg dermatitis (17.8% vs. 8.6%), more patients aged 40 years or more (81.5% vs. 70.5%) and more patients who were tested because of a suspected intolerance reaction to topical medications (34.9% vs. 16.6%). Concomitant positive reactions were mainly seen to fragrances, preservatives and ointment bases.

    CONCLUSIONS: Sensitization to benzyl alcohol occurs very rarely, mainly in patients with stasis dermatitis. In view of our results, benzyl alcohol cannot be regarded as a significant contact allergen, and therefore marking it as skin sensitizer 1B and labelling it with H 317 is not helpful.

    Pubmed
  • Adrenaline autoinjector is underprescribed in typical cold urticaria patients.

    Allergy. 2022;77(7): 2224-2229

    Bizjak M, Košnik M, Dinevski D, Thomsen SF, Fomina D, Borzova E, Kulthanan K, Meshkova R, Aarestrup FM, Ahsan DM, Al-Ahmad M, Altrichter S, Bauer A, Brockstädt M, Costa C, Demir S, Criado RF, Ensina LF, Gelincik A, Giménez-Arnau AM, Gonçalo M, Gotua M, Holm JG, Inomata N, Kasperska-Zajac A, Khoshkhui M, Klyucharova A, Kocatürk E, Lu R, Makris M, Maltseva N, Pasali M, Paulino M, Pesqué D, Peter J, Ramón GD, Ritchie C, Rodrigues Valle SO, Rudenko M, Sikora A, Wagner N, Xepapadaki P, Xue X, Zhao Z, Terhorst-Molawi D, Maurer M

    Pubmed
  • Alzheimer's disease protease-containing plasma extracellular vesicles transfer to the hippocampus via the choroid plexus.

    EBioMedicine. 2022;77():

    Lee JH, Ostalecki C, Oberstein T, Schierer S, Zinser E, Eberhardt M, Blume K, Plosnita B, Stich L, Bruns H, Coras R, Vera-Gonzales J, Maler M, Baur AS

    BACKGROUND: Plasma extracellular vesicles (pEV) can harbor a diverse array of factors including active proteases and the amyloid-precursor-protein (APP) cleavage product Aβ, involved in plaque formation in Alzheimer`s diseases (AD). A potential role of such vesicles in AD pathology is unexplored.

    METHODS: In a case-control study of randomly selected patients with AD and other neurological diseases (n = 14), and healthy controls (n = 7), we systematically analyzed the content of pEV, using different assay systems. In addition, we determined their entry path into brain tissue, employing animal (mice) injection experiments with ex vivo generated EV that were similar to AD-pEV, followed by multi antigen analysis (MAA) of brain tissue (n = 4 per condition). The results were compared with an IHC staining of human brain tissue in a small cohort of AD patients (n = 3) and controls with no neurodegenerative diseases (n = 3).

    FINDINGS: We show that pEV levels are considerably upregulated in AD patients. Besides numerous inflammatory effectors, AD-pEV contained α-, β- and γ-secretases, able to cleave APP in in target cells. In vitro generated EV with similar characteristics as AD-pEV accumulated in the choroid plexus (CP) of injected animals and reached primarily hippocampal neurons. Corroborating findings were made in human brain samples. An inhibitor of hyaluronic-acid-synthetase (HAS) blocked uploading of proteases and Hyaluronan onto EV in vitro and abolished CP targeting in animal injection experiments.

    INTERPRETATION: We conclude that protease-containing pEV could be part of a communication axis between the periphery and the brain that could be become detrimental depending on pEV concentration and duration of target cell impact.

    FUNDING: See the Acknowledgements section.

    Pubmed
  • Efficacy of Therapies for Actinic Keratosis-Reply.

    JAMA Dermatol. 2022;158(6): 703-704

    Heppt MV, Steeb T, Berking C

    Pubmed
  • Short Term and Long-Term Efficacy of Calcipotriene/ Betamethasone Dipropionate Foam Combination.

    Clin Cosmet Investig Dermatol. 2022;15(): 809-814

    Jalili A, Bewley A, Sticherling M, Stein Gold L

    Psoriasis is a well-known chronic disease characterized by the development of erythematous, indurated, scaly, pruritic plaques on the skin with cycles of remission and symptom flare-ups. The management of patients with chronic plaque psoriasis has been more challenging since the Covid-19 pandemic as health care professionals have had to adapt to remote consultations for some patients, and patients have had to adapt to the changing health landscape. The rapid resolution of psoriasis symptoms especially those with a substantial impact on quality of life can improve patient satisfaction and adherence, making it an important factor in successful treatment. Cal/BD foam contributes to improved patient adherence and treatment outcome through its rapid action and superior efficacy versus Cal or BD monotherapy, Cal/BD ointment and gel and clobetasol cream in the short-term flare treatment of psoriasis. Moreover, the benefits of proactive long-term management of psoriasis compared to reactive management and its favourable safety profile are higher efficacy and a better health-related quality of life. Cal/BD foam should be considered an effective topical treatment for short-term flare treatment and long-term control of adult psoriatic patients.

    Pubmed
  • Epidermotropie von Immunzellen unterscheidet Pyoderma gangraenosum vom Ulcus cruris venosum.

    J Dtsch Dermatol Ges. 2022;20(5): 619-628

    Ronicke M, Baur A, Kirr M, Erdmann M, Erfurt-Berge C, Ostalecki C

    HINTERGRUND UND ZIELE: Pyoderma gangraenosum ist eine ulzerierende, autoinflammatorische Erkrankung. Es gibt keine eindeutigen histopathologischen Merkmale zur Differenzierung von anderen Ursachen chronischer Wunden wie dem Ulcus cruris venosum. Ziel dieser Studie war es, histopathologische Merkmale von Pyoderma gangraenosum und Unterschiede zu venösen Ulzerationen zu detektieren.

    PATIENTEN UND METHODIK: Acht Gewebeproben von Pyoderma gangraenosum, zwölf Proben von Ulcus cruris venosum und sechs Proben von gesunder Haut wurden einer immunhistologischen Multi-Antigen-Analyse unterzogen. Das Immuninfiltrat und seine räumliche Verteilung wurden anhand von Fluoreszenzbildern mit einer Gewebezytometriesoftware analysiert.

    ERGEBNISSE: Die dichte epidermale Präsenz von CD45RO+ -T-Gedächtnis-Zellen und die Rarefizierung von CD1a+ -Langerhans-Zellen in der Epidermis waren Marker für Pyoderma gangraenosum, welche auch auf eine epidermale Immunreaktion schließen lassen. Darüber hinaus konnte dermal eine hohe Anzahl CD11c+ CD68+ pro-inflammatorischer M1-Makrophagen nachgewiesen werden. Diese überstieg die Anzahl der in venösen Ulzerationen beobachteten Makrophagen deutlich.

    SCHLUSSFOLGERUNGEN: Die histopathologischen Unterschiede zwischen Pyoderma gangraenosum und Ulcus cruris venosum können zur Unterscheidung der beiden Erkrankungen herangezogen werden und somit eine wichtige Hilfe zur schnellen Einleitung einer adäquaten Therapie sein. Darüber hinaus deuten unsere Daten auf einen antigengesteuerten Prozess in der Epidermis hin, möglicherweise unter Beteiligung von CD1a+ Langerhans-Zellen.

    Pubmed
  • Checkpoint-inhibitor induced Polyserositis with Edema.

    Cancer Immunol Immunother. 2022;71(12): 3087-3092

    Zierold S, Akcetin LS, Gresser E, Maier AM, König A, Kramer R, Theurich S, Tomsitz D, Erdmann M, French LE, Rudelius M, Heinzerling L

    BACKGROUND: As immune checkpoint inhibitors (ICI) are increasingly being used due to effectiveness in various tumor entities, rare side effects occur more frequently. Pericardial effusion has been reported in patients with advanced non-small cell lung cancer (NSCLC) after or under treatment with immune checkpoint inhibitors. However, knowledge about serositis and edemas induced by checkpoint inhibitors in other tumor entities is scarce.

    METHODS AND RESULTS: Four cases with sudden onset of checkpoint inhibitor induced serositis (irSerositis) are presented including one patient with metastatic cervical cancer, two with metastatic melanoma and one with non-small cell lung cancer (NSCLC). In all cases treatment with steroids was successful in the beginning, but did not lead to complete recovery of the patients. All patients required multiple punctures. Three of the patients presented with additional peripheral edema; in one patient only the lower extremities were affected, whereas the entire body, even face and eyelids were involved in the other patients. In all patients serositis was accompanied by other immune-related adverse events (irAEs).

    CONCLUSION: ICI-induced serositis and effusions are complex to diagnose and treat and might be underdiagnosed. For differentiation from malignant serositis pathology of the punctured fluid can be helpful (lymphocytes vs. malignant cells). Identifying irSerositis as early as possible is essential since steroids can improve symptoms.

    Pubmed
  • Deficiency of the Intramembrane Protease SPPL2a Alters Antimycobacterial Cytokine Responses of Dendritic Cells.

    J Immunol. 2021;206(1): 164-180

    Gradtke AC, Mentrup T, Lehmann CHK, Cabrera-Cabrera F, Desel C, Okakpu D, Assmann M, Dalpke A, Schaible UE, Dudziak D, Schröder B

    Signal peptide peptidase-like 2a (SPPL2a) is an aspartyl intramembrane protease essential for degradation of the invariant chain CD74. In humans, absence of SPPL2a leads to Mendelian susceptibility to mycobacterial disease, which is attributed to a loss of the dendritic cell (DC) subset conventional DC2. In this study, we confirm depletion of conventional DC2 in lymphatic tissues of SPPL2a-/- mice and demonstrate dependence on CD74 using SPPL2a-/- CD74-/- mice. Upon contact with mycobacteria, SPPL2a-/- bone marrow-derived DCs show enhanced secretion of IL-1β, whereas production of IL-10 and IFN-β is reduced. These effects correlated with modulated responses upon selective stimulation of the pattern recognition receptors TLR4 and Dectin-1. In SPPL2a-/- bone marrow-derived DCs, Dectin-1 is redistributed to endosomal compartments. Thus, SPPL2a deficiency alters pattern recognition receptor pathways in a CD74-dependent way, shifting the balance from anti- to proinflammatory cytokines in antimycobacterial responses. We propose that in addition to the DC reduction, this altered DC functionality contributes to Mendelian susceptibility to mycobacterial disease upon SPPL2a deficiency.

    Pubmed
  • Th17 Cell-Mediated Colitis Is Positively Regulated by Interferon Regulatory Factor 4 in a T Cell-Extrinsic Manner.

    Front Immunol. 2021;11():

    Buchele V, Konein P, Vogler T, Kunert T, Enderle K, Khan H, Büttner-Herold M, Lehmann CHK, Amon L, Wirtz S, Dudziak D, Neurath MF, Neufert C, Hildner K

    Inflammatory bowel diseases (IBDs) are characterized by chronic, inflammatory gastrointestinal lesions and often require life-long treatment with immunosuppressants and repetitive surgical interventions. Despite progress in respect to the characterization of molecular mechanisms e.g. exerted by TNF-alpha, currently clinically approved therapeutics fail to provide long-term disease control for most patients. The transcription factor interferon regulatory factor 4 (IRF4) has been shown to play important developmental as well as functional roles within multiple immune cells. In the context of colitis, a T cell-intrinsic role of IRF4 in driving immune-mediated gut pathology is established. Here, we conversely addressed the impact of IRF4 inactivation in non-T cells on T cell driven colitis in vivo. Employing the CD4+CD25- naïve T cell transfer model, we found that T cells fail to elicit colitis in IRF4-deficient compared to IRF4-proficient Rag1 -/- mice. Reduced colitis activity in the absence of IRF4 was accompanied by hampered T cell expansion both within the mesenteric lymph node (MLN) and colonic lamina propria (cLP). Furthermore, the influx of various myeloids, presumably inflammation-promoting cells was abrogated overall leading to a less disrupted intestinal barrier. Mechanistically, gene profiling experiments revealed a Th17 response dominated molecular expression signature in colon tissues of IRF4-proficient, colitic Rag1 -/- but not in colitis-protected Rag1 -/- Irf4 -/- mice. Colitis mitigation in Rag1 -/- Irf4 -/- T cell recipients resulted in reduced frequencies and absolute numbers of IL-17a-producing T cell subsets in MLN and cLP possibly due to a regulation of conventional dendritic cell subset 2 (cDC2) known to impact Th17 differentiation. Together, extending the T cell-intrinsic role for IRF4 in the context of Th17 cell driven colitis, the provided data demonstrate a Th17-inducing and thereby colitis-promoting role of IRF4 through a T cell-extrinsic mechanism highlighting IRF4 as a putative molecular master switch among transcriptional regulators driving immune-mediated intestinal inflammation through both T cell-intrinsic and T cell-extrinsic mechanisms. Future studies need to further dissect IRF4 controlled pathways within distinct IRF4-expressing myeloid cell types, especially cDC2s, to elucidate the precise mechanisms accounting for hampered Th17 formation and, according to our data, the predominant mechanism of colitis protection in Rag1 -/- Irf4 -/- T cell receiving mice.

    Pubmed
  • Secukinumab 2-weekly vs. 4-weekly dosing in patients with plaque-type psoriasis: results from the randomized GAIN study.

    Br J Dermatol. 2021;184(5): 849-856

    Reich K, Körber A, Mrowietz U, Sticherling M, Sieder C, Früh J, Bachhuber T

    BACKGROUND: Secukinumab is a fully human monoclonal antibody that selectively neutralizes interleukin-17A and shows long-lasting efficacy and safety in plaque psoriasis. More evidence is required to optimize secukinumab dosing according to clinical response.

    OBJECTIVES: GAIN compared the efficacy and safety of secukinumab 300 mg every 2 weeks (q2w) with 300 mg every 4 weeks (q4w) in patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) but not PASI 90 after 16 weeks.

    METHODS: In total, 772 patients with moderate-to-severe plaque psoriasis received secukinumab 300 mg subcutaneously at baseline and weeks 1, 2, 3 and 4, then q4w until week 16. At week 16, patients with PASI ≥ 75 to PASI < 90 were randomized 1: 1 to continue q4w dosing (n = 162) or switch to q2w (n = 163) to week 32. The primary endpoint was superiority of q2w to q4w dosing for PASI 90 response at week 32.

    RESULTS: PASI 90 response at week 32 was numerically greater with secukinumab 300 mg q2w than with secukinumab 300 mg q4w in suboptimal responders, but this did not reach statistical significance (64·4% vs. 57·4%; odds ratio 0·64, 95% confidence interval 0·39-1·07; P = 0·087). Although the primary endpoint was not met, absolute PASI was significantly lower at week 32 in q2w vs. q4w patients (2·11 vs. 2·84, P = 0·024). Significantly more patients with q2w vs. q4w dosing showed minimal disease activity (Investigator's Global Assessment score 0 or 1: 73·0% vs. 64·1%, P < 0·05) and improved quality of life (Dermatology Life Quality Index score 0 or 1: 58·9% vs. 50·6%, P < 0·05) at week 32. No new or unexpected safety signals arose.

    CONCLUSIONS: Most patients achieved PASI 90 response with secukinumab q4w. There was potential benefit of q2w dosing in some suboptimal responders. Continued q4w treatment can improve response even after 16 weeks.

    Pubmed
  • Chemical peelings for the treatment of actinic keratosis: a systematic review and meta-analysis.

    J Eur Acad Dermatol Venereol. 2021;35(3): 641-649

    Steeb T, Koch EAT, Wessely A, Wiest LG, Schmitz L, Berking C, Heppt MV

    BACKGROUND: Actinic keratosis (AK) is a common precancerous lesion of the skin that may be treated with chemical peelings. Despite their long-standing usage and clinical experience, no evidence-based recommendation regarding the efficacy and safety of chemical peelings for AK exists.

    OBJECTIVES: To systematically review and synthesize the current knowledge on chemically exfoliative peelings as interventions for AK.

    METHODS: We performed a systematic literature research in Medline, Embase and CENTRAL and hand-searched pertinent trial registers for eligible records until 5 August 2019. Results from individual studies were pooled using a random-effects model or described in a qualitative synthesis. The risk of bias was estimated with the tools provided by the Cochrane Collaboration (randomized and non-randomized trials) and the Evidence Project (single-arm trials).

    RESULTS: Four randomized controlled trials, two non-randomized controlled trials and two single-arm studies with a total sample size of n = 170 patients were included. Trichloroacetic acid (TCA) plus Jessner's solution showed significantly lower participant complete clearance (RR 0.36, 95% CI: 0.14-0.90, two studies, I2  = 0%, P = 0.03) and lower lesion clearance (RR 0.92, 95% CI: 0.85-0.99, one study, P = 0.03) compared to 5-fluorouracil (5-FU) 5% cream. TCA as monotherapy showed lower lesion complete clearance (RR 0.75, 95% CI: 0.69-0.82, two studies, I2  = 7%, P < 0.001) and lower mean lesion reduction per patient compared to conventional photodynamic therapy (cPDT) (MD -20.48, 95% CI: -31.55 to -9.41, two studies, I2  = 43%, P = 0.0003). Pain was more pronounced in patients treated with cPDT in comparison with TCA (MD -1.71 95% CI: -3.02 to -0.41, two studies, I2  = 55%, P = 0.01). In the single-arm studies, 5-FU plus glycolic acid showed 92% lesion clearance and phenol peeling 90.6% participant complete clearance. All studies showed a high risk for bias.

    CONCLUSIONS: Future high-quality studies and a standardization of peeling protocols are warranted to determine the value of chemical peelings in the treatment of AK.

    Pubmed
  • A Critical Appraisal of Evidence- and Consensus-Based Guidelines for Actinic Keratosis.

    Curr Oncol. 2021;28(1): 950-960

    Wessely A, Steeb T, Heppt F, Hornung A, Kaufmann MD, Koch EAT, Toussaint F, Erdmann M, Berking C, Heppt MV

    Actinic keratoses (AK) are common lesions of the skin that can be effectively treated with several lesion- and field-directed treatments. Clinical practice guidelines assist physicians in choosing the appropriate treatment options for their patients. Here, we aimed to systematically identify and evaluate the methodological quality of currently available guidelines for AK. Guidelines published within the last 5 years were identified in a systematic search of guideline databases, Medline and Embase. Then, six independent reviewers evaluated the methodological quality using the tools "Appraisal of Guidelines for Research and Evaluation" (AGREE II) and "Recommendation EXcellence" (AGREE-REX). The Kruskal-Wallis (H) test was used to explore differences among subgroups and Spearman's correlation to examine the relationship between individual domains. Three guidelines developed by consortia from Canada, Germany and the United Kingdom were eligible for the evaluation. The German guideline achieved the highest scores, fulfilling 65 to 92% of the criteria in AGREE II and 67 to 84% in AGREE-REX, whereas the Canadian guideline scored 31 to 71% of the criteria in AGREE II and 33 to 46% in AGREE-REX. The domains "stakeholder involvement" and "values and preferences" were identified as methodological weaknesses requiring particular attention and improvement in future guideline efforts.

    Pubmed
  • Malignant Tumours Presenting as Chronic Leg or Foot Ulcers.

    J Clin Med. 2021;10(11):

    Toussaint F, Erdmann M, Berking C, Erfurt-Berge C

    Our purpose was to collect data on the incidence of malignant skin tumours presenting as chronic leg or foot ulcers in a tertiary centre, and to analyse the frequency and type of initial clinical misdiagnoses in these cases. A retrospective chart review of cases with melanoma or other malignant neoplasms of the skin of the lower extremity treated in a tertiary centre during January 2010 until February 2020 was conducted to identify cases that presented as chronic ulcers. Out of 673 cases, 26 (3.9%) were identified with a total of 27 malignant tumours presenting as chronic ulcers of the lower leg or foot. Therefrom, seven were diagnosed as melanoma, eight as squamous cell carcinoma, and twelve as basal cell carcinoma. The mean interval until diagnosis for all tumour types was 44.4 months (median 24 months). A delay in correct treatment occurred in 12 out of 26 cases (46%) as a result of misdiagnosis with subsequent treatment as chronic leg or foot ulcers of a different etiology. Misdiagnoses were venous ulcer, traumatic wound, mixed arterial and venous ulcer, arterial ulcer, and ulcer of an unknown origin. Malignant ulcers presenting as chronic ulcers are rare, but often lead to misdiagnosis.

    Pubmed
  • Sustainable responses in metastatic melanoma patients with and without brain metastases after elective discontinuation of anti-PD1-based immunotherapy due to complete response.

    Eur J Cancer. 2021;149(): 37-48

    Dimitriou F, Zaremba A, Allayous C, Kähler KC, Gerard CL, Festino L, Schäfer S, Toussaint F, Heinzerling L, Hassel JC, Ascierto PA, Michielin O, Hauschild A, Lebbe C, Livingstone E, Ramelyte E, Cheng PF, Dummer R, Mangana J

    BACKGROUND: Anti-PD1-based immunotherapy is currently used in most patients with advanced melanoma. Despite the remarkable data regarding overall survival, the optimal treatment duration is still unknown.

    METHODS: We evaluated the outcome of 125 patients with advanced melanoma with and without brain metastases (MBM), treated either with anti-PD1 monotherapy (N = 97) or combined with anti-CTLA4 (N = 28) after elective treatment discontinuation due to complete response (CR) (group A, N = 86), or treatment-limiting toxicity (N = 33) and investigator's decision (ID, N = 6) (group B) with subsequent CR.

    RESULTS: For group A, median duration of treatment (mDoT) was 22 months (range 5-49) and median time to CR 9 months (range 2-47). Accordingly, mDoT for group B was 3 months (range 0-36) and median time to CR 7 months (range 1-32). Seven patients from group A and three from group B experienced disease recurrence. Off-treatment survival was not reached. Median off-treatment response time (mOTRt) was 19 months (range 0-42) and 25 months (range 0-66), respectively. For MBM, mOTRt was 17 months (range 7-41) and 28 months (range 9-39), respectively. After a median follow-up of 38 months (range 9-70), seven (5.6%) patients had deceased, one (0.8%) due to melanoma.

    CONCLUSIONS: Treatment discontinuation is feasible also in patients with MBM. Efficacy outcomes seemed to be similar in both groups of patients who achieved CR, regardless of reason for discontinuation. In patients who experienced disease relapse, treatment re-challenge with anti-PD1 resulted in subsequent renewed response.

    Pubmed
  • Clinical impact of COVID-19 on patients with cancer treated with immune checkpoint inhibition.

    J Immunother Cancer. 2021;9(1):

    Rogiers A, Pires da Silva I, Tentori C, Tondini CA, Grimes JM, Trager MH, Nahm S, Zubiri L, Manos M, Bowling P, Elkrief A, Papneja N, Vitale MG, Rose AAN, Borgers JSW, Roy S, Mangana J, Pimentel Muniz T, Cooksley T, Lupu J, Vaisman A, Saibil SD, Butler MO, Menzies AM, Carlino MS, Erdmann M, Berking C, Zimmer L, Schadendorf D, Pala L, Queirolo P, Posch C, Hauschild A, Dummer R, Haanen J, Blank CU, Robert C, Sullivan RJ, Ascierto PA, Miller WH, Stephen Hodi F, Suijkerbuijk KPM, Reynolds KL, Rahma OE, Lorigan PC, Carvajal RD, Lo S, Mandala M, Long GV

    BACKGROUND: Patients with cancer who are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to develop severe illness and die compared with those without cancer. The impact of immune checkpoint inhibition (ICI) on the severity of COVID-19 illness is unknown. The aim of this study was to investigate whether ICI confers an additional risk for severe COVID-19 in patients with cancer.

    METHODS: We analyzed data from 110 patients with laboratory-confirmed SARS-CoV-2 while on treatment with ICI without chemotherapy in 19 hospitals in North America, Europe and Australia. The primary objective was to describe the clinical course and to identify factors associated with hospital and intensive care (ICU) admission and mortality.

    FINDINGS: Thirty-five (32%) patients were admitted to hospital and 18 (16%) died. All patients who died had advanced cancer, and only four were admitted to ICU. COVID-19 was the primary cause of death in 8 (7%) patients. Factors independently associated with an increased risk for hospital admission were ECOG ≥2 (OR 39.25, 95% CI 4.17 to 369.2, p=0.0013), treatment with combination ICI (OR 5.68, 95% CI 1.58 to 20.36, p=0.0273) and presence of COVID-19 symptoms (OR 5.30, 95% CI 1.57 to 17.89, p=0.0073). Seventy-six (73%) patients interrupted ICI due to SARS-CoV-2 infection, 43 (57%) of whom had resumed at data cut-off.

    INTERPRETATION: COVID-19-related mortality in the ICI-treated population does not appear to be higher than previously published mortality rates for patients with cancer. Inpatient mortality of patients with cancer treated with ICI was high in comparison with previously reported rates for hospitalized patients with cancer and was due to COVID-19 in almost half of the cases. We identified factors associated with adverse outcomes in ICI-treated patients with COVID-19.

    Pubmed
  • Evaluation of Long-term Clearance Rates of Interventions for Actinic Keratosis: A Systematic Review and Network Meta-analysis.

    JAMA Dermatol. 2021;157(9): 1066-1077

    Steeb T, Wessely A, Petzold A, Brinker TJ, Schmitz L, Leiter U, Garbe C, Schöffski O, Berking C, Heppt MV

    Importance: Multiple interventions are available for the treatment of actinic keratosis (AK). However, most randomized clinical trials and meta-analyses focus on short-term efficacy outcomes.

    Objective: To investigate and synthesize the long-term efficacy (≥12 months) of interventions for AK from parallel-arm randomized clinical trials.

    Data Sources: Searches in MEDLINE, Embase, and Central were conducted from inception until April 6, 2020. The reference lists of the included studies and pertinent trial registers were hand searched. The study was completed February 27, 2021.

    Study Selection: Two reviewers screened the titles and abstracts of 2741 records. Finally, 17 published reports (original studies and follow-up reports) referring to 15 independent randomized clinical trials with an overall sample size of 4252 patients were included.

    Data Extraction and Synthesis: Two reviewers independently extracted data on study, patient, and intervention characteristics. Network meta-analysis (NMA) of each outcome was conducted with a frequentist approach. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidance for NMA was used to assess the certainty of evidence. The revised Cochrane risk-of-bias tool for randomized clinical trials was used to evaluate the methodologic quality.

    Main Outcomes and Measures: Participant complete clearance, participant partial clearance, and lesion-specific clearance were the outcomes, with each assessed at least 12 months after the end of treatment.

    Results: Data from 15 independent randomized clinical trials including 4252 patients were extracted and synthesized. Ten studies were included in an NMA for the outcome of participant complete clearance, with photodynamic therapy with aminolevulinate (ALA-PDT) showing the most favorable risk ratio (RR) compared with placebo (RR, 8.06; 95% CI, 2.07-31.37; GRADE, moderate), followed by imiquimod, 5% (RR, 5.98; 95% CI, 2.26-15.84; GRADE, very low), photodynamic therapy with methyl aminolevulinate (MAL-PDT) (RR, 5.95; 95% CI, 1.21-29.41; GRADE, low), and cryosurgery (RR, 4.67; 95% CI, 1.36-16.66; GRADE, very low). Similarly, ALA-PDT had the highest RR in the NMA for lesion-specific clearance (RR, 5.08; 95% CI, 2.49-10.33; GRADE, moderate). No NMA was possible for participant partial clearance owing to poor reporting of this outcome.

    Conclusions and Relevance: This systematic review and network meta-analysis found that therapy including ALA-PDT, imiquimod, 5%, MAL-PDT, and cryosurgery was associated with significant long-term efficacy in the NMA. This study provides data for a possible use in an evidence-based framework for selecting interventions with sustained lesion clearance.

    Pubmed
  • "I Feel I'm in Best Hands with You!": A Survey of Patient Satisfac-tion in a German University Skin Cancer Centre.

    Acta Derm Venereol. 2021;101(6):

    Steeb T, Wessely A, Merkl H, Kirchberger MC, Voskens C, Erdmann M, Heinzerling L, Berking C, Heppt MV

    An important measure of hospital quality is the satisfaction of patients. The aim of this cross-sectional study, performed in the dermato-oncology unit of the university hospital in Erlangen, Germany, was to assess skin cancer patients' degree of satisfaction with healthcare services. Self-administered questionnaires on patient satisfaction regarding contact with staff, need for information, and recommendation of the skin cancer centre were distributed in the day-care unit and the outpatient department to patients between April and June 2017. Results were reported descriptively and subgroup differences were explored using the Mann-Whitney U test, binary logistic regression, or χ2 test. Overall, 496 of 571 questionnaires were returned (86.9%). The median of all satisfaction items ranged between 1 (very good) and 2 (good). The majority of patients wanted more detailed information about skin cancer (46.7%, 142/304). Long waiting times were often criticized (22.8%; 80/351). Particular attention in addressing specific needs and fears may further increase patient satisfaction.

    Pubmed
  • A benchmark for neural network robustness in skin cancer classification.

    Eur J Cancer. 2021;155(): 191-199

    Maron RC, Schlager JG, Haggenmüller S, von Kalle C, Utikal JS, Meier F, Gellrich FF, Hobelsberger S, Hauschild A, French L, Heinzerling L, Schlaak M, Ghoreschi K, Hilke FJ, Poch G, Heppt MV, Berking C, Haferkamp S, Sondermann W, Schadendorf D, Schilling B, Goebeler M, Krieghoff-Henning E, Hekler A, Fröhling S, Lipka DB, Kather JN, Brinker TJ

    BACKGROUND: One prominent application for deep learning-based classifiers is skin cancer classification on dermoscopic images. However, classifier evaluation is often limited to holdout data which can mask common shortcomings such as susceptibility to confounding factors. To increase clinical applicability, it is necessary to thoroughly evaluate such classifiers on out-of-distribution (OOD) data.

    OBJECTIVE: The objective of the study was to establish a dermoscopic skin cancer benchmark in which classifier robustness to OOD data can be measured.

    METHODS: Using a proprietary dermoscopic image database and a set of image transformations, we create an OOD robustness benchmark and evaluate the robustness of four different convolutional neural network (CNN) architectures on it.

    RESULTS: The benchmark contains three data sets-Skin Archive Munich (SAM), SAM-corrupted (SAM-C) and SAM-perturbed (SAM-P)-and is publicly available for download. To maintain the benchmark's OOD status, ground truth labels are not provided and test results should be sent to us for assessment. The SAM data set contains 319 unmodified and biopsy-verified dermoscopic melanoma (n = 194) and nevus (n = 125) images. SAM-C and SAM-P contain images from SAM which were artificially modified to test a classifier against low-quality inputs and to measure its prediction stability over small image changes, respectively. All four CNNs showed susceptibility to corruptions and perturbations.

    CONCLUSIONS: This benchmark provides three data sets which allow for OOD testing of binary skin cancer classifiers. Our classifier performance confirms the shortcomings of CNNs and provides a frame of reference. Altogether, this benchmark should facilitate a more thorough evaluation process and thereby enable the development of more robust skin cancer classifiers.

    Pubmed
  • c-Kit inhibitors for unresectable or metastatic mucosal, acral or chronically sun-damaged melanoma: a systematic review and one-arm meta-analysis.

    Eur J Cancer. 2021;157(): 348-357

    Steeb T, Wessely A, Petzold A, Kohl C, Erdmann M, Berking C, Heppt MV

    BACKGROUND: Activating genomic alterations of the receptor tyrosine kinase KIT are found preferentially in certain melanoma subtypes such as acral and mucosal melanoma or melanoma arising in chronically sun-damaged skin. However, the therapeutic value of c-Kit inhibitors for these subtypes currently remains unclear.

    OBJECTIVES: The objective of this study was to summarise the efficacy and safety of c-Kit inhibitors for unresectable or metastatic mucosal, acral or chronically sun-damaged melanoma.

    METHODS: We performed a systematic literature research in MEDLINE, Embase and CENTRAL and hand searched pertinent trial registers and conference abstracts for eligible trials until 23rd June 2020. Results were pooled using a random-effects model to calculate pooled proportions of objective response rates (ORRs) and severe adverse events (sAEs) from unselected KIT mutant or amplified cohorts.

    RESULTS: Nineteen single-arm studies with an overall sample size of 601 patients were included. The studies investigated imatinib (n = 8), nilotinib (n = 7), dasatinib (n = 3) and sunitinib (n = 1). The pooled ORR for all inhibitors was 15% (95% confidence interval [CI]: 12-18%). Subgroup analysis revealed the highest ORR (20%; 95% CI: 14-26%) for nilotinib. The ORR for mucosal melanoma was 14% (95% CI: 6-24%) and 22% for acral lentiginous melanoma (95% CI: 14-30%). At least one sAE was reported in 42% of patients (95% CI: 34-50%).

    CONCLUSIONS: c-Kit inhibitors represent a valuable treatment option for patients with KIT-mutant melanoma, in particular for mutations of exons 11 and 13. Furthermore, high-quality trials are urgently needed to investigate putative combinations of specific targeted therapies with immunotherapy.

    Pubmed
  • Die NVKH launcht das Informationsportal Hautkrebs.

    J Dtsch Dermatol Ges. 2021;19(5):

    Meier F, Weber C, Berking C, Schadendor D, Steeb T, Doppler A

    Pubmed
  • Inflammatory markers in autoimmunity induced by checkpoint inhibitors.

    J Cancer Res Clin Oncol. 2021;147(6): 1623-1630

    Husain B, Kirchberger MC, Erdmann M, Schüpferling S, Abolhassani AR, Fröhlich W, Berking C, Heinzerling L

    PURPOSE: Immune checkpoint inhibitors (ICI) are highly effective in several cancer entities, but also invoke a variety of immune-related adverse events (irAE). These are mostly reversible, but can be life-threatening or even fatal. Currently, the pathogenesis is not fully understood, but crucial for effective treatment. Prediction and early detection of irAE could be facilitated and treatment optimized if relevant biomarkers and effector mechanisms were better characterized.

    METHODS: This study included a total of 45 irAE in patients with metastatic melanoma who were treated with ICI. All patients underwent a complete work-up with exclusion of other causes. Longitudinal blood samples were analyzed for a panel of soluble markers and compared to baseline and to patients who did not experience any irAE. Measurements included LDH, interleukin (IL)-6, IL-1β, IL-17, C-reactive protein (CRP) and tumor necrosis factor (TNF)-alpha as well as tumor markers S100 and melanoma inhibitory activity (MIA).

    RESULTS: During the early onset of irAE increases in serum IL-6 (from mean 24.4 pg/ml at baseline to 51.0 pg/ml; p = 0.003) and CRP (from mean 7.0 mg/l at baseline to 17.7 mg/l; p = 0.001) and a decrease in MIA (from mean 5.4 pg/ml at baseline to 4.8 pg/ml; p = 0.035) were detected. No changes in IL-17 were noted. These effects were observed for irAE of different organ systems.

    CONCLUSION: Increases of a combination of IL-6 and CRP serum levels can be used for the early detection of irAE and tailored management. Interestingly, changes in MIA serum levels also correlate with irAE onset.

    Pubmed
  • How Neural Crest Transcription Factors Contribute to Melanoma Heterogeneity, Cellular Plasticity, and Treatment Resistance.

    Int J Mol Sci. 2021;22(11):

    Wessely A, Steeb T, Berking C, Heppt MV

    Cutaneous melanoma represents one of the deadliest types of skin cancer. The prognosis strongly depends on the disease stage, thus early detection is crucial. New therapies, including BRAF and MEK inhibitors and immunotherapies, have significantly improved the survival of patients in the last decade. However, intrinsic and acquired resistance is still a challenge. In this review, we discuss two major aspects that contribute to the aggressiveness of melanoma, namely, the embryonic origin of melanocytes and melanoma cells and cellular plasticity. First, we summarize the physiological function of epidermal melanocytes and their development from precursor cells that originate from the neural crest (NC). Next, we discuss the concepts of intratumoral heterogeneity, cellular plasticity, and phenotype switching that enable melanoma to adapt to changes in the tumor microenvironment and promote disease progression and drug resistance. Finally, we further dissect the connection of these two aspects by focusing on the transcriptional regulators MSX1, MITF, SOX10, PAX3, and FOXD3. These factors play a key role in NC initiation, NC cell migration, and melanocyte formation, and we discuss how they contribute to cellular plasticity and drug resistance in melanoma.

    Pubmed
  • Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Patterns of Response and Survival According to the Presence of Hepatic and Extrahepatic Metastasis.

    Cancers (Basel). 2021;13(13):

    Koch EAT, Petzold A, Wessely A, Dippel E, Gesierich A, Gutzmer R, Hassel JC, Haferkamp S, Hohberger B, Kähler KC, Knorr H, Kreuzberg N, Leiter U, Loquai C, Meier F, Meissner M, Mohr P, Pföhler C, Rahimi F, Schadendorf D, Schell B, Schlaak M, Terheyden P, Thoms KM, Schuler-Thurner B, Ugurel S, Ulrich J, Utikal J, Weichenthal M, Ziller F, Berking C, Heppt MV, On Behalf Of The German Dermatologic Cooperative Oncology Group DeCOG Committee Ocular Melanoma

    BACKGROUND: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB.

    METHODS: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan-Meier method. Log-rank tests, χ2 tests, and t-tests were performed to detect significant differences between both cohorts.

    RESULTS: The median OS of the overall population was 16 months (95% CI 13.4-23.7) and the median PFS, 2.8 months (95% CI 2.5-3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts.

    CONCLUSION: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.

    Pubmed
  • Online consensus conferences for the development and update of clinical practice guidelines: A survey among participants of the German S3 guideline on actinic keratosis and cutaneous squamous cell carcinoma.

    J Dtsch Dermatol Ges. 2021;19(4): 608-610

    Steeb T, Follmann M, Langer T, Nothacker M, Wessely A, Garbe C, Leiter U, Berking C, Heppt MV

    Pubmed
  • Safety of topical interventions for the treatment of actinic keratosis.

    Expert Opin Drug Saf. 2021;20(7): 801-814

    Koch EAT, Wessely A, Steeb T, Berking C, Heppt MV

    Introduction: Actinic keratosis (AK) are proliferations of atypical keratinocytes that may eventually progress to cutaneous squamous cell carcinoma. Therefore, AK requires consequent and early treatment. Areas covered: A variety of effective approaches is currently available for the clearance of AK. These interventions may be applied either in a lesion-directed or field-directed mode as AK can occur as single or multiple lesions. Field-directed approaches typically comprise topical drug-mediated interventions which aim at eliminating all visible lesions and also at clearing subclinical changes of the actinically damaged field. However, most treatment options are associated with local adverse events such as erythema, scaling, pain, and rarely with systemic symptoms. This expert review provides a comprehensive and up-to-date overview of the safety considerations of the commonly prescribed topical treatment agents cyclooxygenase inhibitors, 5-fluorouracil, imiquimod, ingenol mebutate, and photodynamic therapy. All these therapies have been proven efficient, yet they differ considerably regarding their safety profile. Expert opinion: In the future, safety concerns will relate to long-term and irreversible adverse drug events instead of application site reactions. In particular, the rate of treatment-associated non-melanoma skin cancers will increasingly come into focus and warrant investigation in postmarketing surveillance trials with a long-term follow-up.

    Pubmed
  • The Value of Total Body Photography for the Early Detection of Melanoma: A Systematic Review.

    Int J Environ Res Public Health. 2021;18(4):

    Hornung A, Steeb T, Wessely A, Brinker TJ, Breakell T, Erdmann M, Berking C, Heppt MV

    Early detection of melanoma is critical to reduce the mortality and morbidity rates of this tumor. Total body photography (TBP) may aid in the early detection of melanoma. To summarize the current evidence on TBP for the early detection of melanoma, we performed a systematic literature search in Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) for eligible records up to 6th August 2020. Outcomes of interest included melanoma incidence, incisional and excisional biopsy rates, as well as the Breslow's index of detected tumors. Results from individual studies were described qualitatively. The risks of bias and applicability of the included studies was assessed using the QUADAS-2 checklist. In total, 14 studies published between 1997 and 2020 with an overall sample size of n = 12082 (range 100-4692) were included in the qualitative analysis. Individuals undergoing TBP showed a trend towards a lower Breslow's thickness and a higher proportion of in situ melanomas compared to those without TBP. The number needed to excise one melanoma varied from 3:1 to 14.3:1 and was better for lesions that arose de novo than for tracked ones. The included studies were judged to be of unclear methodological concern with specific deficiencies in the domains "flow and timing" and "reference standard". The use of TBP can improve the early detection of melanoma in high-risk populations. Future studies are warranted to reduce the heterogeneity of phenotypic risk factor definition and the technical implementation of TBP. Artificial intelligence-assisted analysis of images derived from 3-D TBP systems and digital dermoscopy may further improve the early detection of melanoma.

    Pubmed
  • Risk Factors for Relapse after Intentional Discontinuation of Immune Checkpoint Inhibitors in Melanoma Patients.

    J Immunother. 2021;44(6): 239-241

    Persa OD, Schatton K, Rübben A, Berking C, Erdmann M, Schlaak M, Mauch C, Steeb T

    Immune checkpoint inhibitors (ICIs) have tremendously changed the therapeutic landscape of melanoma since they are associated with a durable response, allowing for intentional discontinuation of therapy after complete or partial remission. However, a subset of patients develops a relapse after cessation of ICI treatment and may not respond to reinduction of ICIs. The aim of the present study was to identify risk factors for relapse after intentional discontinuation of ICI therapy. Patients with intentional discontinuation of ICI therapy for metastatic or unresectable melanoma from 5 German university hospitals were analyzed retrospectively. Clinicopathologic and follow-up data of 87 patients were collected and analyzed by univariate and multivariate Cox proportional-hazards models. The following parameters were associated with relapse after cessation of ICI treatment in the univariate Cox regression analysis: concurrent radiotherapy and ICI, best overall response, and presence of brain metastases. Duration of treatment, type of primary tumor, body mass index, programmed-death ligand 1 expression, and lactate dehydrogenase levels did not significantly influence the risk for relapse. In the multivariate analysis, partial remission [hazard ratio 4.217 (95% confidence interval: 1.424-12.49), P=0.009] and stable disease [3.327 (1.204-9.19), P=0.02] were associated with a significant decrease in progression-free survival compared with complete remission. Concurrent radiotherapy and ICI [3.619 (1.288-10.168), P=0.015] are additional independent risk factors for decreased progression-free survival upon ICI discontinuation, whereas the presence of brain metastasis did not reach statistical significance on multivariate analysis.

    Pubmed
  • Sudden Otovestibular Dysfunction in 3 Metastatic Melanoma Patients Treated With Immune Checkpoint Inhibitors.

    J Immunother. 2021;44(5): 193-197

    Stürmer SH, Lechner A, Berking C

    Immune-related adverse events have been described in 86%-96% of high-risk melanoma patients treated with immune checkpoint inhibitors (ICI), while in 17%-59% of cases these are classified as severe or even life-threatening. The most common immune-related adverse events include diarrhea, fatigue, hypothyroidism, and hepatitis. Bilateral uveitis and unspecific vertigo have been described in 1% of cases, respectively, in the pivotal studies of ICIs, but the affection of the vestibule-cochlear system has not been reported before. In this case series, we present 3-stage IV melanoma patients with sudden onset of otovestibular dysfunction (hearing loss and vestibulopathy), partly combined with uveitis because of ICIs. We describe detailed diagnostic work-up and therapeutic interventions and discuss possible pathogenic mechanisms of this rare and disabling event.

    Pubmed
  • Contrary immediate effect of abatacept on skin and joint manifestations in psoriatic arthritis.

    Rheumatology (Oxford). 2021;60(9): e312-e313

    Valor-Méndez L, Kleyer A, Schett G, Manger B, Sticherling M

    Pubmed
  • COVID-19 and immune-mediated inflammatory diseases: effect of disease and treatment on COVID-19 outcomes and vaccine responses.

    Lancet Rheumatol.. 2021;3(10): e724-e736

    Fagni F, Simon D, Tascilar K, Schoenau V, Sticherling M, Neurath MF, Schett G

    At the beginning of the COVID-19 pandemic, patients with immune-mediated inflammatory diseases were considered to be at high risk for SARS-CoV-2 infection and the development of severe COVID-19. Data collected over the past year, however, suggest that a diagnosis of inflammatory arthritis, psoriasis, or inflammatory bowel diseases does not increase risk for SARS-CoV-2 infection or severe COVID-19 compared with people without these diseases. Furthermore, substantial data suggest that certain medications frequently used in patients with immune-mediated inflammatory diseases, in particular cytokine inhibitors, might even lower the risk for severe COVID-19. Conversely, glucocorticoids and potentially B-cell-depleting treatments seem to worsen COVID-19 outcomes. Additionally, the first data on SARS-CoV-2 vaccination in patients with these diseases suggest that tolerability of vaccination in patients with immune-mediated inflammatory diseases is good, although the immune response to vaccination can be somewhat reduced in this patient group, particularly those taking methotrexate or CD20-targeted treatment.

    Pubmed
  • SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases.

    Ann Rheum Dis. 2021;80(10): 1312-1316

    Simon D, Tascilar K, Fagni F, Krönke G, Kleyer A, Meder C, Atreya R, Leppkes M, Kremer AE, Ramming A, Pachowsky ML, Schuch F, Ronneberger M, Kleinert S, Hueber AJ, Manger K, Manger B, Berking C, Sticherling M, Neurath MF, Schett G

    OBJECTIVES: To better understand the factors that influence the humoral immune response to vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs).

    METHODS: Patients and controls from a large COVID-19 study, with (1) no previous history of COVID-19, (2) negative baseline anti-SARS-CoV-2 IgG test and (3) SARS-CoV-2 vaccination at least 10 days before serum collection were measured for anti-SARS-CoV-2 IgG. Demographic, disease-specific and vaccination-specific data were recorded.

    RESULTS: Vaccination responses from 84 patients with IMID and 182 controls were analysed. While all controls developed anti-SARS-CoV-2 IgG, five patients with IMID failed to develop a response (p=0.003). Moreover, 99.5% of controls but only 90.5% of patients with IMID developed neutralising antibody activity (p=0.0008). Overall responses were delayed and reduced in patients (mean (SD): 6.47 (3.14)) compared with controls (9.36 (1.85); p<0.001). Estimated marginal means (95% CI) adjusted for age, sex and time from first vaccination to sampling were 8.48 (8.12-8.85) for controls and 6.90 (6.45-7.35) for IMIDs. Significantly reduced vaccination responses pertained to untreated, conventionally and anticytokine treated patients with IMID.

    CONCLUSIONS: Immune responses against the SARS-CoV-2 are delayed and reduced in patients with IMID. This effect is based on the disease itself rather than concomitant treatment.

    Pubmed
  • Pretreatment metastatic growth rate determines clinical outcome of advanced melanoma patients treated with anti-PD-1 antibodies: a multicenter cohort study.

    J Immunother Cancer. 2021;9(5):

    Wagner NB, Lenders MM, Kühl K, Reinhardt L, André F, Dudda M, Ring N, Ebel C, Stäger R, Zellweger C, Lang R, Paar M, Gussek P, Richtig G, Stürmer SH, Kimeswenger S, Oellinger A, Forschner A, Leiter U, Weide B, Gassenmaier M, Schraag A, Klumpp B, Hoetzenecker W, Berking C, Richtig E, Ziemer M, Mangana J, Terheyden P, Loquai C, Nguyen VA, Gebhardt C, Meier F, Diem S, Cozzio A, Flatz L, Röcken M, Garbe C, Eigentler TK

    BACKGROUND: Checkpoint inhibitors revolutionized the treatment of metastatic melanoma patients. Although tumor burden and lactate dehydrogenase (LDH) are associated with overall survival (OS), the impact of tumor growth kinetics remains elusive and in part contradictory. The aims of this study were to develop a novel simple and rapid method that estimates pretreatment metastatic growth rate (MGR) and to investigate its prognostic impact in melanoma patients treated with antiprogrammed death receptor-1 (PD-1) antibodies.

    METHODS: MGR was assessed in three independent cohorts of a total of 337 unselected consecutive metastasized stage IIIB-IV melanoma patients (discovery cohort: n=53, confirmation cohort: n=126, independent multicenter validation cohort: n=158). MGR was computed during the pretreatment period before initiation of therapy with anti-PD-1 antibodies nivolumab or pembrolizumab by measuring the increase of the longest diameter of the largest target lesion. Tumor doubling time served as quality control. Kaplan-Meier analysis and univariable as well as multivariable Cox regression were used to examine the prognostic impact of MGR.

    RESULTS: Pretreatment MGR >3.9 mm/month was associated with impaired OS in the discovery cohort (HR 6.19, 95% CI 2.92 to 13.10, p<0.0001), in the confirmation cohort (HR 3.62, 95% CI 2.19 to 5.98, p<0.0001) and in the independent validation cohort (HR 2.57, 95% CI 1.56 to 4.25, p=0.00023). Prior lines of systemic treatment did not influence the significance of MGR. Importantly, the prognostic impact of MGR was independent of total tumor burden, diameter of the largest metastasis, number of prior lines of systemic treatment, LDH, as well as liver and brain metastasis (discovery and confirmation cohorts: both p<0.0001). Superiority of MGR compared with these variables was confirmed in the independent multicenter validation cohort (HR 2.92, 95% CI 1.62 to 5.26, p=0.00036).

    CONCLUSIONS: High pretreatment MGR is an independent strong prognostic biomarker associated with unfavorable survival of melanoma patients receiving anti-PD-1 antibodies. Further investigations are warranted to assess the predictive impact of MGR in distinct systemic therapeutic regimens.

    Pubmed
  • Beyond-Mild Psoriasis: A Consensus Statement on Calcipotriol and Betamethasone Dipropionate Foam for the Topical Treatment of Adult Patients.

    Dermatol Ther (Heidelb). 2021;11(5): 1791-1804

    Aschoff R, Bewley A, Dattola A, De Simone C, Lahfa M, Llamas-Velasco M, Martorell A, Pavlovic M, Sticherling M

    INTRODUCTION: There are clear treatment options for mild psoriasis where topical therapies are the mainstay, and for severe psoriasis where systemic therapy (biologic or non-biologic) is necessary. However, there is less clarity in the 'grey zone' of patients in the moderate or so-called 'beyond-mild' segment. There are frequent delays to the initiation, discontinuation, switching and dose change in treatment, and many patients fail to continue treatment because of concerns about safety or lack of efficacy. Treatment with topical therapies, such as calcipotriol and betamethasone dipropionate (Cal/BD) combinations, may be suitable for these patients.

    METHOD: These consensus recommendations on the use of topical therapies including Cal/BD foam for beyond-mild psoriasis originated from a modified Delphi process of European clinical experts. In the process, the experts iteratively refined a series of draft statements, which had to receive ≥ 80% approval to be incorporated into the consensus.

    RESULTS: The experts identified three main themes: Cal/BD foam as monotherapy, as an add-on to non-biologic systemic therapies and as an add-on to systemic biologics. The consensus emphasises disease factors and patient preference in treatment choice, summarises the evidence base for Cal/BD foam monotherapy for flare treatment as well as long-term management, and identifies the potential for improved treatment outcomes, such as reduced time to onset of action and reduced systemic dose to minimise side effects for add-on Cal/BD therapy to non-biologic systemics. The recommendations regarding add-on Cal/BD foam to biologics are similar to those for non-biologic systemic therapies, but also include suggestions for patients on biologics who are late responders. As clinical choices of Cal/BD combination vary, we have here often used 'Cal/BD' without reference to any particular formulation.

    CONCLUSIONS: These recommendations aim to give practical guidance to those treating patients with beyond-mild psoriasis, to support patients' use of topical preparations and to optimise treatment outcomes.

    Pubmed
  • Skin cancer classification via convolutional neural networks: systematic review of studies involving human experts.

    Eur J Cancer. 2021;156(): 202-216

    Haggenmüller S, Maron RC, Hekler A, Utikal JS, Barata C, Barnhill RL, Beltraminelli H, Berking C, Betz-Stablein B, Blum A, Braun SA, Carr R, Combalia M, Fernandez-Figueras MT, Ferrara G, Fraitag S, French LE, Gellrich FF, Ghoreschi K, Goebeler M, Guitera P, Haenssle HA, Haferkamp S, Heinzerling L, Heppt MV, Hilke FJ, Hobelsberger S, Krahl D, Kutzner H, Lallas A, Liopyris K, Llamas-Velasco M, Malvehy J, Meier F, Müller CSL, Navarini AA, Navarrete-Dechent C, Perasole A, Poch G, Podlipnik S, Requena L, Rotemberg VM, Saggini A, Sangueza OP, Santonja C, Schadendorf D, Schilling B, Schlaak M, Schlager JG, Sergon M, Sondermann W, Soyer HP, Starz H, Stolz W, Vale E, Weyers W, Zink A, Krieghoff-Henning E, Kather JN, von Kalle C, Lipka DB, Fröhling S, Hauschild A, Kittler H, Brinker TJ

    BACKGROUND: Multiple studies have compared the performance of artificial intelligence (AI)-based models for automated skin cancer classification to human experts, thus setting the cornerstone for a successful translation of AI-based tools into clinicopathological practice.

    OBJECTIVE: The objective of the study was to systematically analyse the current state of research on reader studies involving melanoma and to assess their potential clinical relevance by evaluating three main aspects: test set characteristics (holdout/out-of-distribution data set, composition), test setting (experimental/clinical, inclusion of metadata) and representativeness of participating clinicians.

    METHODS: PubMed, Medline and ScienceDirect were screened for peer-reviewed studies published between 2017 and 2021 and dealing with AI-based skin cancer classification involving melanoma. The search terms skin cancer classification, deep learning, convolutional neural network (CNN), melanoma (detection), digital biomarkers, histopathology and whole slide imaging were combined. Based on the search results, only studies that considered direct comparison of AI results with clinicians and had a diagnostic classification as their main objective were included.

    RESULTS: A total of 19 reader studies fulfilled the inclusion criteria. Of these, 11 CNN-based approaches addressed the classification of dermoscopic images; 6 concentrated on the classification of clinical images, whereas 2 dermatopathological studies utilised digitised histopathological whole slide images.

    CONCLUSIONS: All 19 included studies demonstrated superior or at least equivalent performance of CNN-based classifiers compared with clinicians. However, almost all studies were conducted in highly artificial settings based exclusively on single images of the suspicious lesions. Moreover, test sets mainly consisted of holdout images and did not represent the full range of patient populations and melanoma subtypes encountered in clinical practice.

    Pubmed
  • Primary Biliary Cirrhosis and Granulomatous Hepatitis After Immune Checkpoint Blockade in Patients With Metastatic Melanoma: Report of 2 Cases and Literature Discussion.

    J Immunother. 2021;44(2): 71-75

    Ruini C, Haas C, Mastnik S, Knott M, French LE, Schlaak M, Berking C

    Immune-related adverse events (irAEs) of immune checkpoint inhibitors can potentially affect every organ system, are sometimes challenging, and require a multidisciplinary approach. Most common irAEs are very well characterized, but some other such rare autoimmune liver diseases are probably underdiagnosed and less explored. We present here the case of a 69-year-old man with metastatic melanoma developing a severe primary biliary cirrhosis under pembrolizumab, and of a 52-year-old woman with metastatic melanoma with granulomatous hepatitis in the context of an immune-related multiorgan inflammatory reaction due to ipilimumab and nivolumab. Both cases were in part steroid refractory and required a complex diagnostic assessment and long-term therapeutic management. The liver biopsy was crucial for ensuring a correct diagnosis. Clinicians should be aware of rare liver diseases in the context of increased liver enzymes under immune checkpoint inhibitors, especially if not responding to corticosteroids. The primary diagnostic workup should localize the liver damage (biliary or parenchymal) and distinguish irAEs from other pathologic conditions such as metastasis, second benign and malignant tumors, viral hepatitis, and cholelithiasis. If in doubt, a liver biopsy should be performed. Early diagnosis and accurate assessment of hepatic adverse events is necessary for prompt and effective treatment, with reduction of inappropriate discontinuation of immunotherapy, morbidity, and mortality.

    Pubmed
  • Lipase elevation and type 1 diabetes mellitus related to immune checkpoint inhibitor therapy - A multicentre study of 90 patients from the German Dermatooncology Group.

    Eur J Cancer. 2021;149(): 1-10

    Grimmelmann I, Momma M, Zimmer L, Hassel JC, Heinzerling L, Pföhler C, Loquai C, Ruini C, Utikal J, Thoms KM, Kähler KC, Eigentler T, Herbst RA, Meier F, Debus D, Berking C, Kochanek C, Ugurel S, Gutzmer R, German Dermatooncology Group (DeCOG)

    AIM: Immune checkpoint inhibition (ICI) triggers immune-related adverse events (irAEs). The relevance of lipase elevation remains unclear.

    PATIENTS AND METHODS: Skin cancer patients with newly detected serum lipase elevation (at least twofold upper normal limit) or newly diagnosed type I diabetes mellitus upon ICI therapy were retrospectively collected at 14 German skin cancer centres.

    RESULTS: We identified 68 patients with lipase elevation occurring after a median time of 19 (range 1-181) weeks on ICI, 15 (22%) thereof had symptoms consistent with pancreatitis. Forty-seven patients (73%) had other irAE, mainly colitis. Discontinuation (n = 24, 35%) or interruption (n = 26, 38%) of ICI resulted in decrease of lipase after reinduction of ICI lipase levels increased again in 12 of 24 patients. In 18 patients (27%), ICI was continued unchanged, and in 12 (67%) of them, lipase levels normalised. Twenty-two patients were identified with newly diagnosed type I diabetes mellitus related to ICI, and 12 (55%) thereof had also lipase elevation mainly shortly before or after the diagnosis of diabetes. Fourteen (64%) patients had other irAE, mainly thyroiditis. Irrespective of lipase elevation, patients frequently showed a rapid onset with ketoacidosis, decreased c-peptide, and strongly increased blood glucose levels.

    CONCLUSION: Increased serum lipase during ICI is often not associated with pancreatitis but with other irAE as possible cause. Therefore, it might be sufficient to regularly monitor blood glucose levels and perform further workup only in case of signs or symptoms of pancreatitis and/or exocrine pancreas insufficiency.

    Pubmed
  • Hematological immune related adverse events after treatment with immune checkpoint inhibitors.

    Eur J Cancer. 2021;147(): 170-181

    Kramer R, Zaremba A, Moreira A, Ugurel S, Johnson DB, Hassel JC, Salzmann M, Gesierich A, Weppler A, Spain L, Loquai C, Dudda M, Pföhler C, Hepner A, Long GV, Menzies AM, Carlino MS, Sachse MM, Lebbé C, Baroudjian B, Enokida T, Tahara M, Schlaak M, Hayani K, Bröckelmann PJ, Meier F, Reinhardt L, Friedlander P, Eigentler T, Kähler KC, Berking C, Zimmer L, Heinzerling L

    INTRODUCTION: With the increasing use of checkpoint inhibitors, rare immune-related adverse events (irAE) are being identified. Haematological irAE (hem-irAE) are difficult to treat and have shown high mortality rates. In order to improve side-effect management for these potentially life-threatening events, we analysed frequency, severity and outcomes.

    PATIENTS AND METHODS: Patients who developed hem-irAE while being treated with immune checkpoint inhibitors (ICI) therapy were retrospectively identified from 18 international cancer centres.

    RESULTS: In total, more than 7626 patients treated with ICI were screened, and 50 patients with hem-irAE identified. The calculated incidence amounts to 0.6% and median onset was 6 weeks after the ICI initiation (range 1-128 weeks). Thrombocytopenia and leucopaenia were the most frequent hem-irAE with 34% (17/50) and 34% (17/50), respectively, followed by anaemia 28% (14/50), hemophagocytic lymphohistiocytosis (4% (2/50)), aplastic anaemia (2% (1/50)), acquired haemophilia A (2% (1/50)) and coagulation deficiency (2% (1/50)). Simultaneous thrombocytopenia and neutropenia occurred in two patients, concurrent anaemia and thrombocytopenia in one patient. Other than cessation of ICI (in 60%) and corticosteroids (in 78%), treatment included second-line immunosuppression in 24% of cases. Events resolved in 78% (39/50), while 18% (9/50) had persistent changes, and 2% (1/50) had fatal outcomes (agranulocytosis).

    CONCLUSION: Hem-irAE can affect all haematopoietic blood cell lineages and may persist or even be fatal. Management may require immunosuppression beyond corticosteroids. Although these irAE are rare, treating physicians should be aware, monitor blood counts regularly and promptly act upon detection.

    Pubmed
  • Factors Influencing the Adjuvant Therapy Decision: Results of a Real-World Multicenter Data Analysis of 904 Melanoma Patients

    Cancers (Basel). 2021;13(10):

    Lodde G, Forschner A, Hassel J, Wulfken LM, Meier F, Mohr P, Kaehler K, Schilling B, Loquai C, Berking C, Huening S, Schatton K, Gebhardt C, Eckardt J, Gutzmer R, Reinhardt L, Glutsch V, Nikfarjam U, Erdmann M, Stang A, Kowall B, Roesch A, Ugurel S, Zimmer L, Schadendorf D, Livingstone E

    Simple Summary

    Adjuvant treatment of stage III/IV melanoma patients with immune-checkpoint inhibition or targeted therapy can significantly improve recurrence-free survival. However, it is unknown how many patients with an indication for adjuvant therapy do indeed choose to receive it and what the reasons for declining are. In patients with a BRAF mutation, it is not known whether more patients prefer targeted or immunotherapy. This study investigates the real-world situation of 904 patients from 13 German Dermatologic Cooperative Oncology Group skin cancer centers with an indication for adjuvant treatment since the approval of the corresponding drugs as adjuvant treatment. Aims of this study were to investigate the patient groups who opt for or against adjuvant treatment, respectively targeted or immunotherapy, and the reasons for refusal. Findings of this study show the current acceptance and choice of adjuvant melanoma treatment and may support patients and physicians in the therapy decision-making process.

    Adjuvant treatment of melanoma patients with immune-checkpoint inhibition (ICI) and targeted therapy (TT) significantly improved recurrence-free survival. This study investigates the real-world situation of 904 patients from 13 German skin cancer centers with an indication for adjuvant treatment since the approval of adjuvant ICI and TT. From adjusted log-binomial regression models, we estimated relative risks for associations between various influence factors and treatment decisions (adjuvant therapy yes/no, TT vs. ICI in BRAF mutant patients). Of these patients, 76.9% (95% CI 74-80) opted for a systemic adjuvant treatment. The probability of starting an adjuvant treatment was 26% lower in patients >65 years (RR 0.74, 95% CI 68-80). The most common reasons against adjuvant treatment given by patients were age (29.4%, 95% CI 24-38), and fear of adverse events (21.1%, 95% CI 16-28) and impaired quality of life (11.9%, 95% CI 7-16). Of all BRAF-mutated patients who opted for adjuvant treatment, 52.9% (95% CI 47-59) decided for ICI. Treatment decision for TT or ICI was barely associated with age, gender and tumor stage, but with comorbidities and affiliated center. Shortly after their approval, adjuvant treatments have been well accepted by physicians and patients. Age plays a decisive role in the decision for adjuvant treatment, while pre-existing autoimmune disease and regional differences influence the choice between TT or ICI.

    Pubmed
  • Outcome of melanoma patients with elevated LDH treated with first-line targeted therapy or PD-1-based immune checkpoint inhibition.

    Eur J Cancer. 2021;148(): 61-75

    Knispel S, Gassenmaier M, Menzies AM, Loquai C, Johnson DB, Franklin C, Gutzmer R, Hassel JC, Weishaupt C, Eigentler T, Schilling B, Schummer P, Sirokay J, Kiecker F, Owen CN, Fleischer MI, Cann C, Kähler KC, Mohr P, Bluhm L, Niebel D, Thoms KM, Goldinger SM, Reinhardt L, Meier F, Berking C, Reinhard R, Susok L, Ascierto PA, Drexler K, Pföhler C, Tietze J, Heinzerling L, Livingstone E, Ugurel S, Long GV, Stang A, Schadendorf D, Zimmer L

    BACKGROUND: Elevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanoma patients with elevated LDH because prospective studies in this area are lacking.

    METHODS: This multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanoma patients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting.

    RESULTS: Among 173 BRAFV600-mutant patients, PFS at 12 months in the TT group was 22% compared with 52% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.6, 95% CI 0.4-1.0, p = 0.07) and 18% in the anti-PD-1 monotherapy group (HR 1.8, 95% CI 1.2-2.8, p = 0.003). Twelve months' OS was 48% in the TT group compared with 83% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.5, 95% CI 0.3-1.0, p = 0.03) and 50% in the anti-PD-1 monotherapy group (HR 1.2, 95% CI 0.8-2.0, p = 0.37). The ORR in the TT group was 63%, compared with 55% and 20% in the combined anti-PD-1 and anti-CTLA-4 and anti-PD-1 monotherapy group, respectively. Among 314 patients receiving ICI first-line, PFS at 12 months was 33% in the anti-PD-1 group versus 38% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.8, 95% CI 0.6-1.0; p = 0.07). OS at 12 months was 54% in the anti-PD-1 group versus 66% in the combined ICI group (HR 0.7, 95% CI 0.5-1.0; p = 0.03). The ORR was 30% in the anti-PD-1 monotherapy group and 43% in the combined anti-PD-1 and anti-CTLA-4 group. Results from multivariate analysis confirmed the absence of qualitative confounding.

    CONCLUSIONS: Among BRAF-mutant patients with elevated LDH, combined anti-PD-1 and anti-CTLA-4 blockade seems to be associated with prolonged OS compared with first-line TT. Among patients receiving ICI as a first-line treatment, OS appears to be longer for the combination of anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone.

    Pubmed
  • [Treatment of psoriasis with secukinumab : Practical guidance].

    Hautarzt. 2021;72(11): 984-991

    Körber A, Augustin M, Behrens F, Gerdes S, von Kiedrowski R, Schäkel K, Sticherling M, Wilsmann-Theis D, Wohlrab J, Simon JC

    BACKGROUND: Moderate to severe plaque psoriasis can be treated effectively with immunomodulating biologicals such as the interleukin-17A inhibitor secukinumab. In practice, however, questions often arise as to how to proceed in special situations, such as infections, comorbidity, pregnancy, or surgery.

    OBJECTIVES: To address frequent questions about the treatment of plaque psoriasis with secukinumab in a consensus document of German psoriasis experts that supplements current guidelines.

    METHODS: In a virtual expert meeting in May 2020, practical aspects of the treatment of psoriasis were discussed based on the experience of the participants and on current literature. The results of this discussion were summarized in the present consensus document.

    RESULTS: This article provides practical guidance on case history, documentation of previous therapies, severity of psoriasis, and comorbidities before starting therapy with secukinumab. For patients treated with secukinumab, the course of action in case of vaccinations, chronic or acute infections, surgical interventions, special manifestations of psoriasis, and comorbidities including history of cancer and autoimmune disorders is discussed. Questions regarding family planning and health policy regulations are also addressed.

    DISCUSSION: The recommendations for the treatment of psoriasis with secukinumab summarized in this consensus document may contribute to achieve optimal therapy for patients and to improve their quality of life.

    Pubmed
  • Sister-Mary-Joseph-Knoten der Brust - Beschreibung einer neuen Entität?

    J Dtsch Dermatol Ges. 2021;19 Suppl 1(): 14-16

    Popp J, Heppt M, Berking C, Heppt F

    Pubmed
  • [Talking about vaccinations-also relevant for dermatology?]

    Hautarzt. 2021;72(2):

    Sticherling M

    Pubmed
  • [Vaccinations in dermatology].

    Hautarzt. 2021;72(2): 100-105

    Sticherling M

    Vaccinations are among the most successful prophylactic measures in medicine. As they are applied to healthy subjects, regulatory steps before licensing of any vaccination are strictly based on clinically controlled studies as well as on registry data in the further course. The probability and relevance of adverse reactions to vaccinations have to be weighed against any harm through the respective natural infection as well as the vaccination-induced protection against infections. Intolerance reactions to vaccinations are far more suspected than proven and altogether rare. Among these, specific dermatoses like psoriasis, atopic dermatitis and lichen planus are found as well as allergic reactions and a number of more nonspecific skin symptoms. Apart from provocation or exacerbation of an underlying dermatological disease, various intolerance reactions may be encountered which are classically allergologic or anaphylactoid. People with chronic dermatoses, especially those on immunosuppressive and immunomodulatory therapy, should have all recommended standard vaccinations. Vaccinations should not be administered during acute skin manifestations and relevant comedication-especially if immunomodulatory or immunosuppressive-has be taken into account in the decision to vaccinate and to define the time point of any vaccination. Inactivated vaccines may be administered even during ongoing immunosuppressive therapy, but may result in decreased immunological reactions and protection to infection. Live vaccines should be avoided.

    Pubmed
  • Onkologische Systemtherapie bis zum bitteren Ende?

    J Dtsch Dermatol Ges. 2021;19(9): 1259-1260

    Berking C

    Pubmed
  • Real-world effectiveness of guselkumab in patients with psoriasis: Health-related quality of life and efficacy data from the noninterventional, prospective, German multicenter PERSIST trial.

    J Dermatol. 2021;48(12): 1854-1862

    Gerdes S, Bräu B, Hoffmann M, Korge B, Mortazawi D, Wiemers F, Wegner S, Personke Y, Gomez M, Sticherling M

    Psoriasis is a common, chronic inflammatory skin disorder negatively impacting health-related quality of life (HRQoL). Guselkumab, targeting interleukin-23 (IL-23), is an approved biologic therapy for psoriasis. PERSIST is an ongoing prospective, noninterventional, long-term, German multicenter study evaluating the effect of guselkumab on HRQoL, and its efficacy and safety in patients with moderate-to-severe psoriasis in a real-world setting. The primary endpoint is the proportion of patients with a Dermatology Life Quality Index (DLQI) score ≤ 1 at week 28. Of 303 patients enrolled and treated with guselkumab, mean age and disease duration were 49.7 and 21.0 years, respectively, and 51.2% (n = 155) of patients had received ≥1 prior biologic therapy. Mean baseline DLQI score was 13.7, and mean symptom and sign scores in the Psoriasis Symptoms and Signs Diary (PSSD) were 51.9 and 60.8, respectively. Baseline Psoriasis Area Severity Index (PASI) and body surface area (%) scores were 16.4 and 27.5. Following 28 weeks of guselkumab treatment, the mean DLQI score decreased to 2.8, and 56.8% of patients (n = 150) achieved DLQI ≤ 1. Mean PSSD symptom and sign scores also improved, decreasing to 12.5 and 15.9, respectively. At week 28, PASI 90 response was 55.3%; significant improvement was observed in patients with psoriasis in difficult-to-treat areas. Overall, analyses demonstrated that guselkumab was effective in the real-world setting, as measured by HRQoL and skin improvements, even in patients with a high burden of disease and those who have received multiple biologic therapies. No new safety signals were observed.

    Pubmed
  • Documentation of psoriasis in routine care - expert consensus on a German data set.

    J Dtsch Dermatol Ges. 2021;19(10): 1463-1475

    Otten M, Mrowietz U, von Kiedrowski RM, Otto R, Altenburg A, Aschoff R, Beissert S, Beiteke U, Bonnekoh B, Hoffmann M, Körber A, Maaßen D, Mössner R, Navarini A, Petering H, Ramaker-Brunke J, Rosenbach T, Schwichtenberg U, Sticherling M, Sondermann W, Thaci D, Timmel A, Tsianakas A, Werfel T, Wilsmann-Theis D, Augustin M

    BACKGROUND AND OBJECTIVES: Documenting patient data in psoriasis clinical practice can improve care, but standardized and transparent documentation is rare. The current project aimed to develop a data set for the documentation of psoriasis in daily practice.

    MATERIAL AND METHODS: In four online Delphi rounds and one in-person meeting, 27 psoriasis experts allocated variables to a standard, an optimal and an optional data set. Most of the questions were standardized. Open questions were included to allow for the provision of reasons and to enlarge the data sets. Furthermore, in the in-person meeting we considered a) patients' attitudes and b) dermatologists' information on the current usage and acceptability in Germany.

    RESULTS: The consensus approach resulted in a data set with 69 variables. The standard data set includes 20, the optimal data set 31 and the optional data set 18 variables. In summary, the data set can mainly be grouped into master data, general status and medical history data, medical history of psoriasis, status of psoriasis, diagnostics and comorbidity, therapies and patient-reported outcomes.

    CONCLUSIONS: The consensus recommendation of a standard, an optimal and an optional data set for routine care of psoriasis intends to be a decision-making aid and an orientation for both daily practice and further development of documentation systems.

    Pubmed
  • S2k guideline: Diagnosis and management of cutaneous lupus erythematosus - Part 1: Classification, diagnosis, prevention, activity scores.

    J Dtsch Dermatol Ges. 2021;19(8): 1236-1247

    Worm M, Zidane M, Eisert L, Fischer-Betz R, Foeldvari I, Günther C, Iking-Konert C, Kreuter A, Müller-Ladner U, Nast A, Ochsendorf F, Schneider M, Sticherling M, Tenbrock K, Wenzel J, Kuhn A

    Pubmed
  • S2k guideline: Diagnosis and management of cutaneous lupus erythematosus - Part 2: Therapy, risk factors and other special topics.

    J Dtsch Dermatol Ges. 2021;19(9): 1371-1395

    Worm M, Zidane M, Eisert L, Fischer-Betz R, Foeldvari I, Günther C, Iking-Konert C, Kreuter A, Müller-Ladner U, Nast A, Ochsendorf F, Schneider M, Sticherling M, Tenbrock K, Wenzel J, Kuhn A

    Pubmed
  • Dedifferentiated and Undifferentiated Melanomas: Report of 35 New Cases With Literature Review and Proposal of Diagnostic Criteria.

    Am J Surg Pathol. 2021;45(2): 240-254

    Agaimy A, Stoehr R, Hornung A, Popp J, Erdmann M, Heinzerling L, Hartmann A

    Dedifferentiated melanoma (DM) and undifferentiated melanoma (UM) is defined as a primary or metastatic melanoma showing transition between conventional and undifferentiated components (DM) or lacking histologic and immunophenotypic features of melanoma altogether (UM). The latter is impossible to verify as melanoma by conventional diagnostic tools alone. We herein describe our experience with 35 unpublished cases to expand on their morphologic, phenotypic, and genotypic spectrum, along with a review of 50 previously reported cases (total: 85) to establish the diagnostic criteria. By definition, the dedifferentiated/undifferentiated component lacked expression of 5 routinely used melanoma markers (S100, SOX10, Melan-A, HMB45, Pan-melanoma). Initial diagnoses (known in 66 cases) were undifferentiated/unclassified pleomorphic sarcoma (n=30), unclassified epithelioid malignancy (n=7), pleomorphic rhabdomyosarcoma (n=5), other specific sarcoma types (n=6), poorly differentiated carcinoma (n=2), collision tumor (n=2), atypical fibroxanthoma (n=2), and reactive osteochondromatous lesion (n=1). In only 11 cases (16.6%) was a diagnosis of melanoma considered. Three main categories were identified: The largest group (n=56) comprised patients with a history of verified previous melanoma who presented with metastatic DM or UM. Axillary or inguinal lymph nodes, soft tissue, bone, and lung were mainly affected. A melanoma-compatible mutation was detected in 35 of 48 (73%) evaluable cases: BRAF (n=20; 40.8%), and NRAS (n=15; 30.6%). The second group (n=15) had clinicopathologic features similar to group 1, but a melanoma history was lacking. Axillary lymph nodes (n=6) was the major site in this group followed by the lung, soft tissue, and multiple site involvement. For this group, NRAS mutation was much more frequent (n=9; 60%) than BRAF (n=3; 20%) and NF1 (n=1; 6.6%). The third category (n=14) comprised primary DM (12) or UM (2). A melanoma-compatible mutation was detected in only 7 cases: BRAF (n=2), NF1 (n=2), NRAS (n=2), and KIT exon 11 (n=1). This extended follow-up study highlights the high phenotypic plasticity of DM/UM and indicates significant underrecognition of this aggressive disease among general surgical pathologists. The major clues to the diagnosis of DM and UM are: (1) presence of minimal differentiated clone in DM, (2) earlier history of melanoma, (3) undifferentiated histology that does not fit any defined entity, (4) locations at sites that are unusual for undifferentiated/unclassified pleomorphic sarcoma (axilla, inguinal, neck, digestive system, etc.), (5) unusual multifocal disease typical of melanoma spread, (6) detection of a melanoma-compatible gene mutation, and (7) absence of another genuine primary (eg, anaplastic carcinoma) in other organs.

    Pubmed
  • Comparative Transcriptomics of Immune Checkpoint Inhibitor Myocarditis Identifies Guanylate Binding Protein 5 and 6 Dysregulation.

    Cancers (Basel). 2021;13(10):

    Finke D, Heckmann MB, Salatzki J, Riffel J, Herpel E, Heinzerling LM, Meder B, Völkers M, Müller OJ, Frey N, Katus HA, Leuschner F, Kaya Z, Lehmann LH

    Immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment. Nevertheless, their increasing use leads to an increase of immune-related adverse events (irAEs). Among them, ICI-associated myocarditis (ICIM) is a rare irAE with a high mortality rate. We aimed to characterize the transcriptional changes of ICIM myocardial biopsies and their possible implications. Patients suspected for ICIM were assessed in the cardio-oncology units of University Hospitals Heidelberg and Kiel. Via RNA sequencing of myocardial biopsies, we compared transcriptional changes of ICIM (n = 9) with samples from dilated cardiomyopathy (DCM, n = 11), virus-induced myocarditis (VIM, n = 5), and with samples of patients receiving ICIs without any evidence of myocarditis (n = 4). Patients with ICIM (n = 19) showed an inconsistent clinical presentation, e.g., asymptomatic elevation of cardiac biomarkers (hs-cTnT, NT-proBNP, CK), a drop in left ventricular ejection fraction, or late gadolinium enhancement in cMRI. We found 3784 upregulated genes in ICIM (FDR < 0.05). In the overrepresented pathway 'response to interferon-gamma', we found guanylate binding protein 5 and 6 (compared with VIM: GBP5 (log2 fc 3.21), GBP6 (log2 fc 5.37)) to be significantly increased in ICIM on RNA- and protein-level. We conclude that interferon-gamma and inflammasome-regulating proteins, such as GBP5, may be of unrecognized significance in the pathophysiology of ICIM.

    Pubmed
  • Combining CNN-based histologic whole slide image analysis and patient data to improve skin cancer classification.

    Eur J Cancer. 2021;149(): 94-101

    Höhn J, Krieghoff-Henning E, Jutzi TB, von Kalle C, Utikal JS, Meier F, Gellrich FF, Hobelsberger S, Hauschild A, Schlager JG, French L, Heinzerling L, Schlaak M, Ghoreschi K, Hilke FJ, Poch G, Kutzner H, Heppt MV, Haferkamp S, Sondermann W, Schadendorf D, Schilling B, Goebeler M, Hekler A, Fröhling S, Lipka DB, Kather JN, Krahl D, Ferrara G, Haggenmüller S, Brinker TJ

    BACKGROUND: Clinicians and pathologists traditionally use patient data in addition to clinical examination to support their diagnoses.

    OBJECTIVES: We investigated whether a combination of histologic whole slides image (WSI) analysis based on convolutional neural networks (CNNs) and commonly available patient data (age, sex and anatomical site of the lesion) in a binary melanoma/nevus classification task could increase the performance compared with CNNs alone.

    METHODS: We used 431 WSIs from two different laboratories and analysed the performance of classifiers that used the image or patient data individually or three common fusion techniques. Furthermore, we tested a naive combination of patient data and an image classifier: for cases interpreted as 'uncertain' (CNN output score <0.7), the decision of the CNN was replaced by the decision of the patient data classifier.

    RESULTS: The CNN on its own achieved the best performance (mean ± standard deviation of five individual runs) with AUROC of 92.30% ± 0.23% and balanced accuracy of 83.17% ± 0.38%. While the classification performance was not significantly improved in general by any of the tested fusions, naive strategy of replacing the image classifier with the patient data classifier on slides with low output scores improved balanced accuracy to 86.72% ± 0.36%.

    CONCLUSION: In most cases, the CNN on its own was so accurate that patient data integration did not provide any benefit. However, incorporating patient data for lesions that were classified by the CNN with low 'confidence' improved balanced accuracy.

    Pubmed
  • Monitoring skin metastases during immuno- and targeted therapy using total-body 3D photography.

    J Eur Acad Dermatol Venereol. 2021;35(1): e61-e63

    Erdmann M, Heinzerling L, Schuler G, Berking C, Schliep S

    Pubmed
  • Electrocardiographic features of immune checkpoint inhibitor associated myocarditis.

    J Immunother Cancer. 2021;9(3):

    Zlotoff DA, Hassan MZO, Zafar A, Alvi RM, Awadalla M, Mahmood SS, Zhang L, Chen CL, Ederhy S, Barac A, Banerji D, Jones-O'Connor M, Murphy SP, Armanious M, Forrestal BJ, Kirchberger MC, Coelho-Filho OR, Rizvi MA, Sahni G, Mandawat A, Tocchetti CG, Hartmann S, Gilman HK, Zatarain-Nicolás E, Mahmoudi M, Gupta D, Sullivan R, Ganatra S, Yang EH, Heinzerling LM, Thuny F, Zubiri L, Reynolds KL, Cohen JV, Lyon AR, Groarke J, Thavendiranathan P, Nohria A, Fradley MG, Neilan TG

    BACKGROUND: Myocarditis is a highly morbid complication of immune checkpoint inhibitor (ICI) use that remains inadequately characterized. The QRS duration and the QTc interval are standardized electrocardiographic measures that are prolonged in other cardiac conditions; however, there are no data on their utility in ICI myocarditis.

    METHODS: From an international registry, ECG parameters were compared between 140 myocarditis cases and 179 controls across multiple time points (pre-ICI, on ICI prior to myocarditis, and at the time of myocarditis). The association between ECG values and major adverse cardiac events (MACE) was also tested.

    RESULTS: Both the QRS duration and QTc interval were similar between cases and controls prior to myocarditis. When compared with controls on an ICI (93±19 ms) or to baseline prior to myocarditis (97±19 ms), the QRS duration prolonged with myocarditis (110±22 ms, p<0.001 and p=0.009, respectively). In contrast, the QTc interval at the time of myocarditis (435±39 ms) was not increased compared with pre-myocarditis baseline (422±27 ms, p=0.42). A prolonged QRS duration conferred an increased risk of subsequent MACE (HR 3.28, 95% CI 1.98 to 5.62, p<0.001). After adjustment, each 10 ms increase in the QRS duration conferred a 1.3-fold increase in the odds of MACE (95% CI 1.07 to 1.61, p=0.011). Conversely, there was no association between the QTc interval and MACE among men (HR 1.33, 95% CI 0.70 to 2.53, p=0.38) or women (HR 1.48, 95% CI 0.61 to 3.58, p=0.39).

    CONCLUSIONS: The QRS duration is increased in ICI myocarditis and is associated with increased MACE risk. Use of this widely available ECG parameter may aid in ICI myocarditis diagnosis and risk-stratification.

    Pubmed
  • Myocardial T1 and T2 Mapping by Magnetic Resonance in Patients With Immune Checkpoint Inhibitor-Associated Myocarditis.

    J Am Coll Cardiol. 2021;77(12): 1503-1516

    Thavendiranathan P, Zhang L, Zafar A, Drobni ZD, Mahmood SS, Cabral M, Awadalla M, Nohria A, Zlotoff DA, Thuny F, Heinzerling LM, Barac A, Sullivan RJ, Chen CL, Gupta D, Kirchberger MC, Hartmann SE, Weinsaft JW, Gilman HK, Rizvi MA, Kovacina B, Michel C, Sahni G, González-Mansilla A, Calles A, Fernández-Avilés F, Mahmoudi M, Reynolds KL, Ganatra S, Gavira JJ, González NS, García de Yébenes Castro M, Kwong RY, Jerosch-Herold M, Coelho-Filho OR, Afilalo J, Zataraín-Nicolás E, Baksi AJ, Wintersperger BJ, Calvillo-Arguelles O, Ederhy S, Yang EH, Lyon AR, Fradley MG, Neilan TG

    BACKGROUND: Myocarditis is a potentially fatal complication of immune checkpoint inhibitor (ICI) therapy. Data on the utility of cardiovascular magnetic resonance (CMR) T1 and T2 mapping in ICI myocarditis are limited.

    OBJECTIVES: This study sought to assess the value of CMR T1 and T2 mapping in patients with ICI myocarditis.

    METHODS: In this retrospective study from an international registry of patients with ICI myocarditis, clinical and CMR findings (including T1 and T2 maps) were collected. Abnormal T1 and T2 were defined as 2 SD above site (vendor/field strength specific) reference values and a z-score was calculated for each patient. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block.

    RESULTS: Of 136 patients with ICI myocarditis with a CMR, 86 (63%) had T1 maps and 79 (58%) also had T2 maps. Among the 86 patients (66.3 ± 13.1 years of age), 36 (41.9%) had a left ventricular ejection fraction <55%. Across all patients, mean z-scores for T1 and T2 values were 2.9 ± 1.9 (p < 0.001) and 2.2 ± 2.1 (p < 0.001), respectively. On Siemens 1.5-T scanner (n = 67), native T1 (1,079.0 ± 55.5 ms vs. 1,000.3 ± 22.1 ms; p < 0.001) and T2 (56.2 ± 4.9 ms vs. 49.8 ± 2.2 ms; p < 0.001) values were elevated compared with reference values. Abnormal T1 and T2 values were seen in 78% and 43% of the patients, respectively. Applying the modified Lake Louise Criteria, 95% met the nonischemic myocardial injury criteria and 53% met the myocardial edema criteria. Native T1 values had excellent discriminatory value for subsequent MACE, with an area under the curve of 0.91 (95% confidence interval: 0.84 to 0.98). Native T1 values (for every 1-unit increase in z-score, hazard ratio: 1.44; 95% confidence interval: 1.12 to 1.84; p = 0.004) but not T2 values were independently associated with subsequent MACE.

    CONCLUSIONS: The use of T1 mapping and application of the modified Lake Louise Criteria provides important diagnostic value, and T1 mapping provides prognostic value in patients with ICI myocarditis.

    Pubmed
  • Transient response to nivolumab and relapse after infliximab in a patient with primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma.

    Br J Dermatol. 2021;184(2): 345-347

    Toussaint F, Erdmann M, Grosch E, Schliep S, Schuler G, Dummer R, Heinzerling L

    Pubmed
  • MAPK blockade, toxicities, pathogenesis and management.

    Curr Opin Oncol. 2021;33(2): 139-145

    Moreira A, Lebbé C, Heinzerling L

    PURPOSE OF REVIEW: BRAF/MEK inhibitor has changed the treatment landscape in patients with advanced and metastatic melanoma with prolonged overall survival and progression-free survival. Since three treatment combinations exist with similar efficacy therapy decisions are often made based on the side effect profile. Additionally, on-target side effects or class effects have to be properly managed to ensure treatment adherence.

    RECENT FINDINGS: Sequential treatment with BRAF/MEK inhibition and immunotherapy might increase toxicity with a sepsis-like syndrome and triple therapy with concomitant BRAF/MEK inhibition and anti-PD1/PD-L1 antibody therapy induces severe side effects in the vast majority of patients.

    SUMMARY: Toxicity of combination therapy with BRAF/MEK inhibitors is generally manageable, reversible and infrequently associated with treatment discontinuation. In case of persisting off-target effects the change to another combination therapy can resolve side effects.

    Pubmed
  • Four cases of erysipelas-like inflammation in patients with metastatic melanoma treated with checkpoint inhibitors.

    J Dtsch Dermatol Ges. 2021;19(4): 598-602

    Pföhler C, Hassel JC, Heinzerling L, Müller CSL

    Pubmed
  • Multicomponent compression system use in patients with chronic venous insufficiency: a real-life prospective study.

    J Wound Care. 2021;30(5): 400-412

    Stücker M, Münter KC, Erfurt-Berge C, Lützkendorf S, Eder S, Möller U, Dissemond J

    OBJECTIVE: Compression therapy is the cornerstone of therapeutic management of patients with chronic venous insufficiency (CVI). This study aimed to evaluate the efficacy and safety of a multicomponent compression system in an unselected population of patients with CVI problems under real-life conditions.

    METHOD: A prospective, multicentre, observational study with a multicomponent two-bandage compression system (UrgoK2, Laboratoires Urgo, France) was conducted in 103 centres in Germany. Main outcomes included wound healing rate, wound healing progression, assessment of oedema and ankle mobility, local tolerability and acceptance of the compression therapy.

    RESULTS: A total of 702 patients with venous leg ulcers (VLU) and/or with lower limb oedema due to CVI were treated with the evaluated system for a mean (±standard deviation) duration of 27±17 days. By the last visit, 30.9% of wounds had healed and 61.8% had improved. Limb oedema was resolved in 66.7% of patients and an improvement of ankle mobility was reported in 44.2% of patients. The skin condition under the compression therapy was also considered as improved in 73.9% of patients and a substantial reduction of pain was achieved, both in number of patients reporting pain and in pain intensity. Compression therapy with the evaluated system was 'very well' or 'well' tolerated and 'very well' or 'well' accepted by >95% of patients. These positive outcomes were in line with the general opinion of physicians on the evaluated compression bandages, which were judged 'very useful' or 'useful' for >96.6% of patients. Similar results were reported regardless of the treated condition, VLU and/or limb oedema.

    CONCLUSION: Real-life data documented in this large observational study of non-selected patients receiving compression therapy in daily practice confirm the benefits and safety profile of the evaluated compression system. This study also confirms the high-level of performance and acceptability of the system, regardless of the characteristics of the wounds or patients at initiation of the treatment. The data support the use of this multicomponent compression system as one first-line intervention in patients with symptoms caused by CVI.

    Pubmed
  • Impaired Wound Healing with Imatinib Mesylate Therapy.

    Adv Skin Wound Care. 2021;34(2): 109-111

    Ronicke M, Erfurt-Berge C

    ABSTRACT: Medication-induced ulcers are generally rare. Although the tyrosine kinase inhibitor imatinib mesylate is frequently prescribed, the occurrence of ulcers related to the medication has not been previously described. Herein, the authors report a case of a patient with impaired wound healing that was attributed to imatinib mesylate treatment. Providers should maintain suspicion for medication-induced ulcers, particularly if treatment for the presumed underlying cause of an ulcer fails.

    Pubmed
  • [Standard of patient-centred care before admission to a university wound centre].

    Hautarzt. 2021;72(6): 517-524

    Erfurt-Berge C, Michler M, Renner R

    BACKGROUND AND OBJECTIVES: Health care for patients with chronic wounds is often protracted. This can result in decreased quality of care or delayed diagnosis of the actual cause of disease. Concurrently, there are already certified facilities for these patients. The present work investigates possible reasons for delayed referral and whether a specific selection of patients is sent to these university-based centres.

    PATIENTS AND METHODS: A retrospective patient data chart review at the point of first admission to the certified wound centre was performed to identify concerning variables about the standard of care before university presentation.

    RESULTS: Records of 177 patients were analysed (53% women, 47% men; patient age range 27-95 years). The mean duration of the wound was 22 months. Vascular diagnostics had already been performed in 32% (arterial diagnostics) and 36% (phlebological diagnostics), respectively. A tissue sample had been analysed in 9% of cases, especially when wound duration exceeded > 24 months. In only 45% of cases was the external diagnosis in accord with the final diagnosis in the wound centre.

    DISCUSSION: The health care situation for patients with chronic wounds outside of specialised care structures is insufficient. Early and standardized diagnostics and therapy and a reasonable admission to specialised centres is desired.

    Pubmed
  • Multi-Antigen Imaging Reveals Inflammatory DC, ADAM17 and Neprilysin as Effectors in Keloid Formation.

    Int J Mol Sci. 2021;22(17):

    Rath M, Pitiot A, Kirr M, Fröhlich W, Plosnita B, Schliep S, Bauerschmitz J, Baur AS, Ostalecki C

    Keloid is an aberrant scarring process of the skin, characterized by excessive extracellular matrix synthesis and deposition. The pathogenesis of this prevalent cutaneous disorder is not fully understood; however, a persistent inflammatory process is observed. To obtain more insight into this process, we analyzed lesional, perilesional and healthy tissue using multi-antigen-analysis (MAA) in conjunction with a data mining approach. Here, we demonstrate that monocyte-derived inflammatory dendritic cells (CD1a+, CD11c+, CD14+) and activated CD4+ T lymphocytes (CD45 RO+) dominated the immune infiltration in keloids while associating with fibroblasts. In perilesional tissue, precursor immune cells were dominant in the perivascular area, suggesting that they were attracted by an immune process, potentially in the lesional area. Supporting this hypothesis, only in keloid lesions, high levels of ADAM10/17 and Neprilysin (CD10) were observed in both fibroblasts and leukocytes. The spatial proximity of these two cell types, which could be confirmed by image analysis only in lesional tissue, could be a potential factor leading to the activation of fibroblasts. Our findings provide new insight into the pathogenesis of keloid formation and reveal metalloproteinases as a target for therapeutical intervention.

    Pubmed
  • Treatment-resistant actinic keratoses are characterized by distinct clinical and histological features.

    Ital J Dermatol Venerol. 2021;156(2): 213-219

    Schmitz L, Brehmer A, Falkenberg C, Gambichler T, Heppt MV, Steeb T, Gupta G, Malvehy J, Dirschka T

    BACKGROUND: Actinic keratoses (AK) are generally treated to reduce the risk of progression into invasive cutaneous squamous cell carcinoma (cSCC). However, this risk of transformation is low, and rather than focusing on these lesions, current treatment studies report on complete clearance of AKs in an entire field. This study aimed to investigate treatment-resistant AKs (trAK) after field therapy compared to randomly chosen AKs prior to treatment.

    METHODS: AKs were clinically assessed according to the grade of hyperkeratosis and pain on palpation, prior to treatment. TrAKs were biopsied and compared to AKs which were biopsied prior to any treatment. AKs were evaluated regarding histological severity (AKI-III), their basal growth grading (PROI-III), acantholysis, elastosis, follicular extension of atypical keratinocytes and accompanying infiltrate.

    RESULTS: Two hundred eleven AKs in 171 patients were identified. TrAKs (N.=79) were significantly more painful (64.6% vs. 22.0%; P<0.0001), showing acantholysis (57.0% vs. 33.3%; P=0.0007); and with distinct basal proliferation (PROIII) (64.4% vs. 46.2%; P=0.0099) compared to the control group (N.=132). In a multivariate analysis using logistic regression, pain and PRO III graded lesions were significant independent (P<0.0001 and P=0.0179) predictors for trAKs. Focusing on individual histological features in the trAK group, AKs with grade AKIII, PROIII or follicular extension reaching the sebaceous gland were the most common findings with 51.9%, 64.6%, and 59.5% AKs demonstrating this, respectively.

    CONCLUSIONS: TrAKs are often painful, showing a distinct basal proliferation (PROIII) and acantholysis. As these features are also seen in invasive cSCCs, trAKs may represent a subgroup of AKs and, for this reason, it requires further evaluations.

    Pubmed
  • Response to letter entitled: 'Re: Hematological immune related adverse events after treatment with immune checkpoint inhibitors'.

    Eur J Cancer. 2021;153(): 272-273

    Heinzerling L, La Rosée P, Gutzmer R, Kramer R, Keller-Stanislawski B, Zierold S, Mentzer D

    Pubmed
  • Patch test results with the European baseline series and additions thereof in the ESSCA network, 2015-2018.

    Contact Dermatitis. 2021;84(2): 109-120

    Uter W, Bauer A, Belloni Fortina A, Bircher AJ, Brans R, Buhl T, Cooper SM, Czarnecka-Operacz M, Dickel H, Dugonik A, Geier J, Giménez-Arnau AM, Gonçalo M, Johansen JD, Johnston GA, Mahler V, Rustemeyer T, Sanchez-Perez J, Schuttelaar MLA, Simon D, Spiewak R, Valiukevičienė S, Weisshaar E, White IR, Wilkinson M, ESSCA Working Group , Aberer W, Ballmer-Weber B, Becker D, Beiteke U, Brasch J, Chowdhury MM, Corradin MT, Dietrich C, Gallo R, Grabbe J, John SM, Pandurovic MK, Kecelj N, Kmecl T, Kränke B, Filon FL, Lunder T, Mercader P, Navarini A, Peserico A, Pesonen M, Ruiz I, Sadowska-Przytocka A, Scherer-Hofmeier K, Schliemann S, Godnič MS, Stingeni L, Stone N, Vok M, Wagner N, Werfel T

    BACKGROUND: Clinical surveillance of the prevalence of contact allergy in consecutively patch tested patients is a proven instrument to continually assess the importance of contact allergens (haptens) assembled in a baseline series.

    OBJECTIVES: To present current results from the European Surveillance System on Contact Allergies, including 13 countries represented by 1 to 11 departments.

    METHODS: Anonymized or pseudonymized patch test and clinical data from various data capture systems used locally or nationally as transferred to the Erlangen data centre were pooled and descriptively analysed after quality control.

    RESULTS: In the 4 years (2015-2018), data from 51 914 patients patch tested with the European baseline series (EBS) of contact allergens were analysed. Contact allergy to nickel was most frequent (17.6% positive), followed by contact allergy to fragrance mix I (6.9%), methylisothiazolinone (MI; 6.2%), and Myroxylon pereirae resin (balsam of Peru; 5.8%).

    CONCLUSIONS: While the prevalence of MI contact allergy decreased substantially following regulatory intervention, the persistently high levels of allergy to metals, fragrances, other preservatives, and rubber chemicals point to problems needing further research and, potentially, preventive efforts. Results with national additions to the baseline series provide important information on substances possibly to be considered for inclusion in the EBS.

    Pubmed
  • Phenotype and risk factors of venom-induced anaphylaxis: A case-control study of the European Anaphylaxis Registry.

    J Allergy Clin Immunol. 2021;147(2): 653-662.e9

    Francuzik W, Ruëff F, Bauer A, Bilò MB, Cardona V, Christoff G, Dölle-Bierke S, Ensina L, Fernández Rivas M, Hawranek T, O'B Hourihane J, Jakob T, Papadopoulos NG, Pföhler C, Poziomkowska-Gęsicka I, Van der Brempt X, Scherer Hofmeier K, Treudler R, Wagner N, Wedi B, Worm M

    BACKGROUND: Venom-induced anaphylaxis (VIA) is a common, potentially life-threatening hypersensitivity reaction associated with (1) a specific symptom profile, 2) specific cofactors, and 3) specific management. Identifying the differences in phenotypes of anaphylaxis is crucial for future management guidelines and development of a personalized medicine approach.

    OBJECTIVE: This study aimed to evaluate the phenotype and risk factors of VIA.

    METHODS: Using data from the European Anaphylaxis Registry (12,874 cases), we identified 3,612 patients with VIA and analyzed their cases in comparison with sex- and age-matched anaphylaxis cases triggered by other elicitors (non-VIA cases [n = 3,605]).

    RESULTS: VIA more frequently involved more than 3 organ systems and was associated with cardiovascular symptoms. The absence of skin symptoms during anaphylaxis was correlated with baseline serum tryptase level and was associated with an increased risk of a severe reaction. Intramuscular or intravenous epinephrine was administered significantly less often in VIA, in particular, in patients without a history of anaphylaxis. A baseline serum tryptase level within the upper normal range (8-11.5 ng/mL) was more frequently associated with severe anaphylaxis.

    CONCLUSION: Using a large cohort of VIA cases, we have validated that patients with intermediate baseline serum tryptase levels (8-11 ng/mL) and without skin involvement have a higher risk of severe VIA. Patients receiving β-blockers or angiotensin-converting enzyme inhibitors had a higher risk of developing severe cardiovascular symptoms (including cardiac arrest) in VIA and non-VIA cases. Patients experiencing VIA received epinephrine less frequently than did cases with non-VIA.

    Pubmed
  • A Chimeric IL-15/IL-15Rα Molecule Expressed on NFκB-Activated Dendritic Cells Supports Their Capability to Activate Natural Killer Cells.

    Int J Mol Sci. 2021;22(19):

    Bosch NC, Martin LM, Voskens CJ, Berking C, Seliger B, Schuler G, Schaft N, Dörrie J

    Natural killer (NK) cells, members of the innate immune system, play an important role in the rejection of HLA class I negative tumor cells. Hence, a therapeutic vaccine, which can activate NK cells in addition to cells of the adaptive immune system might induce a more comprehensive cellular response, which could lead to increased tumor elimination. Dendritic cells (DCs) are capable of activating and expanding NK cells, especially when the NFκB pathway is activated in the DCs thereby leading to the secretion of the cytokine IL-12. Another prominent NK cell activator is IL-15, which can be bound by the IL-15 receptor alpha-chain (IL-15Rα) to be transpresented to the NK cells. However, monocyte-derived DCs do neither secrete IL-15, nor express the IL-15Rα. Hence, we designed a chimeric protein consisting of IL-15 and the IL-15Rα. Upon mRNA electroporation, the fusion protein was detectable on the surface of the DCs, and increased the potential of NFκB-activated, IL-12-producing DC to activate NK cells in an autologous cell culture system with ex vivo-generated cells from healthy donors. These data show that a chimeric IL-15/IL-15Rα molecule can be expressed by monocyte-derived DCs, is trafficked to the cell surface, and is functional regarding the activation of NK cells. These data represent an initial proof-of-concept for an additional possibility of further improving cellular DC-based immunotherapies of cancer.

    Pubmed
  • Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial.

    Lancet Oncol. 2021;22(5): 643-654

    Eggermont AMM, Blank CU, Mandalà M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C, EORTC Melanoma Group , Menzies A, Lesimple T, Maio M, Linette G, Brown M, Hersey P, Svane IM, Mortier L, Schachter J, Barrow C, Kudchadkar R, Song X, Dutriaux C, Quaglino P, Meier F, Queirolo P, Stroyakovskiy D, Bastholt L, Guillot B, Garbe C, Ortiz Romero PL, Grange F, Mohr P, Algazi A, Bechter O, Hernberg M, Arnault JP, Saiag P, Loquai C, Meiss F, Simon JC, Bar-Sela G, Chiarion Sileni V, Fitzharris B, McCrystal M, Parente P, Baurain JF, Combemale P, Lebbe C, Hauschild A, Yamazaki N, Dummer R, Milhem M, Dzienis M, Walker J, Geoffrois L, Leccia MT, Kretschmer L, Hendler D, Lotem M, Mackiewicz A, Sekulovic L, Dunwoodie E, Hoeller C, Machet L, Hassel J, Hospers GAP, Passos MJ, Levin M, Fehr M, Corrie P, Waterston A, Hallmeyer S, Schmidt H, Descamps V, Lacour JP, Berking C, Kiecker F, Ferrucci PF, Yokota K, Aarts M, Jameson M, Winge-Main AK, Ferreira P, Kim K, McNeil C, Hofmann-Wellenhof R, Kerger J, Aubin F, Utikal J, Ferraresi V, Inozume T, Kiyohara Y, Groenewegen G, Kapiteijn H, Matkovic S, Boehncke WH, Casasola R, Crook T, Marshall E, Skytta T, Avril MF, Jouary T, Hein R, Terheyden P, Aoi J, Takenouchi T, Straume O, Martins C, Mukhametshina G, Nathan P

    BACKGROUND: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43-0·74], p<0·0001) compared with placebo, leading to its approval in the USA and Europe. This report provides the final results for the secondary efficacy endpoint, distant metastasis-free survival and an update of the recurrence-free survival results.

    METHODS: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with complete resection of cutaneous melanoma metastatic to lymph node, classified as American Joint Committee on Cancer staging system, seventh edition (AJCC-7) stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37.

    FINDINGS: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5-45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9-69·5] in the pembrolizumab group vs 49·4% [44·8-53·8] in the placebo group; HR 0·60 [95% CI 0·49-0·73]; p<0·0001). In the 853 patients with PD-L1-positive tumours, 3·5-year distant metastasis-free survival was 66·7% (95% CI 61·8-71·2) in the pembrolizumab group and 51·6% (46·6-56·4) in the placebo group (HR 0·61 [95% CI 0·49-0·76]; p<0·0001). Recurrence-free survival remained longer in the pembrolizumab group 59·8% (95% CI 55·3-64·1) than the placebo group 41·4% (37·0-45·8) at this 3·5-year follow-up in the ITT population (HR 0·59 [95% CI 0·49-0·70]) and in those with PD-L1-positive tumours 61·4% (56·3-66·1) in the pembrolizumab group and 44·1% (39·2-48·8) in the placebo group (HR 0·59 [95% CI 0·49-0·73]).

    INTERPRETATION: Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma.

    FUNDING: Merck Sharp & Dohme.

    Pubmed
  • 30 years German Dermatologic Cooperative Oncology Group (DeCOG).

    J Dtsch Dermatol Ges. 2021;19(11): 1682-1697

    Garbe C, Schadendorf D, Tilgen W, Gutzmer R, Berking C, Mohr P, Kaufmann R, Breitbart E, Weber C, Volkenandt M, Hauschild A

    Pubmed
  • Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial.

    Lancet Oncol. 2021;22(5): 655-664

    Bottomley A, Coens C, Mierzynska J, Blank CU, Mandalà M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Puig S, Ascierto PA, Larkin J, Lorigan PC, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C, Eggermont AMM, EORTC Melanoma Group , Lesimple T, Maio M, Linette G, Mortier L, Svane IM, Schachter J, Brown M, Hersey P, Barrow C, Kudchadkar R, Dutriaux C, Song X, Quaglino P, Queirolo P, Meier F, Stroyakovskiy D, Guillot B, Romero PLO, Bastholt L, Garbe C, Grange F, Mohr P, Algazi A, Bechter O, Hernberg M, Loquai C, Meiss F, Chiarion Sileni V, Bar-Sela G, Fitzharris B, Saiag P, Arnault JP, Simon JC, Stephens R, Baurain JF, Lebbe C, Combemale P, Dummer R, Hauschild A, Parente P, Yamazaki N, Milhem M, Leccia MT, Geoffrois L, Kretschmer L, Dunwoodie E, Walker J, Lotem M, Hendler D, Mackiewicz A, Sekulovic L, Dzienis M, Hospers GAP, Siano M, Hassel J, Corrie P, Passos MJ, Levin M, Hoeller C, Machet L, Hallmeyer S, Waterston A, Descamps V, Kiecker F, Aarts M, Schmidt H, Raimundo A, Nyakas M, Lacour JP, Berking C, Ferrucci PF, Jameson M, Kim K, Yokota K, Kerger J, Aubin F, Groenewegen G, Kapiteijn H, Boehncke WH, Utikal J, Casasola R, Marshall E, Ferraresi V, Richtig E, Matkovic S, Inozume T, Crook T, McNeil C, Kiyohara Y, Avril MF, Hein R, Terheyden P, Nathan P, Aoi J, Skytta T, Jouary T, Takenouchi T, Straume O, Martins C, Mukhametshina G

    BACKGROUND: The European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 trial in patients with resected, high-risk stage III melanoma demonstrated improved recurrence-free survival with adjuvant pembrolizumab compared with placebo (hazard ratio 0·57 [98·4% CI 0·43-0·74]; p<0·0001). This study reports the results from the health-related quality-of-life (HRQOL) exploratory endpoint.

    METHODS: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with previously untreated histologically confirmed stage IIIA, IIIB, or IIIC resected cutaneous melanoma, and an Eastern Cooperative Oncology Group performance status score of 1 or 0 were eligible. Patients were randomly assigned (1:1) using a central interactive voice-response system on the basis of a minimisation technique stratified for stage and geographic region to receive intravenously 200 mg pembrolizumab or placebo. Treatment was administered every 3 weeks for 1 year, or until disease recurrence, unacceptable toxicity, or death. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, with global health/quality of life (GHQ) over 2 years measured by the EORTC QLQ-C30 as the primary analysis. Analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37, and long-term follow-up is ongoing.

    FINDINGS: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to pembrolizumab (n=514) or placebo (n=505). Median follow-up was 15·1 months (IQR 12·8-16·9) at the time of this analysis. HRQOL compliance was greater than 90% at baseline, greater than 70% during the first year, and greater than 60% thereafter for both groups. Because of low absolute compliance numbers at later follow-up, the analysis was truncated to week 84. Baseline GHQ scores were similar between groups (77·55 [SD 18·20] in the pembrolizumab group and 76·54 [17·81] in the placebo group) and remained stable over time. The difference in average GHQ score between the two groups over the 2 years was -2·2 points (95% CI -4·3 to -0·2). The difference in average score during treatment was -1·1 points (95% CI -3·2 to 0·9) and the difference in average score after treatment was -2·2 points (-4·8 to 0·4). These differences are within the 5-point clinical relevance threshold for the QLQ-C30 and are therefore clinically non-significant.

    INTERPRETATION: Pembrolizumab does not result in a clinically significant decrease in HRQOL compared with placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting.

    FUNDING: Merck Sharp & Dohme.

    Pubmed
  • Citrate-Coated Superparamagnetic Iron Oxide Nanoparticles Enable a Stable Non-Spilling Loading of T Cells and Their Magnetic Accumulation.

    Cancers (Basel). 2021;13(16):

    Boosz P, Pfister F, Stein R, Friedrich B, Fester L, Band J, Mühlberger M, Schreiber E, Lyer S, Dudziak D, Alexiou C, Janko C

    T cell infiltration into a tumor is associated with a good clinical prognosis of the patient and adoptive T cell therapy can increase anti-tumor immune responses. However, immune cells are often excluded from tumor infiltration and can lack activation due to the immune-suppressive tumor microenvironment. To make T cells controllable by external forces, we loaded primary human CD3+ T cells with citrate-coated superparamagnetic iron oxide nanoparticles (SPIONs). Since the efficacy of magnetic targeting depends on the amount of SPION loading, we investigated how experimental conditions influence nanoparticle uptake and viability of cells. We found that loading in the presence of serum improved both the colloidal stability of SPIONs and viability of T cells, whereas stimulation with CD3/CD28/CD2 and IL-2 did not influence nanoparticle uptake. Furthermore, SPION loading did not impair cytokine secretion after polyclonal stimulation. We finally achieved 1.4 pg iron loading per cell, which was both located intracellularly in vesicles and bound to the plasma membrane. Importantly, nanoparticles did not spill over to non-loaded cells. Since SPION-loading enabled efficient magnetic accumulation of T cells in vitro under dynamic conditions, we conclude that this might be a good starting point for the investigation of in vivo delivery of immune cells.

    Pubmed
  • How to Assess the Efficacy of Interventions for Actinic Keratosis? A Review with a Focus on Long-Term Results.

    J Clin Med. 2021;10(20):

    Steeb T, Wessely A, Petzold A, Schmitz L, Dirschka T, Berking C, Heppt MV

    Actinic keratoses (AK) are common lesions of the skin caused by cumulative sun exposure. Since AK may progress to invasive cutaneous squamous cell carcinoma (cSCC), guidelines uniformly recommend early and consequent treatment. A variety of interventions are available; however, most randomized controlled trials, meta-analyses, and guidelines focus on outcomes that are usually evaluated 8-12 weeks after the end of treatment. Importantly, these assessments can capture the short-term, transient outcomes, but do not allow any conclusions about long-term results to be drawn and do not reflect the probability of transition towards cSCC. Until now, few studies have assessed the long-term results of interventions for AK. Indeed, finding the most appropriate end-point and adjunct time point for determining the long-term results of interventions for AK remains a challenge. Here, we provide an overview of the different ways of measuring the efficacy of AK treatments, such as using recurrence rates or sustained clearance rates, and discuss methodological aspects. Furthermore, we highlight the importance of evidence from post-marketing surveillance trials for the detection of efficacy values and safety signals. Additionally, we emphasize that a follow-up period of 12 months might not be sufficient to reflect the long-term results and stress the urgent need for a longer follow-up period and regular risk-stratified surveillance.

    Pubmed
  • Environmental signals rather than layered ontogeny imprint the function of type 2 conventional dendritic cells in young and adult mice.

    Nat Commun. 2021;12(1):

    Papaioannou NE, Salei N, Rambichler S, Ravi K, Popovic J, Küntzel V, Lehmann CHK, Fiancette R, Salvermoser J, Gajdasik DW, Mettler R, Messerer D, Carrelha J, Ohnmacht C, Haller D, Stumm R, Straub T, Jacobsen SEW, Schulz C, Withers DR, Schotta G, Dudziak D, Schraml BU

    Conventional dendritic cells (cDC) are key activators of naive T cells, and can be targeted in adults to induce adaptive immunity, but in early life are considered under-developed or functionally immature. Here we show that, in early life, when the immune system develops, cDC2 exhibit a dual hematopoietic origin and, like other myeloid and lymphoid cells, develop in waves. Developmentally distinct cDC2 in early life, despite being distinguishable by fate mapping, are transcriptionally and functionally similar. cDC2 in early and adult life, however, are exposed to distinct cytokine environments that shape their transcriptional profile and alter their ability to sense pathogens, secrete cytokines and polarize T cells. We further show that cDC2 in early life, despite being distinct from cDC2 in adult life, are functionally competent and can induce T cell responses. Our results thus highlight the potential of harnessing cDC2 for boosting immunity in early life.

    Pubmed
  • Six-Color Confocal Immunofluorescence Microscopy with 4-Laser Lines.

    Methods Mol Biol. 2021;2350(): 21-30

    Heger L, Lühr JJ, Amon L, Smith AS, Eissing N, Dudziak D

    Confocal immunofluorescence microscopy is an advanced imaging technique routinely applied in the laboratory and clinics. Histological analyses are performed from tissue material. In general, a single fluorochrome per laser is employed, limiting simultaneous analysis to four antigens in one staining with a conventional 4-laser line microscope. Here, we describe a protocol for combining fluorochromes with the same excitation but different emission properties that allows for the analysis of six different antigens in confocal immunofluorescence microscopy with a conventional 4-laser line microscope. The proposed multiplexed method permits the identification and characterization of complex cell populations in rare tissue material.

    Pubmed
  • Select hyperactivating NLRP3 ligands enhance the TH1- and TH17-inducing potential of human type 2 conventional dendritic cells.

    Sci Signal. 2021;14(680):

    Hatscher L, Lehmann CHK, Purbojo A, Onderka C, Liang C, Hartmann A, Cesnjevar R, Bruns H, Gross O, Nimmerjahn F, Ivanović-Burmazović I, Kunz M, Heger L, Dudziak D

    The detection of microorganisms and danger signals by pattern recognition receptors on dendritic cells (DCs) and the consequent formation of inflammasomes are pivotal for initiating protective immune responses. Although the activation of inflammasomes leading to secretion of the cytokine IL-1β is typically accompanied by pyroptosis (an inflammatory form of lytic programmed cell death), some cells can survive and exist in a state of hyperactivation. Here, we found that the conventional type 2 DC (cDC2) subset is the major human DC subset that is transcriptionally and functionally poised for inflammasome formation and response without pyroptosis. When cDC2 were stimulated with ligands that relatively weakly activated the inflammasome, the cells did not enter pyroptosis but instead secreted IL-12 family cytokines and IL-1β. These cytokines induced prominent T helper type 1 (TH1) and TH17 responses that were superior to those seen in response to Toll-like receptor (TLR) stimulation alone or to stronger, classical inflammasome ligands. These findings not only define the human cDC2 subpopulation as a prime target for the treatment of inflammasome-dependent inflammatory diseases but may also inform new approaches for adjuvant and vaccine development.

    Pubmed
  • Characterization and Manipulation of the Crosstalk Between Dendritic and Natural Killer Cells Within the Tumor Microenvironment.

    Front Immunol. 2021;12():

    Jacobs B, Gebel V, Heger L, Grèze V, Schild H, Dudziak D, Ullrich E

    Cellular therapy has entered the daily clinical life with the approval of CAR T cell therapeutics and dendritic cell (DCs) vaccines in the US and the EU. In addition, numerous other adoptive cellular products, including natural killer (NK) cells, are currently evaluated in early phase I/ II clinical trials for the treatment of cancer patients. Despite these promising accomplishments, various challenges remain to be mastered in order to ensure sustained therapeutic success. These include the identification of strategies by which tumor cells escape the immune system or establish an immunosuppressive tumor microenvironment (TME). As part of the innate immune system, DCs and NK cells are both present within the TME of various tumor entities. While NK cells are well known for their intrinsic anti-tumor activity by their cytotoxicity capacities and the secretion of pro-inflammatory cytokines, the role of DCs within the TME is a double-edged sword as different DC subsets have been described with either tumor-promoting or -inhibiting characteristics. In this review, we will discuss recent findings on the interaction of DCs and NK cells under physiological conditions and within the TME. One focus is the crosstalk of various DC subsets with NK cells and their impact on the progression or inhibition of tumor growth. In addition, we will provide suggestions to overcome the immunosuppressive outcome of the interaction of DCs and NK cells within the TME.

    Pubmed
  • NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism.

    Cell. 2021;184(16): 4268-4283.e20

    Allouche J, Rachmin I, Adhikari K, Pardo LM, Lee JH, McConnell AM, Kato S, Fan S, Kawakami A, Suita Y, Wakamatsu K, Igras V, Zhang J, Navarro PP, Lugo CM, Noonan HR, Christie KA, Itin K, Mujahid N, Lo JA, Won CH, Evans CL, Weng QY, Wang H, Osseiran S, Lovas A, Németh I, Cozzio A, Navarini AA, Hsiao JJ, Nguyen N, Kemény LV, Iliopoulos O, Berking C, Ruzicka T, Gonzalez-José R, Bortolini MC, Canizales-Quinteros S, Acuna-Alonso V, Gallo C, Poletti G, Bedoya G, Rothhammer F, Ito S, Schiaffino MV, Chao LH, Kleinstiver BP, Tishkoff S, Zon LI, Nijsten T, Ruiz-Linares A, Fisher DE, Roider E

    Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation. Additionally, genetic modification of NNT in zebrafish alters melanocytic pigmentation. Analysis of four diverse human cohorts revealed significant associations of skin color, tanning, and sun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individuals with postinflammatory hyperpigmentation or lentigines displayed decreased skin NNT levels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for medical and cosmetic purposes.

    Pubmed
  • Plasma-derived extracellular vesicles discriminate type-1 allergy subjects from non-allergic controls.

    World Allergy Organ J. 2021;14(9):

    Wagner N, Eberhardt M, Vera J, Cuomo F, Blume K, Galster S, Achenbach S, Laffert B, Kahlert H, Schuler G, Berking C, Baur A

    BACKGROUND: Allergies are on the rise globally, with an enormous impact on affected individuals' quality of life as well as health care resources. They cause a wide range of symptoms, from slightly inconvenient to potentially fatal immune reactions. While allergies have been described and classified phenomenologically, there is an unmet need for easily accessible biomarkers to stratify the severity of clinical symptoms. Furthermore, biomarkers marking the success of specific immunotherapy are urgently needed.

    OBJECTIVES: Plasma extracellular vesicles (pEV) play a role in coordinating the immune response and may be useful future biomarkers. A pilot study on differences in pEV content was carried out between patients with type I allergy, suffering from rhinoconjunctivitis with or without asthma, and voluntary non-allergic donors.

    METHODS: We examined pEV from 38 individuals (22 patients with allergies and 16 controls) for 38 chemokines, cytokines, and soluble factors using high-throughput data mining approaches.

    RESULTS: Patients with allergies had a distinct biomarker pattern, with 7 upregulated (TNF-alpha, IL-4, IL-5, IL-6, IL-17F, CCL2, and CCL17) and 3 downregulated immune mediators (IL-11, IL-27, and CCL20) in pEV compared to controls. This reduced set of 10 factors was able to discriminate controls and allergic patients better than the total array.

    CONCLUSIONS: The content of pEV showed potential as a target for biomarker research in allergies. Plasma EV, which are readily measurable via blood test, may come to play an important role in allergy diagnosis. In this proof-of-principle study, it could be shown that pEV's discriminate patients with allergies from controls. Further studies investigating whether the content of pEVs may predict the severity of allergic symptoms or even the induction of tolerance to allergens are needed.

    Pubmed
  • Siglec-H-Deficient Mice Show Enhanced Type I IFN Responses, but Do Not Develop Autoimmunity After Influenza or LCMV Infections.

    Front Immunol. 2021;12():

    Szumilas N, Corneth OBJ, Lehmann CHK, Schmitt H, Cunz S, Cullen JG, Chu T, Marosan A, Mócsai A, Benes V, Zehn D, Dudziak D, Hendriks RW, Nitschke L

    Siglec-H is a DAP12-associated receptor on plasmacytoid dendritic cells (pDCs) and microglia. Siglec-H inhibits TLR9-induced IFN-α production by pDCs. Previously, it was found that Siglec-H-deficient mice develop a lupus-like severe autoimmune disease after persistent murine cytomegalovirus (mCMV) infection. This was due to enhanced type I interferon responses, including IFN-α. Here we examined, whether other virus infections can also induce autoimmunity in Siglec-H-deficient mice. To this end we infected Siglec-H-deficient mice with influenza virus or with Lymphocytic Choriomeningitis virus (LCMV) clone 13. With both types of viruses we did not observe induction of autoimmune disease in Siglec-H-deficient mice. This can be explained by the fact that both types of viruses are ssRNA viruses that engage TLR7, rather than TLR9. Also, Influenza causes an acute infection that is rapidly cleared and the chronicity of LCMV clone 13 may not be sufficient and may rather suppress pDC functions. Siglec-H inhibited exclusively TLR-9 driven type I interferon responses, but did not affect type II or type III interferon production by pDCs. Siglec-H-deficient pDCs showed impaired Hck expression, which is a Src-family kinase expressed in myeloid cells, and downmodulation of the chemokine receptor CCR9, that has important functions for pDCs. Accordingly, Siglec-H-deficient pDCs showed impaired migration towards the CCR9 ligand CCL25. Furthermore, autoimmune-related genes such as Klk1 and DNase1l3 are downregulated in Siglec-H-deficient pDCs as well. From these findings we conclude that Siglec-H controls TLR-9-dependent, but not TLR-7 dependent inflammatory responses after virus infections and regulates chemokine responsiveness of pDCs.

    Pubmed
  • Inflammasomes in dendritic cells: Friend or foe?

    Immunol Lett. 2021;234(): 16-32

    Hatscher L, Amon L, Heger L, Dudziak D

    Inflammasomes are cytosolic multiprotein complexes that crucially contribute to host defense against pathogens but are also involved in the pathogenesis of autoinflammatory diseases. Inflammasome formation leads to activation of effector caspases (caspase-1, 4, 5, or 11), the proteolytic maturation of IL-1β and IL-18 as well as cleavage of the pore-forming protein Gasdermin D. Dendritic cells are major regulators of immune responses as they bridge innate and adaptive immunity. We here summarize the current knowledge on inflammasome expression and formation in murine bone marrow-, human monocyte-derived as well as murine and human primary dendritic cells. Further, we discuss both, the beneficial and detrimental, involvement of inflammasome activation in dendritic cells in cancer, infections, and autoimmune diseases. As inflammasome activation is typically accompanied by Gasdermin d-mediated pyroptosis, which is an inflammatory form of programmed cell death, inflammasome formation in dendritic cells seems ill-advised. Therefore, we propose that hyperactivation, which is inflammasome activation without the induction of pyroptosis, may be a general model of inflammasome activation in dendritic cells to enhance Th1, Th17 as well as cytotoxic T cell responses.

    Pubmed
  • Melanocytes as emerging key players in niche regulation of limbal epithelial stem cells.

    Ocul Surf. 2021;22(): 172-189

    Polisetti N, Gießl A, Zenkel M, Heger L, Dudziak D, Naschberger E, Stich L, Steinkasserer A, Kruse FE, Schlötzer-Schrehardt U

    PURPOSE: Limbal melanocytes (LMel) represent essential components of the corneal epithelial stem cell niche and are known to protect limbal epithelial stem/progenitor cells (LEPCs) from UV damage by transfer of melanosomes. Here, we explored additional functional roles for LMel in niche homeostasis, immune regulation and angiostasis.

    METHODS: Human corneoscleral tissues were morphologically analyzed in normal, inflammatory and wound healing conditions. The effects of LMel on LEPCs were analyzed in direct and indirect co-culture models using electron microscopy, immunocytochemistry, qRT-PCR, Western blotting and functional assays; limbal mesenchymal stromal cells and murine embryonic 3T3 fibroblasts served as controls. The immunophenotype of LMel was assessed by flow cytometry before and after interferon-γ stimulation, and their immunomodulatory properties were analyzed by mixed lymphocytes reaction, monocyte adhesion assays and cytometric bead arrays. Their angiostatic effects on human umbilical cord endothelial cells (HUVECs) were evaluated by proliferation, migration, and tube formation assays.

    RESULTS: LMel and LEPCs formed structural units in the human limbal stem cell niche in situ, which could be functionally replicated, including melanosome transfer, by co-cultivation in vitro. LMel supported LEPCs during clonal expansion and during epithelial wound healing by stimulating proliferation and migration, and suppressed their differentiation through direct contact and paracrine effects. Under inflammatory conditions, LMel were increased in numbers and upregulated expression of ICAM-1 and MHC II molecules (HLA-DR), but lacked expression of HLA-G, -DP, -DQ and costimulatory molecules CD80 and CD86. They were also found to be potent suppressors of alloreactive T- cell proliferation and cytokine secretion, which largely depended on direct cell-cell interaction. Moreover, the LMel secretome exerted angiostatic activity by inhibiting vascular endothelial cell proliferation and capillary network formation.

    CONCLUSION: These findings suggest that LMel are not only professional melanin-producing cells, but exert various non-canonical functions in limbal niche homeostasis by regulating LEPC maintenance, immune responses, and angiostasis. Their potent regulatory, immunomodulatory and anti-angiogenic properties may have important implications for future regenerative cell therapies.

    Pubmed
  • MicroRNA miR-29b regulates diabetic aortic remodeling and stiffening.

    Mol Ther Nucleic Acids. 2021;24(): 188-199

    Schellinger IN, Wagenhäuser M, Chodisetti G, Mattern K, Dannert A, Petzold A, Jakubizka-Smorag J, Emrich F, Haunschild J, Schuster A, Schwob E, Schulz K, Maegdefessel L, Spin JM, Stumvoll M, Hasenfuß G, Tsao PS, Raaz U

    Patients with type 2 diabetes (T2D) are threatened by excessive cardiovascular morbidity and mortality. While accelerated arterial stiffening may represent a critical mechanistic factor driving cardiovascular risk in T2D, specific therapies to contain the underlying diabetic arterial remodeling have been elusive. The present translational study investigates the role of microRNA-29b (miR-29b) as a driver and therapeutic target of diabetic aortic remodeling and stiffening. Using a murine model (db/db mice), as well as human aortic tissue samples, we find that diabetic aortic remodeling and stiffening is associated with medial fibrosis, as well as fragmentation of aortic elastic layers. miR-29b is significantly downregulated in T2D and miR-29b repression is sufficient to induce both aortic medial fibrosis and elastin breakdown through upregulation of its direct target genes COL1A1 and MMP2 thereby increasing aortic stiffness. Moreover, antioxidant treatment restores aortic miR-29b levels and counteracts diabetic aortic remodeling. Concluding, we identify miR-29b as a comprehensive-and therefore powerful-regulator of aortic remodeling and stiffening in T2D that moreover qualifies as a (redox-sensitive) target for therapeutic intervention.

    Pubmed
  • Robustness of convolutional neural networks in recognition of pigmented skin lesions.

    Eur J Cancer. 2021;145(): 81-91

    Maron RC, Haggenmüller S, von Kalle C, Utikal JS, Meier F, Gellrich FF, Hauschild A, French LE, Schlaak M, Ghoreschi K, Kutzner H, Heppt MV, Haferkamp S, Sondermann W, Schadendorf D, Schilling B, Hekler A, Krieghoff-Henning E, Kather JN, Fröhling S, Lipka DB, Brinker TJ

    BACKGROUND: A basic requirement for artificial intelligence (AI)-based image analysis systems, which are to be integrated into clinical practice, is a high robustness. Minor changes in how those images are acquired, for example, during routine skin cancer screening, should not change the diagnosis of such assistance systems.

    OBJECTIVE: To quantify to what extent minor image perturbations affect the convolutional neural network (CNN)-mediated skin lesion classification and to evaluate three possible solutions for this problem (additional data augmentation, test-time augmentation, anti-aliasing).

    METHODS: We trained three commonly used CNN architectures to differentiate between dermoscopic melanoma and nevus images. Subsequently, their performance and susceptibility to minor changes ('brittleness') was tested on two distinct test sets with multiple images per lesion. For the first set, image changes, such as rotations or zooms, were generated artificially. The second set contained natural changes that stemmed from multiple photographs taken of the same lesions.

    RESULTS: All architectures exhibited brittleness on the artificial and natural test set. The three reviewed methods were able to decrease brittleness to varying degrees while still maintaining performance. The observed improvement was greater for the artificial than for the natural test set, where enhancements were minor.

    CONCLUSIONS: Minor image changes, relatively inconspicuous for humans, can have an effect on the robustness of CNNs differentiating skin lesions. By the methods tested here, this effect can be reduced, but not fully eliminated. Thus, further research to sustain the performance of AI classifiers is needed to facilitate the translation of such systems into the clinic.

    Pubmed
  • Integrating Patient Data Into Skin Cancer Classification Using Convolutional Neural Networks: Systematic Review.

    J Med Internet Res. 2021;23(7):

    Höhn J, Hekler A, Krieghoff-Henning E, Kather JN, Utikal JS, Meier F, Gellrich FF, Hauschild A, French L, Schlager JG, Ghoreschi K, Wilhelm T, Kutzner H, Heppt M, Haferkamp S, Sondermann W, Schadendorf D, Schilling B, Maron RC, Schmitt M, Jutzi T, Fröhling S, Lipka DB, Brinker TJ

    BACKGROUND: Recent years have been witnessing a substantial improvement in the accuracy of skin cancer classification using convolutional neural networks (CNNs). CNNs perform on par with or better than dermatologists with respect to the classification tasks of single images. However, in clinical practice, dermatologists also use other patient data beyond the visual aspects present in a digitized image, further increasing their diagnostic accuracy. Several pilot studies have recently investigated the effects of integrating different subtypes of patient data into CNN-based skin cancer classifiers.

    OBJECTIVE: This systematic review focuses on the current research investigating the impact of merging information from image features and patient data on the performance of CNN-based skin cancer image classification. This study aims to explore the potential in this field of research by evaluating the types of patient data used, the ways in which the nonimage data are encoded and merged with the image features, and the impact of the integration on the classifier performance.

    METHODS: Google Scholar, PubMed, MEDLINE, and ScienceDirect were screened for peer-reviewed studies published in English that dealt with the integration of patient data within a CNN-based skin cancer classification. The search terms skin cancer classification, convolutional neural network(s), deep learning, lesions, melanoma, metadata, clinical information, and patient data were combined.

    RESULTS: A total of 11 publications fulfilled the inclusion criteria. All of them reported an overall improvement in different skin lesion classification tasks with patient data integration. The most commonly used patient data were age, sex, and lesion location. The patient data were mostly one-hot encoded. There were differences in the complexity that the encoded patient data were processed with regarding deep learning methods before and after fusing them with the image features for a combined classifier.

    CONCLUSIONS: This study indicates the potential benefits of integrating patient data into CNN-based diagnostic algorithms. However, how exactly the individual patient data enhance classification performance, especially in the case of multiclass classification problems, is still unclear. Moreover, a substantial fraction of patient data used by dermatologists remains to be analyzed in the context of CNN-based skin cancer classification. Further exploratory analyses in this promising field may optimize patient data integration into CNN-based skin cancer diagnostics for patients' benefits.

    Pubmed
  • Deep learning approach to predict sentinel lymph node status directly from routine histology of primary melanoma tumours.

    Eur J Cancer. 2021;154(): 227-234

    Brinker TJ, Kiehl L, Schmitt M, Jutzi TB, Krieghoff-Henning EI, Krahl D, Kutzner H, Gholam P, Haferkamp S, Klode J, Schadendorf D, Hekler A, Fröhling S, Kather JN, Haggenmüller S, von Kalle C, Heppt M, Hilke F, Ghoreschi K, Tiemann M, Wehkamp U, Hauschild A, Weichenthal M, Utikal JS

    AIM: Sentinel lymph node status is a central prognostic factor for melanomas. However, the surgical excision involves some risks for affected patients. In this study, we therefore aimed to develop a digital biomarker that can predict lymph node metastasis non-invasively from digitised H&E slides of primary melanoma tumours.

    METHODS: A total of 415 H&E slides from primary melanoma tumours with known sentinel node (SN) status from three German university hospitals and one private pathological practice were digitised (150 SN positive/265 SN negative). Two hundred ninety-one slides were used to train artificial neural networks (ANNs). The remaining 124 slides were used to test the ability of the ANNs to predict sentinel status. ANNs were trained and/or tested on data sets that were matched or not matched between SN-positive and SN-negative cases for patient age, ulceration, and tumour thickness, factors that are known to correlate with lymph node status.

    RESULTS: The best accuracy was achieved by an ANN that was trained and tested on unmatched cases (61.8% ± 0.2%) area under the receiver operating characteristic (AUROC). In contrast, ANNs that were trained and/or tested on matched cases achieved (55.0% ± 3.5%) AUROC or less.

    CONCLUSION: Our results indicate that the image classifier can predict lymph node status to some, albeit so far not clinically relevant, extent. It may do so by mostly detecting equivalents of factors on histological slides that are already known to correlate with lymph node status. Our results provide a basis for future research with larger data cohorts.

    Pubmed
  • Increased prevalence of irritant hand eczema in health care workers in a dermatological clinic due to increased hygiene measures during the SARS-CoV-2 pandemic.

    Eur J Dermatol. 2021;31(3): 392-395

    Reinholz M, Kendziora B, Frey S, Oppel EM, Ruëff F, Clanner-Engelshofen BM, Heppt MV, French LE, Wollenberg A

    BACKGROUND: Hand hygiene measures in the general population and in health care workers have increased considerably since the outbreak of the COVID-19 pandemic.

    OBJECTIVES: To investigate the prevalence and symptoms of hand eczema, as well as hygiene measures and concepts of care, in German health care workers.

    MATERIALS & METHODS: This was an observational questionnaire study to investigate hygiene and skin care habits, as well as the prevalence and symptoms of hand eczema in 66 nurses and doctors of our dermatology department before and during the SARS-CoV-2 pandemic.

    RESULTS: Hand washing and hand disinfection procedures increased significantly during the COVID-19 pandemic. Self-diagnosed hand eczema was reported by 33% of the participants, with a median duration of 14 days. The majority of staff currently affected by hand eczema were free of eczema a month previously (82%) and would treat their skin condition with emollients (77%). Erythema, scaling, burning and fissures were reported by 66.1% of the participants and were classified as predominant signs of toxic-irritant hand dermatitis rather than contact allergy.

    CONCLUSION: Overall, the SARS-CoV-2 pandemic has led to a significant increase in the incidence of signs of irritant hand eczema despite intensified emollient use as a preventive measure. Awareness of the prevalence of hand eczema in health care workers in Germany during the COVID-19 pandemic should be raised, and preventive measures should be intensified.

    Pubmed
  • Early Exanthema Upon Vemurafenib Plus Cobimetinib Is Associated With a Favorable Treatment Outcome in Metastatic Melanoma: A Retrospective Multicenter DeCOG Study.

    Front Oncol. 2021;11():

    Kähler KC, Gutzmer R, Meier F, Zimmer L, Heppt M, Gesierich A, Thoms KM, Utikal J, Hassel JC, Loquai C, Pföhler C, Heinzerling L, Kaatz M, Göppner D, Pflugfelder A, Bohne AS, Satzger I, Reinhardt L, Placke JM, Schadendorf D, Ugurel S

    Background: The combination of BRAF and MEK inhibitors has become standard of care in the treatment of metastatic BRAF V600-mutated melanoma. Clinical factors for an early prediction of tumor response are rare. The present study investigated the association between the development of an early exanthema induced by vemurafenib or vemurafenib plus cobimetinib and therapy outcome.

    Methods: This multicenter retrospective study included patients with BRAF V600-mutated irresectable AJCC-v8 stage IIIC/D to IV metastatic melanoma who received treatment with vemurafenib (VEM) or vemurafenib plus cobimetinib (COBIVEM). The development of an early exanthema within six weeks after therapy start and its grading according to CTCAEv4.0 criteria was correlated to therapy outcome in terms of best overall response, progression-free (PFS), and overall survival (OS).

    Results: A total of 422 patients from 16 centers were included (VEM, n=299; COBIVEM, n=123). 20.4% of VEM and 43.1% of COBIVEM patients developed an early exanthema. In the VEM cohort, objective responders (CR/PR) more frequently presented with an early exanthema than non-responders (SD/PD); 59.0% versus 38.7%; p=0.0027. However, median PFS and OS did not differ between VEM patients with or without an early exanthema (PFS, 6.9 versus 6.0 months, p=0.65; OS, 11.0 versus 12.4 months, p=0.69). In the COBIVEM cohort, 66.0% of objective responders had an early exanthema compared to 54.3% of non-responders (p=0.031). Median survival times were significantly longer for patients who developed an early exanthema compared to patients who did not (PFS, 9.7 versus 5.6 months, p=0.013; OS, not reached versus 11.6 months, p=0.0061). COBIVEM patients with a mild early exanthema (CTCAEv4.0 grade 1-2) had a superior survival outcome as compared to COBIVEM patients with a severe (CTCAEv4.0 grade 3-4) or non early exanthema, respectively (p=0.047). This might be caused by the fact that 23.6% of patients with severe exanthema underwent a dose reduction or discontinuation of COBIVEM compared to only 8.9% of patients with mild exanthema.

    Conclusions: The development of an early exanthema within 6 weeks after treatment start indicates a favorable therapy outcome upon vemurafenib plus cobimetinib. Patients presenting with an early exanthema should therefore be treated with adequate supportive measures to provide that patients can stay on treatment.

    Pubmed
  • Identification and Purification of Novel Low-Molecular-Weight Lupine Allergens as Components for Personalized Diagnostics.

    Nutrients. 2021;13(2):

    Jappe U, Karstedt A, Warneke D, Hellmig S, Böttger M, Riffelmann FW, Treudler R, Lange L, Abraham S, Dölle-Bierke S, Worm M, Wagner N, Ruëff F, Reese G, Knulst AC, Becker WM

    Lupine flour is a valuable food due to its favorable nutritional properties. In spite of its allergenic potential, its use is increasing. Three lupine species, Lupinus angustifolius, L. luteus, and L. albus are relevant for human nutrition. The aim of this study is to clarify whether the species differ with regard to their allergen composition and whether anaphylaxis marker allergens could be identified in lupine. Patients with the following characteristics were included: lupine allergy, suspected lupine allergy, lupine sensitization only, and peanut allergy. Lupine sensitization was detected via CAP-FEIA (ImmunoCAP) and skin prick test. Protein, DNA and expressed sequence tag (EST) databases were queried for lupine proteins homologous to already known legume allergens. Different extraction methods applied on seeds from all species were examined by SDS-PAGE and screened by immunoblotting for IgE-binding proteins. The extracts underwent different and successive chromatography methods. Low-molecular-weight components were purified and investigated for IgE-reactivity. Proteomics revealed a molecular diversity of the three species, which was confirmed when investigated for IgE-reactivity. Three new allergens, L. albus profilin, L. angustifolius and L. luteus lipid transfer protein (LTP), were identified. LTP as a potential marker allergen for severity is a valuable additional candidate for molecular allergy diagnostic tests.

    Pubmed
  • Patch test results with caine mix III and its three constituents in consecutive patients of the IVDK.

    Contact Dermatitis. 2021;84(6): 481-483

    Uter W, Worm M, Brans R, Wagner N, Bauer A, Geier J, Information Network of Departments of Dermatology (IVDK)

    Pubmed
  • Wheat Anaphylaxis in Adults Differs from Reactions to Other Types of Food.

    J Allergy Clin Immunol Pract. 2021;9(7): 2844-2852.e5

    Kraft M, Dölle-Bierke S, Renaudin JM, Ruëff F, Scherer Hofmeier K, Treudler R, Pföhler C, Hawranek T, Poziomkowska-Gęsicka I, Jappe U, Christoff G, Müller S, Fernandez-Rivas M, García BE, De Vicente Jiménez TM, Cardona V, Kleinheinz A, Kreft B, Bauer A, Wagner N, Wedi B, Wenzel M, Bilò MB, Worm M

    BACKGROUND: Wheat is one of the most commonly consumed foods and a known elicitor of anaphylaxis in children and adults. Reactions in adults are often cofactor dependent and characterized by a prolonged time between food intake and the onset of symptoms making the diagnosis of wheat anaphylaxis challenging.

    OBJECTIVE: To characterize a cohort of patients with the history of wheat anaphylaxis to better understand this atypical phenotype of anaphylaxis.

    METHODS: Data from the European Anaphylaxis Registry from 2007 to 2019 (n = 10,636) including 250 patients (213 adults and 37 children) with a history of anaphylaxis caused by wheat were analyzed.

    RESULTS: Wheat was the most common food elicitor of anaphylaxis in adults in the registry in Central Europe. Reactions to wheat in adults were frequently associated with exercise as a cofactor (82.8%) and partially delayed (57.5%). Only 36.9% of patients had atopic comorbidities, which was uncommonly low for adult patients allergic to other kinds of foods (63.2%). Anaphylaxis to wheat presented frequently with cardiovascular symptoms (86.7%) including severe symptoms such as loss of consciousness (41%) and less often with respiratory symptoms (53.6%). The reactions to wheat were more severe than reactions to other foods (odds ratio [OR] = 4.33), venom (OR = 1.58), or drugs (OR = 2.11).

    CONCLUSIONS: Wheat is a relevant elicitor of anaphylaxis in adults in Central Europe. Wheat anaphylaxis is highly dependent on the presence of cofactors and less frequently associated with atopic diseases compared with other food allergies. More data on mechanisms of wheat-induced anaphylaxis are required to develop preventive measures for this potentially life-threatening disease.

    Pubmed
  • People-centered care for psoriasis and urticaria: Are we overlooking Internet addiction while only considering patients and physician settings?

    J Dermatol. 2021;48(6): 825-834

    Schielein MC, Tizek L, Baeumer D, Hillmann E, Romer K, Wagner N, Zink A

    Psoriasis and chronic urticaria (CU) are chronic skin diseases with a high impact on individuals' life and mental health. Some studies indicate a high prevalence of Internet addiction and many affected individuals seem not to utilize healthcare, but rather search for health-related information online. The aims of the study were to assess Internet addiction as a potential comorbidity in both diseases as well as identify differences in healthcare utilization between individuals with psoriasis and CU. This cross-sectional study is based on self-reported data from individuals with psoriasis and CU living throughout Germany using the framework of an online survey from 12/2018 to 01/2019. Advertisements on Google and Facebook were used to address Internet users who searched online for information on psoriasis or CU. The study questionnaire comprised questions on demographics, current contact with physicians, and disease history as well as validated screening tools for well-being and Internet addiction. Overall, 1686 participants (74.0% female, 38.5% psoriasis) with a mean age of 36.9 ± 12.9 years were analyzed. Participants with CU were more likely female (89.2% vs 49.8%, P < 0.001) and not in medical care compared to participants with psoriasis (60.3% vs 45.9%, P < 0.001). Sixteen percent of the participants overall were screened positive for Internet addiction. Furthermore, not utilizing medical care showed a significant association with being screened positive for Internet addiction in participants with CU (adjusted odds ratio [aOR] = 1.49, 95% confidence interval [CI] 1.10-2.02), but not in those with psoriasis. The study revealed a high proportion of affected individuals not being in medical care and a high prevalence of Internet addiction, with individuals with CU not utilizing medical resources having a higher chance of being screened positive for Internet addiction. This underlines the approach of people-centered care and highlights its importance for further research.

    Pubmed
  • European Surveillance System on Contact Allergies (ESSCA): Characteristics of patients patch tested and diagnosed with irritant contact dermatitis.

    Contact Dermatitis. 2021;85(2): 186-197

    Loman L, Uter W, Armario-Hita JC, Ayala F, Balato A, Ballmer-Weber BK, Bauer A, Bircher AJ, Buhl T, Czarnecka-Operacz M, Dickel H, Fuchs T, Giménez Arnau A, John SM, Kränke B, Kręcisz B, Mahler V, Rustemeyer T, Sadowska-Przytocka A, Sánchez-Pérez J, Scherer Hofmeier K, Schliemann S, Simon D, Spiewak R, Spring P, Valiukevičienė S, Wagner N, Weisshaar E, Pesonen M, Schuttelaar MLA, ESSCA Working Group

    BACKGROUND: Irritant contact dermatitis (ICD) is caused by the acute locally toxic effect of a strong irritant, or the cumulative exposure to various weaker physical and/or chemical irritants.

    OBJECTIVES: To describe the characteristics of patients with ICD in the population patch tested in the European Surveillance System on Contact Allergies (ESSCA; www.essca-dc.org) database.

    METHODS: Data collected by the ESSCA in consecutively patch-tested patients from January 2009 to December 2018 were analyzed.

    RESULTS: Of the 68 072 patients, 8702 were diagnosed with ICD (without concomitant allergic contact dermatitis [ACD]). Hand and face were the most reported anatomical sites, and 45.7% of the ICD was occupational ICD (OICD). The highest proportions of OICD were found in metal turners, bakers, pastry cooks, and confectionery makers. Among patients diagnosed with ICD, 45% were found sensitized with no relevance for the current disease.

    CONCLUSIONS: The hands were mainly involved in OICD also in the subgroup of patients with contact dermatitis, in whom relevant contact sensitization had been ruled out, emphasizing the need for limiting irritant exposures. However, in difficult-to-treat contact dermatitis, unrecognized contact allergy, or unrecognized clinical relevance of identified allergies owing to incomplete or wrong product ingredient information must always be considered.

    Pubmed
  • Despite large choice of effective therapies: Individuals with psoriasis still seem undertreated.

    J Dtsch Dermatol Ges. 2021;19(7): 1003-1011

    Pilz AC, Zink A, Schielein MC, Hell K, Romer K, Hillmann E, Bäumer D, Reinhardt M, Wagner N

    BACKGROUND AND OBJECTIVES: Due to the development of new anti-psoriatic drugs in combination with improved structures for implementation throughout Germany, the medical care of psoriasis patients has markedly improved. In this study we investigated the real-life utilization of the health care system and identified reasons for dissatisfaction in affected individuals.

    PATIENTS AND METHODS: This non-interventional cross-sectional study was conducted as an anonymous online survey from 12/2018 to 01/2019 in Germany. Participants with a self-reported physician-confirmed diagnosis of psoriasis and symptoms answered questions about their disease, its influence on daily life and their medical care.

    RESULTS: 649 participants with a mean age of 42.5 ± 13.7 years and equal gender distribution (male: 50.2 %) were evaluated. 54.1 % received medical treatment at the time of the study, 45.9 % did not. Among the participants with medical care, 59.3 % were only moderately or less satisfied with their treatment. Reasons for dissatisfaction with the medication included lack of efficacy and side effects. Participants without medical treatment specified a physician's lack of time as a main reason for not seeking medical help.

    CONCLUSIONS: Despite the availability of efficient therapeutic options in Germany, many individuals with psoriasis are not satisfied. This under-treated group was identified as a new target population.

    Pubmed
  • Expert consensus on practical aspects in the treatment of chronic urticaria.

    Allergo J Int. 2021;30(2): 64-75

    Bauer A, Dickel H, Jakob T, Kleinheinz A, Lippert U, Metz M, Schliemann S, Schwichtenberg U, Staubach P, Valesky E, Wagner N, Wedi B, Maurer M

    Background: Chronic urticaria (CU) is a common disease which represents a considerable burden for many patients. The current urticaria guideline describes the evidence-based diagnosis and treatment of CU. In addition, however, questions often arise in everyday practice that are not addressed by the guideline.

    Methods: In May 2020, a digital meeting with German urticaria experts was held, in which practical aspects of CU treatment were discussed and supporting aids for everyday clinical treatment formulated. The resulting advice in this document focus on practical questions and the available literature and experiences of the participants.

    Results: The diagnosis of CU can be made in a short time by means of a thorough anamnesis, a physical examination, and a basic laboratory chemical diagnosis. For this purpose, practical recommendations for everyday practice are given in this paper. An extended diagnosis is only indicated in a few cases and should always be carried out in parallel with an effective therapy. In general, CU should always be treated in the same way, regardless of whether wheals, angioedema or both occur. Symptomatic therapy should be carried out according to the treatment steps recommended by the guidelines. This publication provides practical advice on issues in everyday practice, such as the procedure in the current coronavirus disease 2019 (COVID-19) pandemic, the cardiac risk under higher dosed H1 antihistamines, the self-administration of omalizumab as well as vaccination under omalizumab therapy. In addition to treatment recommendations, topics such as documentation in the practice and family planning with urticaria will be discussed.

    Discussion: These supporting treatment recommendations serve as an addendum to the current CU guideline and provide support in dealing with CU patients in everyday practice. The aim is to ensure that patients suffering from CU achieve complete freedom of symptoms with the help of an optimal therapy.

    Supplementary Information: The online version of this article (10.1007/s40629-021-00162-w) contains supplementary material, which is available to authorized users.

    Pubmed
  • Anaphylaxis in middle-aged patients.

    Allergol Select. 2021;5(): 133-139

    Francuzik W, Kraft M, Scherer Hofmeier K, Ruëff F, Pföhler C, Treudler R, Lang R, Hawranek T, Wagner N, Worm M

    Age is one of the most important factors influencing the course of anaphylaxis: moreover, the frequency of elicitors of anaphylaxis is age-associated. We analyzed 8,465 anaphylactic episodes in adult patients in three age groups with a focus on patients in the middle-age group (35 - 65 years old). Insect venom was the most frequent trigger in this age group (51.2%) followed by drugs (22.8%) and food (17.3%). Severe reactions were observed in 40.1% of middle-aged patients and occurred more frequently in this age group than in patients below 35 years (27.6%) and less frequently than in patients over 65 years (55.6%). The symptoms and comorbidity profile also changed with age, most significantly regarding the increase in rates of concomitant cardiologic diseases and (severe) cardiovascular symptoms.

    Pubmed
  • Network- and systems-based re-engineering of dendritic cells with non-coding RNAs for cancer immunotherapy.

    Theranostics. 2021;11(3): 1412-1428

    Lai X, Dreyer FS, Cantone M, Eberhardt M, Gerer KF, Jaitly T, Uebe S, Lischer C, Ekici A, Wittmann J, Jäck HM, Schaft N, Dörrie J, Vera J

    Dendritic cells (DCs) are professional antigen-presenting cells that induce and regulate adaptive immunity by presenting antigens to T cells. Due to their coordinative role in adaptive immune responses, DCs have been used as cell-based therapeutic vaccination against cancer. The capacity of DCs to induce a therapeutic immune response can be enhanced by re-wiring of cellular signalling pathways with microRNAs (miRNAs). Methods: Since the activation and maturation of DCs is controlled by an interconnected signalling network, we deploy an approach that combines RNA sequencing data and systems biology methods to delineate miRNA-based strategies that enhance DC-elicited immune responses. Results: Through RNA sequencing of IKKβ-matured DCs that are currently being tested in a clinical trial on therapeutic anti-cancer vaccination, we identified 44 differentially expressed miRNAs. According to a network analysis, most of these miRNAs regulate targets that are linked to immune pathways, such as cytokine and interleukin signalling. We employed a network topology-oriented scoring model to rank the miRNAs, analysed their impact on immunogenic potency of DCs, and identified dozens of promising miRNA candidates, with miR-15a and miR-16 as the top ones. The results of our analysis are presented in a database that constitutes a tool to identify DC-relevant miRNA-gene interactions with therapeutic potential (https://www.synmirapy.net/dc-optimization). Conclusions: Our approach enables the systematic analysis and identification of functional miRNA-gene interactions that can be experimentally tested for improving DC immunogenic potency.

    Pubmed
  • β2-microglobulin triggers NLRP3 inflammasome activation in tumor-associated macrophages to promote multiple myeloma progression.

    Immunity. 2021;54(8): 1772-1787.e9

    Hofbauer D, Mougiakakos D, Broggini L, Zaiss M, Büttner-Herold M, Bach C, Spriewald B, Neumann F, Bisht S, Nolting J, Zeiser R, Hamarsheh S, Eberhardt M, Vera J, Visentin C, De Luca CMG, Moda F, Haskamp S, Flamann C, Böttcher M, Bitterer K, Völkl S, Mackensen A, Ricagno S, Bruns H

    As substantial constituents of the multiple myeloma (MM) microenvironment, pro-inflammatory macrophages have emerged as key promoters of disease progression, bone destruction, and immune impairment. We identify beta-2-microglobulin (β2m) as a driver in initiating inflammation in myeloma-associated macrophages (MAMs). Lysosomal accumulation of phagocytosed β2m promotes β2m amyloid aggregation in MAMs, resulting in lysosomal rupture and ultimately production of active interleukin-1β (IL-1β) and IL-18. This process depends on activation of the NLRP3 inflammasome after β2m accumulation, as macrophages from NLRP3-deficient mice lack efficient β2m-induced IL-1β production. Moreover, depletion or silencing of β2m in MM cells abrogates inflammasome activation in a murine MM model. Finally, we demonstrate that disruption of NLRP3 or IL-18 diminishes tumor growth and osteolytic bone destruction normally promoted by β2m-induced inflammasome signaling. Our results provide mechanistic evidence for β2m's role as an NLRP3 inflammasome activator during MM pathogenesis. Moreover, inhibition of NLRP3 represents a potential therapeutic approach in MM.

    Pubmed
  • The IKZF1-IRF4/IRF5 Axis Controls Polarization of Myeloma-Associated Macrophages.

    Cancer Immunol Res. 2021;9(3): 265-278

    Mougiakakos D, Bach C, Böttcher M, Beier F, Röhner L, Stoll A, Rehli M, Gebhard C, Lischer C, Eberhardt M, Vera J, Büttner-Herold M, Bitterer K, Balzer H, Leffler M, Jitschin S, Hundemer M, Awwad MHS, Busch M, Stenger S, Völkl S, Schütz C, Krönke J, Mackensen A, Bruns H

    The bone marrow niche has a pivotal role in progression, survival, and drug resistance of multiple myeloma cells. Therefore, it is important to develop means for targeting the multiple myeloma bone marrow microenvironment. Myeloma-associated macrophages (MAM) in the bone marrow niche are M2 like. They provide nurturing signals to multiple myeloma cells and promote immune escape. Reprogramming M2-like macrophages toward a tumoricidal M1 phenotype represents an intriguing therapeutic strategy. This is especially interesting in view of the successful use of mAbs against multiple myeloma cells, as these therapies hold the potential to trigger macrophage-mediated phagocytosis and cytotoxicity. In this study, we observed that MAMs derived from patients treated with the immunomodulatory drug (IMiD) lenalidomide skewed phenotypically and functionally toward an M1 phenotype. Lenalidomide is known to exert its beneficial effects by modulating the CRBN-CRL4 E3 ligase to ubiquitinate and degrade the transcription factor IKAROS family zinc finger 1 (IKZF1). In M2-like MAMs, we observed enhanced IKZF1 levels that vanished through treatment with lenalidomide, yielding MAMs with a bioenergetic profile, T-cell stimulatory properties, and loss of tumor-promoting capabilities that resemble M1 cells. We also provide evidence that IMiDs interfere epigenetically, via degradation of IKZF1, with IFN regulatory factors 4 and 5, which in turn alters the balance of M1/M2 polarization. We validated our observations in vivo using the CrbnI391V mouse model that recapitulates the IMiD-triggered IKZF1 degradation. These data show a role for IKZF1 in macrophage polarization and can provide explanations for the clinical benefits observed when combining IMiDs with therapeutic antibodies.See related Spotlight on p. 254.

    Pubmed
  • IL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation.

    Immunity. 2021;54(11): 2531-2546.e5

    Faas M, Ipseiz N, Ackermann J, Culemann S, Grüneboom A, Schröder F, Rothe T, Scholtysek C, Eberhardt M, Böttcher M, Kirchner P, Stoll C, Ekici A, Fuchs M, Kunz M, Weigmann B, Wirtz S, Lang R, Hofmann J, Vera J, Voehringer D, Michelucci A, Mougiakakos D, Uderhardt S, Schett G, Krönke G

    Alternatively activated macrophages (AAMs) contribute to the resolution of inflammation and tissue repair. However, molecular pathways that govern their differentiation have remained incompletely understood. Here, we show that uncoupling protein-2-mediated mitochondrial reprogramming and the transcription factor GATA3 specifically controlled the differentiation of pro-resolving AAMs in response to the alarmin IL-33. In macrophages, IL-33 sequentially triggered early expression of pro-inflammatory genes and subsequent differentiation into AAMs. Global analysis of underlying signaling events revealed that IL-33 induced a rapid metabolic rewiring of macrophages that involved uncoupling of the respiratory chain and increased production of the metabolite itaconate, which subsequently triggered a GATA3-mediated AAM polarization. Conditional deletion of GATA3 in mononuclear phagocytes accordingly abrogated IL-33-induced differentiation of AAMs and tissue repair upon muscle injury. Our data thus identify an IL-4-independent and GATA3-dependent pathway in mononuclear phagocytes that results from mitochondrial rewiring and controls macrophage plasticity and the resolution of inflammation.

    Pubmed
  • Mathematical Modelling in Biomedicine: A Primer for the Curious and the Skeptic.

    Int J Mol Sci. 2021;22(2):

    Vera J, Lischer C, Nenov M, Nikolov S, Lai X, Eberhardt M

    In most disciplines of natural sciences and engineering, mathematical and computational modelling are mainstay methods which are usefulness beyond doubt. These disciplines would not have reached today's level of sophistication without an intensive use of mathematical and computational models together with quantitative data. This approach has not been followed in much of molecular biology and biomedicine, however, where qualitative descriptions are accepted as a satisfactory replacement for mathematical rigor and the use of computational models is seen by many as a fringe practice rather than as a powerful scientific method. This position disregards mathematical thinking as having contributed key discoveries in biology for more than a century, e.g., in the connection between genes, inheritance, and evolution or in the mechanisms of enzymatic catalysis. Here, we discuss the role of computational modelling in the arsenal of modern scientific methods in biomedicine. We list frequent misconceptions about mathematical modelling found among biomedical experimentalists and suggest some good practices that can help bridge the cognitive gap between modelers and experimental researchers in biomedicine. This manuscript was written with two readers in mind. Firstly, it is intended for mathematical modelers with a background in physics, mathematics, or engineering who want to jump into biomedicine. We provide them with ideas to motivate the use of mathematical modelling when discussing with experimental partners. Secondly, this is a text for biomedical researchers intrigued with utilizing mathematical modelling to investigate the pathophysiology of human diseases to improve their diagnostics and treatment.

    Pubmed
  • Identification of two novel bullous pemphigoid- associated alleles, HLA-DQA1*05:05 and -DRB1*07:01, in Germans.

    Orphanet J Rare Dis. 2021;16(1):

    Schwarm C, Gola D, Holtsche MM, Dieterich A, Bhandari A, Freitag M, Nürnberg P, Toliat M, Lieb W, Wittig M, Franke A, Worm M, Sticherling M, Ehrchen J, Günther C, Gläser R, Peitsch WK, Sárdy M, Eming R, Hertl M, Benoit S, Goebeler M, Pföhler C, Kunz M, Kreuter A, van Beek N, Erdmann J, Busch H, Zillikens D, Sadik CD, Hirose M, König IR, Schmidt E, Ibrahim SM, German AIBD Study Group

    Bullous pemphigoid (BP) is the most common autoimmune skin blistering disease characterized by autoimmunity against the hemidesmosomal proteins BP180, type XVII collagen, and BP230. To elucidate the genetic basis of susceptibility to BP, we performed the first genome-wide association study (GWAS) in Germans. This GWAS was combined with HLA locus targeted sequencing in an additional independent BP cohort. The strongest association with BP in Germans tested in this study was observed in the two HLA loci, HLA-DQA1*05:05 and HLA-DRB1*07:01. Further studies with increased sample sizes and complex studies integrating multiple pathogenic drivers will be conducted.

    Pubmed
  • Genetic Analysis of MPO Variants in Four Psoriasis Subtypes in Patients from Germany.

    J Invest Dermatol. 2021;141(8): 2079-2083

    Haskamp S, Horowitz JS, Oji V, Philipp S, Sticherling M, Schäkel K, Schuhmann S, Prinz JC, Burkhardt H, Behrens F, Böhm B, Köhm M, Rech J, Simon D, Schett G, Morrison K, Gerdes S, Assmann G, Nimeh A, Schuster V, Jacobi A, Weyergraf A, Reis A, Uebe S, Wilsmann-Theis D, Mößner R, Hüffmeier U

    Pubmed
  • Another step on the road towards standardized outcome reporting for congenital melanocytic naevi: one more to go!

    Br J Dermatol. 2021;185(5): 881-882

    Heppt MV, Steeb T, Berking C

    Pubmed
  • One set to collect them all? The development of a core domain set for medium-to-giant congenital melanocytic naevi.

    Br J Dermatol. 2021;185(2): 247-248

    Heppt MV, Steeb T, Berking C

    Pubmed
  • Active vitamin D supplementation and COVID-19 infections: review.

    Ir J Med Sci. 2021;190(4): 1271-1274

    Farid N, Rola N, Koch EAT, Nakhoul N

    SARS-CoV-2, causing the lethal disease COVid-19, is a public health emergency in the 2020 global pandemic. The outbreak and fast spreading of SARS-CoV-2 have a high morbidity and mortality specifically in elder patients with chronic diseases such as diabetes mellitus, arterial hypertension, chronic kidney disease, and organ transplanted patients with immunosuppressive therapy. Preliminary results support different treatments such as chloroquine and convalescent plasma infusion in severe cases, with good outcome. On the other hand, the efficacy of supplementation with active vitamin D, an immunomodulator hormone with antiinflammatory and antimicrobial effects, is unproven. A recent study reported that vitamin D attains antiviral effects, via blocking viral replication directly. SARS-CoV-2 primarily uses the immune evasion process during infection via the envelope spike glycoprotein, which is followed by a cytokine storm, causing severe acute respiratory disease syndrome and death. SARS-CoV-2, by using the well-known angiotensin-converting enzyme 2 by the protein spike, as the host receptor to enter into alveolar, myocardial, and renal epithelial cells, can be disrupted by vitamin D. However, the correlation between vitamin D levels and COVID-19 deaths in previous studies was insignificant. Retrospective studies demonstrated a correlation between vitamin D status and COVID-19 severity and mortality, while other studies did not find this correlation. Studies have shown that, vitamin D reduces the risk of acute viral respiratory tract infections and pneumonia via direct inhibition of viral replication, antiinflammatory and immunomodulatory effects. The data available today regarding the beneficial protective effect of vitamin D is unclear and with conflicting results. Large randomized control trials are necessary to test this hypothesis. In this review, we will explain the cross talk between the active vitamin D and the angiotensin-converting enzyme 2, and summarize the data from the literature.

    Pubmed
  • Purple urine in a patient after recovery from a SARS-CoV-2 infection.

    Int J Infect Dis. 2021;105(): 472-473

    Vetter M, Kaufmann MD, Neurath MF, Kremer AE

    Pubmed
  • Results of isolated limb perfusion for metastasized malignant melanoma.

    Surg Oncol. 2021;38():

    Schellerer VS, Frenger J, Merkel S, Goehl J, Kersting S, Gruetzmann R, Erdmann M, Foertsch T

    BACKGROUND AND OBJECTIVES: Locoregional metastases are typical biological manifestations of advanced malignant melanomas. Treatment with hyperthermic isolated limb perfusion (HILP) should be considered in affected patients. In the present study, we have analyzed the results of HILPs performed in our department.

    PATIENTS AND METHODS: Eighty patients with locoregional metastases of the extremities received HILP at the Department of Surgery between January 2007 and December 2016. The mean follow-up was 38 months.

    RESULTS: The study included 50 men and 30 women (mean age: 63 years). The median time between melanoma diagnosis and HILP was 25 months (range: 1-219 months). HILP was performed in curative (n = 45) and palliative (n = 35) intention. Seventy-five patients received a drug combination of melphalan/dactinomycin and five patients received a drug combination of melphalan/tumor necrosis factor-alpha. Remission rates were determined in 72 of 80 patients (90%) as follows: partial response n = 28, complete response n = 25, no response n = 19. Of the 25 patients with complete response, 13 patients developed a new tumor manifestation during follow-up (locoregional recurrences n = 4; distant metastases n = 3; both n = 6). The median overall survival rate was 33 months. Tumor stage influenced the survival rate significantly (p = 0.001). Patients with complete response showed a significantly better overall survival than patients with partial or no response (p = 0.016).

    CONCLUSION: HILP is an effective therapeutic option in patients with locoregional metastases. This procedure carries a certain risk of side effects and adverse events but overall results in good response rates. Therefore, HILP should be offered to selected patients based on an individual discussion, considering their health status and oncological prognosis.

    Pubmed
  • HIV-1 Nef-Induced Secretion of the Proinflammatory Protease TACE into Extracellular Vesicles Is Mediated by Raf-1 and Can Be Suppressed by Clinical Protein Kinase Inhibitors.

    J Virol. 2021;95(9):

    Zhao Z, Fagerlund R, Baur AS, Saksela K

    Chronic immune activation is an important driver of human immunodeficiency virus type 1 (HIV-1) pathogenesis and has been associated with the presence of tumor necrosis factor-α converting enzyme (TACE) in extracellular vesicles (EVs) circulating in infected individuals. We have recently shown that activation of the Src-family tyrosine kinase hematopoietic cell kinase (Hck) by HIV-1 Nef can trigger the packaging of TACE into EVs via an unconventional protein secretion pathway. Using a panel of HIV-1 Nef mutants and natural HIV-2 and simian immunodeficiency virus (SIV) Nef alleles, we now show that the capacity to promote TACE secretion depends on the superior ability of HIV-1-like Nef alleles to induce Hck kinase activity, whereas other Nef effector functions are dispensable. Strikingly, among the numerous Src-family downstream effectors, serine/threonine kinase Raf-1 was found to be necessary and alone sufficient to trigger the secretion of TACE into EVs. These data reveal the involvement of Raf-1 in regulation of unconventional protein secretion and highlight the importance of Raf-1 as a cellular effector of Nef, thereby suggesting a novel rationale for testing pharmacological inhibitors of the Raf-MAPK pathway to treat HIV-associated immune activation.IMPORTANCE Chronic immune activation contributes to the immunopathogenesis of human immunodeficiency virus type 1 (HIV-1) infection and is associated with poor recovery of the immune system despite potent antiretroviral therapy, which is observed in 10% to 40% drug-treated patients depending on the definition of immune reconstitution. We have previously shown that the HIV pathogenicity factor Nef can promote loading of the proinflammatory protease TACE into extracellular vesicles (EVs), and the levels of such TACE-containing EVs circulating in the blood correlate with low CD4 lymphocyte counts in HIV patients receiving antiretroviral therapy. Here, we show that Nef promotes uploading of TACE into EVs by triggering unconventional secretion via activation of the Hck/Raf/mitogen-activated protein kinase (MAPK) cascade. We find that several pharmaceutical inhibitors of these kinases that are currently in clinical use for other diseases can potently suppress this pathogenic deregulation and could thus provide a novel strategy for treating HIV-associated immune activation.

    Pubmed
  • Landscape of Bone Marrow Metastasis in Human Neuroblastoma Unraveled by Transcriptomics and Deep Multiplex Imaging.

    Cancers (Basel). 2021;13(17):

    Lazic D, Kromp F, Rifatbegovic F, Repiscak P, Kirr M, Mivalt F, Halbritter F, Bernkopf M, Bileck A, Ussowicz M, Ambros IM, Ambros PF, Gerner C, Ladenstein R, Ostalecki C, Taschner-Mandl S

    While the bone marrow attracts tumor cells in many solid cancers leading to poor outcome in affected patients, comprehensive analyses of bone marrow metastases have not been performed on a single-cell level. We here set out to capture tumor heterogeneity and unravel microenvironmental changes in neuroblastoma, a solid cancer with bone marrow involvement. To this end, we employed a multi-omics data mining approach to define a multiplex imaging panel and developed DeepFLEX, a pipeline for subsequent multiplex image analysis, whereby we constructed a single-cell atlas of over 35,000 disseminated tumor cells (DTCs) and cells of their microenvironment in the metastatic bone marrow niche. Further, we independently profiled the transcriptome of a cohort of 38 patients with and without bone marrow metastasis. Our results revealed vast diversity among DTCs and suggest that FAIM2 can act as a complementary marker to capture DTC heterogeneity. Importantly, we demonstrate that malignant bone marrow infiltration is associated with an inflammatory response and at the same time the presence of immuno-suppressive cell types, most prominently an immature neutrophil/granulocytic myeloid-derived suppressor-like cell type. The presented findings indicate that metastatic tumor cells shape the bone marrow microenvironment, warranting deeper investigations of spatio-temporal dynamics at the single-cell level and their clinical relevance.

    Pubmed
  • T-Cell Responses in Merkel Cell Carcinoma: Implications for Improved Immune Checkpoint Blockade and Other Therapeutic Options.

    Int J Mol Sci. 2021;22(16):

    Gehrcken L, Sauerer T, Schaft N, Dörrie J

    Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with rising incidence and high mortality. Approximately 80% of the cases are caused by the human Merkel cell polyomavirus, while the remaining 20% are induced by UV light leading to mutations. The standard treatment of metastatic MCC is the use of anti-PD-1/-PD-L1-immune checkpoint inhibitors (ICI) such as Pembrolizumab or Avelumab, which in comparison with conventional chemotherapy show better overall response rates and longer duration of responses in patients. Nevertheless, 50% of the patients do not respond or develop ICI-induced, immune-related adverse events (irAEs), due to diverse mechanisms, such as down-regulation of MHC complexes or the induction of anti-inflammatory cytokines. Other immunotherapeutic options such as cytokines and pro-inflammatory agents or the use of therapeutic vaccination offer great ameliorations to ICI. Cytotoxic T-cells play a major role in the effectiveness of ICI, and tumour-infiltrating CD8+ T-cells and their phenotype contribute to the clinical outcome. This literature review presents a summary of current and future checkpoint inhibitor therapies in MCC and demonstrates alternative therapeutic options. Moreover, the importance of T-cell responses and their beneficial role in MCC treatment is discussed.

    Pubmed
  • Human AZFb deletions cause distinct testicular pathologies depending on their extensions in Yq11 and the Y haplogroup: new cases and review of literature.

    Cell Biosci. 2021;11(1):

    Vogt PH, Bender U, Deibel B, Kiesewetter F, Zimmer J, Strowitzki T

    Genomic AZFb deletions in Yq11 coined "classical" (i.e. length of Y DNA deletion: 6.23 Mb) are associated with meiotic arrest (MA) of patient spermatogenesis, i.e., absence of any postmeiotic germ cells. These AZFb deletions are caused by non-allelic homologous recombination (NAHR) events between identical sequence blocks located in the proximal arm of the P5 palindrome and within P1.2, a 92 kb long sequence block located in the P1 palindrome structure of AZFc in Yq11. This large genomic Y region includes deletion of 6 protein encoding Y genes, EIFA1Y, HSFY, PRY, RBMY1, RPS4Y, SMCY. Additionally, one copy of CDY2 and XKRY located in the proximal P5 palindrome and one copy of BPY1, two copies of DAZ located in the P2 palindrome, and one copy of CDY1 located proximal to P1.2 are included within this AZFb microdeletion. It overlaps thus distally along 2.3 Mb with the proximal part of the genomic AZFc deletion. However, AZFb deletions have been also reported with distinct break sites in the proximal and/or distal AZFb breakpoint intervals on the Y chromosome of infertile men. These so called "non-classical" AZFb deletions are associated with variable testicular pathologies, including meiotic arrest, cryptozoospermia, severe oligozoospermia, or oligoasthenoteratozoospermia (OAT syndrome), respectively. This raised the question whether there are any specific length(s) of the AZFb deletion interval along Yq11 required to cause meiotic arrest of the patient's spermatogenesis, respectively, whether there is any single AZFb Y gene deletion also able to cause this "classical" AZFb testicular pathology? Review of the literature and more cases with "classical" and "non-classical" AZFb deletions analysed in our lab since the last 20 years suggests that the composition of the genomic Y sequence in AZFb is variable in men with distinct Y haplogroups especially in the distal AZFb region overlapping with the proximal AZFc deletion interval and that its extension can be "polymorphic" in the P3 palindrome. That means this AZFb subinterval can be rearranged or deleted also on the Y chromosome of fertile men. Any AZFb deletion observed in infertile men with azoospermia should therefore be confirmed as "de novo" mutation event, i.e., not present on the Y chromosome of the patient's father or fertile brother before it is considered as causative agent for man's infertility. Moreover, its molecular length in Yq11 should be comparable to that of the "classical" AZFb deletion, before meiotic arrest is prognosed as the patient's testicular pathology.

    Pubmed
  • Nectin-1 Expression Correlates with the Susceptibility of Malignant Melanoma to Oncolytic Herpes Simplex Virus In Vitro and In Vivo.

    Cancers (Basel). 2021;13(12):

    Schwertner B, Lindner G, Toledo Stauner C, Klapproth E, Magnus C, Rohrhofer A, Gross S, Schuler-Thurner B, Öttl V, Feichtgruber N, Drexler K, Evert K, Krahn MP, Berneburg M, Schmidt B, Schuster P, Haferkamp S

    Talimogene laherparepvec (T-VEC), an oncolytic herpes simplex virus, is approved for intralesional injection of unresectable stage IIIB/IVM1a melanoma. However, it is still unclear which parameter(s) predict treatment response or failure. Our study aimed at characterizing surface receptors Nectin-1 and the herpes virus entry mediator (HVEM) in addition to intracellular molecules cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) as potential bio-markers for oncolytic virus treatment. In 20 melanoma cell lines, oncolytic activity of T-VEC was correlated with the expression of Nectin-1 but not HVEM, as evaluated via flow cytometry and immunohistochemistry. Knockout using CRISPR/Cas9 technology confirmed the superior role of Nectin-1 over HVEM for entry and oncolytic activity of T-VEC. Neither cGAS nor STING as evaluated by Western Blot and immunohistochemistry correlated with T-VEC induced oncolysis. The role of these biomarkers was retrospectively analyzed for the response of 35 cutaneous melanoma metastases of 21 patients to intralesional T-VEC injection, with 21 (60.0%) of these lesions responding with complete (n = 16) or partial regression (n = 5). Nectin-1 expression in pretreatment biopsies significantly predicted treatment outcome, while the expression of HVEM, cGAS, and STING was not prognostic. Altogether, Nectin-1 served as biomarker for T-VEC-induced melanoma regression in vitro and in vivo.

    Pubmed
  • Grade 4 Neutropenia Secondary to Immune Checkpoint Inhibition - A Descriptive Observational Retrospective Multicenter Analysis.

    Front Oncol. 2021;11():

    Zaremba A, Kramer R, De Temple V, Bertram S, Salzmann M, Gesierich A, Reinhardt L, Baroudjian B, Sachse MM, Mechtersheimer G, Johnson DB, Weppler AM, Spain L, Loquai C, Dudda M, Pföhler C, Hepner A, Long GV, Menzies AM, Carlino MS, Lebbé C, Enokida T, Tahara M, Bröckelmann PJ, Eigentler T, Kähler KC, Gutzmer R, Berking C, Ugurel S, Stadtler N, Sucker A, Becker JC, Livingstone E, Meier F, Hassel JC, Schadendorf D, Hanoun M, Heinzerling L, Zimmer L

    Introduction: Immune checkpoint inhibitors (ICI) are increasingly being used to treat numerous cancer types. Together with improved recognition of toxicities, this has led to more frequent identification of rare immune-related adverse events (irAE), for which specific treatment strategies are needed. Neutropenia is a rare hematological irAE that has a potential for a high mortality rate because of its associated risk of sepsis. Prompt recognition and timely treatment of this life-threatening irAE are therefore critical to the outcome of patients with immune-related neutropenia.

    Methods: This multicenter international retrospective study was conducted at 17 melanoma centers to evaluate the clinical characteristics, diagnostics, treatment, and outcomes of melanoma patients with grade 4 neutropenia (<500 neutrophils/µl blood) treated with ICI between 2014 and 2020. Some of these patients received metamizole in addition to ICI (ICI+/met+). Bone marrow biopsies (BMB) of these patients were compared to BMB from non-ICI treated patients with metamizole-induced grade 4 neutropenia (ICI-/met+).

    Results: In total, 10 patients (median age at neutropenia onset: 66 years; seven men) with neutropenia were identified, equating to an incidence of 0.14%. Median onset of neutropenia was 6.4 weeks after starting ICI (range 1.4-49.1 weeks). Six patients showed inflammatory symptoms, including fever (n=3), erysipelas (n=1), pharyngeal abscess (n=1), and mucositis (n=1). Neutropenia was diagnosed in all patients by a differential blood count and additionally performed procedures including BMB (n=5). Nine of 10 patients received granulocyte colony-stimulating factors (G-CSF) to treat their grade 4 neutropenia. Four patients received systemic steroids (including two in combination with G-CSF, and one in combination with G-CSF and additional ciclosporin A). Four patients were treated with one or more antibiotic treatment lines, two with antimycotic treatment, and one with additional antiviral therapy. Five patients received metamizole concomitantly with ICI. One fatal outcome was reported. BMB indicated a numerically lower CD4+ to CD8+ T cells ratio in patients with irNeutropenia than in those with metamizole-induced neutropenia.

    Conclusion: Grade 4 neutropenia is a rare but potentially life-threatening side effect of ICI treatment. Most cases were sufficiently managed using G-CSF; however, adequate empiric antibiotic, antiviral, and antimycotic treatments should be administered if neutropenic infections are suspected. Immunosuppression using corticosteroids may be considered after other causes of neutropenia have been excluded.

    Pubmed
  • Fertility preservation and management of pregnancy in melanoma patients requiring systemic therapy.

    ESMO Open. 2021;6(5):

    Hassel JC, Livingstone E, Allam JP, Behre HM, Bojunga J, Klein HH, Landsberg J, Nawroth F, Schüring A, Susok L, Thoms KM, Kiesel L, Berking C

    Melanoma is one of the most common cancers in adolescents and adults at fertile age, especially in women. With novel and more effective systemic therapies that began to profoundly change the dismal outcome of melanoma by prolonging overall survival, the wish for fertility preservation or even parenthood has to be considered for a growing portion of melanoma patients-from the patients' as well as from the physicians' perspective. The dual blockade of the mitogen-activated protein kinase pathway by B-Raf proto-oncogene serine/threonine kinase and mitogen-activated protein kinase inhibitors and the immune checkpoint inhibition by anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte-associated protein-4 monoclonal antibodies constitute the current standard systemic approaches to combat locally advanced or metastatic melanoma. Here, the preclinical data and clinical evidence of these systemic therapies are reviewed in terms of their potential gonadotoxicity, teratogenicity, embryotoxicity and fetotoxicity. Recommendations for routine fertility and contraception counseling of melanoma patients at fertile age are provided in line with interdisciplinary recommendations for the diagnostic work-up of these patients and for fertility-protective measures. Differentiated recommendations for the systemic therapy in both the adjuvant and the advanced, metastatic treatment situation are given. In addition, the challenges of pregnancy during systemic melanoma therapy are discussed.

    Pubmed
  • Effectiveness, safety and utilization of vismodegib in locally advanced basal cell carcinoma under real-world conditions in Germany - The non-interventional study NIELS.

    J Eur Acad Dermatol Venereol. 2021;35(8): 1678-1685

    Gutzmer R, Schulze HJ, Hauschild A, Leiter U, Meier F, Haferkamp S, Ulrich C, Wahl RU, Berking C, Herbst R, Häckl M, Schadendorf D

    BACKGROUND: Basal cell carcinoma (BCC) can arise by the uncontrolled proliferation of cells from multiple epidermal compartments due to aberrant activation of the Hedgehog (Hh) signalling pathway. Vismodegib, a small-molecule inhibitor of this pathway, is approved for treatment of patients with locally advanced (la) BCC inappropriate for surgery or radiotherapy or patients with symptomatic metastatic (m) BCC.

    OBJECTIVES: The aim of this non-interventional study was to assess effectiveness with a special focus on duration of response (DOR), safety and utilization of vismodegib for treatment of laBCC in daily practice in Germany.

    METHODS: This non-interventional study (NIS) observed treatment of laBCC with vismodegib according to the German label in clinical practice. All available patients who had received at least one dose of vismodegib between commercial availability of vismodegib in Germany (02 August 2013) and 3 years before end of study (31 March 2016) could be included and were documented retrospectively and/or prospectively for up to 3 years. Primary effectiveness variable was DOR. Assessment of tumour response was carried out by the treating physicians. Exploratory variables included utilization of vismodegib, decision makers for therapy and method of tumour response evaluation. All statistical analyses were descriptive.

    RESULTS: Between September 2015 and March 2019, 66 patients were observed at 26 German centres. The objective response rate (ORR) was 74.2% and the disease control rate (DCR) was 90.9%. The median DOR was 15.9 months (95% CI: 9.2; 25.7; n = 49 patients with response). The median progression-free survival (PFS) was 19.1 months and the median time to response (TTR) 2.7 months. A total of 340 adverse events were reported in 63 (95.5%) patients; no new safety signals were identified.

    CONCLUSIONS: The NIS NIELS shows effectiveness and safety of vismodegib in patients with laBCC. It confirms the transferability of the results of the pivotal trial into routine clinical practice.

    Pubmed
  • A phase 4, randomized, head-to-head trial comparing the efficacy of subcutaneous injections of brodalumab to oral administrations of fumaric acid esters in adults with moderate-to-severe plaque psoriasis (CHANGE).

    J Eur Acad Dermatol Venereol. 2021;35(3): 701-711

    Pinter A, Hoffmann M, Reich K, Augustin M, Kaplan K, Gudjónsdóttir SD, Delvin T, Mrowietz U, CHANGE investigator group , Beissert S, Effendy I, Eyerich K, Gonser L, Kleinheinz A, Leitz N, Niesmann J, Pauser S, Philipp S, Radny P, Rothhaar A, Rotterdam S, Schaarschmidt ML, Schäkel K, Staubach P, Sticherling M, Szeimies RM, Tsianakas A, Weber R, Weirich O, Werfel T, Wildfeuer T, Wilsman-Theis D

    BACKGROUND: Brodalumab is a fully human monoclonal immunoglobulin IgG2 antibody that binds to the human IL-17 receptor subunit A and by that inhibits the biologic action of IL-17A, IL-17F, IL-17C and IL-17E. Therapy with fumaric acid esters (FAE) is a well established and widely used first-line systemic treatment for subjects with moderate-to-severe plaque psoriasis.

    OBJECTIVES: To compare brodalumab to FAE in terms of clinical efficacy, patient-reported outcomes and safety in subjects with moderate-to-severe plaque psoriasis who were naïve to systemic treatment.

    METHODS: Eligible subjects were randomized 1 : 1 to 210 mg brodalumab injections or oral FAE according to product label in this 24-week, open-label, assessor-blinded, multi-centre, head-to-head phase 4 trial. The primary endpoints were having PASI75 and having sPGA score of 0 or 1 (sPGA 0/1). Subjects with missing values for the primary endpoints were considered non-responders.

    RESULTS: A total of 210 subjects were randomized. 91/105 subjects completed brodalumab treatment and 58/105 subjects completed FAE treatment. At Week 24, significantly more subjects in the brodalumab group compared to the FAE group had PASI75 (81.0% vs. 38.1%, P < 0.001) and sPGA 0/1 (64.8% vs. 20.0%, P < 0.001). In the brodalumab group, the median time to both PASI75 and to PASI90 was significantly shorter than in the FAE group (4.1 weeks vs. 16.4 weeks, and 7.4 weeks vs. 24.4 weeks, respectively, P < 0.0001 for both). The rate of adverse events was lower in subjects treated with brodalumab compared to subjects treated with FAE (616.4 vs. 1195.8 events per 100 exposure years). No new safety signals were detected for brodalumab.

    CONCLUSIONS: Brodalumab was associated with rapid and significant improvements in signs and symptoms of moderate-to-severe plaque psoriasis, with a superior efficacy profile to what was observed with FAE in systemic-naïve subjects over 24 weeks.

    Pubmed
  • The global impact of the COVID-19 pandemic on the management and course of chronic urticaria

    Allergy. 2021;76(3): 816-830

    Kocaturk E, Salman A, Cherrez-Ojeda I, Criado PR, Peter J, Comert-Ozer E, Abuzakouk M, Agondi RC, Al-Ahmad M, Altrichter S, Arnaout R, Arruda LK, Asero R, Bauer A, Ben-Shoshan M, Bernstein JA, Bizjak M, Boccon-Gibod I, Bonnekoh H, Bouillet L, Brzoza Z, Busse P, Campos RA, Carne E, Conlon N, Criado RF, de Souza Lima EMD, Demir S, Dissemond J, Gunaydin SD, Dorofeeva I, Ensina LF, Ertas R, Ferrucci SM, Figueras-Nart I, Fomina D, Franken SM, Fukunaga A, Gimenez-Arnau AM, Godse K, Goncalo M, Gotua M, Grattan C, Guillet C, Inomata N, Jakob T, Karakaya G, Kasperska-Zajac A, Katelaris CH, Kosnik M, Krasowska D, Kulthanan K, Kumaran MS, Lang C, Ignacio Larco-Sousa JI, Lazaridou E, Leslie TA, Lippert U, Llosa OC, Makris M, Marsland A, Medina IV, Meshkova R, Palitot EB, Parisi CAS, Pickert J, Ramon GD, Rodriguez-Gonzalez M, Rosario N, Rudenko M, Rutkowski K, Sanchez J, Schliemann S, Sekerel BE, Serpa FS, Serra-Baldrich E, Song ZQ, Soria A, Staevska M, Staubach P, Tagka A, Takahagi S, Thomsen SF, Treudler R, Vadasz Z, Rodrigues Valle SOR, Van Doorn MBA, Vestergaard C, Wagner N, Wang DH, Wang LC, Wedi B, Xepapadaki P, Yucel E, Zalewska-Janowska A, Zhao ZT, Zuberbier T, Maurer M

    Introduction The COVID-19 pandemic dramatically disrupts health care around the globe. The impact of the pandemic on chronic urticaria (CU) and its management are largely unknown.

    Aim To understand how CU patients are affected by the COVID-19 pandemic; how specialists alter CU patient management; and the course of CU in patients with COVID-19.

    Materials and Methods Our cross-sectional, international, questionnaire-based, multicenter UCARE COVID-CU study assessed the impact of the pandemic on patient consultations, remote treatment, changes in medications, and clinical consequences.

    Results The COVID-19 pandemic severely impairs CU patient care, with less than 50% of the weekly numbers of patients treated as compared to before the pandemic. Reduced patient referrals and clinic hours were the major reasons. Almost half of responding UCARE physicians were involved in COVID-19 patient care, which negatively impacted on the care of urticaria patients. The rate of face-to-face consultations decreased by 62%, from 90% to less than half, whereas the rate of remote consultations increased by more than 600%, from one in 10 to more than two thirds. Cyclosporine and systemic corticosteroids, but not antihistamines or omalizumab, are used less during the pandemic. CU does not affect the course of COVID-19, but COVID-19 results in CU exacerbation in one of three patients, with higher rates in patients with severe COVID-19.

    Conclusions The COVID-19 pandemic brings major changes and challenges for CU patients and their physicians. The long-term consequences of these changes, especially the increased use of remote consultations, require careful evaluation.

    Pubmed
  • Formaldehyde 2% is not a useful means of detecting allergy to formaldehyde releasers- results of the ESSCA network, 2015-2018.

    Contact Dermatitis. 2021;84(2): 95-102

    Whitehouse H, Uter W, Geier J, Ballmer-Weber B, Bauer A, Cooper S, Czarnecka-Operacz M, Dagmar S, Dickel H, Fortina AB, Gallo R, Giménez-Arnau AM, Johnston GA, Filon FL, Mahler V, Pesonen M, Rustemeyer T, Schuttelaar MLA, Valiukevičienė S, Weisshaar E, Werfel T, Wilkinson SM

    BACKGROUND: Studies suggest that patch testing with formaldehyde releasers (FRs) gives significant additional information to formaldehyde 1% aq. and should be considered for addition to the European baseline series (EBS). It is not known if this is also true for formaldehyde 2% aq.

    OBJECTIVES: To determine the frequency of sensitization to formaldehyde 2% aq. and co-reactivity with FRs. To establish whether there is justification for including FRs in the EBS.

    MATERIALS AND METHODS: A 4-year, multi-center retrospective analysis of patients with positive patch test reactions to formaldehyde 2% aq. and five FRs.

    RESULTS: A maximum of 15 067 patients were tested to formaldehyde 2% aq. and at least one FR. The percentage of isolated reactions to FR, without co-reactivity to, formaldehyde 2% aq. for each FR were: 46.8% for quarternium-15 1% pet.; 67.4% imidazolidinyl urea 2% pet.; 64% diazolidinyl urea 2% pet.; 83.3% 1,3-dimethylol-5, 5-dimethyl hydantoin (DMDM) hydantoin 2% pet. and 96.3% 2-bromo-2-nitropropane-1,3-diol 0.5% pet. This demonstrates that co-reactivity varies between FRs and formaldehyde, from being virtually non-existent in 2-bromo-2-nitropropane-1,3-diol 0.5% pet. (Cohen's kappa: 0, 95% confidence interval [CI] -0.02 to 0.02)], to only weak concordance for quaternium-15 [Cohen's kappa: 0.22, 95%CI 0.16 to 0.28)], where Cohen's kappa value of 1 would indicate full concordance.

    CONCLUSIONS: Formaldehyde 2% aq. is an inadequate screen for contact allergy to the formaldehyde releasers, which should be considered for inclusion in any series dependant on the frequency of reactions to and relevance of each individual allergen.

    Pubmed
  • Developing a cosmetic series: Results from the ESSCA network, 2009-2018.

    Contact Dermatitis. 2021;84(2): 82-94

    Horton E, Uter W, Geier J, Ballmer-Weber B, Bauer A, Bircher A, Dickel H, Giménez-Arnau A, Gonçalo M, John SM, Mahler V, Schuttelaar MLA, Simon D, Sanchez-Perez J, Rustemeyer T, Weisshaar E, Wilkinson SM

    BACKGROUND: There is considerable variability across European patch test centres as to which allergens are included in local and national cosmetics series.

    OBJECTIVES: To propose a standardized, evidence-based cosmetic series for Europe based on up-to-date analysis of relevant contact allergens.

    METHODS: We collated data from the European Surveillance System on Contact Allergies (ESSCA) from 2009 to 2018 to determine which cosmetic allergens produce a high yield of contact allergy. Contact allergens with a prevalence of >0.3% that were considered relevant were included. Rare contact allergens were excluded if deemed no longer relevant or added to a supplemental cosmetic series for further analysis.

    RESULTS: Sensitization prevalences of 39 cosmetic contact allergens were tabulated. Thirty of these allergens yielded >0.3% positive reactions and are therefore included in our proposed European cosmetic series. Six were considered no longer relevant and therefore excluded. Three were included in a supplementary European cosmetic series. An additional nine allergens were included in either the core or supplemental European cosmetic series following literature review.

    CONCLUSION: We have derived a potential European cosmetic series based upon the above methods. This will require ongoing investigation based upon the changing exposure profiles of cosmetic allergens as well as new and evolving substances.

    Pubmed
  • Investigation of the Expression of Inflammatory Markers in Oral Biofilm Samples in Patients with Systemic Scleroderma and the Association with Clinical Periodontal Parameters-A Preliminary Study.

    Life (Basel). 2021;11(11):

    Buchbender M, Lugenbühl A, Fehlhofer J, Kirschneck C, Ries J, Lutz R, Sticherling M, Kesting MR

    BACKGROUND: Systemic scleroderma (SSc) has multiple orofacial effects. The aim of this study was to analyze the expression of inflammatory mediators in biofilm samples. It was hypothesized that different expression levels and clinical associations might be drawn.

    METHODS: A total of 39 biofilm samples from group 1 = SSc and group 2 = healthy control were examined for the expression levels of interleukin (IL)-2,-6, and -10; matrix metalloprotease (MMP)-9; and surface antigens CD90 and CD34 by quantitative real-time PCR and clinical parameters. Relative quantitative (RQ) gene expression was determined using the ∆∆CT method.

    RESULTS: The mean bleeding on probing values (p = 0.006), clinical attachment loss (CAL) (p = 0.009), gingival recession (p = 0.020), limited mouth opening (p = 0.001) and cervical tooth defects (p = 0.011) were significantly higher in group 1. RQ expressions of IL-2 and CD34 were significantly lower, IL-6, MMP-9, and CD90 were significantly higher. There was a significant positive correlation of IL-6/MMP-9 and negative correlation of mouth opening/CAL and IL-6/CAL.

    CONCLUSION: Different expression levels of IL-2, IL-6, MMP-9, CD34 and CD90 were detected in biofilm samples from patients with SSc compared to control. An immunological correlation to the clinical parameters of mouth opening and CAL was shown; thus, we conclude that SSc might have an impact on periodontal tissues.

    Pubmed
  • Increasing Participation Rates in Germany's Skin Cancer Screening Program (HELIOS): Protocol for a Mixed Methods Study.

    JMIR Res Protoc. 2021;10(12):

    Steeb T, Heppt MV, Erdmann M, Wessely A, Klug SJ, Berking C

    BACKGROUND: In 2008, a nationwide skin cancer screening (SCS) program was implemented in Germany. However, participation rates remain low.

    OBJECTIVE: The overall objective of the HELIOS study is to identify subgroup-specific invitation and communication strategies to increase informed SCS participation in Germany.

    METHODS: Focus group discussions will be performed in Erlangen, Germany, to explore potential invitation and communication strategies as well as possible barriers and motivating factors to participate in SCS. Male and female patients of different age groups who have already been diagnosed with skin cancer, as well as participants without a prior diagnosis of skin cancer, will be invited. Based on these results, an online questionnaire will be developed to identify subgroup-specific invitation strategies. A random sample of 2500 persons from the general population aged >35 years from the Munich area will be contacted to complete the questionnaire. Besides descriptive analysis, multinomial logistic regression will be performed. Additionally, a cluster analysis will be conducted to discover patterns or similarities among the participants.

    RESULTS: Recruitment for the focus group studies started in February 2021 and is ongoing. As of August 2021, we have enrolled 39 participants. We expect to end enrollment in the qualitative study in September 2021 and to finish the analysis in December 2021. The second part of the study will then start in January 2022.

    CONCLUSIONS: The results of this project will enable us to derive improved and more efficient invitation and communication strategies for SCS. These may be implemented in the future to facilitate increased SCS uptake and early skin cancer detection.

    INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31860.

    Pubmed
  • BRAF and MEK Inhibitors Affect Dendritic-Cell Maturation and T-Cell Stimulation.

    Int J Mol Sci. 2021;22(21):

    Hoyer S, Eberlein V, Schuler G, Berking C, Heinzerling L, Schaft N, Dörrie J

    BRAF and MEK inhibitor (BRAFi/MEKi) combinations are currently the standard treatment for patients with BRAFV600 mutant metastatic melanoma. Since the RAS/RAF/MEK/ERK-pathway is crucial for the function of different immune cells, we postulated an effect on their function and thus interference with anti-tumor immunity. Therefore, we examined the influence of BRAFi/MEKi, either as single agent or in combination, on the maturation of monocyte-derived dendritic cells (moDCs) and their interaction with T cells. DCs matured in the presence of vemurafenib or vemurafenib/cobimetinib altered their cytokine secretion and surface marker expression profile. Upon the antigen-specific stimulation of CD8+ and CD4+ T cells with these DCs or with T2.A1 cells in the presence of BRAFi/MEKi, we detected a lower expression of activation markers on and a lower cytokine secretion by these T cells. However, treatment with any of the inhibitors alone or in combination did not change the avidity of CD8+ T cells in peptide titration assays with T2.A1 cells. T-helper cell/DC interaction is a bi-directional process that normally results in DC activation. Vemurafenib and vemurafenib/cobimetinib completely abolished the helper T-cell-mediated upregulation of CD70, CD80, and CD86 but not CD25 on the DCs. The combination of dabrafenib/trametinib affected DC maturation and activation as well as T-cell activation less than combined vemurafenib/cobimetinib did. Hence, for a potential combination with immunotherapy, our data indicate the superiority of dabrafenib/trametinib treatment.

    Pubmed
  • Safety and tolerability of a single infusion of autologous ex vivo expanded regulatory T cells in adults with ulcerative colitis (ER-TREG 01): protocol of a phase 1, open-label, fast-track dose-escalation clinical trial.

    BMJ Open. 2021;11(12):

    Voskens CJ, Stoica D, Roessner S, Vitali F, Zundler S, Rosenberg M, Wiesinger M, Wunder J, Siegmund B, Schuler-Thurner B, Schuler G, Berking C, Atreya R, Neurath MF

    INTRODUCTION: Accumulating evidence suggests that the adoptive transfer of ex vivo expanded regulatory T cells (Treg) may overcome colitogenic immune responses in patients with inflammatory bowel diseases. The objective of the ER-TREG 01 trial is to assess safety and tolerability of a single infusion of autologous ex vivo expanded Treg in adults with ulcerative colitis.

    METHODS AND ANALYSIS: The study is designed as a single-arm, fast-track dose-escalation trial. The study will include 10 patients with ulcerative colitis. The study intervention consists of (1) a baseline visit; (2) a second visit that includes a leukapheresis to generate the investigational medicinal product, (3) a third visit to infuse the investigational medicinal product and (4) five subsequent follow-up visits within the next 26 weeks to assess safety and tolerability. Patients will intravenously receive a single dose of 0.5×106, 1×106, 2×106, 5×106 or 10×106 autologous Treg/kg body weight. The primary objective is to define the maximum tolerable dose of a single infusion of autologous ex vivo expanded Treg. Secondary objectives include the evaluation of safety of one single infusion of autologous ex vivo expanded Treg, efficacy assessment and accompanying immunomonitoring to measure Treg function in the peripheral blood and intestinal mucosa.

    ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of the Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany (number 417_19 Az). In addition, the study was approved by the Paul-Ehrlich Institute, Federal Institute for Vaccines and Biomedicines, Langen, Germany (number 3652/01). The study is funded by the German Research Foundation (DFG, KFO 257 project 08 and SFB/TransRegio 241 project C04). The trial will be conducted in compliance with this study protocol, the Declaration of Helsinki, Good Clinical Practice and Good Manufacturing Practice. The results will be published in peer-reviewed scientific journals and disseminated in scientific conferences and media.

    TRIAL REGISTRATION NUMBER: NCT04691232.

    Pubmed
  • CXCR4 blockade reduces the severity of murine heart allograft rejection by plasmacytoid dendritic cell-mediated immune regulation.

    Sci Rep. 2021;11(1):

    Fu J, Lehmann CHK, Wang X, Wahlbuhl M, Allabauer I, Wilde B, Amon L, Dolff S, Cesnjevar R, Kribben A, Woelfle J, Rascher W, Hoyer PF, Dudziak D, Witzke O, Hoerning A

    Allograft-specific regulatory T cells (Treg cells) are crucial for long-term graft acceptance after transplantation. Although adoptive Treg cell transfer has been proposed, major challenges include graft-specificity and stability. Thus, there is an unmet need for the direct induction of graft-specific Treg cells. We hypothesized a synergism of the immunotolerogenic effects of rapamycin (mTOR inhibition) and plerixafor (CXCR4 antagonist) for Treg cell induction. Thus, we performed fully-mismatched heart transplantations and found combination treatment to result in prolonged allograft survival. Moreover, fibrosis and myocyte lesions were reduced. Although less CD3+ T cell infiltrated, higher Treg cell numbers were observed. Noteworthy, this was accompanied by a plerixafor-dependent plasmacytoid dendritic cells-(pDCs)-mobilization. Furthermore, in vivo pDC-depletion abrogated the plerixafor-mediated Treg cell number increase and reduced allograft survival. Our pharmacological approach allowed to increase Treg cell numbers due to pDC-mediated immune regulation. Therefore pDCs can be an attractive immunotherapeutic target in addition to plerixafor treatment.

    Pubmed
  • Upregulation of CCR4 in activated CD8+ T cells indicates enhanced lung homing in patients with severe acute SARS-CoV-2 infection.

    Eur J Immunol. 2021;51(6): 1436-1448

    Spoerl S, Kremer AN, Aigner M, Eisenhauer N, Koch P, Meretuk L, Löffler P, Tenbusch M, Maier C, Überla K, Heinzerling L, Frey B, Lutzny-Geier G, Winkler TH, Krönke G, Vetter M, Bruns H, Neurath MF, Mackensen A, Kremer AE, Völkl S

    COVID-19 is a life-threatening disease leading to bilateral pneumonia and respiratory failure. The underlying reasons why a smaller percentage of patients present with severe pulmonary symptoms whereas the majority is only mildly affected are to date not well understood. Comparing the immunological phenotype in healthy donors and patients with mild versus severe COVID-19 shows that in COVID-19 patients, NK-/B-cell activation and proliferation are enhanced independent of severity. As an important precondition for effective antibody responses, T-follicular helper cells and antibody secreting cells are increased both in patients with mild and severe SARS-CoV-2 infection. Beyond this, T cells in COVID-19 patients exhibit a stronger activation profile with differentiation toward effector cell phenotypes. Importantly, when looking at the rates of pulmonary complications in COVID-19 patients, the chemokine receptor CCR4 is higher expressed by both CD4 and CD8 T cells of patients with severe COVID-19. This raises the hypothesis that CCR4 upregulation on T cells in the pathogenesis of COVID-19 promotes stronger T-cell attraction to the lungs leading to increased immune activation with presumably higher pulmonary toxicity. Our study contributes significantly to the understanding of the immunological changes during COVID-19, as new therapeutic agents, preferentially targeting the immune system, are highly warranted.

    Pubmed
  • Patients with Chronic Urticaria Remain Largely Undertreated: Results from the DERMLINE Online Survey.

    Dermatol Ther (Heidelb). 2021;11(3): 1027-1039

    Wagner N, Zink A, Hell K, Reinhardt M, Romer K, Hillmann E, Baeumer D, Schielein MC

    INTRODUCTION: Chronic urticaria (CU) is an unpredictable disease, with high disease burden and a significant negative impact on quality of life, especially in patients of working age. Many patients are undertreated, and there is poor awareness of strategies to manage patients with CU in the real-world setting. The current study aimed to gain a better understanding of CU from the patients' perspective, including the body areas most affected by wheals and angioedema, the disease burden and current use of the healthcare system.

    METHODS: A nationwide online survey was performed in Germany involving individuals who reported a diagnosis of CU and experienced symptoms within 3 months prior to inclusion.

    RESULTS: This self-report survey included 1037 participants (89.2% female), with a mean ± standard deviation (SD) age of 33.4 ± 11.0 years and a mean ± SD disease duration of 10.0 ± 9.4 years. On average, participants suffered from urticaria symptoms for 3.0 ± 4.3 years before diagnosis. In 73% of participants, symptoms worsened due to external factors, with the majority specifying stress in their personal life or work-related stress as eliciting factors. Within the previous 3 months, 87.4 and 44.1% of participants experienced wheals and angioedema, respectively, at multiple body areas, and most (79.6%) participants had uncontrolled symptoms as measured with the Urticaria Control Test. Despite the high burden of disease, 60.3% of participants stated that they were not currently receiving treatment. The most commonly used therapies to treat CU were oral (72.8%) and non-prescription (43.3%) and prescription (47.3%) topical drugs, with 18.0% of the participants receiving injectable/infused drugs.

    CONCLUSION: The majority of the participants responding to the survey reported that CU is not sufficiently controlled, thereby severely influencing a highly productive time in their life. The body areas most affected by wheals and angioedema are specified, based on data provided by a large group of affected participants. A greater awareness of disease burden and available treatment options is needed.

    Pubmed
  • Modern diabetes devices for continuous blood sugar measuring: Limitations due to contact allergies.

    J Dtsch Dermatol Ges. 2021;19(12): 1715-1721

    Kamann S, Wagner N, Oppel E

    During the past years, diabetes diseases have increased significantly worldwide. However, new technologies such as continuous glucose measurement using a subcutaneous sensor are developing just as rapidly. A continuous improvement in insulin pump therapy is also contributing to an improved quality of life. A common feature of these modern devices for diabetes therapy is that they remain fixed in place on the skin for several days. In recent years, skin reactions, in particular pronounced contact dermatitis due to the devices and their adhesives have been increasingly reported. In particular, isobornyl acrylate, which used to be included in a glucose measurement sensor set, was identified as a main allergen. Development of contact allergy can result both in a necessity to quit the measuring system and in allergic cross-reactions to other systems.

    Pubmed
  • Computational decomposition reveals reshaping of the SARS-CoV-2-ACE2 interface among viral variants expressing the N501Y mutation.

    J Cell Biochem. 2021;122(12): 1863-1872

    Socher E, Conrad M, Heger L, Paulsen F, Sticht H, Zunke F, Arnold P

    Variants of concern of the SARS-CoV-2 virus with an asparagine-to-tyrosine substitution at position 501 (N501Y) in the receptor-binding domain (RBD) show enhanced infectivity compared to wild-type, resulting in an altered pandemic situation in affected areas. These SARS-Cov-2 variants comprise the two Alpha variants (B.1.1.7, United Kingdom and B.1.1.7 with the additional E484K mutation), the Beta variant (B.1.351, South Africa), and the Gamma variant (P.1, Brazil). Understanding the binding modalities between these viral variants and the host cell receptor ACE2 allows to depict changes, but also common motifs of virus-host cell interaction. The trimeric spike protein expressed at the viral surface contains the RBD that forms the molecular interface with ACE2. All the above-mentioned variants carry between one and three amino acid exchanges within the interface-forming region of the RBD, thereby altering the binding interface with ACE2. Using molecular dynamics (MD) simulations and decomposition of intermolecular contacts between the RBD and ACE2, we identified phenylalanine 486, glutamine 498, threonine 500, and tyrosine 505 as important interface-forming residues across viral variants. However, especially the N501Y exchange increased contact formation for this residue and also induced some local conformational changes. Comparing here, the in silico generated B.1.1.7 RBD-ACE2 complex with the now available experimentally solved structure reveals very similar behavior during MD simulation. We demonstrate, how computational methods can help to identify differences in conformation as well as contact formation for newly emerging viral variants. Altogether, we provide extensive data on all N501Y expressing SARS-CoV-2 variants of concern with respect to their interaction with ACE2 and how this induces reshaping of the RBD-ACE2 interface.

    Pubmed
  • Mutations in the B.1.1.7 SARS-CoV-2 Spike Protein Reduce Receptor-Binding Affinity and Induce a Flexible Link to the Fusion Peptide.

    Biomedicines. 2021;9(5):

    Socher E, Conrad M, Heger L, Paulsen F, Sticht H, Zunke F, Arnold P

    The B.1.1.7 variant of the SARS-CoV-2 virus shows enhanced infectiousness over the wild type virus, leading to increasing patient numbers in affected areas. Amino acid exchanges within the SARS-CoV-2 spike protein variant of B.1.1.7 affect inter-monomeric contact sites within the trimer (A570D and D614G) as well as the ACE2-receptor interface region (N501Y), which comprises the receptor-binding domain (RBD) of the spike protein. However, the molecular consequences of mutations within B.1.1.7 on spike protein dynamics and stability or ACE2 binding are largely unknown. Here, molecular dynamics simulations comparing SARS-CoV-2 wild type with the B.1.1.7 variant revealed inter-trimeric contact rearrangements, altering the structural flexibility within the spike protein trimer. Furthermore, we found increased flexibility in direct spatial proximity of the fusion peptide due to salt bridge rearrangements induced by the D614G mutation in B.1.1.7. This study also implies a reduced binding affinity for B.1.1.7 with ACE2, as the N501Y mutation restructures the RBD-ACE2 interface, significantly decreasing the linear interaction energy between the RBD and ACE2. Our results demonstrate how mutations found within B.1.1.7 enlarge the flexibility around the fusion peptide and change the RBD-ACE2 interface. We anticipate our findings to be starting points for in depth biochemical and cell biological analyses of B.1.1.7.

    Pubmed
  • The impact of brain involvement in metastatic melanoma patients treated with pembrolizumab

    J Transl Med. 2021;19 Suppl 1(SUPPL 1):

    Weichenthal M, Emilie S, Chandwani S, Mohr P, Leiter U, Ugurel S, Kaehler KC, Gutzmer R, Pfoehler C, Hassel J, Terheyden P, Schell B, Utikal J, Kreuter A, Haferkamp S, Sindrilaru A, Hassel J, Nashan D, Kaune KM, Berking C, Debus D, Ulrich J, Dabrowski E, Eigentler T, Herbst R, Welzel J, Loquai C, Meier F, Schadendorf D

    Pubmed
  • Results from the phase Ib of the SENSITIZE trial combining domatinostat with pembrolizumab in advanced melanoma patients refractory to prior checkpoint inhibitor therapy.

    J Clin Oncol. 2021;39 Suppl S(15):

    Hassel JC, Berking C, Schlaak M, Eigentler T, Gutzmer R, Ascierto PA, Schilling B, Hamm S, Hermann F, Reimann PG, Schadendorf D

    Pubmed
  • PATIENTS WITH IMMUNE MEDIATED INFLAMMATORY DISEASES ARE OVERREPRESENTED IN LOW-FREQUENCY VIRAL SYMPTOM CLUSTERS

    Ann Rheum Dis. 2021;80 Suppl 1(): 996-997

    Tascilar K, Simon D, Kroenke G, Kleyer A, Ramming A, Atreya R, Tenbusch M, Ueberla K, Berking C, Sticherling M, Neurath MF, Schett G

    Pubmed
  • Dermatological Quality of Life and Neurodermatitis: Results from the German Neurodermatitis Registry TREATgermany

    J Dtsch Dermatol Ges. 2021;19 Suppl 2(): 119-120

    Helmert C, Haufe E, Abraham S, Heratizadeh A, Harder I, Kleinheinz A, Wollenberg A, Wiemers F, Weisshaar E, Augustin M, Zink A, von Kiedrowski R, Wildberger J, Pawlak M, Hilgers M, Worm M, Schaekel K, Sticherling M, Effendy I, Staubach-Renz P, Handrick C, Bell M, Asmussen A, Schwarz B, Werfel T, Weidinger S, Schmitt J, Treatgermany Study Grp

    Pubmed
  • Psoriasis in routine clinical care: Complete skin clearance rates with guselkumab increase through week 52-Results from the real-life PERSIST study

    J Am Acad Dermatol. 2021;85 Suppl S(3): AB177-AB177

    Hoffmann M, Sticherling M, Korge B, Mortazawi D, Personke Y, Gomez M, Wegner S, Gerdes S

    Pubmed
  • B-cells in psoriasis?

    Exp Dermatol. 2021;30(3): E80-E80

    Banki S, Heusinger J, Herter-Kermann T, Sticherling M

    Pubmed
  • Do B-Cells play a Role in Patients with Psoriasis?

    J Dtsch Dermatol Ges. 2021;19 Suppl 2(): 41-41

    Banki S, Heusinger J, Herter-Kermann T, Sticherling M

    Pubmed
  • THE GERMAN AD REGISTRY TREATGERMANY: RESULTS FROM AN INTERIM DATA ANALYSIS ON BASELINE CHARACTERISTICS, COMORBIDITIES AND TREATMENT HISTORY

    Acta Derm Venereol. 2021;101 Suppl 221(): 24-25

    Heratizadeh A, Haufe E, Stoelzl D, Abraham S, Heinrich L, Kleinheinz A, Wollenberg A, Weisshaar E, Augustin M, Wiemers F, Zink A, von Kiedrowski R, Hilgers M, Worm M, Pawlak M, Sticherling M, Fell I, Handrick C, Schaekel K, Staubach-Renz P, Asmussen A, Schwarz B, Bell M, Effendy I, Bieber T, Homey B, Gerlach B, Tchitcherina E, Stahl M, Schwichtenberg U, Rossbacher J, Buck P, Mempel M, Beissert S, Biedermann T, Weidinger S, Schmitt J, Werfel T, TREATgermany Study grp

    Pubmed
  • Proactive Management with twice-a-week Use of topical Cal/BD Spray Foam Management extends the Effectiveness of the Treatment in Comparison to Reactive Management in Patients with Plaque Psoriasis

    J Dtsch Dermatol Ges. 2021;19 Suppl 2(): 67-67

    Stein-Gold L, Alonso-Llamazares J, Laws P, Perrussel M, Yamauchi P, Thoning H, Toxvaerd C, Sticherling M

    Pubmed
  • Multiple thoracic Erosions after Vacation in Tunisia

    J Dtsch Dermatol Ges. 2021;19 Suppl 2(): 111-111

    Meder C, Sticherling M

    Pubmed
  • Association of Fabry Disease and Psoriasis - therapeutically significant?

    J Dtsch Dermatol Ges. 2021;19 Suppl 2(): 85-85

    Sollfrank L, Sticherling M

    Pubmed
  • H. E. Becher - his Importance as a Sculptor and Medalist for Moulage Art in Germany

    J Dtsch Dermatol Ges. 2021;19 Suppl 2(): 19-19

    Sticherling M, Emmerling J

    Pubmed
  • German S1 guideline: diagnosis and treatment of livedovasculopathy.

    J Dtsch Dermatol Ges. 2021;19(11): 1668-1678

    Schiffmann ML, Dissemond J, Erfurt-Berge C, Hafner J, Itzlinger-Monshi BA, Jungkunz HW, Kahle B, Kreuter A, Scharffetter-Kochanek K, Lutze S, Rappersberger K, Schneider SW, Stroelin A, Sunderkoetter C, Goerge T

    Pubmed
  • Spectrum of peristomal Dermatoses

    J Dtsch Dermatol Ges. 2021;19 Suppl 2(): 137-137

    Dietmaier L, Summa S, Erfurt-Berge C

    Pubmed
  • Development of a digital Teaching Project on the Topic of "Immunooncology"

    J Dtsch Dermatol Ges. 2021;19 Suppl 4(): 62-63

    Kaufmann MD, Berking C, French LE, Meyerolbersle-Ben M, Reinholz M, Steeb T, Heppt M

    Pubmed
  • Checkpoint inhibition in cancer

    Onkologe. 2021;27(11): 1075-1084

    Ben Khaled N, Piseddu I, Boehmer DFR, Zierold S, Heinzerling L, Mayerle J, De Toni EN

    Background The introduction of immune checkpoint inhibitors (ICI) into the therapeutic landscape in oncology over the last decade represents a fundamental advancement in cancer immunotherapy. Objectives We review the mechanism of action of ICI and their current use in the systemic therapy of various cancers. Materials and methods Relevant articles were identified in the PubMed database. Clinical trial information was extracted from the Clinicaltrials.gov registry; information on drug approvals were obtained from the European Medicines Agency and the U.S. Food and Drug Administration databases. Conclusions Although substantial improvements in the treatment of many types of cancer have been achieved by ICI, durable responses and long-term survival can only be observed in a small number of patients. The development of predictive biomarkers to maximize efficacy and minimize immune-related toxicity, in addition to new combination regimens, may help unleash the full potential of ICI in cancer immunotherapy.

    Pubmed
  • Long-term Effectiveness of Interventions for actinic Keratoses: Results of a systematic Review and Network Meta-Analysis

    J Dtsch Dermatol Ges. 2021;19 Suppl 4(): 11-11

    Steeb T, Wessely A, Petzold A, Brinker T, Schmitz L, Lei-ter-Stoppke U, Garbe C, Schoffski O, Berking C, Heppt M

    Pubmed
  • Management of cutaneous squamous cell carcinoma

    Onkologe. 2021;27(6): 579-586

    Leiter U, Gutzmer R, Alter M, Ulrich C, Meiwes A, Heppt M, Steeb T, Berking C, Lonsdorf AS, Sachse M, Hillen U, Arbeitsgemeinschaft Dermatologisch

    Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers of the Caucasian population and accounts for 20% of all skin tumors. An S3 guideline of the German Oncology Guidelines Program has been available since 2019. The diagnosis is based on the clinical examination. Excision and histological confirmation is required for all clinically suspicious lesions to allow prognostic assessment and correct treatment. The therapy of first choice is complete excision with histological control of the surgical margin. In cutaneous SCC with risk factors such as tumor thickness > 6 mm, sentinel lymph node biopsy (SLNB) may be discussed, but there is currently no clear evidence regarding its prognostic and therapeutic relevance. Adjuvant radiotherapy may be considered if there is a high risk of recurrence, radiotherapy should be considered in case of inoperable tumors. For inoperable local or locoregional recurrence, electrochemotherapy can also be indicated. In case of inoperable/or metastasized SCC, the immune checkpoint inhibitor cemiplimab is approved and recommended as the therapy of first choice. In case of contraindications, chemotherapeutics, epidermal growth factor receptor (EGFR) inhibitors or palliative radiotherapy can be used. Since evidence is limited, systemic therapy should preferably be performed in clinical studies. Follow-up should be risk-adapted and includes dermatological examinations supplemented by ultrasound examinations in high-risk patients.

    Pubmed
  • What is the current State of Knowledge of Skin Cancer Patients about fertility-preserving Measures? an exploratory Cross Sectional Survey

    J Dtsch Dermatol Ges. 2021;19 Suppl 4(): 4-4

    Hornung-Eichler A, Steeb T, Erdmann M, Berking C, Heppt M

    Pubmed
  • Elective Discontinuation of Checkpoint Inhibitor Therapy in Patients with advanced Melanoma

    J Dtsch Dermatol Ges. 2021;19 Suppl 4(): 40-40

    Persa OD, Schatton K, Ruebben A, Berking C, Erdmann M, Schlaak M, Mauch C, Steeb T

    Pubmed
  • YouTube (R)-Videos about Skin Cancer as an Information Source for Patients: Assessment of quality, Comprehensibility and Reliability

    J Dtsch Dermatol Ges. 2021;19 Suppl 4(): 63-64

    Reinhardt L, Steeb T, Harlass M, Brutting J, Berking C, Meier F

    Pubmed
  • Efficacy of different Interventions for the Treatment of cutaneous Squamous Cell Carcinoma in situ (Bowen's Disease) - a systematic Literature Review and Meta-Analysis

    J Dtsch Dermatol Ges. 2021;19 Suppl 4(): 44-44

    Petzold A, Steeb T, Wessely A, Berking C, Heppt M

    Pubmed
  • Sequelae of immunotherapy Checkpoint inhibitor-induced immune-related adverse events

    Onkologe. 2021;27(8): 739-746

    Duong SL, Zierold S, Kramer R, Reincke M, Kerl-French K, Boehmerle W, Pavel M, Weckbach L, French LE, Knauss S, Heinzerling L

    Background Immune checkpoint inhibitors (ICIs) are potent immunotherapeutic agents for many tumor entities. However, ICIs can induce immune-related adverse events (irAE) that can potentially affect any organ system, causing life-changing sequelae or even death. These irAEs can occur months after termination of immunotherapy and long-term effects may persist for years after finishing therapy. Due to expanding clinical indications for ICIs including therapy in earlier tumor stages, the risk-benefit analysis needs to take into account these long-term side effects. Objectives The sequelae of ICI therapy are reviewed and the international online registry Side Effect Registry Immuno-Oncology (SERIO) for the unified collection and characterization of irAEs is introduced. Materials and methods We analyzed data from SERIO and performed a selective literature search in the databases PubMed, Cochrane Central Register of Controlled Trials and Google Scholar to characterize, analyze and summarize long-term sequelae of irAE induced by ICI therapy. Results The most commonly observed irAEs with long-term sequelae involve the skin (leucotrichia, melanoma-associated hypopigmentation) and endocrine irAEs (thyroiditis, hypophysitis, adrenalitis and diabetes). While the former is especially stigmatizing, endocrine irAEs usually require long-term hormone substitution. Neurologic and cardiologic irAEs are relatively rare, but they are associated with severe complications leading to increased morbidity and mortality. Conclusions Until now, prospective data about long-term consequences of irAEs are lacking. The SERIO registry addresses this need as irAEs are collected to enable long-term follow-up and optimized management.

    Pubmed
  • Single-Molecule RNA Sequencing Reveals IFNγ-Induced Differential Expression of Immune Escape Genes in Merkel Cell Polyomavirus-Positive MCC Cell Lines.

    Front Microbiol. 2021;12():

    Sauerer T, Lischer C, Weich A, Berking C, Vera J, Dörrie J

    Merkel cell carcinoma (MCC) is a rare and highly aggressive cancer, which is mainly caused by genomic integration of the Merkel cell polyomavirus and subsequent expression of a truncated form of its large T antigen. The resulting primary tumor is known to be immunogenic and under constant pressure to escape immune surveillance. Because interferon gamma (IFNγ), a key player of immune response, is secreted by many immune effector cells and has been shown to exert both anti-tumoral and pro-tumoral effects, we studied the transcriptomic response of MCC cells to IFNγ. In particular, immune modulatory effects that may help the tumor evade immune surveillance were of high interest to our investigation. The effect of IFNγ treatment on the transcriptomic program of three MCC cell lines (WaGa, MKL-1, and MKL-2) was analyzed using single-molecule sequencing via the Oxford Nanopore platform. A significant differential expression of several genes was detected across all three cell lines. Subsequent pathway analysis and manual annotation showed a clear upregulation of genes involved in the immune escape of tumor due to IFNγ treatment. The analysis of selected genes on protein level underlined our sequencing results. These findings contribute to a better understanding of immune escape of MCC and may help in clinical treatment of MCC patients. Furthermore, we demonstrate that single-molecule sequencing can be used to assess characteristics of large eukaryotic transcriptomes and thus contribute to a broader access to sequencing data in the community due to its low cost of entry.

    Pubmed
  • Inhibition of the Neural Crest Transcription Factor SOX10 induces Cell Cycle Arrest and Apoptosis in Uveal Melanoma cells

    J Dtsch Dermatol Ges. 2021;19 Suppl 4(): 33-33

    Wessely A, Kammerbauer C, Lischer C, Vera J, Berking C, Heppt M

    Pubmed
  • Brn3a expression is epigenetically controlled by HDAC2 in melanocytes and melanoma

    Exp Dermatol. 2021;30(3): E96-E96

    Heppt M, Wessely A, Hornig E, Kammerbauer C, Graf S, Besch R, French LE, Kuphal S, Kappelmann-Fenzl M, Bosserhoff A, Bosserhoff A, Berking C

    Pubmed
  • Inhibiting the neural crest transcription factor SOX10 leads to cell cycle arrest and apoptosis in uveal melanoma cells

    Exp Dermatol. 2021;30(3): E95-E95

    Wessely A, Kammerbauer C, Lischer C, Vera J, Berking C, Heppt M

    Pubmed
  • Clinical Prognostic Factors in metastatic Choroidal Melanoma

    J Dtsch Dermatol Ges. 2021;19 Suppl 4(): 82-83

    Koch E, Petzold A, Wessely A, Dippel E, Erdmann M, Heinzerling L, Hohberger B, Knorr H, Leiter-Stoppke U, Meier F, Mohr P, Rahimi F, Schell B, Schlaak M, Terhey-Den P, Schuler-Thurner B, Ugurel S, Utikal JS, Vera J, Weichenthal M, Ziller F, Berking C, Heppt M

    Pubmed
  • Preclinical evaluation of a combination of checkpoint blockade and dendritic cell vaccination against Merkel cell carcinoma

    Exp Dermatol. 2021;30(3): E64-E65

    Sauerer T, Gerer K, Hoyer S, Erdmann M, Berking C, Voll R, Schuler-Thurner B, Schuler G, Schaft N, Doerrie J

    Pubmed
  • The Nectin-1 Expression correlates with the Susceptibility of malignant Melanoma to oncolytic Herpes Simplex Viruses in vitro and in vivo

    J Dtsch Dermatol Ges. 2021;19 Suppl 4(): 30-30

    Schwertner B, Linder G, Stauner CT, Klapproth E, Magnus C, Rohrhofer A, Gross S, Schuler-Thurner B, Oettl V, Feichtgruber N, Drexler K, Evert K, Krahn MP, Berneburg M, Schmidt B, Schuster P, Haferkamp S

    Pubmed
  • BRAF and MEK inhibitors affect dendritic cell maturation and T cell stimulation

    Exp Dermatol. 2021;30(3): E68-E68

    Hoyer S, Eberlein V, Schuler G, Berking C, Heinzerling L, Schaft N, Doerrie J

    Pubmed
  • Analysis of IFN gamma-mediated Transcriptome Changes in Merkel Cell Carcinoma Cell Lines via Nanopore Sequencing

    J Dtsch Dermatol Ges. 2021;19 Suppl 4(): 32-32

    Sauerer T, Lischer C, Berking C, Vera-Gonzalez J, Doerrie J

    Pubmed
  • Mechanical Regulation of Epithelial Tissue Homeostasis

    Phys Rev X. 2021;11(3):

    Kaliman S, Hubert M, Wollnik C, Nuic L, Vurnek D, Gehrer S, Lovric J, Dudziak D, Rehfeldt F, Smith AS

    Despite recent efforts to understand homeostasis in epithelial tissues, there are many unknowns surrounding this steady state. It is considered to be regulated by mechanoresponse, but unlike for single cells, this idea remains heavily debated for tissues. Here, we show that changes in matrix stiffness induce a nonequilibrium transition from tubular to squamous Madin-Darby Canine Kidney II tissues. Nonetheless, despite different cell morphologies and densities, all homeostatic tissues display equivalent topologies, which, hence, must be actively targeted and regulated. On the contrary, the mechanoresponse induces dramatic changes in the large-scale organization of the colonies. On stiff gels, this yields an unreported cooperative state of motile cells displaying higher densities than in the arrested homeostatic state, which suggests a more complex relation between cell density and motility than previously anticipated. Our results unequivocally relate the mechanosensitive properties of individual cells to the evolving macroscopic structures, an effect that could be important for understanding the emergent pathologies of living tissues.

    Pubmed
  • Development and evaluation of a digital education tool for medical students in wound care.

    Int Wound J. 2021;18(1): 8-16

    Schlupeck M, Stubner B, Erfurt-Berge C

    The aim of this study was to develop and evaluate an interactive, video-enhanced, and case-based online course for medical students. We chose a case about wound care since this topic is still underrepresented in the medical curriculum. First, instructional videos were created to teach practical skills in wound care. These were implemented into a case-based online course, using the online learning platform ILIAS. In a comparative initial and final survey, numbers of users were assessed, content and structure of the course, as well as the thematic interest of the students and self-assessed gain of competence, were evaluated. Since the summer of 2019, 310 students have successfully completed the course. The survey data showed a high participation rate and a positive response regarding the content as well as the structural concept. Most of the students rated the content within the course as useful for their future medical work (86.1%) and the gain of knowledge superior to a traditional lecture (69.4%). Self-assessments of video-mediated skills showed a significant increase in subjectively perceived competence. The online course is an efficient way to reach many students by the small use of resources. It resembles an option to arouse growing interest in wound care in medical students.

    Pubmed
  • Successful treatment of refractory palmoplantar psoriasis in a psoriatic arthritis patient with the JAK inhibitor tofacitinib.

    Clin Exp Rheumatol. 2021;39(1):

    Valor-Méndez L, Sticherling M, Kleyer A, Schett G

    Pubmed
  • S2k guidelines for the therapy of pathological scars (hypertrophic scars and keloids) - Update 2020.

    J Dtsch Dermatol Ges. 2021;19(2): 312-327

    Nast A, Gauglitz G, Lorenz K, Metelmann HR, Paasch U, Strnad V, Weidmann M, Werner RN, Bauerschmitz J

    Pubmed
  • Immune Checkpoint Inhibitor-induced Bilateral Vestibulopathy.

    J Immunother. 2021;44(3): 114-117

    Koch EAT, Nickel FT, Heinzerling L, Schulz YK, Berking C, Erdmann M

    Checkpoint inhibitors (CPI), such as anti-programmed death-1 and anti-cytotoxic T-lymphocyte antigen-4antibodies cause serious, rarely fatal immune-related adverse events (irAE) potentially in all organ systems. Neurological immune-related adverse events occur in 1%-5% of patients on CPI therapy and may present with dramatic clinical symptoms of the sensory organs. After exclusion of other causes, a high-dose treatment with corticosteroids is crucial for clinical outcome with lower risk of sequelae. We present a severe case of CPI-related ongoing and most likely irreversible bilateral vestibular affection. A 59-year-old male melanoma patient with brain metastasis undergoing immunotherapy with anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed death-1 antibodies developed severe debilitating rotatory vertigo. Bilateral vestibulopathy was diagnosed as a result of the CPI therapy after a thorough analysis including magnetic resonance imaging, laboratory tests of blood and cerebrospinal fluid as well as neurological and otorhinolaryngology examinations. The vertigo improved slightly during a 10-day course of steroid therapy and intensive balance training but did not resolve completely.

    Pubmed
  • Patterns of care and follow-up care of patients with uveal melanoma in German-speaking countries: a multinational survey of the German Dermatologic Cooperative Oncology Group (DeCOG).

    J Cancer Res Clin Oncol. 2021;147(6): 1763-1771

    Steeb T, Wessely A, Alter M, Bayerl C, Bender A, Bruning G, Dabrowski E, Debus D, Devereux N, Dippel E, Drexler K, Dücker P, Dummer R, Emmert S, Elsner P, Enk A, Gebhardt C, Gesierich A, Goebeler M, Goerdt S, Goetze S, Gutzmer R, Haferkamp S, Hansel G, Hassel JC, Heinzerling L, Kähler KC, Kaume KM, Krapf W, Kreuzberg N, Lehmann P, Livingstone E, Löffler H, Loquai C, Mauch C, Mangana J, Meier F, Meissner M, Moritz RKC, Maul LV, Müller V, Mohr P, Navarini A, Van Nguyen A, Pfeiffer C, Pföhler C, Posch C, Richtig E, Rompel R, Sachse MM, Sauder S, Schadendorf D, Schatton K, Schulze HJ, Schultz E, Schilling B, Schmuth M, Simon JC, Streit M, Terheyden P, Thiem A, Tüting T, Welzel J, Weyandt G, Wesselmann U, Wollina U, Ziemer M, Zimmer L, Zutt M, Berking C, Schlaak M, Heppt MV, German Dermatologic Cooperative Oncology Group (DeCOG, committee ocular melanoma)

    PURPOSE: Uveal melanoma (UM) is an orphan cancer of high unmet medical need. Current patterns of care and surveillance remain unclear as they are situated in an interdisciplinary setting.

    METHODS: A questionnaire addressing the patterns of care and surveillance in the management of patients with uveal melanoma was distributed to 70 skin cancer centers in Austria, Germany and Switzerland. Frequency distributions of responses for each item of the questionnaire were calculated.

    RESULTS: 44 of 70 (62.9%) skin cancer centers completed the questionnaire. Thirty-nine hospitals were located in Germany (88.6%), three in Switzerland (6.8%) and two in Austria (4.5%). The majority (68.2%) represented university hospitals. Most patients with metastatic disease were treated in certified skin cancer centers (70.7%, 29/41). Besides, the majority of patients with UM were referred to the respective skin cancer center by ophthalmologists (87.2%, 34/39). Treatment and organization of follow-up of patients varied across the different centers. 35.1% (14/37) of the centers stated to not perform any screening measures.

    CONCLUSION: Treatment patterns of patients with uveal melanoma in Germany, Austria and Switzerland remain extremely heterogeneous. A guideline for the treatment and surveillance is urgently needed.

    Pubmed
  • Surveillance of patients with conjunctival melanoma in German-speaking countries: A multinational survey of the German dermatologic cooperative oncology group.

    Eur J Cancer. 2021;143(): 43-45

    Wessely A, Steeb T, Berking C, Schlaak M, Heppt MV, German Dermatologic Cooperative Oncology Group (DeCOG, committee ocular melanoma) , Alter M, Bayerl C, Bender A, Bruning G, Dabrowski E, Debus D, Devereux N, Dippel E, Drexler K, Dücker P, Dummer R, Emmert S, Elsner P, Enk A, Gebhardt C, Gesierich A, Goebeler M, Goerdt S, Goetze S, Gutzmer R, Haferkamp S, Hansel G, Hassel JC, Heinzerling L, Kähler KC, Kaume KM, Krapf W, Kreuzberg N, Lehmann P, Livingstone E, Löffler H, Loquai C, Mauch C, Mangana J, Meier F, Meissner M, Moritz RKC, Maul LV, Müller V, Mohr P, Navarini A, Van Nguyen A, Pfeiffer C, Pföhler C, Posch C, Richtig E, Rompel R, Sachse MM, Sauder S, Schadendorf D, Schatton K, Schulze HJ, Schultz E, Schilling B, Schmuth M, Simon JC, Streit M, Terheyden P, Thiem A, Tüting T, Welzel J, Weyandt G, Wesselmann U, Wollina U, Ziemer M, Zimmer L, Zutt M

    Pubmed
  • Interventions for Actinic Keratosis in Nonscalp and Nonface Localizations: Results from a Systematic Review with Network Meta-Analysis.

    J Invest Dermatol. 2021;141(2): 345-354.e8

    Steeb T, Wessely A, Schmitz L, Heppt F, Kirchberger MC, Berking C, Heppt MV

    Myriad interventions are available for the treatment of actinic keratosis located on the face or scalp. However, lesions located outside the head and neck have received little attention until now. We aimed to synthesize the current knowledge of interventions for actinic keratosis in nonscalp and nonface localizations. Randomized controlled trials reporting data for these localizations were searched in MEDLINE, Embase, and The Cochrane Library CENTRAL, as well as in pertinent trial registers until 25 March 2020. A total of 13 randomized controlled trials with 1,380 patients were included in a systematic review. Five treatment modalities were evaluated and compared with placebo in a frequentist network meta-analysis, including cryosurgery, ingenol mebutate, photodynamic therapy, colchicine, and 5-fluorouracil. In the network meta-analysis, cryosurgery showed the highest participant complete clearance rates (risk ratio, 7.73; 95% confidence interval = 3.21-18.61; 10 studies; I2 = 20.3%; Grading of Recommendations Assessment, Development, and Evaluation, ++--) and lesion clearance rates (risk ratio, 2.97; 95% confidence interval = 2.45-3.59; 4 studies; I2 = 0%; Grading of Recommendations Assessment, Development, and Evaluation, ++--) compared with placebo. Ingenol mebutate demonstrated the highest participant partial clearance rates compared with placebo (risk ratio, 7.12; 95% confidence interval = 4.36-11.64; 5 studies; I2 = 0%; Grading of Recommendations Assessment, Development, and Evaluation, +++-). The mean reduction of lesions and occurrence of adverse events was poorly reported. The certainty of the evidence varied from very low to high and was limited by imprecision and study limitations.

    Pubmed
  • Experiences of In-Patients with Skin Cancer in a German University Hospital Setting: A Cross-Sectional Survey.

    Patient Prefer Adherence. 2021;15(): 41-48

    Steeb T, Wessely A, Merkl H, Voskens C, Erdmann M, Heinzerling L, Berking C, Heppt MV

    Purpose: An important measure of hospital quality is the satisfaction of the patients receiving in-patient care. This cross-sectional study aimed to assess skin cancer patients' experiences in a university hospital setting as a measure of quality of cancer care.

    Patients and Methods: Questionnaires were mailed to patients with skin cancer after receiving in-patient overnight treatment in the dermatological unit of the university hospital Erlangen (Germany) from 1 September to 30 November 2017. Patients were asked to evaluate their overall experience of this episode of care and to complete the Picker Inpatient Survey questionnaire on specific aspects of their care, such as patient satisfaction regarding contact with staff, need for information, recommendation of the hospital as well as tumor-specific questions. The results were re-coded as problems and reported as frequencies and their percentage.

    Results: A total of 103 of 159 questionnaires were returned (64.8%). All patients rated the treatment and care they had received to be good or very good. Additionally, all patients would recommend our in-patient clinic to their families or friends. The patients most commonly criticized inconsistency of care delivered by the same physician (29.7%, 30/101) and feeling of insufficient involvement in the decision-making processes (21.1%, 20/95). Besides this, 19.0% (11/58) and 34.6% (18/52) of patients were not satisfied with physicians and nurses, respectively, appropriately addressing their fears or anxieties. In the cancer-specific questionnaire, the majority of patients were dissatisfied with further support regarding professional and social rehabilitation possibilities (85.7%, 30/35) and psycho-oncology (56.3%, 18/32).

    Conclusion: Overall, the majority of patients were satisfied with the in-patient skin cancer treatment. However, physicians and nurses can enhance patient satisfaction by addressing patients' fears and anxieties regarding their disease and treatment. Besides, our results highlight the importance of psycho-oncological support.

    Pubmed
  • Ileal immune tonus is a prognosis marker of proximal colon cancer in mice and patients.

    Cell Death Differ. 2021;28(5): 1532-1547

    Picard M, Yonekura S, Slowicka K, Petta I, Rauber C, Routy B, Richard C, Iebba V, Tidjani Alou M, Becharef S, Ly P, Pizzato E, Lehmann CHK, Amon L, Klein C, Opolon P, Gomperts Boneca I, Scoazec JY, Hollebecque A, Malka D, Ghiringhelli F, Dudziak D, Berx G, Vereecke L, van Loo G, Kroemer G, Zitvogel L, Roberti MP

    Ileal epithelial cell apoptosis and the local microbiota modulate the effects of oxaliplatin against proximal colon cancer by modulating tumor immunosurveillance. Here, we identified an ileal immune profile associated with the prognosis of colon cancer and responses to chemotherapy. The whole immune ileal transcriptome was upregulated in poor-prognosis patients with proximal colon cancer, while the colonic immunity of healthy and neoplastic areas was downregulated (except for the Th17 fingerprint) in such patients. Similar observations were made across experimental models of implanted and spontaneous murine colon cancer, showing a relationship between carcinogenesis and ileal inflammation. Conversely, oxaliplatin-based chemotherapy could restore a favorable, attenuated ileal immune fingerprint in responders. These results suggest that chemotherapy inversely shapes the immune profile of the ileum-tumor axis, influencing clinical outcome.

    Pubmed
  • Maturation of monocyte-derived DCs leads to increased cellular stiffness, higher membrane fluidity, and changed lipid composition

    Eur J Immunol. 2021;51 Suppl 1(): 235-235

    Luhr JJ, Alex N, Amon L, Kraeter M, Kubankova M, Sezgin E, Lehmann CHK, Heger L, Heidkamp GF, Smith AS, Zaburdaev V, Boeckmann RA, Levental I, Dustin ML, Eggeling C, Guck J, Dudziak D

    Pubmed
  • DC subset-specific induction of T cell responses upon antigen uptake via Fc. receptors in vivo

    Eur J Immunol. 2021;51 Suppl 1(): 241-241

    Lehmann CHK, Baranska A, Heidkamp GF, Heger L, Neubert K, Luehr JJ, Hofmann A, Reimer KC, Brueckner C, Beck S, Seeling M, Kiessling M, Soulat D, Krug AB, Ravetch JV, Leusen JHW, Nimmerjahn F, Dudziak D

    Pubmed
  • Select hyperactivating NLRP3 ligands enhance the TH1-and TH17-inducing potential of human type 2 conventional dendritic cells

    Eur J Immunol. 2021;51 Suppl 1(): 234-234

    Heger L, Hatscher L, Lehmann CHK, Amon L, Purbojo A, Onderka C, Liang CG, Hartmann A, Cesnjevar R, Bruns H, Gross O, Nimmerjahn F, Burmazovic II, Kunz M, Dudziak D

    Pubmed
  • Targeting Immune Cell Trafficking - Insights From Research Models and Implications for Future IBD Therapy.

    Front Immunol. 2021;12():

    Wiendl M, Becker E, Müller TM, Voskens CJ, Neurath MF, Zundler S

    Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC) are multifactorial diseases with still unknown aetiology and an increasing prevalence and incidence worldwide. Despite plentiful therapeutic options for IBDs, the lack or loss of response in certain patients demands the development of further treatments to tackle this unmet medical need. In recent years, the success of the anti-α4β7 antibody vedolizumab highlighted the potential of targeting the homing of immune cells, which is now an important pillar of IBD therapy. Due to its complexity, leukocyte trafficking and the involved molecules offer a largely untapped resource for a plethora of potential therapeutic interventions. In this review, we aim to summarise current and future directions of specifically interfering with immune cell trafficking. We will comment on concepts of homing, retention and recirculation and particularly focus on the role of tissue-derived chemokines. Moreover, we will give an overview of the mode of action of drugs currently in use or still in the pipeline, highlighting their mechanisms and potential to reduce disease burden.

    Pubmed
  • Patient-oriented Comparison of Systems Therapies for advanced Melanoma: a multicenter Cross-Sectional Study

    J Dtsch Dermatol Ges. 2021;19 Suppl 3(): 4-5

    Thiem A, Mashhadiakbar P, Cussigh C, Hassel JC, Grimmelmann I, Gutzmer R, Schlaak M, Heppt MV, Ducker P, Huning S, Schulmeyer L, Schilling B, Haferkamp S, Ziemer M, Moritz RKC, Hagelstein V, Terheyden P, Posch C, Gaiser MR, Muller B, Kropp P, Emmert S, Tietze JK

    Pubmed
  • DIVERSITY OF CD4(+) BLOOD T-CELL CLONALITY PREDICTS LONGER SURVIVAL WITH CTLA4 OR PD-1 CHECKPOINT INHIBITION IN ADVANCED MELANOMA

    J Immunother Cancer. 2021;9 Suppl 1(): A17-A17

    Arakawa A, Vollmer S, Tietze J, Galinski A, Heppt MV, Berking C, Prinz JC

    Pubmed
  • A negative breakdown test in a fragrance mix I-positive patient does not rule out contact allergy to its fragrance constituents.

    Contact Dermatitis. 2021;84(6): 407-418

    Geier J, Schubert S, Schnuch A, Szliska C, Weisshaar E, Kränke B, Werfel T, Ruëff F, Schröder-Kraft C, Buhl T, Information Network of Departments of Dermatology , Baron JM, Grabbe J, Siedlecki K, Strom K, Hofmeier KS, Worm M, Simon D, Effendy I, Dickel H, Fartasch M, Vieluf D, Beiteke U, Bauer A, Koch A, Wagner N, Dissemond J, Gina M, Grunwald-Delitz H, Jünger M, Kreft B, Witte J, Schäkel K, Löffler H, Pföhler C, Schliemann S, Heine G, Spring P, Treudler R, Nestoris S, Recke A, Becker D, Schmieder A, Pfützner W, Stadler R, Coras-Stepanek B, Brockow K, Brehler R, Baur V, Raap U, Skudlik C, Prager W, Emmert S, Rieker-Schwienbacher J, Wilfinger D, Forchhammer S, Weiß J, Trautmann A, Mechtel D, Lang C

    BACKGROUND: In about half of the patients reacting positive to fragrance mix I (FM I), breakdown testing remains negative. This raises the question of whether the reaction to FM I is false-positive, or the breakdown test is false-negative.

    OBJECTIVES: To identify characteristics and sensitization patterns of patients positive to FM I, but not to its fragrance constituents.

    PATIENTS AND METHODS: Retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK) between 2005 and 2019. Three patient groups were defined according to their reaction pattern: Group I, FM I positive and ≥1 single fragrance positive in the breakdown test (n = 1912); Group II, FM I positive and breakdown test negative (n = 1318); Group III, FM I negative (n = 19 790).

    RESULTS: Regarding the pattern of concomitant reactions to other fragrances, Group II had an intermediate position between Group I and Group III. In other respects (age and sex distribution, frequency of sensitization to non-fragrance baseline series allergens), Group II rather resembled Group I.

    CONCLUSIONS: Not every positive reaction to FM I in patients with negative breakdown tests is false-positive. There may be false-negative reactions to the single fragrance components when patch tested at 1% pet. Raising patch concentrations of some single fragrances is recommended.

    Pubmed
  • Rapid Response of a multilocular metastatic Merkel Cell Carcinoma with an unclear Primarius to Avelumab

    J Dtsch Dermatol Ges. 2021;19 Suppl 4(): 46-46

    Bender-Saebelkampf S, Berking C, Erdmann M

    Pubmed
  • Rapid Response of locally distinct CD30 positive primary cutaneous anaplastic large T-Cell Lymphoma under Brentuximab Vedotin

    J Dtsch Dermatol Ges. 2021;19 Suppl 4(): 50-50

    Bender-Sabelkampf S, Berking C, Erdmann M

    Pubmed
  • PaM - Development and Validation of a palliative medical Integration Model for Melanoma

    J Dtsch Dermatol Ges. 2021;19 Suppl 4(): 13-14

    Bender-Sabelkampf S, Heckel M, Ostgathe C, Berking C, Heppt M

    Pubmed
  • Cathepsin S provokes interleukin-6 (IL-6) trans-signaling through cleavage of the IL-6 receptor in vitro.

    Sci Rep. 2020;10(1):

    Flynn CM, Garbers Y, Düsterhöft S, Wichert R, Lokau J, Lehmann CHK, Dudziak D, Schröder B, Becker-Pauly C, Rose-John S, Aparicio-Siegmund S, Garbers C

    The cytokine interleukin-6 (IL-6) fulfills its pleiotropic functions via different modes of signaling. Regenerative and anti-inflammatory activities are mediated via classic signaling, in which IL-6 binds to the membrane-bound IL-6 receptor (IL-6R). For IL-6 trans-signaling, which accounts for the pro-inflammatory properties of the cytokine, IL-6 activates its target cells via soluble forms of the IL-6R (sIL-6R). We have previously shown that the majority of sIL-6R in human serum originates from proteolytic cleavage and mapped the cleavage site of the IL-6R. The cleavage occurs between Pro-355 and Val-356, which is the same cleavage site that the metalloprotease ADAM17 uses in vitro. However, sIL-6R serum levels are unchanged in hypomorphic ADAM17ex/ex mice, making the involvement of ADAM17 questionable. In order to identify other proteases that could be relevant for sIL-6R generation in vivo, we perform a screening approach based on the known cleavage site. We identify several candidate proteases and characterize the cysteine protease cathepsin S (CTSS) in detail. We show that CTSS is able to cleave the IL-6R in vitro and that the released sIL-6R is biologically active and can induce IL-6 trans-signaling. However, CTSS does not use the Pro-355/Val-356 cleavage site, and sIL-6R serum levels are not altered in Ctss-/- mice. In conclusion, we identify a novel protease of the IL-6R that can induce IL-6 trans-signaling, but does not contribute to steady-state sIL-6R serum levels.

    Pubmed
  • Immune checkpoint inhibition therapy for advanced skin cancer in patients with concomitant hematological malignancy: a retrospective multicenter DeCOG study of 84 patients.

    J Immunother Cancer. 2020;8(2):

    Leiter U, Loquai C, Reinhardt L, Rafei-Shamsabadi D, Gutzmer R, Kaehler K, Heinzerling L, Hassel JC, Glutsch V, Sirokay J, Schlecht N, Rübben A, Gambichler T, Schatton K, Pfoehler C, Franklin C, Terheyden P, Haferkamp S, Mohr P, Bischof L, Livingstone E, Zimmer L, Weichenthal M, Schadendorf D, Meiwes A, Keim U, Garbe C, Becker JC, Ugurel S

    BACKGROUND: Skin cancers are known for their strong immunogenicity, which may contribute to a high treatment efficacy of immune checkpoint inhibition (ICI). However, a considerable proportion of patients with skin cancer is immuno-compromised by concomitant diseases. Due to their previous exclusion from clinical trials, the ICI treatment efficacy is poorly investigated in these patients. The present study analyzed the ICI treatment outcome in advanced patients with skin cancer with a concomitant hematological malignancy.

    METHODS: This retrospective multicenter study included patients who were treated with ICI for locally advanced or metastatic melanoma (MM), cutaneous squamous cell carcinoma (cSCC), or Merkel cell carcinoma (MCC), and had a previous diagnosis of a hematological malignancy irrespective of disease activity or need of therapy at ICI treatment start. Comparator patient cohorts without concomitant hematological malignancy were extracted from the prospective multicenter skin cancer registry ADOREG. Treatment outcome was measured as best overall response, progression-free (PFS), and overall survival (OS).

    RESULTS: 84 patients (MM, n=52; cSCC, n=15; MCC, n=17) with concomitant hematological malignancy were identified at 20 skin cancer centers. The most frequent concomitant hematological malignancies were non-Hodgkin's lymphoma (n=70), with chronic lymphocytic leukemia (n=32) being the largest entity. While 9 patients received ICI in an adjuvant setting, 75 patients were treated for advanced non-resectable disease (55 anti-PD-1; 8 anti-PD-L1; 5 anti-CTLA-4; 7 combinations). In the latter 75 patients, best objective response (complete response+partial response) was 28.0%, disease stabilization was 25.3%, and 38.6% showed progressive disease (PD). Subdivided by skin cancer entity, best objective response was 31.1% (MM), 26.7% (cSCC), and 18.8% (MCC). Median PFS was 8.4 months (MM), 4.0 months (cSCC), and 5.7 months (MCC). 1-year OS rates were 78.4% (MM), 65.8% (cSCC), and 47.4% (MCC). Comparison with respective ADOREG patient cohorts without hematological malignancy (n=392) revealed no relevant differences in ICI therapy outcome for MM and MCC, but a significantly reduced PFS for cSCC (p=0.002).

    CONCLUSIONS: ICI therapy showed efficacy in advanced patients with skin cancer with a concomitant hematological malignancy. Compared with patients without hematological malignancy, the observed ICI therapy outcome was impaired in cSCC, but not in MM or MCC patients.

    Pubmed
  • Prognosis of Patients With Stage III Melanoma According to American Joint Committee on Cancer Version 8: A Reassessment on the Basis of 3 Independent Stage III Melanoma Cohorts.

    J Clin Oncol. 2020;38(22): 2543-2551

    Garbe C, Keim U, Suciu S, Amaral T, Eigentler TK, Gesierich A, Hauschild A, Heinzerling L, Kiecker F, Schadendorf D, Stadler R, Sunderkötter C, Tüting T, Utikal J, Wollina U, Zouboulis CC, Keilholz U, Testori A, Martus P, Leiter U, Eggermont AMM, German Central Malignant Melanoma Registry and the European Organisation for Research and Treatment of Cancer

    PURPOSE: Three new therapies have been approved recently for the adjuvant treatment of stage III melanoma, substantially reducing the risk of tumor recurrences. This study evaluates 3 independent data sets to clarify the survival probabilities of patients with stage III melanoma.

    PATIENTS AND METHODS: The Central Malignant Melanoma Registry (CMMR) evaluated 1,553 patients with a primary diagnosis of stage III melanoma from 2000 to 2012. Studies from the European Organisation for Research and Treatment of Cancer (EORTC), of 573 patients in the observation arm of the 18991 study and 445 patients in the placebo arm of the 18071 study, were evaluated as reference cohorts. The survival outcomes were compared with the published American Joint Committee on Cancer version 8 (AJCCv8) stage III survival data.

    RESULTS: For the CMMR stage III cohort versus the AJCCv8 cohort, the melanoma-specific survival (MSS) rates at 5 years were 67% versus 77%, and at 10 years were 56% versus 69%, respectively. For stage IIIA, the MSS rates at 5 years were 80% versus 93%, and at 10 years were 71% versus 88%; for stage IIIB, the MSS rates at 5 years were 75% versus 83%, and at 10 years were 61% versus 77%. The MSS rates of the EORTC studies either overlapped with or were lower than, the CMMR data.

    CONCLUSION: The MSS rates in the CMMR and EORTC cohorts over the entire stage III are less favorable than those published in AJCCv8. This is particularly true for substages IIIA and IIIB.

    Pubmed
  • ALK Inhibitors Do Not Increase Sensitivity to Radiation in EML4-ALK Non-small Cell Lung Cancer.

    Anticancer Res. 2020;40(9): 4937-4946

    Fleschutz K, Walter L, Leistner R, Heinzerling L

    BACKGROUND/AIM: ALK inhibitors like Crizotinib, Ceritinib and Alectinib are targeted therapies used in patients with anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer (NSCLC). Since in this tumor entity radiotherapy is employed sequentially or concomitantly, potential synergistic effects were investigated, which may support the hypothesis of induced radiosensitization by using ALK inhibitors.

    MATERIALS AND METHODS: Two cell lines expressing wild-type (WT) or echinoderm microtubule-associated protein-like 4 (EML4)-ALK were treated with ALK inhibitors, followed by irradiation. Cell survival, cell death, cell cycle and phosphorylation of H2A histone family, member X (H2AX) were examined.

    RESULTS: Combined treatment with ALK-inhibitors plus 10 Gy-irradiation led to effects similar to those of sole radiotherapy, but was more effective than sole drug treatment.

    CONCLUSION: There is no clear evidence of sensitization to radiation by treating EML4-ALK mutated cells with ALK inhibitors.

    Pubmed
  • Therapy preferences in melanoma treatment-Willingness to pay and preference of quality versus length of life of patients, physicians, healthy individuals and physicians with oncological disease.

    Cancer Med. 2020;9(17): 6132-6140

    Weiss J, Kirchberger MC, Heinzerling L

    BACKGROUND: In recent years, monoclonal antibodies such as ipilimumab, nivolumab, and pembrolizumab have made a significant impact on the treatment of advanced melanoma. Combination of immune checkpoint inhibitors leads to improved survival and response rates of 58%-61% as compared to monotherapy (36%-44%). However, the price for the better response rates is also a higher frequency of severe adverse events (59%) as compared to monotherapy (17%-21%). This study examines attitudes towards melanoma therapy options of physicians, healthy individuals, melanoma patients, and physicians with oncological disease, their willingness to pay, and preference of quality versus length of life.

    METHODS: After obtaining ethical approval and informed consent surveys were conducted in 111 participants divided into four groups: melanoma patients (n = 30), healthy individuals as controls (n = 30), physicians (n = 27), and physicians with oncological disease (n = 24). Statistical analyses were conducted using SPSS statistics (version 25, IBM), applying the Pearson´s chi-squared test, Spearman correlation coefficient, Wilcoxon-Mann-Whitney test, and Kruskal-Wallis test.

    RESULTS: Life prolongation is more valued by melanoma patients and physicians with oncological disease compared to healthy controls and healthy physicians. In total, 30% of melanoma patients opt for a life prolonging therapy in all cases, even if this life prolongation is only marginal. Physicians are the strongest proponents of combination immunotherapy.    CONCLUSION: The valuation of the different treatment options differs in the four study groups with affected people valuing life prolongation much more. The individual value of cancer therapies is high, but differs from the societal standpoint.

    Pubmed
  • PARP inhibitors combined with ionizing radiation induce different effects in melanoma cells and healthy fibroblasts.

    BMC Cancer. 2020;20(1):

    Weigert V, Jost T, Hecht M, Knippertz I, Heinzerling L, Fietkau R, Distel LV

    BACKGROUND: PARP inhibitors niraparib and talazoparib are FDA approved for special cases of breast cancer. PARP is an interesting repair protein which is frequently affected in cancer cells. We studied the combined action of talazoparib or niraparib with ionizing radiation in melanoma cells and healthy fibroblasts.

    METHODS: Homologous recombination (HR) status in six different melanoma cell lines and healthy fibroblasts was assessed. Cell cultures were treated with PARP inhibitors talazoparib or niraparib and ionizing radiation (IR). Apoptosis, necrosis and cell cycle distribution was analyzed via flow cytometry. Cell migration was studied by scratch assays.

    RESULTS: Studied melanoma cell cultures are HR deficient. Studied healthy fibroblasts are HR proficient. Talazoparib and niraparib have congruent effects within the same cell cultures. In all cell cultures, combined treatment increases cell death and G2/M arrest compared to IR. Combined treatment in melanoma cells distinctly increases G2/M arrest. Healthy fibroblasts are less affected by G2/M arrest. Treatment predominantly decelerates or does not modify migration. In two cell cultures migration is enhanced under the inhibitors.

    CONCLUSIONS: Although the two PARP inhibitors talazoparib and niraparib appear to be suitable for a combination treatment with ionizing radiation in our in vitro studies, a combination treatment cannot generally be recommended. There are clear interindividual differences in the effect of the inhibitors on different melanoma cells. Therefore, the effect on the cancer cells should be studied prior to a combination therapy. Since melanoma cells increase more strongly than fibroblasts in G2/M arrest, the fractional application of combined treatment should be further investigated.

    Pubmed
  • Trial watch : the gut microbiota as a tool to boost the clinical efficacy of anticancer immunotherapy.

    Oncoimmunology. 2020;9(1):

    Daillère R, Derosa L, Bonvalet M, Segata N, Routy B, Gariboldi M, Budinská E, De Vries IJM, Naccarati AG, Zitvogel V, Caldas C, Engstrand L, Loilbl S, Fieschi J, Heinzerling L, Kroemer G, Zitvogel L

    Accumulating evidence demonstrates the decisive role of the gut microbiota in determining the effectiveness of anticancer therapeutics such as immunogenic chemotherapy or immune checkpoint blockade in preclinical tumor models, as well as in cancer patients. In synthesis, it appears that a normal intestinal microbiota supports therapeutic anticancer responses, while a dysbiotic microbiota that lacks immunostimulatory bacteria or contains overabundant immunosuppressive species causes treatment failure. These findings have led to the design of clinical trials that evaluate the capacity of modulation of the gut microbiota to synergize with treatment and hence limit tumor progression. Along the lines of this Trial Watch, we discuss the rationale for harnessing the gut microbiome in support of cancer therapy and the progress of recent clinical trials testing this new therapeutic paradigm in cancer patients.

    Pubmed
  • Dual mTOR/DNA-PK Inhibitor CC-115 Induces Cell Death in Melanoma Cells and Has Radiosensitizing Potential.

    Int J Mol Sci. 2020;21(23):

    Bürkel F, Jost T, Hecht M, Heinzerling L, Fietkau R, Distel L

    CC-115 is a dual inhibitor of the mechanistic target of rapamycin (mTOR) kinase and the DNA-dependent protein kinase (DNA-PK) that is currently being studied in phase I/II clinical trials. DNA-PK is essential for the repair of DNA-double strand breaks (DSB). Radiotherapy is frequently used in the palliative treatment of metastatic melanoma patients and induces DSBs. Melanoma cell lines and healthy-donor skin fibroblast cell lines were treated with CC‑115 and ionizing irradiation (IR). Apoptosis, necrosis, and cell cycle distribution were analyzed. Colony forming assays were conducted to study radiosensitizing effects. Immunofluorescence microscopy was performed to determine the activity of homologous recombination (HR). In most of the malign cell lines, an increasing concentration of CC-115 resulted in increased cell death. Furthermore, strong cytotoxic effects were only observed in malignant cell lines. Regarding clonogenicity, all cell lines displayed decreased survival fractions during combined inhibitor and IR treatment and supra-additive effects of the combination were observable in 5 out of 9 melanoma cell lines. CC-115 showed radiosensitizing potential in 7 out of 9 melanoma cell lines, but not in healthy skin fibroblasts. Based on our data CC-115 treatment could be a promising approach for patients with metastatic melanoma, particularly in the combination with radiotherapy.

    Pubmed
  • Non-professional phagocytosis: a general feature of normal tissue cells (vol 9, 11875, 2019)

    Sci Rep. 2020;10(1):

    Seeberg JC, Loibl M, Moser F, Schwegler M, Buttner-Herold M, Daniel C, Engel FB, Hartmann A, Schlotzer-Schrehardt U, Goppelt-Struebe M, Schellerer V, Naschberger E, Ganzleben I, Heinzerling L, Fietkau R, Distel LV

    Pubmed
  • Long-term efficacy of canakinumab in the treatment of Schnitzler syndrome.

    J Allergy Clin Immunol. 2020;145(6): 1681-1686.e5

    Krause K, Bonnekoh H, Ellrich A, Tsianakas A, Wagner N, Fischer J, Maurer M

    Pubmed
  • Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis.

    Eur Heart J. 2020;41(18): 1733-1743

    Zhang L, Awadalla M, Mahmood SS, Nohria A, Hassan MZO, Thuny F, Zlotoff DA, Murphy SP, Stone JR, Golden DLA, Alvi RM, Rokicki A, Jones-O'Connor M, Cohen JV, Heinzerling LM, Mulligan C, Armanious M, Barac A, Forrestal BJ, Sullivan RJ, Kwong RY, Yang EH, Damrongwatanasuk R, Chen CL, Gupta D, Kirchberger MC, Moslehi JJ, Coelho-Filho OR, Ganatra S, Rizvi MA, Sahni G, Tocchetti CG, Mercurio V, Mahmoudi M, Lawrence DP, Reynolds KL, Weinsaft JW, Baksi AJ, Ederhy S, Groarke JD, Lyon AR, Fradley MG, Thavendiranathan P, Neilan TG

    AIMS: Myocarditis is a potentially fatal complication of immune checkpoint inhibitors (ICI). Sparse data exist on the use of cardiovascular magnetic resonance (CMR) in ICI-associated myocarditis. In this study, the CMR characteristics and the association between CMR features and cardiovascular events among patients with ICI-associated myocarditis are presented.

    METHODS AND RESULTS: From an international registry of patients with ICI-associated myocarditis, clinical, CMR, and histopathological findings were collected. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. In 103 patients diagnosed with ICI-associated myocarditis who had a CMR, the mean left ventricular ejection fraction (LVEF) was 50%, and 61% of patients had an LVEF ≥50%. Late gadolinium enhancement (LGE) was present in 48% overall, 55% of the reduced EF, and 43% of the preserved EF cohort. Elevated T2-weighted short tau inversion recovery (STIR) was present in 28% overall, 30% of the reduced EF, and 26% of the preserved EF cohort. The presence of LGE increased from 21.6%, when CMR was performed within 4 days of admission to 72.0% when CMR was performed on Day 4 of admission or later. Fifty-six patients had cardiac pathology. Late gadolinium enhancement was present in 35% of patients with pathological fibrosis and elevated T2-weighted STIR signal was present in 26% with a lymphocytic infiltration. Forty-one patients (40%) had MACE over a follow-up time of 5 months. The presence of LGE, LGE pattern, or elevated T2-weighted STIR were not associated with MACE.

    CONCLUSION: These data suggest caution in reliance on LGE or a qualitative T2-STIR-only approach for the exclusion of ICI-associated myocarditis.

    Pubmed
  • Major Adverse Cardiovascular Events and the Timing and Dose of Corticosteroids in Immune Checkpoint Inhibitor-Associated Myocarditis.

    Circulation. 2020;141(24): 2031-2034

    Zhang L, Zlotoff DA, Awadalla M, Mahmood SS, Nohria A, Hassan MZO, Thuny F, Zubiri L, Chen CL, Sullivan RJ, Alvi RM, Rokicki A, Murphy SP, Jones-O'Connor M, Heinzerling LM, Barac A, Forrestal BJ, Yang EH, Gupta D, Kirchberger MC, Shah SP, Rizvi MA, Sahni G, Mandawat A, Mahmoudi M, Ganatra S, Ederhy S, Zatarain-Nicolas E, Groarke JD, Tocchetti CG, Lyon AR, Thavendiranathan P, Cohen JV, Reynolds KL, Fradley MG, Neilan TG

    Pubmed
  • Mycobacterial Cord Factor Reprograms the Macrophage Response to IFN-γ towards Enhanced Inflammation yet Impaired Antigen Presentation and Expression of GBP1.

    J Immunol. 2020;205(6): 1580-1592

    Huber A, Killy B, Grummel N, Bodendorfer B, Paul S, Wiesmann V, Naschberger E, Zimmer J, Wirtz S, Schleicher U, Vera J, Ekici AB, Dalpke A, Lang R

    Mycobacteria survive in macrophages despite triggering pattern recognition receptors and T cell-derived IFN-γ production. Mycobacterial cord factor trehalose-6,6-dimycolate (TDM) binds the C-type lectin receptor MINCLE and induces inflammatory gene expression. However, the impact of TDM on IFN-γ-induced macrophage activation is not known. In this study, we have investigated the cross-regulation of the mouse macrophage transcriptome by IFN-γ and by TDM or its synthetic analogue trehalose-6,6-dibehenate (TDB). As expected, IFN-γ induced genes involved in Ag presentation and antimicrobial defense. Transcriptional programs induced by TDM and TDB were highly similar but clearly distinct from the response to IFN-γ. The glycolipids enhanced expression of a subset of IFN-γ-induced genes associated with inflammation. In contrast, TDM/TDB exerted delayed inhibition of IFN-γ-induced genes, including pattern recognition receptors, MHC class II genes, and IFN-γ-induced GTPases, with antimicrobial function. TDM downregulated MHC class II cell surface expression and impaired T cell activation by peptide-pulsed macrophages. Inhibition of the IFN-γ-induced GTPase GBP1 occurred at the level of transcription by a partially MINCLE-dependent mechanism that may target IRF1 activity. Although activation of STAT1 was unaltered, deletion of Socs1 relieved inhibition of GBP1 expression by TDM. Nonnuclear Socs1 was sufficient for inhibition, suggesting a noncanonical, cytoplasmic mechanism. Taken together, unbiased analysis of transcriptional reprogramming revealed a significant degree of negative regulation of IFN-γ-induced Ag presentation and antimicrobial gene expression by the mycobacterial cord factor that may contribute to mycobacterial persistence.

    Pubmed
  • An integrative network-driven pipeline for systematic identification of lncRNA-associated regulatory network motifs in metastatic melanoma.

    BMC Bioinformatics. 2020;21(1):

    Singh N, Eberhardt M, Wolkenhauer O, Vera J, Gupta SK

    BACKGROUND: Melanoma phenotype and the dynamics underlying its progression are determined by a complex interplay between different types of regulatory molecules. In particular, transcription factors (TFs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) interact in layers that coalesce into large molecular interaction networks. Our goal here is to study molecules associated with the cross-talk between various network layers, and their impact on tumor progression.

    RESULTS: To elucidate their contribution to disease, we developed an integrative computational pipeline to construct and analyze a melanoma network focusing on lncRNAs, their miRNA and protein targets, miRNA target genes, and TFs regulating miRNAs. In the network, we identified three-node regulatory loops each composed of lncRNA, miRNA, and TF. To prioritize these motifs for their role in melanoma progression, we integrated patient-derived RNAseq dataset from TCGA (SKCM) melanoma cohort, using a weighted multi-objective function. We investigated the expression profile of the top-ranked motifs and used them to classify patients into metastatic and non-metastatic phenotypes.

    CONCLUSIONS: The results of this study showed that network motif UCA1/AKT1/hsa-miR-125b-1 has the highest prediction accuracy (ACC = 0.88) for discriminating metastatic and non-metastatic melanoma phenotypes. The observation is also confirmed by the progression-free survival analysis where the patient group characterized by the metastatic-type expression profile of the motif suffers a significant reduction in survival. The finding suggests a prognostic value of network motifs for the classification and treatment of melanoma.

    Pubmed
  • The Role of Age, Neutrophil Infiltration and Antibiotics Timing in the Severity of Streptococcus pneumoniae Pneumonia. Insights from a Multi-Level Mathematical Model Approach.

    Int J Mol Sci. 2020;21(22):

    Santos G, Vera J

    Bacterial pneumonia is one of the most prevalent infectious diseases and has high mortality in sensitive patients (children, elderly and immunocompromised). Although an infection, the disease alters the alveolar epithelium homeostasis and hinders normal breathing, often with fatal consequences. A special case is hospitalized aged patients, which present a high risk of infection and death because of the community acquired version of the Streptococcus pneumoniae pneumonia. There is evidence that early antibiotics treatment decreases the inflammatory response during pneumonia. Here, we investigate mechanistically this strategy using a multi-level mathematical model, which describes the 24 first hours after infection of a single alveolus from the key signaling networks behind activation of the epithelium to the dynamics of the local immune response. With the model, we simulated pneumonia in aged and young patients subjected to different antibiotics timing. The results show that providing antibiotics to elderly patients 8 h in advance compared to young patients restores in aged individuals the effective response seen in young ones. This result suggests the use of early, probably prophylactic, antibiotics treatment in aged hospitalized people with high risk of pneumonia.

    Pubmed
  • Transcriptional analysis identifies potential biomarkers and molecular regulators in pneumonia and COPD exacerbation.

    Sci Rep. 2020;10(1):

    Bertrams W, Griss K, Han M, Seidel K, Klemmer A, Sittka-Stark A, Hippenstiel S, Suttorp N, Finkernagel F, Wilhelm J, Greulich T, Vogelmeier CF, Vera J, Schmeck B

    Lower respiratory infections, such as community-acquired pneumonia (CAP), and chronic obstructive pulmonary disease (COPD) rank among the most frequent causes of death worldwide. Improved diagnostics and profound pathophysiological insights are urgent clinical needs. In our cohort, we analysed transcriptional networks of peripheral blood mononuclear cells (PBMCs) to identify central regulators and potential biomarkers. We investigated the mRNA- and miRNA-transcriptome of PBMCs of healthy subjects and patients suffering from CAP or AECOPD by microarray and Taqman Low Density Array. Genes that correlated with PBMC composition were eliminated, and remaining differentially expressed genes were grouped into modules. One selected module (120 genes) was particularly suitable to discriminate AECOPD and CAP and most notably contained a subset of five biologically relevant mRNAs that differentiated between CAP and AECOPD with an AUC of 86.1%. Likewise, we identified several microRNAs, e.g. miR-545-3p and miR-519c-3p, which separated AECOPD and CAP. We furthermore retrieved an integrated network of differentially regulated mRNAs and microRNAs and identified HNF4A, MCC and MUC1 as central network regulators or most important discriminatory markers. In summary, transcriptional analysis retrieved potential biomarkers and central molecular features of CAP and AECOPD.

    Pubmed
  • Heterogeneous fate choice of genetically modulated adult neural stem cells in gray and white matter of the central nervous system.

    Glia. 2020;68(2): 393-406

    Beyer F, Jadasz J, Samper Agrelo I, Schira-Heinen J, Groh J, Manousi A, Bütermann C, Estrada V, Reiche L, Cantone M, Vera J, Viganò F, Dimou L, Müller HW, Hartung HP, Küry P

    Apart from dedicated oligodendroglial progenitor cells, adult neural stem cells (aNSCs) can also give rise to new oligodendrocytes in the adult central nervous system (CNS). This process mainly confers myelinating glial cell replacement in pathological situations and can hence contribute to glial heterogeneity. Our previous studies demonstrated that the p57kip2 gene encodes an intrinsic regulator of glial fate acquisition and we here investigated to what degree its modulation can affect stem cell-dependent oligodendrogenesis in different CNS environments. We therefore transplanted p57kip2 knockdown aNSCs into white and gray matter (WM and GM) regions of the mouse brain, into uninjured spinal cords as well as in the vicinity of spinal cord injuries and evaluated integration and differentiation in vivo. Our experiments revealed that under healthy conditions intrinsic suppression of p57kip2 as well as WM localization promote differentiation toward myelinating oligodendrocytes at the expense of astrocyte generation. Moreover, p57kip2 knockdown conferred a strong benefit on cell survival augmenting net oligodendrocyte generation. In the vicinity of hemisectioned spinal cords, the gene knockdown led to a similar induction of oligodendroglial features; however, newly generated oligodendrocytes appeared to suffer more from the hostile environment. This study contributes to our understanding of mechanisms of adult oligodendrogenesis and glial heterogeneity and further reveals critical factors when considering aNSC mediated cell replacement in injury and disease.

    Pubmed
  • Autophagy in diabetic nephropathy: a review.

    Int Urol Nephrol. 2020;52(9): 1705-1712

    Koch EAT, Nakhoul R, Nakhoul F, Nakhoul N

    Diabetes mellitus (DM) is the leading cause of end stage renal disease. 40% of the patients worldwide will require replacement therapy after 20 years of DM worldwide. Early-stage diabetic nephropathy is characterized by hyperfiltration related to hypeglycemia-induced afferent artery vasodilatation with micro-and macroalbuminuria. Later on, proteinuria with arterial hypertension may appear, culminating in glomerular filtration rate (GFR) decline and end stage renal disease. Forty percent of diabetic patients develop microvascular and macrovascular complications, with increased risk among patients with genetic predisposition, such as Haptoglobin 2-2 phenotype. The most frequent complications in the daily clinical practice are diabetic kidney disease, diabetic retinopathy and vascular disease, such as coronary artery disease and stroke. Various pathways are involved in the pathogenesis of diabetic kidney disease. Chronic systemic inflammation and the inflammatory response, such as increased circulating cytokines (Interleukins), have been recognized as main players in the development and progression of diabetic kidney disease. DM is also associated with increased oxidative stress, and alterations in carbohydrate, lipid and protein metabolism. Overexpression of the renin-angiotensin-aldosterone system (RAAS) in the kidney, the vitamin D-Vitamin D receptor-klotho axis, and autophagy. Differences in the ATG5 protein levels or ATG5 gene expression involved in the autophagy process have been associated with diabetic complications such as diabetic kidney disease. Under normal blood glucose level, autophagy is an important protective mechanism in renal epithelial cells, including podocytes, proximal tubular, mesangial and endothelial cells. Down regulation of the autophagic mechanism, as in hyperglycemic condition, can contribute to the development and progression of diabetic kidney disease.

    Pubmed
  • [Cutaneous squamous cell carcinoma].

    Hautarzt. 2020;71(8): 597-606

    Leiter U, Gutzmer R, Alter M, Ulrich C, Meiwes A, Heppt MV, Steeb T, Berking C, Lonsdorf AS, Sachse MM, Garbe C, Hillen U

    Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers of the Caucasian population and accounts for 20% of all skin tumours. An S3 guideline of the German Guideline Program in Oncology has been available since 2019. The diagnosis is based on the clinical examination. Excision and histological confirmation is required for all clinically suspicious lesions to allow prognostic assessment and correct treatment. The therapy of first choice is complete excision with histological control of the surgical margin. In cSCC with risk factors such as tumor thickness >6 mm, sentinel lymph node biopsy may be discussed, but there is currently no clear evidence of its prognostic and therapeutic relevance. Adjuvant radiation therapy may be considered in cases of high risk of recurrence and should be tested in cases of inoperable tumors. The indication for electrochemotherapy should also be considered in the treatment of local or locoregional recurrence. The immune checkpoint inhibitor cemiplimab is approved for the treatment of inoperable or metastasized cSCC. In case of contraindications, chemotherapeutic agents, epidermal growth factor receptor (EGFR) inhibitors or palliative radiotherapy can be used. Since the evidence is low in these cases, a systemic therapy should be used preferentially within clinical studies. Follow-up care should be risk-adapted and includes a dermatological control, supplemented by ultrasound examinations in high-risk patients.

    Pubmed
  • [Sun protection, surgery, radiation, topical and systemic therapy : The huge playing field of dermatologists in the fight against epithelial skin cancer].

    Hautarzt. 2020;71(8): 570-571

    Berking C, Szeimies RM

    Pubmed
  • Contact sensitization in metalworkers: Data from the information network of departments of dermatology (IVDK), 2010-2018.

    Contact Dermatitis. 2020;83(6): 487-496

    Schubert S, Brans R, Reich A, Buhl T, Skudlik C, Schröder-Kraft C, Gina M, Weisshaar E, Mahler V, Dickel H, Schön MP, John SM, Geier J, IVDK

    BACKGROUND: Metalworkers are exposed to a variety of contact allergens by handling tools, metals, metalworking fluids (MWFs), oils and greases, rubber materials, and so on. Most large-scale reports on contact allergy due to MWFs are more than 10-years-old, and there are only few studies on contact allergy in mechanics and other metal workers not exposed to MWFs.

    OBJECTIVES: To describe a current spectrum of contact sensitization in metalworkers with occupational dermatitis (OD).

    PATIENTS AND METHODS: Retrospective analysis of patch test data collected by the Information Network of Departments of Dermatology (IVDK; 2010-2018), stratifying for 804 cutting metalworkers, 2197 mechanics, and 355 other metalworkers.

    RESULTS: Cutting metalworkers were most frequently sensitized to monoethanolamine (12.6%), colophonium/abietic acid (11.4%) and formaldehyde releasers (up to 8.5%) from the MWF series, and formaldehyde (4.6%) and iodopropynyl butylcarbamate (4.6%) from the baseline series. Sensitization among mechanics and other metalworkers indicates possible occupational exposure to MWFs, glues, and resins, although this may not be expected from their job titles.

    CONCLUSIONS: The spectrum of MWF contact allergens remained largely unchanged during the last years. Taking a comprehensive occupational history is indispensable in order to not miss relevant allergen exposures.

    Pubmed
  • Guideline on diagnostic procedures for suspected hypersensitivity to beta-lactam antibiotics: Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) in collaboration with the German Society of Allergology (AeDA), German Society for Pediatric Allergology and Environmental Medicine (GPA), the German Contact Dermatitis Research Group (DKG), the Austrian Society for Allergology and Immunology (ÖGAI), and the Paul-Ehrlich Society for Chemotherapy (PEG).

    Allergol Select. 2020;4(): 11-43

    Wurpts G, Aberer W, Dickel H, Brehler R, Jakob T, Kreft B, Mahler V, Merk HF, Mülleneisen N, Ott H, Pfützner W, Röseler S, Ruëff F, Sitter H, Sunderkötter C, Trautmann A, Treudler R, Wedi B, Worm M, Brockow K

    This guideline on diagnostic procedures for suspected beta-lactam antibiotic (BLA) hypersensitivity was written by the German and Austrian professional associations for allergology, and the Paul-Ehrlich Society for Chemotherapy in a consensus procedure according to the criteria of the German Association of Scientific Medical Societies. BLA such as penicillins and cephalosporins represent the drug group that most frequently triggers drug allergies. However, the frequency of reports of suspected allergy in patient histories clearly exceeds the number of confirmed cases. The large number of suspected BLA allergies has a significant impact on, e.g., the quality of treatment received by the individual patient and the costs to society as a whole. Allergies to BLA are based on different immunological mechanisms and often manifest as maculopapular exanthema, as well as anaphylaxis; and there are also a number of less frequent special clinical manifestations of drug allergic reactions. All BLA have a beta-lactam ring. BLA are categorized into different classes: penicillins, cephalosporins, carbapenems, monobactams, and beta-lactamase inhibitors with different chemical structures. Knowledge of possible cross-reactivity is of considerable clinical significance. Whereas allergy to the common beta-lactam ring occurs in only a small percentage of all BLA allergic patients, cross-reactivity due to side chain similarities, such as aminopenicillins and aminocephalosporins, and even methoxyimino cephalosporins, are more common. However, the overall picture is complex and its elucidation may require further research. Diagnostic procedures used in BLA allergy are usually made up of four components: patient history, laboratory diagnostics, skin testing (which is particularly important), and drug provocation testing. The diagnostic approach - even in cases where the need to administer a BLA is acute - is guided by patient history and risk - benefit ratio in the individual case. Here again, further studies are required to extend the present state of knowledge. Performing allergy testing for suspected BLA hypersensitivity is urgently recommended not only in the interests of providing the patient with good medical care, but also due to the immense impact of putative BLA allergies on society as a whole.

    Pubmed
  • Atopy patch testing with aeroallergens in a large clinical population of dermatitis patients in Germany and Switzerland, 2000-2015: a retrospective multicentre study.

    J Eur Acad Dermatol Venereol. 2020;34(9): 2086-2095

    Dickel H, Kuhlmann L, Bauer A, Bircher AJ, Breuer K, Fuchs T, Grabbe J, Mahler V, Pföhler C, Przybilla B, Rieker-Schwienbacher J, Schröder-Kraft C, Simon D, Treudler R, Weisshaar E, Worm M, Trinder E, Geier J

    BACKGROUND: The diagnostic significance of the atopy patch test for the management of dermatitis possibly triggered by aeroallergens is still controversial. However, sufficiently large studies with routinely tested standardized aeroallergen patch test preparations in dermatitis patients are lacking.

    OBJECTIVE: To evaluate the reaction frequency and the reaction profiles of 10 until mid-2015 commercially available, standardized aeroallergen patch test preparations of the 'Stallerpatch' test series (Stallergenes, Antony Cedex, France) in a large multicentre patient cohort.

    METHODS: A retrospective data analysis of patients with suspected aeroallergen-dependent eczematous skin lesions was performed, who were patch tested in 15 Information Network of Departments of Dermatology-associated clinics between 2000 and 2015. Patients were stratified according to their atopic dermatitis (AD) status.

    RESULTS: The study group included 3676 patients (median age 41 years, 34.8% males, 54.5% AD). The most common aeroallergens causing positive patch test reactions were Dermatophagoides pteronyssinus (19.6%), Dermatophagoides farinae (16.9%), birch (6.2%), timothy grass (6.0%), cat dander (5.4%), mugwort (4.9%) and dog dander (4.6%). Reactions to other pollen allergen preparations, that is 5 grasses (3.2%), cocksfoot (2.1%) and plantain (1.6%), were less common. Positive patch test reactions to aeroallergens were consistently more frequent in patients with AD. These patients showed proportionally less dubious, follicular, irritant and weak positive reactions. Independent of AD status, a patient history of past or present allergic rhinitis was associated with an increased chance of a positive aeroallergen patch test reaction to pollen allergens.

    CONCLUSION: The aeroallergen patch test is a useful add-on tool in clinical routine, especially in patients with AD and/or respiratory allergy. A patch test series comprising Dermatophagoides pteronyssinus, Dermatophagoides farinae, birch, timothy grass, cat dander and mugwort seems to be suitable. Controlled studies with specific provocation and elimination procedures are required to further evaluate the diagnostic significance of the proposed screening series.

    Pubmed
  • Identification and Characterization of IgE-Reactive Proteins and a New Allergen (Cic a 1.01) from Chickpea (Cicer arietinum).

    Mol Nutr Food Res. 2020;64(19):

    Wangorsch A, Kulkarni A, Jamin A, Spiric J, Bräcker J, Brockmeyer J, Mahler V, Blanca-López N, Ferrer M, Blanca M, Torres M, Gomez P, Bartra J, García-Moral A, Goikoetxea MJ, Vieths S, Toda M, Zoccatelli G, Scheurer S

    SCOPE: Chickpea (Cicer arietinum) allergy has frequently been reported particularly in Spain and India. Nevertheless, chickpea allergens are poorly characterized. The authors aim to identify and characterize potential allergens from chickpea.

    METHODS AND RESULTS: Candidate proteins are selected by an in silico approach or immunoglobuline E (IgE)-testing. Potential allergens are prepared as recombinant or natural proteins and characterized for structural integrity by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), circular dichroism (CD)-spectroscopy, and mass spectrometry (MS) analysis. IgE-sensitization pattern of Spanish chickpea allergic and German peanut and birch pollen sensitized patients are investigated using chickpea extracts and purified proteins. Chickpea allergic patients show individual and heterogeneous IgE-sensitization profiles with extracts from raw and boiled chickpeas. Chickpea proteins pathogenesis related protein family 10 (PR-10), a late embryogenesis abundant protein (LEA/DC-8), and a vicilin-containing fraction, but not 2S albumin, shows IgE reactivity with sera from chickpea, birch pollen, and peanut sensitized patients. Remarkably, allergenic vicilin, DC-8, and PR-10 are detected in the extract of boiled chickpeas.

    CONCLUSION: Several IgE-reactive chickpea allergens are identified. For the first time a yet not classified DC-8 protein is characterized as minor allergen (Cic a 1). Finally, the data suggest a potential risk for peanut allergic patients by IgE cross-reactivity with homologous chickpea proteins.

    Pubmed
  • LAMP-LFD Based on Isothermal Amplification of Multicopy Gene ORF160b: Applicability for Highly Sensitive Low-Tech Screening of Allergenic Soybean (Glycine max) in Food.

    Foods. 2020;9(12):

    Allgöwer SM, Hartmann CA, Lipinski C, Mahler V, Randow S, Völker E, Holzhauser T

    Soybean (Glycine max) allergy can be life threatening. A lack of causative immunotherapy of soybean allergy makes soybean avoidance indispensable. Detection methods are essential to verify allergen labeling and unintentional allergen cross contact during food manufacture. Here, we aimed at evaluating our previously described primers for loop-mediated isothermal amplification (LAMP) of multicopy gene ORF160b, combined with a lateral flow dipstick (LFD)-like detection, for their performance of soybean detection in complex food matrices. The results were compared with those obtained using quantitative real-time Polymerase Chain Reaction (qPCR) as the current standard of DNA-based allergen detection, and antibody-based commercial lateral flow device (LFD) as the current reference of protein-based rapid allergen detection. LAMP-LFD allowed unequivocal and reproducible detection of 10 mg/kg soybean incurred in three representative matrices (boiled sausage, chocolate, instant tomato soup), while clear visibility of positive test lines of two commercial LFD tests was between 10 and 102 mg/kg and depending on the matrix. Sensitivity of soybean detection in incurred food matrices, commercial retail samples, as well as various processed soybean products was comparable between LAMP-LFD and qPCR. The DNA-based LAMP-LFD proved to be a simple and low-technology soybean detection tool, showing sensitivity and specificity that is comparable or superior to the investigated commercial protein-based LFD.

    Pubmed
  • Iron should be restricted in acute infection.

    Front Biosci (Landmark Ed). 2020;25(): 673-682

    Scott CR, Holbein BE, Lehmann CD

    The trace element iron plays important roles in biological systems. Vital functions of both host organisms and pathogens require iron. During infection, the innate immune system reduces iron availability for invading organisms. Pathogens acquire iron through different mechanisms, primarily through the secretion of high-affinity iron chelating compounds known as siderophores. Bacterial siderophores have been used clinically for iron chelation, however synthetic iron chelators are superior for treating infection because - in contrast to siderophore-bound iron - bacteria are not able to utilize iron bound to those molecules. Additionally, utilizing siderophores-dependent iron uptake in a "trojan horse" manner represents a potential option to carry antibiotics into bacterial cells. Recently, synthetic iron chelators have been shown to enhance antibiotic effectiveness and overcome antibiotic resistance. This has implications for the treatment of infections through combination therapy of iron chelators and antibiotics.

    Pubmed
  • Checkpoint inhibitor treatment in patients with isolated in-transit melanoma metastases.

    J Clin Oncol. 2020;38 Suppl S(15):

    Storey L, Abdul-Latif M, Kreft S, Barrett E, Pickering LM, Rohaan MW, Ahmed S, Eigentler TK, Hassel JC, Haferkamp S, Meiss F, Steeb T, Shaw HM, Blank CU, Van Akkooi ACJ, Larkin JMG, Schilling B, Lorigan P, Nathan PD

    Pubmed
  • TYPE 3 INNATE LYMPHOID CELLS ARE KEY DRIVERS OF PSORIATIC ARTHRITIS

    Ann Rheum Dis. 2020;79 Suppl 1(): 1119-1120

    Raimondo MG, Rauber S, Luber M, Rigau AR, Weber S, Anchang CG, Agarwal R, Soare A, Sticherling M, Rech J, Kleyer A, Distler J, Schett G, Ramming A

    Pubmed
  • STRUCTURAL ENTHESEAL LESIONS IN PSORIASIS PATIENTS ARE ASSOCIATED WITH AN INCREASED RISK OF PROGRESSION TO PSORIATIC ARTHRITIS - A PROSPECTIVE COHORT STUDY

    Ann Rheum Dis. 2020;79 Suppl 1(): 33-34

    Simon D, Tascilar K, Kleyer A, Bayat S, Kampylafka E, Hueber A, Rech J, Schuster L, Engel K, Sticherling M, Schett G

    Pubmed
  • Guselkumab is superior to fumaric acid esters in patients with moderate-to-severe plaque psoriasis who are naive to systemic treatment: results from a randomized, active-comparator-controlled phase IIIb trial (POLARIS) (vol 183, pg 265, 2020)

    Br J Dermatol. 2020;183(5): 980-980

    Thaci D, Pinter A, Sebastian M, Termeer C, Sticherling M, Gerdes S, Wegner S, Krampe S, Bartz H, Rausch C, Mensch A, Eyerich K

    Pubmed
  • A PHASE I DOSE ESCALATION AND EXPANSION STUDY OF INTRATUMORALLY ADMINISTERED CV8102 AS A SINGLE-AGENT OR IN COMBINATION WITH ANTI-PD-1 ANTIBODIES IN PATIENTS WITH ADVANCED SOLID TUMORS

    J Immunother Cancer. 2020;8 Suppl 3(): A478-A479

    Eigentler T, Heinzerling L, Krauss J, Weishaupt C, Mohr P, Ochsenreither S, Terheyden P, Martin-Liberal J, Oliva M, Lebbe C, Fluck M, Brossart P, Trigo Perez JMT, Bauernfeind FG, Kays SK, Seibel T, Schoenborn-Kellenberger O, Stosnach C, Daehling A, Schmitt-Bormann B, Gnad-Vogt U

    Pubmed
  • The Neural Crest Transcription Factor SOX10 is essential for the Survival of Uveal Melanoma Cells

    J Dtsch Dermatol Ges. 2020;18 Suppl 2(): 8-8

    Wessely A, Kammerbauer C, Berking C, Heppt M

    Pubmed
  • The Quality of Guidelines for the Treatment of Cutaneous Melanoma: A methodological Assessment

    J Dtsch Dermatol Ges. 2020;18 Suppl 2(): 65-65

    Steeb T, Wessely A, Drexler K, Salzmann M, Toussaint F, Heinzerling L, Reinholz M, Berking C, Heppt M

    Pubmed
  • Merkel Cell Carcinoma of the Head and Neck Compared to Other Anatomical Sites in a Real-World Setting: Importance of Surgical Therapy for Facial Tumors.

    Facial Plast Surg. 2020;36(3): 249-254

    Kirchberger MC, Heppt MV, Schuler G, Berking C, Heinzerling L

    Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin tumor with a high propensity for nodal involvement, local recurrence, and distant metastases. Up to 50% of MCC arises on head and neck (HN), which may impede oncological treatment due to insufficiently wide excisions and a lower rate of sentinel lymph node detection due to more complicated lymph drainage. Several studies have compared the clinical outcome of HN-MCC with those of non-head and neck (NHN) MCC yielding inconsistent results. This single-center, retrospective analysis compared the clinical outcome of 26 HN-MCC patients with 30 NHN-MCC patients. Overall survival (OS) and disease-free survival (DFS) were calculated with the Kaplan-Meier method assuming proportional hazards. The mean resection margins were 1.6 and 2.0 cm for the HN and NHN cohort, respectively. Local relapses were more frequently observed in patients with HN-MCC (19 vs. 10%). Patients with HN-MCC had a median OS of 4.3 years compared with 7.5 years in patients with NHN-MCC (p = 0.277). The median OS by tumor stage was 11, 3, 2, and 3 years in stage I, II, III, and IV disease, respectively (p = 0.009). The median DFS in HN-MCC was 10 years and not reached in the cohort with NHN-MCC patients (p = 0.939). Our data suggest a trend toward poorer outcomes of HN-MCC compared with NHN-MCC. Patients with MCC on the head and neck carry a higher risk for local relapse, requiring resolute surgical treatment also in facial localizations at early stages.

    Pubmed
  • Guselkumab is superior to fumaric acid esters in patients with moderate-to-severe plaque psoriasis who are naive to systemic treatment: results from a randomized, active-comparator-controlled phase IIIb trial (POLARIS).

    Br J Dermatol. 2020;183(2): 265-275

    Thaҫi D, Pinter A, Sebastian M, Termeer C, Sticherling M, Gerdes S, Wegner S, Krampe S, Bartz H, Rausch C, Mensch A, Eyerich K

    BACKGROUND: Guselkumab, a fully human interleukin-23 antibody, is approved for systemic treatment of patients with moderate-to-severe plaque psoriasis.

    OBJECTIVES: To compare the efficacy and safety of guselkumab with those of fumaric acid esters (FAE) in patients with moderate-to-severe plaque psoriasis who are naive to systemic treatment.

    METHODS: Eligible patients were randomized to this multicentre, randomized, open-label, assessor-blinded, active-comparator-controlled phase IIIb study to receive guselkumab 100 mg by subcutaneous injection or oral FAE according to local label guidelines.

    RESULTS: Through week 24, 56 of 60 patients completed guselkumab treatment and 36 of 59 completed FAE treatment. The primary endpoint (proportion of patients with ≥ 90% improvement from their baseline Psoriasis Area and Severity Index; PASI 90 response) was achieved by significantly more patients receiving guselkumab than FAE at week 24 (82% vs. 14%, P < 0·001). Analysis of the major secondary endpoints confirmed a statistically significant difference between the treatments with regards to PASI 75 response (90% vs. 27%, P < 0·001) and Dermatology Life Quality Index score of 0 or 1 (no effect at all on the patient's quality of life; 62% vs. 17%, P < 0·001). More patients in the guselkumab group achieved completely clear skin (PASI 100 response) than in the FAE group (32% vs. 3%, P < 0·001). The incidence of adverse events was lower with guselkumab than with FAE (73% vs. 98%). Overall, 28% of patients on FAE discontinued due to an adverse event, compared with none receiving guselkumab. No new safety findings were observed for guselkumab.

    CONCLUSIONS: Guselkumab demonstrated superiority over FAE in systemic-treatment-naive patients with moderate-to-severe plaque psoriasis through 24 weeks.

    Pubmed
  • Baseline characteristics, disease severity and treatment history of patients with atopic dermatitis included in the German AD Registry TREATgermany.

    J Eur Acad Dermatol Venereol. 2020;34(6): 1263-1272

    Heratizadeh A, Haufe E, Stölzl D, Abraham S, Heinrich L, Kleinheinz A, Wollenberg A, Weisshaar E, Augustin M, Wiemers F, Zink A, von Kiedrowski R, Hilgers M, Worm M, Pawlak M, Sticherling M, Fell I, Handrick C, Schäkel K, Staubach-Renz P, Asmussen A, Schwarz B, Bell M, Effendy I, Bieber T, Homey B, Gerlach B, Tchitcherina E, Stahl M, Schwichtenberg U, Rossbacher J, Buck P, Mempel M, Beissert S, Biedermann T, Weidinger S, Schmitt J, Werfel T, TREATgermany Study Group

    BACKGROUND: The Atopic Dermatitis (AD) TREATgermany registry was initiated by the German Society for Dermatology (DDG) in 2011 to evaluate the 'real-life' situation of health care for patients with AD.

    OBJECTIVES: Interim data analysis on baseline characteristics as well as current and prescribed systemic treatments of the TREATgermany registry patients.

    METHODS: Patients (≥18 years) with moderate-to-severe AD [objective (o)SCORAD > 20], or with current or previous anti-inflammatory systemic treatment for AD within 24 months, were included and are followed up over at least 24 months. To assess clinical signs, the eczema area severity index (EASI, 0-72), the oSCORAD (0-83) and the Investigator Global Assessment (IGA; 6-point scale) were used. The disease severity was globally scored by the patients [Patient Global Assessment (PGA); six-step Likert scale]. Disease symptoms were assessed by the patient-oriented eczema measure (POEM, 0-28) and numeric rating scales (NRS, 0-10). Health-related quality of life was measured using the dermatological life quality index (DLQI, 0-30).

    RESULTS: A total of 612 patients were recruited across 32 sites between 06/2016 and 01/2019 (mean age: 42.6 ± 14.2 years; mean oSCORAD: 40.8 ± 16.3). The mean POEM score was 16.3 ± 7.5. Pruritus was rated highest among subjective symptoms (NRS: 5.4 ± 2.7). The mean DLQI value was 11.3 ± 7.5. The frequency of arterial hypertension was lower (20.8%) compared with the general population, whilst this was higher for depression (10%). More than 60% of the patients had received systemic glucocorticosteroids, and 36.8% had received cyclosporine A prior to inclusion. Dupilumab was the leading substance documented as either 'current' (12.1%) or 'prescribed' (31.4%) at baseline.

    CONCLUSIONS: These 'real-life' data clearly demonstrate the substantial disease burden. Most of TREATgermany patients were already treated with or prescribed dupilumab at baseline. Moreover, current findings indicate the urgent need for further alternative agents in order to achieve a perceptible improvement of quality of life of patients with moderate-to-severe AD.

    Pubmed
  • [Management of malignant wounds].

    Z Gerontol Geriatr. 2020;53(6): 572-576

    Kirchberger MC, Erfurt-Berge C

    Malignant wounds arise either primary or secondary in the context of a malignant transformation of already existing wounds. A plethora of skin tumors, such as basal cell carcinoma, squamous cell carcinoma, melanoma, lymphoma as well as cutaneous metastases of other malignancies can ulcerate and be the cause of malignant wounds. Ulcerating tumors or metastases of the skin can however mimic chronic wounds from other causes and remain unrecognized over a longer period. In patients with chronic ulcerations, the correct and timely diagnosis is paramount. Based on this, the stage and disease-oriented treatment should be chosen in harmony with the wishes of the patient. In addition, general measures, such as atraumatic dressing changes to reduce pain and bleeding and the use of antiseptic dressing materials to prevent bacterial colonization and associated odors should be considered.

    Pubmed
  • Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial.

    Lancet Oncol. 2020;21(2): 294-305

    Migden MR, Khushalani NI, Chang ALS, Lewis KD, Schmults CD, Hernandez-Aya L, Meier F, Schadendorf D, Guminski A, Hauschild A, Wong DJ, Daniels GA, Berking C, Jankovic V, Stankevich E, Booth J, Li S, Weinreich DM, Yancopoulos GD, Lowy I, Fury MG, Rischin D

    BACKGROUND: Cemiplimab has shown substantial antitumour activity in patients with metastatic cutaneous squamous cell carcinoma. Patients with locally advanced cutaneous squamous cell carcinoma have poor prognosis with conventional systemic therapy. We present a primary analysis of the safety and antitumour activity of cemiplimab in patients with locally advanced cutaneous squamous cell carcinoma.

    METHODS: This pivotal open-label, phase 2, single-arm trial was done across 25 outpatient clinics, primarily at academic medical centres, in Australia, Germany, and the USA. Eligible patients (aged ≥18 years with histologically confirmed locally advanced cutaneous squamous cell carcinoma and an Eastern Cooperative Oncology Group performance status of 0-1) received cemiplimab 3 mg/kg intravenously over 30 min every 2 weeks for up to 96 weeks. Tumour measurements were done every 8 weeks. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response, according to independent central review as per Response Evaluation Criteria in Solid Tumors version 1.1 for radiological scans and WHO criteria for medical photography. Data cutoff was Oct 10, 2018, when the fully enrolled cohort reached the prespecified timepoint for the primary analysis. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. This study is registered with ClinicalTrials.gov, number NCT02760498.

    FINDINGS: Between June 14, 2016, and April 25, 2018, 78 patients were enrolled and treated with cemiplimab. The median duration of study follow-up was 9·3 months (IQR 5·1-15·7) at the time of data cutoff. An objective response was observed in 34 (44%; 95% CI 32-55) of 78 patients. The best overall response was ten (13%) patients with a complete response and 24 (31%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 34 (44%) of 78 patients; the most common were hypertension in six (8%) patients and pneumonia in four (5%). Serious treatment-emergent adverse events occurred in 23 (29%) of 78 patients. One treatment-related death was reported that occurred after onset of aspiration pneumonia.

    INTERPRETATION: Cemiplimab showed antitumour activity and an acceptable safety profile in patients with locally advanced cutaneous squamous cell carcinoma for whom there was no widely accepted standard of care.

    FUNDING: Regeneron Pharmaceuticals and Sanofi.

    Pubmed
  • Comparative analysis of the phototoxicity induced by BRAF inhibitors and alleviation through antioxidants.

    Photodermatol Photoimmunol Photomed. 2020;36(2): 126-134

    Heppt MV, Clanner-Engelshofen BM, Marsela E, Wessely A, Kammerbauer C, Przybilla B, French LE, Berking C, Reinholz M

    BACKGROUND: Small molecules tackling mutated BRAF (BRAFi) are an important mainstay of targeted therapy in a variety of cancers including melanoma. Albeit commonly reported as side effect, the phototoxic potential of many BRAFi is poorly characterized. In this study, we evaluated the phototoxicity of 17 distinct agents and investigated whether BRAFi-induced phototoxicity can be alleviated by antioxidants.

    METHODS: The ultraviolet (UV) light absorbance of 17 BRAFi was determined. Their phototoxic potential was investigated independently with a reactive oxygen species (ROS) and the 3T3 neutral red uptake (NRU) assay in vitro. To test for a possible phototoxicity alleviation by antioxidants, vitamin C, vitamin E phosphate, trolox, and glutathione (GSH) were added to the 3T3 assay of selected inhibitors.

    RESULTS: The highest cumulative absorbance for both UVA and UVB was detected for vemurafenib. The formation of ROS was more pronounced for all compounds after irradiation with UVA than with UVB. In the 3T3 NRU assay, 8 agents were classified as phototoxic, including vemurafenib, dabrafenib, and encorafenib. There was a significant correlation between the formation of singlet oxygen (P = .026) and superoxide anion (P < .001) and the phototoxicity observed in the 3T3 NRU assay. The phototoxicity of vemurafenib was fully rescued in the 3T3 NRU assay after GSH was added at different concentrations.

    CONCLUSION: Our study confirms that most of the BRAF inhibitors exhibited a considerable phototoxic potential, predominantly after exposure to UVA. GSH may help treat and prevent the phototoxicity induced by vemurafenib.

    Pubmed
  • The more the better? An appraisal of combination therapies for actinic keratosis.

    J Eur Acad Dermatol Venereol. 2020;34(4): 727-732

    Steeb T, Wessely A, Leiter U, French LE, Berking C, Heppt MV

    Actinic keratoses (AK) are common precancerous lesions of the skin. Numerous interventions exist for the treatment of AK, including lesion- and field-directed approaches. In daily practice, different treatment modalities are often combined to maximize clearance rates. However, whether a combination therapy is preferable to monotherapy in terms of efficacy and safety has been subject of intense debate. In this review, we summarize the current knowledge on the efficacy and safety of local combination therapies for the treatment of patients with AK. Combination approaches of cryosurgery followed by photodynamic therapy (PDT), laser-assisted PDT, PDT in combination with topical interventions and microneedling-assisted PDT have shown slightly better efficacy results with similar tolerability compared to the respective monotherapy. However, the individual usage of combination therapies should be checked on a case-by-case basis and take into account individual patient- and lesion-specific aspects as more resources are needed and because the individual monotherapies are already highly effective.

    Pubmed
  • Microneedling-assisted photodynamic therapy for the treatment of actinic keratosis: Results from a systematic review and meta-analysis.

    J Am Acad Dermatol. 2020;82(2): 515-519

    Steeb T, Niesert AC, French LE, Berking C, Heppt MV

    Pubmed
  • Where do we stand with immune checkpoint blockade for advanced cutaneous squamous cell carcinoma? A systematic review and critical appraisal of the existing evidence.

    Br J Dermatol. 2020;183(2): 380-382

    Steeb T, Wessely A, Heppt F, Harlaß M, Berking C, Heppt MV

    Immune checkpoint blockade (ICB) has tremendously changed the field of oncological therapy. Recently, the PD-1-blocking antibody cemiplimab was approved by the FDA and the EMA for the treatment of advanced cutaneous squamous cell carcinoma (cSCC).1 However, clinical practice guidelines currently do not cover specific recommendations regarding the management of advanced cSCC with ICB. Hence, we have performed a systematic review on the current use of ICB for advanced cSCC.

    Pubmed
  • The Role of Immune Checkpoint Blockade in Uveal Melanoma.

    Int J Mol Sci. 2020;21(3):

    Wessely A, Steeb T, Erdmann M, Heinzerling L, Vera J, Schlaak M, Berking C, Heppt MV

    Uveal melanoma (UM) represents the most common intraocular malignancy in adults and accounts for about 5% of all melanomas. Primary disease can be effectively controlled by several local therapy options, but UM has a high potential for metastatic spread, especially to the liver. Despite its clinical and genetic heterogeneity, therapy of metastatic UM has largely been adopted from cutaneous melanoma (CM) with discouraging results until now. The introduction of antibodies targeting CTLA-4 and PD-1 for immune checkpoint blockade (ICB) has revolutionized the field of cancer therapy and has achieved pioneering results in metastatic CM. Thus, expectations were high that patients with metastatic UM would also benefit from these new therapy options. This review provides a comprehensive and up-to-date overview on the role of ICB in UM. We give a summary of UM biology, its clinical features, and how it differs from CM. The results of several studies that have been investigating ICB in metastatic UM are presented. We discuss possible reasons for the lack of efficacy of ICB in UM compared to CM, highlight the pitfalls of ICB in this cancer entity, and explain why other immune-modulating therapies could still be an option for future UM therapies.

    Pubmed
  • Guidelines for uveal melanoma: a critical appraisal of systematically identified guidelines using the AGREE II and AGREE-REX instrument.

    J Cancer Res Clin Oncol. 2020;146(4): 1079-1088

    Steeb T, Hayani KM, Förster P, Liegl R, Toussaint F, Schlaak M, Berking C, Heppt MV

    PURPOSE: Clinical practice guidelines provide recommendations for the management of diseases. In orphan conditions such as uveal melanoma (UM), guideline developers are challenged to provide practical and useful guidance even in the absence of high-quality evidence. Here, we assessed the methodological quality and identified deficiencies of international guidelines on UM as a base for future guideline development.

    METHODS: A systematic search was carried out in guideline databases, Medline and Embase until 27th May 2019 for guidelines on UM published between 2004 and 2019. Five independent reviewers assessed the methodological quality of the identified guidelines using the instruments "Appraisal of Guidelines for Research and Evaluation II" (AGREE II) and AGREE-REX (Recommendation EXcellence). Descriptive analysis was performed and subgroup differences were explored with the Kruskal-Wallis (H) test. The relationship between the individual domains and items of the instruments were examined using Spearman's correlation.

    RESULTS: Five guidelines published from 2014 to 2018 by consortia of the United States of America, Canada and the United Kingdom (UK) were included. The highest scores were obtained by the UK guideline fulfilling 48-86% of criteria in AGREE II and 30-60% for AGREE-REX. All guidelines showed deficiencies in the domains "editorial independence", "applicability", and "recommendation". Subgroup differences were identified only for the domain "editorial independence".

    CONCLUSION: The UK guideline achieved the highest scores with both instruments and may serve as a basis for future guideline development in UM. The domains "editorial independence", "recommendation", and "applicability" were identified as methodological weaknesses and require particular attention and improvement in future guidelines.

    Pubmed
  • Global Longitudinal Strain and Cardiac Events in Patients With Immune Checkpoint Inhibitor-Related Myocarditis.

    J Am Coll Cardiol. 2020;75(5): 467-478

    Awadalla M, Mahmood SS, Groarke JD, Hassan MZO, Nohria A, Rokicki A, Murphy SP, Mercaldo ND, Zhang L, Zlotoff DA, Reynolds KL, Alvi RM, Banerji D, Liu S, Heinzerling LM, Jones-O'Connor M, Bakar RB, Cohen JV, Kirchberger MC, Sullivan RJ, Gupta D, Mulligan CP, Shah SP, Ganatra S, Rizvi MA, Sahni G, Tocchetti CG, Lawrence DP, Mahmoudi M, Devereux RB, Forrestal BJ, Mandawat A, Lyon AR, Chen CL, Barac A, Hung J, Thavendiranathan P, Picard MH, Thuny F, Ederhy S, Fradley MG, Neilan TG

    BACKGROUND: There is a need for improved methods for detection and risk stratification of myocarditis associated with immune checkpoint inhibitors (ICIs). Global longitudinal strain (GLS) is a sensitive marker of cardiac toxicity among patients receiving standard chemotherapy. There are no data on the use of GLS in ICI myocarditis.

    OBJECTIVES: This study sought to evaluate the role of GLS and assess its association with cardiac events among patients with ICI myocarditis.

    METHODS: This study retrospectively compared echocardiographic GLS by speckle tracking at presentation with ICI myocarditis (cases, n = 101) to that from patients receiving an ICI who did not develop myocarditis (control subjects, n = 92). Where available, GLS was also measured pre-ICI in both groups. Major adverse cardiac events (MACE) were defined as a composite of cardiogenic shock, arrest, complete heart block, and cardiac death.

    RESULTS: Cases and control subjects were similar in age, sex, and cancer type. At presentation with myocarditis, 61 cases (60%) had a normal ejection fraction (EF). Pre-ICI, GLS was similar between cases and control subjects (20.3 ± 2.6% vs. 20.6 ± 2.0%; p = 0.60). There was no change in GLS among control subjects on an ICI without myocarditis (pre-ICI vs. on ICI, 20.6 ± 2.0% vs. 20.5 ± 1.9%; p = 0.41); in contrast, among cases, GLS decreased to 14.1 ± 2.8% (p < 0.001). The GLS at presentation with myocarditis was lower among cases presenting with either a reduced (12.3 ± 2.7%) or preserved EF (15.3 ± 2.0%; p < 0.001). Over a median follow-up of 162 days, 51 (51%) experienced MACE. The risk of MACE was higher with a lower GLS among patients with either a reduced or preserved EF. After adjustment for EF, each percent reduction in GLS was associated with a 1.5-fold increase in MACE among patients with a reduced EF (hazard ratio: 1.5; 95% confidence interval: 1.2 to 1.8) and a 4.4-fold increase with a preserved EF (hazard ratio: 4.4; 95% confidence interval: 2.4 to 7.8).

    CONCLUSIONS: GLS decreases with ICI myocarditis and, compared with control subjects, was lower among cases presenting with either a preserved or reduced EF. Lower GLS was strongly associated with MACE in ICI myocarditis presenting with either a preserved or reduced EF.

    Pubmed
  • Bone microstructure and volumetric bone mineral density in patients with hyperuricemia with and without psoriasis.

    Osteoporos Int. 2020;31(5): 931-939

    Simon D, Haschka J, Muschitz C, Kocijan A, Baierl A, Kleyer A, Schett G, Kapiotis S, Resch H, Sticherling M, Rech J, Kocijan R

    We analyzed volumetric bone mineral density (vBMD) and bone microstructure using HR-pQCT in subjects with normouricemia (NU) and subjects with hyperuricemia (HU) with and without psoriasis (PSO). HU was associated with higher cortical vBMD and thickness. Differences in average and trabecular vBMD were found between patients with PSO + HU and NU.

    INTRODUCTION: Hyperuricemia (HU) and gout are co-conditions of psoriasis and psoriatic arthritis. Current data suggest a positive association between HU and areal bone mineral density (BMD) and a negative influence of psoriasis on local bone, even in the absence of arthritis. However, the influence of the combination of HU and psoriasis on bone is still unclear. The aim of this study was to assess the impact of HU with and without psoriasis on bone microstructure and volumetric BMD (vBMD).

    METHODS: Healthy individuals with uric acid levels within the normal range (NU), with hyperuricemia (HU), patients with hyperuricemia and psoriasis (PSO + HU), and patients with uric acid within the normal range and psoriasis (PSO + NU) were included in our study. Psoriasis patients had no current or past symptoms of arthritis. Average, trabecular, and cortical vBMD (mgHA/cm3); trabecular number (Tb.N, 1/mm) and thickness (Tb.Th, mm); inhomogeneity of the network (1/N.SD, mm); and cortical thickness (Ct.Th., mm) were carried out at the ultradistal radius using high-resolution peripheral quantitative computed tomography. In addition, bone turnover markers such as DKK-1, sclerostin, and P1NP were analyzed.

    RESULTS: In total, 130 individuals were included (44 NU participants (34% female), 50 HU (24%), 16 PSO + HU (6%), 20 PSO + NU (60%)). Subjects were aged: NU 54.5 (42.8, 62.1), HU 57.5 (18.6, 65.1), PSO + HU 52.0 (42.3, 57.8), and PSO + NU 42.5 (34.8, 56.8), respectively. After adjusting for age, sex, BMI, and diabetes, patients in the HU group revealed significantly higher values of cortical vBMD (p < 0.001) as well as cortical thickness (p = 0.04) compared to the NU group. PSO + NU showed no differences to NU, but PSO + HU demonstrated both lower average (p = 0.03) and trabecular vBMD (p = 0.02). P1NP was associated with average, cortical, and trabecular vBMD as well as cortical thickness while sclerostin levels were related to trabecular vBMD.

    CONCLUSION: Hyperuricemia in otherwise healthy subjects was associated with a better cortical vBMD and higher cortical thickness. However, patients with both psoriasis and hyperuricemia revealed a lower vBMD.

    Pubmed
  • Implementation of dupilumab in routine care of atopic eczema: results from the German national registry TREATgermany.

    Br J Dermatol. 2020;183(2): 382-384

    Abraham S, Haufe E, Harder I, Heratizadeh A, Kleinheinz A, Wollenberg A, Weisshaar E, Augustin M, Wiemers F, Zink A, Biedermann T, von Kiedrowski R, Hilgers M, Worm M, Pawlak M, Sticherling M, Fell I, Handrick C, Schäkel K, Staubach P, Asmussen A, Schwarz B, Bell M, Neubert K, Effendy I, Bieber T, Homey B, Gerlach B, Tchitcherina E, Stahl M, Schwichtenberg U, Rossbacher J, Buck P, Mempel M, Beissert S, Werfel T, Weidinger S, Schmitt J, TREATgermany study group

    The German atopic eczema (AE)-registry TREATgermany is a non-interventional multicenter patient cohort study for adult patients with currently moderate-to-severe disease activity or current/previous anti-inflammatory systemic treatment.1,2 Dupilumab has demonstrated to be an effective treatment for patients with moderate-to-severe AE in clinical trials.3-5 Real world evidence is now needed to evaluate its effectiveness and safety in routine care.

    Pubmed
  • Successful treatment of ulcerative necrobiosis lipoidica with janus kinase inhibitor.

    J Eur Acad Dermatol Venereol. 2020;34(7): e331-e333

    Erfurt-Berge C, Sticherling M

    Necrobiosis lipoidica (NL) is a rare granulomatous disease that predominantly affects middle aged women and is often associated with diabetes mellitus and other metabolic disorders 1 . About 30 % of the patients develop ulcerations within NL lesions on the lower leg, which complicate the course of disease and are often recalcitrant to standard wound care procedures 2 . Systemic therapies for NL are reported only for single cases or in small case series with varying outcome 3 . Randomized controlled trials are missing due to the character of NL as an orphan disease.

    Pubmed
  • Dermatology Part 2: Ichthyoses and Psoriasis.

    Handb Exp Pharmacol. 2020;261(): 153-175

    Sticherling M

    Acute and chronic inflammatory skin diseases are frequent in childhood and may be hereditary or acquired. In this context, ichthyosis is rather a symptom than a defined disease as scaling is accompanying a number of disorders and is mostly consequence of a disrupted skin barrier. Ichthyosis is the basic pathogenic trait of atopic dermatitis but on the other side describes a group of rare hereditary diseases. These may only affect the skin or comprise several internal symptoms as well. Psoriasis is another scaling inflammatory skin disease with classical sharply demarcated erythematosquamous plaques and with a distinct immunogenetic background. It comprises several clinical subsets, some of which are characteristic for children and demanding in both diagnostics and therapy. Comorbid diseases point towards a systemic inflammatory response and require ample, often systemic treatment. Both ichthyosis and psoriasis may be topically treated including emollients with and without humectants as well as active agents like corticosteroids, vitamin D derivatives, and calcineurin inhibitors. In moderate to severe diseases, systemic treatment should be applied using methotrexate, ciclosporin, fumarates, or biologics. Their use should be critically discussed yet if necessary and indicated be applied to avoid chronic physical and psychological damage to the affected children.

    Pubmed
  • Developing classification criteria for skin-predominant dermatomyositis: the Delphi process.

    Br J Dermatol. 2020;182(2): 410-417

    Concha JSS, Pena S, Gaffney RG, Patel B, Tarazi M, Kushner CJ, Merola JF, Fiorentino D, Dutz JP, Goodfield M, Nyberg F, Volc-Platzer B, Fujimoto M, Ang CC, Werth VP, Skin Myositis Delphi Group , Abuav R, Aggarwal R, Avashia-Khemka N, Callen JP, Cardones ARG, Chisolm SS, Chong BF, Chung L, Clarke JT, Kari Connolly M, Costner M, Curran M, Dourmishev L, Drage LA, Femia AN, Fernandez AP, Fett N, Foulke G, Franks AG, Haemel A, Hamaguchi Y, Hansen CB, Imadojemu S, Jia Ker K, Kim HJ, Kurtzman DJ, Lam C, Laumann AE, Lin J, Mailhot JD, Meggitt SJ, Micheletti RG, Motegi SI, Muro Y, O'Brien E, Pappas-Taffer L, Paravar T, Parodi A, Pearson DR, Pinard J, Ramachandran S, Rider LG, Rosenbach M, Sontheimer RD, Sticherling M, Vera Kellet CA, Vleugels RA, Wetter DA, Yamaguchi Y

    BACKGROUND: The European League Against Rheumatism/American College of Rheumatology classification criteria for inflammatory myopathies are able to classify patients with skin-predominant dermatomyositis (DM). However, approximately 25% of patients with skin-predominant DM do not meet two of the three hallmark skin signs and fail to meet the criteria.

    OBJECTIVES: To develop a set of skin-focused classification criteria that will distinguish cutaneous DM from mimickers and allow a more inclusive definition of skin-predominant disease.

    METHODS: An extensive literature review was done to generate items for the Delphi process. Items were grouped into categories of distribution, morphology, symptoms, antibodies, histology and contextual factors. Using REDCap™, participants rated these items in terms of appropriateness and distinguishing ability from mimickers. The relevance score ranged from 1 to 100, and the median score determined a rank-ordered list. A prespecified median score cut-off was decided by the steering committee and the participants. There was a pre-Delphi and two rounds of actual Delphi.

    RESULTS: There were 50 participating dermatologists and rheumatologists from North America, South America, Europe and Asia. After a cut-off score of 70 during the first round, 37 of the initial 54 items were retained and carried over to the next round. The cut-off was raised to 80 during round two and a list of 25 items was generated.

    CONCLUSIONS: This project is a key step in the development of prospectively validated classification criteria that will create a more inclusive population of patients with DM for clinical research. What's already known about this topic? Proper classification of patients with skin-predominant dermatomyositis (DM) is indispensable in the appropriate conduct of clinical/translational research in the field. The only validated European League Against Rheumatism/American College of Rheumatology criteria for idiopathic inflammatory myopathies are able to classify skin-predominant DM. However, a quarter of amyopathic patients still fail the criteria and does not meet the disease classification. What does this study add? A list of 25 potential criteria divided into categories of distribution, morphology, symptomatology, pathology and contextual factors has been generated after several rounds of consensus exercise among experts in the field of DM. This Delphi project is a prerequisite to the development of a validated classification criteria set for skin-predominant DM.

    Pubmed
  • Secondary prevention measures in anaphylaxis patients: Data from the anaphylaxis registry.

    Allergy. 2020;75(4): 901-910

    Kraft M, Knop MP, Renaudin JM, Scherer Hofmeier KS, Pfoehler C, Bilo MB, Lang R, Treudler R, Wagner N, Spindler T, Hourihane JO, Maris I, Koehli A, Bauer A, Lange L, Mueller S, Papadopoulos NG, Wedi B, Moeser A, Ensina LF, Fernandez-Rivas M, Cichocka-Jarosz E, Christoff G, Garcia BE, Poziomkowska-Gesicka I, Cardona V, Mustakov TB, Rabe U, Mahler V, Grabenhenrich L, Doelle-Bierke S, Worm M, Gruenhagen J, Dalke M, Beyer K, Kroegel C, Fuchs T, Rueff F, Oppel E, Dickel H, Merk H, Hillen U, Lotz C, Rietschel E, Aurich S, Klimek L, Pfaar O, Reider N, Aberer W, Bogatu B, Riffelmann F, Kreft B, Nemat K, Kinaciyan T, Brehler R, Witte J, Hunzelmann N, Huseynow I, Bieber T, Schmid-Grendelmeier P, Brosi W, Nestoris S, Hawranek T, Bruns R, Lehmann S, Hansen G, Becker S, Krecke N, Santernus R, Varga E, Szepfalusi Z, Eng P, Eng P, Reese T, Polz M, Schweitzer-Krantz S, Rebmann H, Stichtenoth G, Theis S, Yildiz I, Gerstlauer M, Nordwig A, Neustaedter I, Stadlin C, Buecheler M, Volkmuth S, Fischer J, Henschel A, Plank-Habibi S, Schilling B, Kleinheinz A, Schaekel K, Manolaraki I, Xepapadaki P, Douladiris N, Manoussakis E, Kowalski M, Solarewicz-Madajek K, Koener-Rettberg C, Tsheiller S, Hartmann K, Kemen C, Prenzel F, Ebner C, Haak S, Gil Serrano JG, Galvan Blasco PG, Haemmerling S, Arroabarren E, Cabanes Higuero NC, Vega Castro AV, Buesing S, Klettke U, Virchow C, Christoff G, Jappe U, Jakob T, Straube H, Vogelberg C, Knoepfel F, Correard K, Tobin C, Rogala B, Montoro A, Brandes A, Muraro A, Buck T, Buesselberg J, Zimmermann N, Hernandez D, Minale P, Niederwimmer J, Zahel B, Fiocchi A, Reissig A, Horak F, Meller S, Eitelberger F, Ott H, Asero R, Hermann F, Zeidler S, Pistauer S, Geissler M, Tarczon I, Sole D, Guerzet Ayres Bastos PGA, Martins de Aquino BM, Camelo-Nunes I, Cocco R, Plaza Martin AP, Meister J, Hompes S, Stieglitz S, NORA

    BACKGROUND: Patients with a history of anaphylaxis are at risk of future anaphylactic reactions. Thus, secondary prevention measures are recommended for these patients to prevent or attenuate the next reaction.

    METHODS: Data from the Anaphylaxis Registry were analyzed to identify secondary prevention measures offered to patients who experienced anaphylaxis. Our analysis included 7788 cases from 10 European countries and Brazil.

    RESULTS: The secondary prevention measures offered varied across the elicitors. A remarkable discrepancy was observed between prevention measures offered in specialized allergy centers (84% of patients were prescribed adrenaline autoinjectors following EAACI guidelines) and outside the centers: Here, EAACI guideline adherence was only 37%. In the multivariate analysis, the elicitor of the reaction, age of the patient, mastocytosis as comorbidity, severity of the reaction, and reimbursement/availability of the autoinjector influence physician's decision to prescribe one.

    CONCLUSIONS: Based on the low implementation of guidelines concerning secondary prevention measures outside of specialized allergy centers, our findings highlight the importance of these specialized centers and the requirement of better education for primary healthcare and emergency physicians.

    Pubmed
  • Therapeutic Cancer Vaccination with Ex Vivo RNA-Transfected Dendritic Cells-An Update.

    Pharmaceutics. 2020;12(2):

    Dörrie J, Schaft N, Schuler G, Schuler-Thurner B

    Over the last two decades, dendritic cell (DC) vaccination has been studied extensively as active immunotherapy in cancer treatment and has been proven safe in all clinical trials both with respect to short and long-term side effects. For antigen-loading of dendritic cells (DCs) one method is to introduce mRNA coding for the desired antigens. To target the whole antigenic repertoire of a tumor, even the total tumor mRNA of a macrodissected biopsy sample can be used. To date, reports have been published on a total of 781 patients suffering from different tumor entities and HIV-infection, who have been treated with DCs loaded with mRNA. The majority of those were melanoma patients, followed by HIV-infected patients, but leukemias, brain tumors, prostate cancer, renal cell carcinomas, pancreatic cancers and several others have also been treated. Next to antigen-loading, mRNA-electroporation allows a purposeful manipulation of the DCs' phenotype and function to enhance their immunogenicity. In this review, we intend to give a comprehensive summary of what has been published regarding clinical testing of ex vivo generated mRNA-transfected DCs, with respect to safety and risk/benefit evaluations, choice of tumor antigens and RNA-source, and the design of better DCs for vaccination by transfection of mRNA-encoded functional proteins.

    Pubmed
  • COVID-19: risk for cytokine targeting in chronic inflammatory diseases?

    Nat Rev Immunol. 2020;20(5): 271-272

    Schett G, Sticherling M, Neurath MF

    COVID-19, caused by the SARS-CoV-2 virus, has become pandemic. With sharply rising infection rates, patient groups characterized by an enhanced infection risk will be challenged by the virus. In this context, patients with chronic immune-mediated inflammatory diseases are of particular interest, as these diseases are characterized by an intrinsic immune dysfunction leading to inflammation that may enhance risk for severe infection.

    Pubmed
  • S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma (cSCC) - short version, part 2: epidemiology, surgical and systemic treatment of cSCC, follow-up, prevention and occupational disease.

    J Dtsch Dermatol Ges. 2020;18(4): 400-413

    Leiter U, Heppt MV, Steeb T, Amaral T, Bauer A, Becker JC, Breitbart E, Breuninger H, Diepgen T, Dirschka T, Eigentler T, Flaig M, Follmann M, Fritz K, Greinert R, Gutzmer R, Hillen U, Ihrler S, John SM, Kölbl O, Kraywinkel K, Löser C, Nashan D, Noor S, Nothacker M, Pfannenberg C, Salavastru C, Schmitz L, Stockfleth E, Szeimies RM, Ulrich C, Welzel J, Wermker K, Garbe C, Berking C

    Actinic keratoses (AKs) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guidelines for actinic keratosis and cutaneous squamous cell carcinoma were developed using the highest level of methodology (S3) according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF). The guidelines are aimed at dermatologists, general practitioners, ENT specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings as well as other medical specialties involved in the diagnosis and treatment of patients with AKs and cSCC. The guidelines are also aimed at affected patients, their relatives, policy makers and insurance funds. In the second part, we will address aspects relating to epidemiology, etiology, surgical and systemic treatment of cSCC, follow-up and disease prevention, and discuss AKs and cSCC in the context of occupational disease regulations.

    Pubmed
  • Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer.

    Nat Med. 2020;26(6): 919-931

    Roberti MP, Yonekura S, Duong CPM, Picard M, Ferrere G, Tidjani Alou M, Rauber C, Iebba V, Lehmann CHK, Amon L, Dudziak D, Derosa L, Routy B, Flament C, Richard C, Daillère R, Fluckiger A, Van Seuningen I, Chamaillard M, Vincent A, Kourula S, Opolon P, Ly P, Pizzato E, Becharef S, Paillet J, Klein C, Marliot F, Pietrantonio F, Benoist S, Scoazec JY, Dartigues P, Hollebecque A, Malka D, Pagès F, Galon J, Gomperts Boneca I, Lepage P, Ryffel B, Raoult D, Eggermont A, Vanden Berghe T, Ghiringhelli F, Vandenabeele P, Kroemer G, Zitvogel L

    The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (TFH) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of TFH cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of TFH cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1+ TFH cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC.

    Pubmed
  • Loading of Primary Human T Lymphocytes with Citrate-Coated Superparamagnetic Iron Oxide Nanoparticles Does Not Impair Their Activation after Polyclonal Stimulation.

    Cells. 2020;9(2):

    Mühlberger M, Unterweger H, Band J, Lehmann C, Heger L, Dudziak D, Alexiou C, Lee G, Janko C

    For the conversion of immunologically cold tumors, characterized by a low T cell infiltration, into hot tumors, it is necessary to enrich T cells in the tumor area. One possibility is the use of magnetic fields to direct T cells into the tumor. For this purpose, primary T cells that were freshly isolated from human whole blood were loaded with citrate-coated superparamagnetic iron oxide nanoparticles (SPIONCitrate). Cell toxicity and particle uptake were investigated by flow cytometry and atomic emission spectroscopy. The optimum loading of the T cells without any major effect on their viability was achieved with a particle concentration of 75 µg Fe/mL and a loading period of 24 h. The cellular content of SPIONCitrate was sufficient to attract these T cells with a magnet which was monitored by live-cell imaging. The functionality of the T cells was only slightly influenced by SPIONCitrate, as demonstrated by in vitro stimulation assays. The proliferation rate as well as the expression of co-stimulatory and inhibitory surface molecules (programmed cell death 1 (PD-1), lymphocyte activation gene 3 (LAG-3), T cell immunoglobulin and mucin domain containing 3 (Tim-3), C-C motif chemokine receptor 7 (CCR7), CD25, CD45RO, CD69) was investigated and found to be unchanged. Our results presented here demonstrate the feasibility of loading primary human T lymphocytes with superparamagnetic iron oxide nanoparticles without influencing their viability and functionality while achieving sufficient magnetizability for magnetically controlled targeting. Thus, the results provide a strong fundament for the transfer to tumor models and ultimately for new immunotherapeutic approaches for cancer treatment.

    Pubmed
  • Effects of Label Noise on Deep Learning-Based Skin Cancer Classification.

    Front Med (Lausanne). 2020;7():

    Hekler A, Kather JN, Krieghoff-Henning E, Utikal JS, Meier F, Gellrich FF, Upmeier Zu Belzen J, French L, Schlager JG, Ghoreschi K, Wilhelm T, Kutzner H, Berking C, Heppt MV, Haferkamp S, Sondermann W, Schadendorf D, Schilling B, Izar B, Maron R, Schmitt M, Fröhling S, Lipka DB, Brinker TJ

    Recent studies have shown that deep learning is capable of classifying dermatoscopic images at least as well as dermatologists. However, many studies in skin cancer classification utilize non-biopsy-verified training images. This imperfect ground truth introduces a systematic error, but the effects on classifier performance are currently unknown. Here, we systematically examine the effects of label noise by training and evaluating convolutional neural networks (CNN) with 804 images of melanoma and nevi labeled either by dermatologists or by biopsy. The CNNs are evaluated on a test set of 384 images by means of 4-fold cross validation comparing the outputs with either the corresponding dermatological or the biopsy-verified diagnosis. With identical ground truths of training and test labels, high accuracies with 75.03% (95% CI: 74.39-75.66%) for dermatological and 73.80% (95% CI: 73.10-74.51%) for biopsy-verified labels can be achieved. However, if the CNN is trained and tested with different ground truths, accuracy drops significantly to 64.53% (95% CI: 63.12-65.94%, p < 0.01) on a non-biopsy-verified and to 64.24% (95% CI: 62.66-65.83%, p < 0.01) on a biopsy-verified test set. In conclusion, deep learning methods for skin cancer classification are highly sensitive to label noise and future work should use biopsy-verified training images to mitigate this problem.

    Pubmed
  • S2k guidelines for the treatment of pemphigus vulgaris/foliaceus and bullous pemphigoid: 2019 update.

    J Dtsch Dermatol Ges. 2020;18(5): 516-526

    Schmidt E, Sticherling M, Sárdy M, Eming R, Goebeler M, Hertl M, Hofmann SC, Hunzelmann N, Kern JS, Kramer H, Nast A, Orzechowski HD, Pfeiffer C, Schuster V, Sitaru C, Zidane M, Zillikens D, Worm M

    Pubmed
  • Travel-associated infectious skin diseases.

    J Dtsch Dermatol Ges. 2020;18(7): 730-733

    Rongisch R, Schmidt E, Deresz N, Deresz K, Schöfer H, Schäkel K, Jakob T, Maurer M, Sticherling M, Sunderkötter C, Babilas P, Spornraft-Ragaller P, Traidl-Hoffmann C, Gläser R, Hartmann K, Kolb-Mäurer A, Wenzel J, Biedermann T, Homey B, Pfützner W, Weid F, Fischer M, Linder R, von Stebut E

    Pubmed
  • Efficacy and safety of topical delgocitinib in patients with chronic hand eczema: data from a randomized, double-blind, vehicle-controlled phase IIa study.

    Br J Dermatol. 2020;182(5): 1103-1110

    Worm M, Bauer A, Elsner P, Mahler V, Molin S, Nielsen TSS

    BACKGROUND: Management of chronic hand eczema (CHE) remains a challenge; effective topical treatment is limited to corticosteroids.

    OBJECTIVES: To assess the efficacy and safety of a novel, pan-Janus kinase inhibitor (delgocitinib) in patients with CHE.

    METHODS: In this randomized, double-blind, phase IIa study, patients with CHE received delgocitinib ointment 30 mg g-1 or vehicle ointment for 8 weeks. The primary end point was the proportion of patients achieving treatment success ['clear'/'almost clear' skin with ≥ 2-point improvement in the Physician's Global Assessment of disease severity (PGA)] at week 8. Secondary end points included Hand Eczema Severity Index (HECSI) score changes and the proportion of patients achieving treatment success on the Patient's Global Assessment of disease severity (PaGA).

    RESULTS: Ninety-one patients were randomized. More patients receiving delgocitinib (46%) than vehicle (15%) [odds ratio 4·89, 95% confidence interval (CI) 1·49-16·09; P = 0·009] achieved treatment success (PGA). Adjusted mean HECSI score at week 8 was lower with delgocitinib (13·0) than with vehicle (25·8) (adjusted mean difference -12·88, 95% CI -21·47 to -4·30; P = 0·003). More patients receiving delgocitinib than vehicle achieved treatment success by PaGA, but this did not reach statistical significance. The incidence of adverse events was similar with delgocitinib and vehicle; none led to discontinuation of delgocitinib.

    CONCLUSIONS: Delgocitinib ointment was efficacious and well tolerated. As a plateau of efficacy was not observed, a longer treatment period may lead to increased efficacy. Further clinical studies are warranted to confirm these findings in patients with CHE. What's already known about this topic? Chronic hand eczema (CHE) has a significant burden. Few randomized controlled studies have evaluated current treatments for CHE; only limited data are available to inform and guide clinical practice decisions. There is currently an unmet need for efficacious and well-tolerated topical treatment options for patients with CHE. What does this study add? Delgocitinib is a novel, pan-Janus kinase (JAK) inhibitor specific for JAK1, JAK2, JAK3 and tyrosine kinase 2. Topical use of delgocitinib ointment resulted in clearance of CHE after 8 weeks of treatment in a significantly greater number of patients than vehicle; delgocitinib was also well tolerated. Results from this proof-of-concept clinical study suggest that topical delgocitinib may provide therapeutic benefit to patients with CHE with inadequate responses to topical corticosteroids.

    Pubmed
  • German YouTube™ videos as a source of information on cutaneous melanoma: a critical appraisal.

    J Eur Acad Dermatol Venereol. 2020;34(10): e642-e644

    Steeb T, Reinhardt L, Görgmayr C, Weingarten H, Doppler A, Brütting J, Meier F, Berking C, German Skin Cancer Council

    Pubmed
  • Blood Eosinophilia is an on-Treatment Biomarker in Patients with Solid Tumors Undergoing Dendritic Cell Vaccination with Autologous Tumor-RNA.

    Pharmaceutics. 2020;12(3):

    Moreira A, Erdmann M, Uslu U, Vass V, Schuler G, Schuler-Thurner B

    BACKGROUND: The approvals of immune checkpoint inhibitors for several cancer types and the rapidly growing recognition that T cell-based immunotherapy significantly improves outcomes for cancer patients led to a re-emergence of cancer vaccines, including dendritic cell (DC)-based immunotherapy. Blood and tissue biomarkers to identify responders and long-term survivors and to optimize cost and cost-effectiveness of treatment are greatly needed. We wanted to investigate whether blood eosinophilia is a predictive biomarker for patients with solid tumors receiving vaccinations with DCs loaded with autologous tumor-RNA.

    METHODS: In total, 67 patients with metastatic solid tumors, who we treated with autologous monocyte-derived DCs transfected with total tumor mRNA, were serially analyzed for eosinophil counts and survival over the course of up to 14 years. Eosinophilic counts were performed on peripheral blood smears.

    RESULTS: Up to 87% of the patients treated with DC-based immunotherapy experienced at least once an eosinophilia of ≥ 5% after initiation of therapy; 61 % reached levels of ≥ 10% eosinophils, and 13% of patients showed eosinophil counts of 20% or above. While prevaccination eosinophil levels were not associated with survival, patients with blood eosinophilia at any point after initiation of DC-based immunotherapy showed a trend towards longer survival. There was a statistically significant difference for the patients with eosinophil counts of 20% or more (p = 0.03). In those patients, survival was prolonged to a median of 58 months (range 2-111 months), compared to a median of 20 months (range 0-119 months) in patients with lower eosinophil counts. In 12% of the patients, an immediate increase in eosinophil count of at least 10 percentage points could be detected after the first vaccine, which also appeared to correlate with survival (65 vs. 24 months; p = 0.06).

    CONCLUSION: Blood eosinophilia appears to be an early, on-therapy biomarker in patients with solid tumors undergoing vaccination with RNA-transfected DC, specifically autologous tumor mRNA-transfected DC vaccines, and it correlates with long-term patient outcome. Eosinophilia should be systematically investigated in future trials.

    Pubmed
  • Side effect management during immune checkpoint blockade using CTLA-4 and PD-1 antibodies for metastatic melanoma - an update.

    J Dtsch Dermatol Ges. 2020;18(6): 582-609

    Kähler KC, Hassel JC, Heinzerling L, Loquai C, Thoms KM, Ugurel S, Zimmer L, Gutzmer R, committee on “Cutaneous Adverse Events“ of the German Working Group for Dermatological Oncology (Arbeitsgemeinschaft Dermatologische Onkologie, ADO)

    CTLA-4 and PD-1 play a key role in tumor-induced downregulation of lymphocytic immune responses. Immune checkpoint inhibitors have been shown to alter the immune response to various cancer types. Anti-CTLA-4 and anti-PD-1 antibodies affect the interaction between tumor, antigen-presenting cells and T lymphocytes. Clinical studies of the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibodies nivolumab and pembrolizumab have provided evidence of their positive effects on overall survival in melanoma patients. Combined treatment using ipilimumab and nivolumab has been shown to achieve five-year survival rates of 52 %. Such enhancement of the immune response is inevitably associated with adverse events. Knowledge of the spectrum of side effects is essential, both in terms of prevention and management. Adverse events include colitis, dermatitis, hypophysitis, thyroiditis, hepatitis and other, less common autoimmune phenomena. In recent years, considerable progress has been made in the detection and treatment of the aforementioned immune-related adverse events. However, early diagnosis of rare neurological or cardiac side effects, which may be associated with increased mortality, frequently pose a challenge. The present update highlights our current understanding as well as new insights into the spectrum of side effects associated with checkpoint inhibitors and their management.

    Pubmed
  • Definition, aims, and implementation of GA2 LEN/HAEi Angioedema Centers of Reference and Excellence.

    Allergy. 2020;75(8):

    Maurer M, Aberer W, Agondi R, Al-Ahmad M, Al-Nesf MA, Ansotegui I, Arnaout R, Arruda LK, Asero R, Aygören-Pürsün E, Banerji A, Bauer A, Ben-Shoshan M, Berardi A, Bernstein JA, Betschel S, Bindslev-Jensen C, Bizjak M, Boccon-Gibod I, Bork K, Bouillet L, Boysen HB, Brodszki N, Broesby-Olsen S, Busse P, Buttgereit T, Bygum A, Caballero T, Campos RA, Cancian M, Cherrez-Ojeda I, Cohn DM, Costa C, Craig T, Criado PR, Criado RF, Csuka D, Dissemond J, Du-Thanh A, Ensina LF, Ertaş R, Fabiani JE, Fantini C, Farkas H, Ferrucci SM, Figueras-Nart I, Fili NL, Fomina D, Fukunaga A, Gelincik A, Giménez-Arnau A, Godse K, Gompels M, Gonçalo M, Gotua M, Gower R, Grumach AS, Guidos-Fogelbach G, Hide M, Ilina N, Inomata N, Jakob T, Josviack DO, Kang HR, Kaplan A, Kasperska-Zając A, Katelaris C, Kessel A, Kleinheinz A, Kocatürk E, Košnik M, Krasowska D, Kulthanan K, Kumaran MS, Larco Sousa JI, Longhurst HJ, Lumry W, MacGinnitie A, Magerl M, Makris MP, Malbrán A, Marsland A, Martinez-Saguer I, Medina IV, Meshkova R, Metz M, Nasr I, Nicolay J, Nishigori C, Ohsawa I, Özyurt K, Papadopoulos NG, Parisi CAS, Peter JG, Pfützner W, Popov T, Prior N, Ramon GD, Reich A, Reshef A, Riedl MA, Ritchie B, Röckmann-Helmbach H, Rudenko M, Salman A, Sanchez-Borges M, Schmid-Grendelmeier P, Serpa FS, Serra-Baldrich E, Sheikh FR, Smith W, Soria A, Staubach P, Steiner UC, Stobiecki M, Sussman G, Tagka A, Thomsen SF, Treudler R, Valle S, van Doorn M, Varga L, Vázquez DO, Wagner N, Wang L, Weber-Chrysochoou C, Ye YM, Zalewska-Janowska A, Zanichelli A, Zhao Z, Zhi Y, Zuberbier T, Zwiener RD, Castaldo A

    Pubmed
  • Combined immunotherapy with nivolumab and ipilimumab with and without local therapy in patients with melanoma brain metastasis: a DeCOG* study in 380 patients.

    J Immunother Cancer. 2020;8(1):

    Amaral T, Kiecker F, Schaefer S, Stege H, Kaehler K, Terheyden P, Gesierich A, Gutzmer R, Haferkamp S, Uttikal J, Berking C, Rafei-Shamsabadi D, Reinhardt L, Meier F, Karoglan A, Posch C, Gambichler T, Pfoehler C, Thoms K, Tietze J, Debus D, Herbst R, Emmert S, Loquai C, Hassel JC, Meiss F, Tueting T, Heinrich V, Eigentler T, Garbe C, Zimmer L, *German Dermatological Cooperative Oncology Group

    BACKGROUND: Nivolumab combined with ipilimumab have shown activity in melanoma brain metastasis (MBM). However, in most of the clinical trials investigating immunotherapy in this subgroup, patients with symptomatic MBM and/or prior local brain radiotherapy were excluded. We studied the efficacy of nivolumab plus ipilimumab alone or in combination with local therapies regardless of treatment line in patients with asymptomatic and symptomatic MBM.

    METHODS: Patients with MBM treated with nivolumab plus ipilimumab in 23 German Skin Cancer Centers between April 2015 and October 2018 were investigated. Overall survival (OS) was evaluated by Kaplan-Meier estimator and univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic factors associated with OS.

    RESULTS: Three hundred and eighty patients were included in this study and 31% had symptomatic MBM (60/193 with data available) at the time of start nivolumab plus ipilimumab. The median follow-up was 18 months and the 2 years and 3 years OS rates were 41% and 30%, respectively. We identified the following independently significant prognostic factors for OS: elevated serum lactate dehydrogenase and protein S100B levels, number of MBM and Eastern Cooperative Oncology Group performance status. In these patients treated with checkpoint inhibition first-line or later, in the subgroup of patients with BRAFV600-mutated melanoma we found no differences in terms of OS when receiving first-line either BRAF and MEK inhibitors or nivolumab plus ipilimumab (p=0.085). In BRAF wild-type patients treated with nivolumab plus ipilimumab in first-line or later there was also no difference in OS (p=0.996). Local therapy with stereotactic radiosurgery or surgery led to an improvement in OS compared with not receiving local therapy (p=0.009), regardless of the timepoint of the local therapy. Receiving combined immunotherapy for MBM in first-line or at a later time point made no difference in terms of OS in this study population (p=0.119).

    CONCLUSION: Immunotherapy with nivolumab plus ipilimumab, particularly in combination with stereotactic radiosurgery or surgery improves OS in asymptomatic and symptomatic MBM.

    Pubmed
  • Itching and Neurodermatitis: Results from the German Neurodermatitis

    Register TREATgermany

    J Dtsch Dermatol Ges. 2020;18(): 40-41

    Haufe E, Heinrich L, Weisshaar E, Abraham S, Heratizadeh A, Harder I, Kleinheinz A, Wollenberg A, Wiemers F, Augustin M, Zink A, von Kiedrowski R, Fell I, Pawlak M, Hilgers M, Worm M, Schaekel K, Sticherling M, Effendy I, Staubach-Renz P, Handrick C, Bell M, Asmussen A, Schwarz B, Werfel T, Weidinger S, Schmitt J

    Pubmed
  • EMT transcription factor ZEB1 alters the epigenetic landscape of colorectal cancer cells.

    Cell Death Dis. 2020;11(2):

    Lindner P, Paul S, Eckstein M, Hampel C, Muenzner JK, Erlenbach-Wuensch K, Ahmed HP, Mahadevan V, Brabletz T, Hartmann A, Vera J, Schneider-Stock R

    Epigenetic deregulation remarkably triggers mechanisms associated with tumor aggressiveness like epithelial-mesenchymal transition (EMT). Since EMT is a highly complex, but also reversible event, epigenetic processes such as DNA methylation or chromatin alterations must be involved in its regulation. It was recently described that loss of the cell cycle regulator p21 was associated with a gain in EMT characteristics and an upregulation of the master EMT transcription factor ZEB1. In this study, in silico analysis was performed in combination with different in vitro and in vivo techniques to identify and verify novel epigenetic targets of ZEB1, and to proof the direct transcriptional regulation of SETD1B by ZEB1. The chorioallantoic-membrane assay served as an in vivo model to analyze the ZEB1/SETD1B interaction. Bioinformatical analysis of CRC patient data was used to examine the ZEB1/SETD1B network under clinical conditions and the ZEB1/SETD1B network was modeled under physiological and pathological conditions. Thus, we identified a self-reinforcing loop for ZEB1 expression and found that the SETD1B associated active chromatin mark H3K4me3 was enriched at the ZEB1 promoter in EMT cells. Moreover, clinical evaluation of CRC patient data showed that the simultaneous high expression of ZEB1 and SETD1B was correlated with the worst prognosis. Here we report that the expression of chromatin modifiers is remarkably dysregulated in EMT cells. SETD1B was identified as a new ZEB1 target in vitro and in vivo. Our study demonstrates a novel example of an activator role of ZEB1 for the epigenetic landscape in colorectal tumor cells.

    Pubmed
  • Serio - Side Effect Registry in Immuno-Oncology

    Oncology Research and Treatment. 2020;43(): 231-231

    Koutzamanidis R, Mentzer D, Knauss S, Broeckelmann PJ, Hassel JC, Ugurel-Becker S, Pavel M, Nickel F, Landendinger M, Fuchs F, Meidenbauer N, Jefremow A, Manger B, Gutzmer R, Loguai C, Kaehler K, Zimmer L, Berking C, Keller-Stanislawski B, Heinzerling L, Erdrnann M, Kirchberger MC, Toussaint F

    Pubmed
  • [Actinic keratoses : Current guideline and practical recommendations].

    Hautarzt. 2020;71(6): 463-475

    Nashan D, Hüning S, Heppt MV, Brehmer A, Berking C

    The S3 guideline "Actinic keratosis and squamous cell carcinoma of the skin" was published on 30 June 2019. Subsequently, publications, reviews and meta-analyses appeared with new questions regarding the comparability of study data and heterogeneity of the evaluations, which are caused, among other things, by divergent measurement parameters as well as insufficient consideration of pretreatments and combined treatments. This concise overview was written in the context of criticism and in view of necessary developments and research. Topics include epidemiology, pathogenesis, prevention, clinical presentation, therapy and BK5103. Therapy is divided into local destructive procedures and topical applications. Recommendations with quotation marks are based on the actual guideline. Corresponding evidence levels are given. For the implementation in daily routine basic data, side effects and features of therapeutic options are mentioned. The current developments and questions concerning actinic keratoses become clear.

    Pubmed
  • S3-Leitlinie „Aktinische Keratose und Plattenepithelkarzinom der Haut“ - Kurzfassung, Teil 1: Diagnostik, Interventionen bei aktinischen Keratosen, Versorgungsstrukturen und Qualitätsindikatoren.

    J Dtsch Dermatol Ges. 2020;18(3): 275-294

    Heppt MV, Leiter U, Steeb T, Amaral T, Bauer A, Becker JC, Breitbart E, Breuninger H, Diepgen T, Dirschka T, Eigentler T, Flaig M, Follmann M, Fritz K, Greinert R, Gutzmer R, Hillen U, Ihrler S, John SM, Kölbl O, Kraywinkel K, Löser C, Nashan D, Noor S, Nothacker M, Pfannenberg C, Salavastru C, Schmitz L, Stockfleth E, Szeimies RM, Ulrich C, Welzel J, Wermker K, Berking C, Garbe C

    Zusammenfassung Aktinische Keratosen (AK) sind haufige Hautveranderungen bei hellhautigen Menschen mit dem Potenzial, in ein kutanes Plattenepithelkarzinom (PEK) uberzugehen. Beide Erkrankungen konnen mit erheblicher Morbiditat verbunden sein und stellen eine gro ss e Krankheitslast insbesondere in der alteren Bevolkerung dar. Um eine evidenzbasierte, klinische Entscheidungsfindung zu unterstutzen, wurde die Leitlinie "Aktinische Keratose und Plattenepithelkarzinom der Haut" auf der Methodikebene S3 nach dem Regelwerk der AWMF entwickelt. Die Leitlinie richtet sich dabei an Dermatologen, Allgemeinmediziner, HNO-Arzte, Chirurgen, Onkologen, Radiologen und Strahlentherapeuten in Klinik und Praxis sowie an andere medizinische Fachgebiete, die sich mit der Diagnose und Behandlung von Patienten mit AK und PEK befassen. Die Leitlinie richtet sich auch an betroffene Patienten, deren Angehorige, politische Entscheidungstrager und Versicherungsgesellschaften. In diesem Teil behandeln wir die Themen Diagnostik, Interventionen bei AK, Versorgungsstrukturen und Qualitatsindikatoren.

    Pubmed
  • The ontogenetic path of human dendritic cells.

    Mol Immunol. 2020;120(): 122-129

    Amon L, Lehmann CHK, Heger L, Heidkamp GF, Dudziak D

    Dendritic cells (DCs) orchestrate adaptive immune responses. In healthy individuals, DCs are drivers and fine-tuners of T cell responses directed against invading pathogens or cancer cells. In parallel, DCs control autoreactive T cells, thereby maintaining T cell tolerance. Under various disease conditions, a disruption of this delicate balance can lead to chronic infections, tumor evasion, or autoimmunity. While great efforts have been made to unravel the origin and development of this powerful cell type in mice, only little is known about the ontogeny of human DCs. Here, we summarize the current understanding of the developmental path of DCs from hematopoietic stem cells to fully functional DCs in their local tissue environment and provide a template for the identification of DCs across various tissues.

    Pubmed
  • Sinus Pericranii.

    Dtsch Arztebl Int. 2020;116(8): 136-136

    Heppt F, Meder C, Wagner N

    Pubmed
  • [Contact allergy due to insulin pumps and glucose sensor systems].

    Hautarzt. 2020;71(3): 205-210

    Wagner N, Kamann S, Oppel E

    The design and development of insulin pumps and various glucose sensor systems has an enormous impact on life quality of diabetic patients. Surveillance and therapy of diabetes has improved due to the new diabetic devices, which are affixed to the patients' skin for several days. Since their introduction, irritant and allergic contact dermatitis have been frequently reported. Patients often acquire contact sensitization to isobornyl acrylate, N,N-dimethylacrylamide or formerly to 2‑ethyl-cyanoacrylate. These contact allergens were found in the patch, in the glue to affix the box on the patch or in the casing of the system itself. Development of contact allergy to substances of these systems may result in the need to abandon modern diabetic devices.

    Pubmed
  • Phosphatase PTPN22 Regulates Dendritic Cell Homeostasis and cDC2 Dependent T Cell Responses.

    Front Immunol. 2020;11():

    Purvis HA, Clarke F, Montgomery AB, Colas C, Bibby JA, Cornish GH, Dai X, Dudziak D, Rawlings DJ, Zamoyska R, Guermonprez P, Cope AP

    Dendritic cells (DCs) are specialized antigen presenting cells that instruct T cell responses through sensing environmental and inflammatory danger signals. Maintaining the homeostasis of the multiple functionally distinct conventional dendritic cells (cDC) subsets that exist in vivo is crucial for regulating immune responses, with changes in numbers sufficient to break immune tolerance. Using Ptpn22-/- mice we demonstrate that the phosphatase PTPN22 is a highly selective, negative regulator of cDC2 homeostasis, preventing excessive population expansion from as early as 3 weeks of age. Mechanistically, PTPN22 mediates cDC2 homeostasis in a cell intrinsic manner by restricting cDC2 proliferation. A single nucleotide polymorphism, PTPN22R620W, is one of the strongest genetic risk factors for multiple autoantibody associated human autoimmune diseases. We demonstrate that cDC2 are also expanded in mice carrying the orthologous PTPN22619W mutation. As a consequence, cDC2 dependent CD4+ T cell proliferation and T follicular helper cell responses are increased. Collectively, our data demonstrate that PTPN22 controls cDC2 homeostasis, which in turn ensures appropriate cDC2-dependent T cell responses under antigenic challenge. Our findings provide a link between perturbations in DC development and susceptibility to a broad spectrum of PTPN22R620W associated human autoimmune diseases.

    Pubmed
  • [Diagnosis of contact allergy in practice using current guidelines].

    Hautarzt. 2020;71(3): 182-189

    Dickel H, Mahler V

    BACKGROUND: In the case of a contact allergy, there is only allergen avoidance instead of causal therapy. If the allergen is not identified, dermatitis persists, which is a major burden for patients. Patch testing is the diagnostic standard for detecting contact sensitization. Based on a systematic literature search, the German patch test guideline was updated and methodologically upgraded.

    OBJECTIVES: The most important practical aspects of patch testing with contact allergens and drugs are presented.

    MATERIALS AND METHODS: Current consensus guidelines for performing patch tests as well as the results of a supplementary selective literature search are summarized.

    RESULTS: According to the patch test guideline (AWMF registry no. 013-018, 2019), the baseline series, special series and, if necessary, test preparations prepared from the patient's own contact substances should be tested routinely. A new evidence-based recommendation is a late reading after 7-10 days, as otherwise numerous patch test reactions will be missed. Antihistamines may weaken the cellular reactions of the patch test and should be discontinued with a latency of 5 half-lives. Finally, if a false-negative patch test result is suspected, it is recommended to perform a strip patch test according to the validated protocol.

    CONCLUSIONS: All patients with a suspected contact allergy should receive a guideline-based patch test at an early stage. Targeted patch testing identifies clinically relevant allergens and provides suggestions for further systematic investigations.

    Pubmed
  • ARIA Guideline 2019: Treatment of allergic Rhinitis in the German

    Healthcare System

    Allergologie. 2020;43(2): 43-72

    Klimek L, Bachert C, Pfaar O, Becker S, Bieber T, Brehler R, Buhl R, Casper I, Chaker A, Czech W, Fischer J, Fuchs T, Gerstlauer M, Hoermann K, Jakob T, Jung K, Kopp MV, Mahler V, Merk H, Mulleneisen N, Nemat K, Rabe U, Ring J, Saloga J, Schlenter W, Schmidt-Weber C, Seyfarth H, Sperl A, Spindler T, Staubach P, Strieth S, Treudler R, Vogelberg C, Wallrafen A, Wehrmann W, Wrede H, Zuberbier T, Bedbrook A, Canonica GW, Cardona V, Casale TB, Czariewski W, Fokkens WJ, Hamelmann E, Hellings PW, Jute M, Larenas-Linnemann D, Mullol J, Papadopoulos NG, Toppila-Salmi S, Werfel T, Bousquet J

    Pubmed
  • [Occupationally acquired MRSA colonization and occupational dermatological assessments (BK-No. 3101 in the German list of Occupational Diseases) : Analysis of the DGUV documentation and expert opinion on a case with work-related MRSA-triggered atopic dermatitis].

    Hautarzt. 2020;71(8): 613-623

    Erfurt-Berge C, Schmidt A, Angelovska I, Mahler V

    BACKGROUND: Person-to-person transmitted infectious diseases can cause occupational diseases (OD). These are subsumed as BK-No. 3101 in the German list of OD which applies for individuals with a considerably higher risk for infection as a consequence of their professional activity compared to the general population.

    OBJECTIVES: The special medical and insurance law aspects of a work-related MRSA colonization are presented using the example of an expert opinion case and an evaluation of the BK reports of suspected occupational disease (BK No. 3101) of the German Social Accident Insurance (DGUV).

    PATIENTS AND METHODS: The BK documentation of the DGUV from 2007-2012 and the patient cohort from the Department of Dermatology, University Hospital Erlangen, presenting for expert assessment from 2007-2012 were retrospectively analysed for human-to-human transmitted infectious diseases of the skin (BK-No. 3101).

    RESULTS: Person-to-person transmission of infectious diseases of the skin is rare in the field of occupational dermatology. In the DGUV cohort, suspected BK-No. 3101cases amounted to 2.6% of all notified cases; recognized BK-No. 3101 cases accounted for 4.2% of all recognized cases, amongst which 9 were caused by MRSA. In contrast to a symptomatic infection, an asymptomatic MRSA colonization is not being recognized as BK-No. 3101. Bacterial superantigens can trigger atopic dermatitis (AD). In particular cases, occupationally acquired MRSA can elicit AD and may justify classification as an OD (BK-No. 3101).

    CONCLUSIONS: Early detection of MRSA colonization and eradication are necessary for rehabilitation. Management of skin diseases due to infectious diseases within the framework of OD is presented.

    Pubmed
  • The role of cooperativity in a p53-miR34 dynamical mathematical model.

    J Theor Biol. 2020;495():

    Nikolov S, Wolkenhauer O, Vera J, Nenov M

    The objective of this study is to evaluate the role of cooperativity, captured by the Hill coefficient, in a minimal mathematical model describing the interactions between p53 and miR-34a. The model equations are analyzed for negative, none and normal cooperativity using a specific version of bifurcation theory and they are solved numerically. Special attention is paid to the sign of so-called first Lyapunov value. Interpretations of the results are given, both according to dynamic theory and in biological terms. In terms of cell signaling, we propose the hypothesis that when the outgoing signal of a system spends a physiologically significant amount of time outside of its equilibrium state, then the value of that signal can be sampled at any point along the trajectory towards that equilibrium and indeed, at multiple points. Coupled with non-linear behavior, such as that caused by cooperativity, this feature can account for a complex and varied response, which p53 is known for. From dynamical point of view, we found that when cooperativity is negative, the system has only one stable equilibrium point. In the absence of cooperativity, there is a single unstable equilibrium point with a critical boundary of stability. In the case with normal cooperativity, the system can have one, two, or three steady states with both, bi-stability and bi-instability occurring.

    Pubmed
  • Insights From the Apremilast After Switching From Fumaric Acid Ester

    Treatment (APART) Study: An Interim Real-World Safety Analysis

    J Dtsch Dermatol Ges. 2020;18(): 21-22

    Mrowietz U, Ertner K, Sticherling M, Grosse V, Popp G, Schwichtenberg U, Karl L, Schenck F, Ramaker-Brunke J, Roemmler-Zehrer J, Helget U, Gomez NN

    Pubmed
  • Mesenchymal-Like Migration Strategies of Immune Cells in a 3D

    Environment

    Biophys J. 2020;118(3): 600A-600A

    Czerwinski T, Mark C, Roessner S, Bosch-Voskens C, Bhattacharjee T, Angelini TE, Fabry B

    Pubmed
  • Multiplex Tissue Analysis of the Tumor Microenvironment and Crucial

    Factors in Melanoma Pathogenesis

    Oncology Research and Treatment. 2020;43(): 174-175

    Ostalecki C, Lee JH, Schierer S, Collenburg L, Schuler G, Baur A

    Pubmed
  • Patients with Chronic Urticaria need better Treatment: Results of the

    DERMLINE Online Survey

    J Dtsch Dermatol Ges. 2020;18(): 41-42

    Hell K, Zink A, Schielein MC, Hacker E, Romer K, Baeumer D, Wagner N

    Pubmed
  • Psoriasis Patients are still severely underserved: Results of the

    DERMLINE Online Survey

    J Dtsch Dermatol Ges. 2020;18(): 42-42

    Hell K, Schielein MC, Romer K, Hacker E, Baeumer D, Wagner N, Zink A

    Pubmed
  • Treatment Motivations and Expectations in Patients with Actinic Keratosis: A German-Wide Multicenter, Cross-Sectional Trial.

    J. Clin. Med.. 2020;9(5):

    Steeb T, Wessely A, von Bubnoff D, Dirschka T, Drexler K, Falkenberg C, Hassel JC, Hayani K, Hüning S, Kähler KC, Karrer S, Krammer C, Leiter U, Lill D, Marsela E, Meiwes A, Nashan D, Nasifoglu S, Schmitz L, Sirokay J, Thiem A, Utikal J, Zink A, Berking C, Heppt MV

    Patient-centered motives and expectations of the treatment of actinic keratoses (AK) have received little attention until now. Hence, we aimed to profile and cluster treatment motivations and expectations among patients with AK in a nationwide multicenter, cross-sectional study including patients from 14 German skin cancer centers. Patients were asked to complete a self-administered questionnaire. Treatment motives and expectations towards AK management were measured on a visual analogue scale from 1-10. Specific patient profiles were investigated with subgroup and correlation analysis. Overall, 403 patients were included. The highest motivation values were obtained for the items "avoid transition to invasive squamous cell carcinoma" (mean ± standard deviation; 8.98 ± 1.46), "AK are considered precancerous lesions" (8.72 ± 1.34) and "treating physician recommends treatment" (8.10 ± 2.37; p < 0.0001). The highest expectation values were observed for the items "effective lesion clearance" (8.36 ± 1.99), "safety" (8.20 ± 2.03) and "treatment-related costs are covered by health insurance" (8.00 ± 2.41; p < 0.0001). Patients aged ≥77 years and those with ≥7 lesions were identified at high risk of not undergoing any treatment due to intrinsic and extrinsic motivation deficits. Heat mapping of correlation analysis revealed four clusters with distinct motivation and expectation profiles. This study provides a patient-based heuristic tool for a personalized treatment decision in patients with AK.

    Pubmed
  • Impact of a preceding radiotherapy on the outcome of immune checkpoint inhibition in metastatic melanoma: a multicenter retrospective cohort study of the DeCOG.

    J Immunother Cancer. 2020;8(1):

    Knispel S, Stang A, Zimmer L, Lax H, Gutzmer R, Heinzerling L, Weishaupt C, Pföhler C, Gesierich A, Herbst R, Kaehler KC, Weide B, Berking C, Loquai C, Utikal J, Terheyden P, Kaatz M, Schlaak M, Kreuter A, Ulrich J, Mohr P, Dippel E, Livingstone E, Becker JC, Weichenthal M, Chorti E, Gronewold J, Schadendorf D, Ugurel S

    BACKGROUND: Immune checkpoint inhibition (ICI) is an essential treatment option in melanoma. Its outcome may be improved by a preceding radiation of metastases. This study aimed to investigate the impact of a preceding radiotherapy on the clinical outcome of ICI treatment.

    METHODS: This multicenter retrospective cohort study included patients who received anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or anti-programmed cell death protein 1 (PD-1) ICI with or without preceding radiotherapy for unresectable metastatic melanoma. ICI therapy outcome was measured as best overall response (BOR), progression-free (PFS) and overall survival (OS). Response and survival analyses were adjusted for confounders identified by directed acyclic graphs. Adjusted survival curves were calculated using inverse probability treatment weighting.

    RESULTS: 835 patients who received ICI (anti-CTLA-4, n=596; anti-PD-1, n=239) at 16 centers were analyzed, whereof 235 received a preceding radiotherapy of metastatic lesions in stage IV disease. The most frequent organ sites irradiated prior to ICI therapy were brain (51.1%), lymph nodes (17.9%) and bone (17.9%). After multivariable adjustment for confounders, no relevant differences in ICI therapy outcome were observed between cohorts with and without preceding radiotherapy. BOR was 8.7% vs 13.0% for anti-CTLA-4 (adjusted relative risk (RR)=1.47; 95% CI=0.81 to 2.65; p=0.20), and 16.5% vs 25.3% for anti-PD-1 (RR=0.93; 95% CI=0.49 to 1.77; p=0.82). Survival probabilities were similar for cohorts with and without preceding radiotherapy, for anti-CTLA-4 (PFS, adjusted HR=1.02, 95% CI=0.86 to 1.25, p=0.74; OS, HR=1.08, 95% CI=0.81 to 1.44, p=0.61) and for anti-PD-1 (PFS, HR=0.84, 95% CI=0.57 to 1.26, p=0.41; OS, HR=0.73, 95% CI=0.43 to 1.25, p=0.26). Patients who received radiation last before ICI (n=137) revealed no better survival than those who had one or more treatment lines between radiation and start of ICI (n=86). In 223 patients with brain metastases, we found no relevant survival differences on ICI with and without preceding radiotherapy.

    CONCLUSIONS: This study detected no evidence for a relevant favorable impact of a preceding radiotherapy on anti-CTLA-4 or anti-PD-1 ICI treatment outcome in metastatic melanoma.

    Pubmed
  • Cash is king: the balance of costs and effectiveness of treatments for actinic keratosis.

    Br J Dermatol. 2020;183(4):

    Steeb T, Heppt MV, Berking C

    Pubmed
  • The value of convolutional neural networks in the diagnosis of melanoma simulators.

    J Eur Acad Dermatol Venereol. 2020;34(6): 1134-1135

    Heppt MV, Berking C

    Pubmed
  • [Actinic keratosis].

    Hautarzt. 2020;71(8): 588-596

    Heppt MV, Steeb T, Szeimies RM, Berking C

    Actinic keratoses (AK) are common precancerous cutaneous lesions in fair-skinned individuals as a result of cumulative exposure to ultraviolet radiation. Due to their high prevalence, AK account for a large disease burden, in particular in older persons. As AK may potentially progress into invasive cutaneous squamous cell carcinoma, guidelines recommend early and consequent treatment. Numerous lesion- and field-directed interventions with different efficacy and safety profiles are currently licensed in Germany. The appropriate intervention should be chosen together with the patient based on his or her motivation and expectations towards the treatment.

    Pubmed
  • Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial.

    Lancet. 2020;395(10236): 1558-1568

    Zimmer L, Livingstone E, Hassel JC, Fluck M, Eigentler T, Loquai C, Haferkamp S, Gutzmer R, Meier F, Mohr P, Hauschild A, Schilling B, Menzer C, Kieker F, Dippel E, Rösch A, Simon JC, Conrad B, Körner S, Windemuth-Kieselbach C, Schwarz L, Garbe C, Becker JC, Schadendorf D, Dermatologic Cooperative Oncology Group , Berking C, Herbst RA, Martens UM, Sell S, Stadler R, Terheyden P, Utikal J

    BACKGROUND: Nivolumab and ipilimumab, alone or in combination, are widely used immunotherapeutic treatment options for patients with advanced-ie, unresectable or metastatic-melanoma. This criterion, however, excludes patients with stage IV melanoma with no evidence of disease. We therefore aimed to evaluate the safety and efficacy of adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus a placebo in this patient population.

    METHODS: We did a randomised, double-blind, placebo-controlled, phase 2 trial in 20 German academic medical centres. Eligible patients were aged 18-80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Key exclusion criteria included uveal or mucosal melanoma, previous therapy with checkpoint inhibitors, and any previous immunosuppressive therapy within the 30 days before study drug administration. Eligible patients were randomly assigned (1:1:1), using a central, interactive, online system, to the nivolumab plus ipilimumab group (1 mg/kg of intravenous nivolumab every 3 weeks plus 3 mg/kg of intravenous ipilimumab every 3 weeks for four doses, followed by 3 mg/kg of nivolumab every 2 weeks), nivolumab monotherapy group (3 mg/kg of intravenous nivolumab every 2 weeks plus ipilimumab-matching placebo during weeks 1-12), or double-matching placebo group. The primary endpoint was the recurrence-free survival in the intention-to-treat population. The results presented in this report reflect the prespecified interim analysis of recurrence-free survival after 90 events had been reported. This study is registered with ClinicalTrials.gov, NCT02523313, and is ongoing.

    FINDINGS: Between Sept 2, 2015, and Nov 20, 2018, 167 patients were randomly assigned to receive nivolumab plus ipilimumab (n=56), nivolumab (n=59), or placebo (n=52). As of July 2, 2019, at a median follow-up of 28·4 months (IQR 17·7-36·8), median recurrence-free survival was not reached in the nivolumab plus ipilimumab group, whereas median recurrence-free survival was 12·4 months (95% CI 5·3-33·3) in the nivolumab group and 6·4 months (3·3-9·6) in the placebo group. The hazard ratio for recurrence for the nivolumab plus ipilimumab group versus placebo group was 0·23 (97·5% CI 0·12-0·45; p<0·0001), and for the nivolumab group versus placebo group was 0·56 (0·33-0·94; p=0·011). In the nivolumab plus ipilimumab group, recurrence-free survival at 1 year was 75% (95% CI 61·0-84·9) and at 2 years was 70% (55·1-81·0); in the nivolumab group, 1-year recurrence-free survival was 52% (38·1-63·9) and at 2 years was 42% (28·6-54·5); and in the placebo group, this rate was 32% (19·8-45·3) at 1 year and 14% (5·9-25·7) at 2 years. Treatment-related grade 3-4 adverse events were reported in 71% (95% CI 57-82) of patients in the nivolumab plus ipilimumab group and in 27% (16-40) of those in the nivolumab group. Treatment-related adverse events of any grade led to treatment discontinuation in 34 (62%) of 55 patients in the nivolumab plus ipilimumab group and seven (13%) of 56 in the nivolumab group. Three deaths from adverse events were reported but were considered unrelated to the study treatment.

    INTERPRETATION: Adjuvant therapy with nivolumab alone or in combination with ipilimumab increased recurrence-free survival significantly compared with placebo in patients with stage IV melanoma with no evidence of disease. The rates of grade 3-4 treatment-related adverse events in both active treatment groups were higher than the rates reported in previous pivotal trials done in advanced melanoma with measurable disease.

    FUNDING: Bristol-Myers Squibb.

    Pubmed
  • Extracellular vesicles from plasma have higher tumour RNA fraction than platelets.

    J Extracell Vesicles. 2020;9(1):

    Brinkman K, Meyer L, Bickel A, Enderle D, Berking C, Skog J, Noerholm M

    In addition to Circulating Tumour Cells (CTCs), cell-free DNA (cfDNA) and Extracellular Vesicles (EVs), the notion of "Tumour-Educated Platelets" (TEP) has recently emerged as a potential source of tumour-derived biomarkers accessible through blood liquid biopsies. Here we sought to confirm the suitability of the platelet blood fraction for biomarker detection in comparison to their corresponding EV fraction. As publications have claimed that tumour RNA and other tumour-derived material are transferred from tumour cells to the platelets and that tumour-derived transcripts can be detected in platelets, we chose to focus on RNA carrying a mutation as being of bona fide tumour origin. After informed consent, we collected prospective blood samples from a cohort of 12 melanoma patients with tissue-confirmed BRAF V600E mutation. Each blood specimen was processed immediately post collection applying two published standard protocols in parallel selecting for EVs and platelets, respectively. The RNA of each fraction was analysed by a highly sensitive ARMS RT-qPCR enabling the quantification of the mutant allele fraction (%MAF) of BRAF V600E down to 0.01%. In a direct comparative analysis, the EV fraction contained detectable BRAF V600E in 10 out of 12 patients, whereas none of the patient platelet fractions resulted in a mutant allele signal. The platelet fraction of all 12 patients contained high amounts of wild-type BRAF signal, but no mutation signal above background was detectable in any of the samples. Our observations suggest that the phenomenon of tumour RNA transfer to platelets occurs below detection limit since even a very sensitive qPCR assay did not allow for a reliable detection of BRAF V600E in the platelet fraction. In contrast, EV fractions derived from the same patients allowed for detection of BRAF V600E in 10 of 12 blood specimens.

    Pubmed
  • SARS-CoV-2 Transmission from Presymptomatic Meeting Attendee, Germany.

    Emerg Infect Dis. 2020;26(8): 1935-1937

    Hijnen D, Marzano AV, Eyerich K, GeurtsvanKessel C, Giménez-Arnau AM, Joly P, Vestergaard C, Sticherling M, Schmidt E

    During a meeting in Munich, Germany, a presymptomatic attendee with severe acute respiratory syndrome coronavirus 2 infected at least 11 of 13 other participants. Although 5 participants had no or mild symptoms, 6 had typical coronavirus disease, without dyspnea. Our findings suggest hand shaking and face-to-face contact as possible modes of transmission.

    Pubmed
  • A phase II, multicenter study of encorafenib/binimetinib followed by a rational triple-combination after progression in patients with advanced BRAF V600-mutated melanoma (LOGIC2).

    J Clin Oncol. 2020;38 Suppl S(15):

    Dummer R, Sandhu SK, Miller WH, Butler MO, Blank CU, Munoz-Couselo E, Burris HA, Postow MA, Chmielowski B, Middleton MR, Berking C, Hassel JC, Gesierich A, Mauch C, Kleha J, Gollerkeri A, Harney A, Pickard MD, Ascierto PA

    Pubmed
  • Spread of Terbinafine-Resistant Trichophyton mentagrophytes Type VIII (India) in Germany-"The Tip of the Iceberg?"

    J Fungi (Basel). 2020;6(4):

    Nenoff P, Verma SB, Ebert A, Süß A, Fischer E, Auerswald E, Dessoi S, Hofmann W, Schmidt S, Neubert K, Renner R, Sohl S, Hradetzky U, Krusche U, Wenzel HC, Staginnus A, Schaller J, Müller V, Tauer C, Gebhardt M, Schubert K, Almustafa Z, Stadler R, Fuchs A, Sitaru C, Retzlaff C, Overbeck C, Neumann T, Kerschnitzki A, Krause S, Schaller M, Walker B, Walther T, Köhler L, Albrecht M, Willing U, Monod M, Salamin K, Burmester A, Koch D, Krüger C, Uhrlaß S

    Chronic recalcitrant dermatophytoses, due to Trichophyton (T.) mentagrophytes Type VIII are on the rise in India and are noteworthy for their predominance. It would not be wrong to assume that travel and migration would be responsible for the spread of T. mentagrophytes Type VIII from India, with many strains resistant to terbinafine, to other parts of the world. From September 2016 until March 2020, a total of 29 strains of T. mentagrophytes Type VIII (India) were isolated. All patients were residents of Germany: 12 females, 15 males and the gender of the remaining two was not assignable. Patients originated from India (11), Pakistan (two), Bangladesh (one), Iraq (two), Bahrain (one), Libya (one) and other unspecified countries (10). At least two patients were German-born residents. Most samples (21) were collected in 2019 and 2020. All 29 T. mentagrophytes isolates were sequenced (internal transcribed spacer (ITS) and translation elongation factor 1-α gene (TEF1-α)). All were identified as genotype VIII (India) of T. mentagrophytes. In vitro resistance testing revealed 13/29 strains (45%) to be terbinafine-resistant with minimum inhibitory concentration (MIC) breakpoints ≥0.2 µg/mL. The remaining 16 strains (55%) were terbinafine-sensitive. Point mutation analysis revealed that 10/13 resistant strains exhibited Phe397Leu amino acid substitution of squalene epoxidase (SQLE), indicative for in vitro resistance to terbinafine. Two resistant strains showed combined Phe397Leu and Ala448Thr amino acid substitutions, and one strain a single Leu393Phe amino acid substitution. Out of 16 terbinafine-sensitive strains, in eight Ala448Thr, and in one Ala448Thr +, new Val444 Ile amino acid substitutions were detected. Resistance to both itraconazole and voriconazole was observed in three out of 13 analyzed strains. Treatment included topical ciclopirox olamine plus topical miconazole or sertaconazole. Oral itraconazole 200 mg twice daily for four to eight weeks was found to be adequate. Terbinafine-resistant T. mentagrophytes Type VIII are being increasingly isolated. In Germany, transmission of T. mentagrophytes Type VIII from the Indian subcontinent to Europe should be viewed as a significant public health issue.

    Pubmed
  • [Quality of life in patients with chronic wounds].

    Hautarzt. 2020;71(11): 863-869

    Erfurt-Berge C, Renner R

    The quality of life of patients with chronic wounds is significantly reduced. Through pain, wound odor, and exudate, they experience limitations in various areas of their daily life. Pain can lead to reduced mobility, sleep disorders, or reduced food intake. Physical limitations caused by the wound itself, dependence on caregivers, and the financial burden are further influencing factors. At the same time, chronic wounds lead to changes in social life, withdrawal from friends and family, and a feeling of powerlessness over a patient's own life. Pre-existing anxiety or a depressive disorder can further negatively influence the quality of life. There are various general and diagnosis-specific assessment tools for measuring the quality of life of patients with chronic wounds. Such a survey should be carried out regularly in the course of wound therapy. Especially at the beginning of treatment, it is important to identify limiting factors and to evaluate them regularly during wound therapy and to work out possible solutions together with the patient.

    Pubmed
  • A European randomised controlled trial for venous leg ulcers: a mathematical model analysis.

    J Wound Care. 2020;29(11): 678-685

    Renner R

    OBJECTIVE: Mathematical models have the potential to provide valuable insights into complex, biochemical and biomechanical processes. Previously, we developed a mathematical model with a non-linear growth function but could only confirm the feasibility of this model in clinical trials with a small number of patients. This limited the validity of our model. To increase validity, we applied the model to a larger number of patients.

    METHOD: The mathematical model was applied to patient data from a randomised controlled trial as part of the post-evaluation of the model. In this trial, patients with venous leg ulcers were randomised for treatment with either a two-layer bandage or a four-layer bandage.

    RESULTS: Data for 186 patients were analysed (two-layer bandage group, n=93; four-layer bandage group, n=93). Using the non-linear growth function, it was confirmed that the two-layer bandage was not inferior to the four-layer bandage. In addition, the mathematical model calculated individual wound healing trajectories and mean wound healing trajectories for both bandage systems. By extrapolating to t→∞, the two-layer bandage had a marginal benefit and resulted in a persistent wound area that was 7% of the initial wound area compared with 17% for the four-layer bandage.

    CONCLUSION: This analysis supported the previously performed statistical analysis, and allowed us to obtain details of the treated study population that may help in non-inferiority trials via extrapolation. It also provided new insights into the wound healing process by generating wound healing trajectories.

    Pubmed
  • Development and evaluation of an interprofessional teaching concept for modern wound management.

    J Dtsch Dermatol Ges. 2020;18(9): 977-982

    Bergendahl L, Werner F, Schmidt A, Ronicke M, Renner R, Erfurt-Berge C

    BACKGROUND AND OBJECTIVES: The aim of the present study was to establish and evaluate a new interprofessional teaching concept on the topic of wound management.

    METHODS: After determining the status quo using a survey among medical students, we developed a new teaching concept that included a 150-minute course aimed at providing students with the opportunity to gain hands-on wound management skills. This interprofessional course was offered at the existing 'SkillsLab' teaching facility. The participants' subjective level of knowledge was assessed by questionnaire before and after the course.

    RESULTS: Our survey among 190 medical students showed them to be very interested in gaining practical experience in the field of wound management. To date, 120 participants (54.8 % medical students; 45.2 % nursing students) have attended this new interprofessional course, which has been equally well received by both medical and nursing students. For all specific topics (diagnosis, treatment, use of wound dressings, debridement), course participation was associated with a significant increase in knowledge.

    CONCLUSION: Given its relevance in clinical practice, it is important for medical students to learn about the various aspects associated with the care of patients with chronic wounds. By offering new teaching concepts, dermatology in particular is well suited to help students gain a better understanding of the challenges related to wound management and to improve their practical skills. Wound management is an ideal topic for interprofessional learning.

    Pubmed
  • COVID-19 and implications for dermatological and allergological diseases.

    J Dtsch Dermatol Ges. 2020;18(8): 815-824

    Buhl T, Beissert S, Gaffal E, Goebeler M, Hertl M, Mauch C, Reich K, Schmidt E, Schön MP, Sticherling M, Sunderkötter C, Traidl-Hoffmann C, Werfel T, Wilsman-Theis D, Worm M

    COVID-19, caused by the coronavirus SARS-CoV-2, has become pandemic. A further level of complexity opens up as soon as we look at diseases whose pathogenesis and therapy involve different immunological signaling pathways, which are potentially affected by COVID-19. Medical treatments must often be reassessed and questioned in connection with this infection. This article summarizes the current knowledge of COVID-19 in the light of major dermatological and allergological diseases. It identifies medical areas lacking sufficient data and draws conclusions for the management of our patients during the pandemic. We focus on common chronic inflammatory skin diseases with complex immunological pathogenesis: psoriasis, eczema including atopic dermatitis, type I allergies, autoimmune blistering and inflammatory connective tissue diseases, vasculitis, and skin cancers. Since several other inflammatory skin diseases display related or comparable immunological reactions, clustering of the various inflammatory dermatoses into different disease patterns may help with therapeutic decisions. Thus, following these patterns of skin inflammation, our review may supply treatment recommendations and thoughtful considerations for disease management even beyond the most frequent diseases discussed here.

    Pubmed
  • Patients with immune-mediated inflammatory diseases receiving cytokine inhibitors have low prevalence of SARS-CoV-2 seroconversion.

    Nat Commun. 2020;11(1):

    Simon D, Tascilar K, Krönke G, Kleyer A, Zaiss MM, Heppt F, Meder C, Atreya R, Klenske E, Dietrich P, Abdullah A, Kliem T, Corte G, Morf H, Leppkes M, Kremer AE, Ramming A, Pachowsky M, Schuch F, Ronneberger M, Kleinert S, Maier C, Hueber AJ, Manger K, Manger B, Berking C, Tenbusch M, Überla K, Sticherling M, Neurath MF, Schett G

    Immune-mediated inflammatory diseases (IMIDs) of the joints, gut and skin are treated with inhibitors of inflammatory cytokines. These cytokines are involved in the pathogenesis of coronavirus disease 2019 (COVID-19). Investigating anti-SARS-CoV-2 antibody responses in IMIDs we observe a reduced incidence of SARS-CoV-2 seroconversion in IMID patients treated with cytokine inhibitors compared to patients receiving no such inhibitors and two healthy control populations, despite similar social exposure. Hence, cytokine inhibitors seem to at least partially protect from SARS-CoV-2 infection.

    Pubmed
  • Secukinumab leads to shifts from stage-based towards response-based disease clusters-comparative data from very early and established psoriatic arthritis.

    Arthritis Res Ther. 2020;22(1):

    Kampylafka E, Tascilar K, Lerchen V, Linz C, Sokolova M, Zekovic A, Kleyer A, Simon D, Rech J, Sticherling M, Schett G, Hueber AJ

    BACKGROUND: Limited information exists about the very early forms of psoriatic arthritis. In particular, differences and responsiveness of patient-reported outcomes (PROs) in very early as compared to established PsA have not been investigated to date.

    METHODS: Cross-sectional and prospective longitudinal evaluation of PROs related to pain (VAS), physical function (HAQ-DI, SF-36 physical), mental function (SF-36 mental), impact of psoriatic skin (DLQI), joint (PsAID), and global disease (VAS) in two small prospective observational studies on secukinumab 300 mg over 6 months in very early disease patients (IVEPSA study, N = 20) and established PsA (PSARTROS study, N = 20). Cluster analysis was performed at baseline and 24-weeks of follow-up.

    RESULTS: While responses in pain and physical activity-related PROs to secukinumab were more pronounced in established PsA than a very early disease, effects on PROs related to general health perception, as well as those related to emotional and mental well-being, were modified in a similar way in very early disease and established PsA. Cluster analysis based on global disease activity and PROs showed that baseline clusters reflected very early disease and established PsA, while after secukinumab treatment these clusters were abolished and new clusters based on differential responses to physically and mentally oriented PROs formed.

    CONCLUSIONS: Inhibition of IL-17A by secukinumab leads to comprehensive improvement of general health perception and mental well-being in very early and established PsA, while overall responses in pain and physical activity are more pronounced in established disease. Most importantly, treatment restructures the original patients' clusters based on disease stage and leads to the formation of new clusters that reflect their response in physical and mental-orientated PROs.

    TRIAL REGISTRATION: NCT02483234 , registered 26 June 2015, retrospectively registered.

    Pubmed
  • Patients Receiving Cytokine Inhibitors Have Low Prevalence of SARS-CoV-2 Infection

    Arthritis Rheumatol. 2020;72 Suppl 10():

    Simon D, Tascilar K, Kronke G, Kleyer A, Zaiss M, Heppt F, Meder C, Atreya R, Klenske E, Dietrich P, Abdullah A, Kliem T, Corte G, Morf H, Leppkes M, Kremer A, Ramming A, Pachowsky M, Schuch F, Ronneberger M, Kleinert S, Maier C, Hueber A, Manger K, Manger B, Berking C, Tenbusch M, Ueberla K, Sticherling M, Neurath M, Schett G

    Pubmed
  • Interleukin-17 Blockade Leads to Shifts from Stage-based Towards Response-based Disease Clusters- Comparative Data from Very Early and Established Psoriatic Arthritis

    Arthritis Rheumatol. 2020;72 Suppl 10():

    Kampylafka E, Tascilar K, Lerchen V, Linz C, Sokolova M, Zekovic A, Kleyer A, Simon D, Rech J, Sticherling M, Schett G, Hueber A

    Pubmed
  • Similar Impact of Psoriatic Arthritis and Rheumatoid Arthritis on Objective and Subjective Parameters of Hand Function

    Arthritis Rheumatol. 2020;72 Suppl 10():

    Liphardt AM, Manger E, Liehr S, Bieniek L, Kleyer A, Simon D, Tascilar K, Sticherling M, Rech J, Schett G, Hueber A

    Pubmed
  • Structural Entheseal Lesions in Psoriasis Patients Are Associated with an Increased Risk Ofprogression to Psoriatic Arthritis - A Prospective Cohort Study

    Arthritis Rheumatol. 2020;72 Suppl 10():

    Simon D, Tascilar K, Kleyer A, Bayat S, Kampylafka E, Hueber A, Rech J, Schuster L, Engel K, Sticherling M, Schett G

    Pubmed
  • Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases.

    Am J Hum Genet. 2020;107(3): 527-538

    Haskamp S, Bruns H, Hahn M, Hoffmann M, Gregor A, Löhr S, Hahn J, Schauer C, Ringer M, Flamann C, Frey B, Lesner A, Thiel CT, Ekici AB, von Hörsten S, Aßmann G, Riepe C, Euler M, Schäkel K, Philipp S, Prinz JC, Mößner R, Kersting F, Sticherling M, Sefiani A, Lyahyai J, Sondermann W, Oji V, Schulz P, Wilsmann-Theis D, Sticht H, Schett G, Reis A, Uebe S, Frey S, Hüffmeier U

    Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E-08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E-09); this effect was stronger when including IL36RN mutations (1.48E-13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.

    Pubmed
  • Similar Impact of Psoriatic Arthritis and Rheumatoid Arthritis on Objective and Subjective Parameters of Hand Function.

    ACR Open Rheumatol. 2020;2(12): 734-740

    Liphardt AM, Manger E, Liehr S, Bieniek L, Kleyer A, Simon D, Tascilar K, Sticherling M, Rech J, Schett G, Hueber AJ

    OBJECTIVE: The objective of this study was to compare the impact of psoriatic disease (psoriatic arthritis [PsA] and psoriasis) and rheumatoid arthritis (RA) on objective and subjective parameters of hand function.

    METHODS: Hand function was determined in this cross-sectional study by 1) vigorimetric grip strength, 2) the Moberg Picking-Up Test used for assessing fine-motor skills, and 3) self-reported hand function (Michigan Hand Questionnaire). Mixed-effects linear regression models were used to test the relation of hand function with disease group, age, and sex.

    RESULTS: Two hundred ninety-nine subjects were tested, 101 with RA, 92 with PsA, and 106 nonarthritic controls (51 with psoriasis and 55 healthy controls [HCs]). Regression analysis showed that hand function was influenced by age, sex, disease group, and hand dominance (P < 0.001 for all). The impact of PsA and RA on hand function was comparable and generally more pronounced in women. Both PsA and RA led to significantly enhanced age-related loss of grip strength, fine-motor skills, and self-reported hand function in patients with PsA and RA compared with HCs. In addition, patients with psoriasis showed significant impairment of hand function compared with HCs.

    CONCLUSION: RA and PsA have a comparable impact on the decline of strength, fine-motor skills, and self-reported function of the hand. Unexpectedly, patients with psoriasis also show impaired hand function that follows a similar pattern as observed in patients with PsA.

    Pubmed
  • Psoriatic arthritis epidemiology, comorbid disease profiles and risk factors: results from a claims database analysis.

    Rheumatol Adv Pract. 2020;4(2):

    Rech J, Sticherling M, Stoessel D, Biermann MHC, Häberle BM, Reinhardt M

    Objective: Psoriasis is a systemic inflammatory disease often accompanied by comorbidities, including metabolic syndrome, cardiovascular diseases and depression. Up to 41% of psoriasis patients develop psoriatic arthritis (PsA), making it one of the most relevant manifestations. A large health claims data set was analysed to determine the rate of PsA development in psoriasis patients. Furthermore, comorbid disease profiles of psoriasis patients with or without PsA were compared, and potential risk factors for the development of PsA were identified.

    Methods: This was a non-interventional, retrospective analysis of anonymized insurance health claims data using a subset of the Institute of Applied Health Research Berlin (InGef) database. The primary outcome was the prevalence and incidence of diagnosed PsA among psoriasis patients in Germany. Risk factors for the development of PsA in psoriasis patients were determined by conditional logistic regression analysis.

    Results: The cumulative percentage of patients with existing psoriasis developing concomitant PsA over 4 years was 3.44%, with a mean time to diagnosis of PsA of 1.5 years. Psoriasis patients diagnosed with acute rheumatism (odds ratio: 2.93, 95% CI = 1.76, 4.86; P < 0.001) or pain in unspecific joints (odds ratio: 1.74, 95% CI = 1.01, 2.99; P = 0.047) showed an increased risk for development of PsA later on. Interestingly, fewer than half of the patients with concomitant PsA consulted a rheumatologist.

    Conclusions: Unspecific arthritic symptoms are likely to precede PsA diagnoses and can develop soon after onset of psoriasis, with accumulating risk over time. There is a high unmet need for early rheumatological assessment of psoriasis patients.

    Pubmed
  • CARs: Beyond T Cells and T Cell-Derived Signaling Domains.

    Int J Mol Sci. 2020;21(10):

    Sievers NM, Dörrie J, Schaft N

    When optimizing chimeric antigen receptor (CAR) therapy in terms of efficacy, safety, and broadening its application to new malignancies, there are two main clusters of topics to be addressed: the CAR design and the choice of transfected cells. The former focuses on the CAR construct itself. The utilized transmembrane and intracellular domains determine the signaling pathways induced by antigen binding and thereby the cell-specific effector functions triggered. The main part of this review summarizes our understanding of common signaling domains employed in CARs, their interactions among another, and their effects on different cell types. It will, moreover, highlight several less common extracellular and intracellular domains that might permit unique new opportunities. Different antibody-based extracellular antigen-binding domains have been pursued and optimized to strike a balance between specificity, affinity, and toxicity, but these have been reviewed elsewhere. The second cluster of topics is about the cellular vessels expressing the CAR. It is essential to understand the specific attributes of each cell type influencing anti-tumor efficacy, persistence, and safety, and how CAR cells crosstalk with each other and bystander cells. The first part of this review focuses on the progress achieved in adopting different leukocytes for CAR therapy.

    Pubmed
  • The Landscape of CAR-T Cell Clinical Trials against Solid Tumors-A Comprehensive Overview.

    Cancers (Basel). 2020;12(9):

    Schaft N

    CAR-T cells showed great potential in the treatment of patients with hematologic tumors. However, the clinical efficacy of CAR-T cells against solid tumors lags behind. To obtain a comprehensive overview of the landscape of CAR-T cell clinical trials against this type of cancer, this review summarizes all the 196 studies registered at clinicaltrials.gov. Special focus is on: (1) geographical distribution; (2) targeted organs, tumor entities, and antigens; (3) CAR transfer methods, CAR formats, and extra features introduced into the T cells; and (4) patient pretreatments, injection sites, and safety measurements. Finally, the few data on clinical outcome are reported. The last assessment of clinicaltrials.gov for the data summarized in this paper was on 4 August 2020.

    Pubmed
  • Cryopreservation reduces the Ability to migrate and the Cytotoxicity of natural Killer Cells in 3D: Possible Effects on cellular Immunotherapy

    J Dtsch Dermatol Ges. 2020;18 Suppl 2(): 68-68

    Mark C, Czerwinksi T, Roessner S, Mainka A, Hoersch F, Heublein L, Winterl A, Sanokowski S, Richter S, Bauer N, Angelini T, Schuler G, Fabry B, Bosch-Voskens C

    Pubmed
  • Clinical characteristics and outcomes of coronavirus 2019 disease (COVID-19) in cancer patients treated with immune checkpoint inhibitors (ICI).

    Clin Cancer Res. 2020;26 Suppl S(18):

    Rogiers A, Tondini C, Grimes JM, Trager MH, Nahm S, Zubiri L, Papneja N, Elkrief A, Borgers J, Rose A, Mangana J, Erdmann M, da Silva IP, Posch C, Hauschild A, Zimmer L, Queirolo P, Robert C, Suijkerbuijk K, Ascierto PA, Lorigan P, Carvajal R, Rahma OE, Mandala M, Long GV

    Pubmed
  • Immune Checkpoint Blockade in Advanced Cutaneous Squamous Cell Carcinoma: What Do We Currently Know in 2020?

    Int J Mol Sci. 2020;21(23):

    Wessely A, Steeb T, Leiter U, Garbe C, Berking C, Heppt MV

    Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer that predominantly arises in chronically sun-damaged skin. Immunosuppression, genetic disorders such as xeroderma pigmentosum (XP), exposure to certain drugs and environmental noxae have been identified as major risk factors. Surgical removal of cSCC is the therapy of choice and mostly curative in early stages. However, a minority of patients develop locally advanced tumors or distant metastases that are still challenging to treat. Immune checkpoint blockade (ICB) targeting CTLA-4, PD-L1 and PD-1 has tremendously changed the field of oncological therapy and especially the treatment of skin cancers as tumors with a high mutational burden. In this review, we focus on the differences between cSCC and cutaneous melanoma (CM) and their implications on therapy, summarize the current evidence on ICB for the treatment of advanced cSCC and discuss the chances and pitfalls of this therapy option for this cancer entity. Furthermore, we focus on special subgroups of interest such as organ transplant recipients, patients with hematologic malignancies, XP and field cancerization.

    Pubmed
  • Evaluation of PD-L1 Expression and HPV Genotyping in Anal Squamous Cell Carcinoma.

    Cancers (Basel). 2020;12(9):

    Wessely A, Heppt MV, Kammerbauer C, Steeb T, Kirchner T, Flaig MJ, French LE, Berking C, Schmoeckel E, Reinholz M

    Anal squamous cell carcinoma (SCC) is a rare cancer with increasing incidence. Infection with high-risk human papillomavirus (HPV) subtypes is the major cause for its development. We retrospectively analyzed tumor samples from 54 anal SCC patients for infection with a panel of 32 HPV subtypes in a PCR-based approach, determined the PD-L1 expression status, and correlated the findings with the clinical data and the survival of the patients. Forty-two patients (77.8%) were HPV-positive and harbored at least one carcinogenic HPV subtype. HPV16 was the most frequently detected (n = 39, 72.2%). Four patients were infected with multiple HPV subtypes. HPV infection was significantly more often detected in female than in male patients (90.3% vs. 60.9%, p = 0.018). Patients with PD-L1 positive tumors showed a significantly better median overall survival (OS) compared with patients with PD-L1 negative tumors (69.3 vs. 28.3 months, p = 0.006). The median OS was significantly different among the distinct tumor stages (p = 0.029). Sex, grade of differentiation, and HPV infection status did not influence the median OS. Furthermore, HPV infection status and PD-L1 expression were not correlated. A multivariate Cox regression analysis revealed that PD-L1 expression status was an independent prognostic marker for survival (p = 0.012).

    Pubmed
  • A Systematic Review and Meta-Analysis of Interventions for Actinic Keratosis from Post-Marketing Surveillance Trials.

    J Clin Med. 2020;9(7):

    Steeb T, Wessely A, Harlaß M, Heppt F, Koch EAT, Leiter U, Garbe C, Schöffski O, Berking C, Heppt MV

    Multiple interventions are available for the treatment of actinic keratosis (AK) showing high efficacy in pivotal trials. However, data from post-marketing surveillance studies have received little attention until now. Here, we systematically investigate interventions for AK from post-marketing surveillance trials as a proxy for real-world efficacy and tolerability. A systematic literature search was conducted in Medline, Embase, and CENTRAL. Pertinent trial registers were hand-searched until 25 March 2020. Results were pooled using a random-effects model to calculate pooled proportions and relative risks (RR) or were described qualitatively. Eleven records with a total sample size of n = 4109 were included. Three of the studies had an active-controlled design, while seven were single-armed. Participant complete clearance ranged from 23.1% for diclofenac sodium 3% gel to 88.9% for ingenol mebutate 0.05% gel. The lesion-specific clearance rate for photodynamic therapy (PDT) was 74% (95% confidence interval (CI) 56-87%). The recurrence rate was significantly higher for diclofenac sodium 3% in comparison to imiquimod 5% cream (RR 1.10, 95% CI 1.02-1.1.8) and ranged from 10.6% for ingenol mebutate 0.015% gel to 23.5% for PDT. Few patients discontinued the trials due to adverse events. The results from the majority of the post-marketing surveillance studies deviated from those of pivotal trials.

    Pubmed
  • The Quality of Practice Guidelines for Melanoma: A Methodologic Appraisal with the AGREE II and AGREE-REX Instruments.

    Cancers (Basel). 2020;12(6):

    Steeb T, Wessely A, Drexler K, Salzmann M, Toussaint F, Heinzerling L, Reinholz M, Berking C, Heppt MV

    Multiple guidelines on cutaneous melanoma (CM) are available from several consortia and countries. To provide up-to-date guidance in the rapidly changing field of melanoma treatment, guideline developers have to provide regular updates without compromises of quality. We performed a systematic search in guideline databases, Medline and Embase to identify guidelines on CM. The methodological quality of the identified guidelines was independently assessed by five reviewers using the instruments "Appraisal of Guidelines for Research and Evaluation" (AGREE II) and "Recommendation EXcellence" (AGREE-REX). We performed descriptive analysis, explored subgroup differences using the Kruskal-Wallis (H) test and examined the relationship between distinct domains and items of the instruments with Spearman's correlation. Six guidelines by consortia from Australia, France, Germany, Scotland, Spain and the United States of America were included. The German guideline fulfilled 71%-98% of criteria in AGREE II and 78%-96% for AGREE-REX, obtaining the highest scores. Deficiencies in the domains of "applicability" and "values and preferences" were observed in all guidelines. The German and Spanish guidelines significantly differed from each other in most of the domains. The domains "applicability" and "values and preferences" were identified as methodological weaknesses requiring careful revision and improvement in the future.

    Pubmed
  • Patient Perception of Mobile Phone Apps for the Care and Prevention of Sexually Transmitted Diseases: Cross-Sectional Study.

    JMIR Mhealth Uhealth. 2020;8(11):

    Jakob L, Steeb T, Fiocco Z, Pumnea T, Jakob SN, Wessely A, Rothenberger CC, Brinker TJ, French LE, Berking C, Heppt MV

    BACKGROUND: In the emerging era of digitalization and electronic health, various health-related apps have been launched, including apps for sexually transmitted diseases. Until now, little has been known about how patients perceive the value of such apps.

    OBJECTIVE: To investigate patient's attitudes and awareness toward sexually transmitted disease-related apps in an outpatient sexually transmitted disease clinic setting.

    METHODS: A cross-sectional study was conducted at a dermatovenereological outpatient unit between April and July 2019. Patients completed a self-administered questionnaire on their perceptions of the popularity and usefulness of sexually transmitted disease-related apps. Descriptive analysis was performed with expression of categorical variables as frequencies and percentages. For continuous variables, the median, range, and interquartile range were indicated. Contingency tables and chi-square tests were used to investigate associations between sociodemographic data and items of the questionnaire.

    RESULTS: A total of 226 patients were surveyed (heterosexual: 137/193, 71.0%; homosexual: 44/193, 22.8%; bisexual: 12/193, 6.2%); 11.9% (27/225) had previously used health-related apps. Nearly half of the patients (97/214, 45.3%) specifically considered sexually transmitted disease-related apps useful, 47.8% (100/209) voted that they could supplement or support the consultation of a physician. Interestingly, only 35.1% (74/211) preferred a printed patient brochure on sexually transmitted diseases over downloading and using an app, but 64.0% (134/209) would download a sexually transmitted disease-related app recommended by their physician. General information regarding sexually transmitted diseases (93/167, 55.7%), evaluation of skin diseases based on photos or videos (78/167, 53.3%), information on the prevention of sexually transmitted diseases (76/167, 45.5%), mediation of nearby contact points or test sites (74/167, 44.3%), anonymous medical advice (69/167, 41.3%), and calculation of the risk of having a sexually transmitted disease (63/167, 37.3%) were rated as the most important features. Men were more likely than women to find sexually transmitted disease-related apps useful in general (P=.04; χ2=6.28) and to pay for such apps (P=.01; χ2=9.19). Patients aged <40 years would rather download an app recommended by their physician (P=.03; χ2=7.23), whereas patients aged >40 years preferred reading a patient brochure on sexually transmitted diseases (P=.02; χ2=8.14).

    CONCLUSIONS: This study demonstrated high general interest in the use of sexually transmitted disease-related apps in this sample of dermatovenereological outpatients. In particular, young age and male sex were significantly associated with a positive perception, underlining the high potential of apps in the prevention and early recognition of sexually transmitted diseases in this group. Future studies are warranted to validate these findings in other populations.

    Pubmed
  • COVID-19 and immunological regulations - from basic and translational aspects to clinical implications.

    J Dtsch Dermatol Ges. 2020;18(8): 795-807

    Schön MP, Berking C, Biedermann T, Buhl T, Erpenbeck L, Eyerich K, Eyerich S, Ghoreschi K, Goebeler M, Ludwig RJ, Schäkel K, Schilling B, Schlapbach C, Stary G, von Stebut E, Steinbrink K

    The COVID-19 pandemic caused by SARS-CoV-2 has far-reaching direct and indirect medical consequences. These include both the course and treatment of diseases. It is becoming increasingly clear that infections with SARS-CoV-2 can cause considerable immunological alterations, which particularly also affect pathogenetically and/or therapeutically relevant factors. Against this background we summarize here the current state of knowledge on the interaction of SARS-CoV-2/COVID-19 with mediators of the acute phase of inflammation (TNF, IL-1, IL-6), type 1 and type 17 immune responses (IL-12, IL-23, IL-17, IL-36), type 2 immune reactions (IL-4, IL-13, IL-5, IL-31, IgE), B-cell immunity, checkpoint regulators (PD-1, PD-L1, CTLA4), and orally druggable signaling pathways (JAK, PDE4, calcineurin). In addition, we discuss in this context non-specific immune modulation by glucocorticosteroids, methotrexate, antimalarial drugs, azathioprine, dapsone, mycophenolate mofetil and fumaric acid esters, as well as neutrophil granulocyte-mediated innate immune mechanisms. From these recent findings we derive possible implications for the therapeutic modulation of said immunological mechanisms in connection with SARS-CoV-2/COVID-19. Although, of course, the greatest care should be taken with patients with immunologically mediated diseases or immunomodulating therapies, it appears that many treatments can also be carried out during the COVID-19 pandemic; some even appear to alleviate COVID-19.

    Pubmed
  • Implications of the COVID-19 Pandemic for the Development and Update of Clinical Practice Guidelines: Viewpoint.

    J Med Internet Res. 2020;22(12):

    Steeb T, Follmann M, Hagen RM, Berking C, Heppt MV

    Following the rapid spread of a new type of coronavirus (SARS-CoV-2), nearly all countries have introduced temporary restrictions affecting daily life, with "social distancing" as a key intervention for slowing the spread of the virus. Despite the pandemic, the development or actualization of medical guidelines, especially in the rapidly changing field of oncology, needs to be continued to provide up-to-date evidence- and consensus-based recommendations for shared decision making and maintaining the treatment quality for patients. In this viewpoint, we describe the potential strengths and limitations of online conferences for medical guideline development. This viewpoint will assist guideline developers in evaluating whether online conferences are an appropriate tool for their guideline conference and audience.

    Pubmed
  • Phase Ib/II study combining the HDAC inhibitor domatinostat with anti-PD-1 pembrolizumab in patients with advanced melanoma refractory/non-responding to prior checkpoint inhibitor therapy

    J Transl Med. 2020;18 Suppl 1():

    Ascierto PA, Hassel JC, Berking C, Eigentler T, Gutzmer R, Schilling B, Hermann F, Bartz R, Schadendorf D

    Pubmed
  • The COVID-19 pandemic: implications for patients undergoing immunomodulating or immunosuppressive treatments in dermatology.

    Eur J Dermatol. 2020;30(6): 757-758

    Reinholz M, French LE, Berking C, Heppt MV

    Pubmed
  • Clinical Evaluation of the Combination of Checkpoint Blockade and dendritic Cell Vaccination against Merkel Cell Carcinoma

    J Dtsch Dermatol Ges. 2020;18 Suppl 2(): 9-9

    Sauerer T, Gerer K, Hoyer S, Erdmann M, Berking C, Voll RE, Schuler-Thurner B, Schuler G, Schaft N, Doerrie J

    Pubmed
  • Step-by-step Improvement of mRNA-electroporated dendritic Cells in a Phase I/II Clinical Study in cutaneous Melanoma Patients: better Survival correlates with a higher Immunoscore and increased Expression of PEBP1 in the Blood

    J Dtsch Dermatol Ges. 2020;18 Suppl 2(): 8-9

    Doerrie J, Schaft N, Gross S, Ostalecki C, Eberhardt M, Vera-Gonzales J, Uslu U, Moreira A, Koch EAT, Kummer M, Erdmann M, Schliep S, Schuler G, Schuler-Thurner B

    Pubmed
  • Palmitoylated Proteins on AML-Derived Extracellular Vesicles Promote Myeloid-Derived Suppressor Cell Differentiation via TLR2/Akt/mTOR Signaling.

    Cancer Res. 2020;80(17): 3663-3676

    Tohumeken S, Baur R, Böttcher M, Stoll A, Loschinski R, Panagiotidis K, Braun M, Saul D, Völkl S, Baur AS, Bruns H, Mackensen A, Jitschin R, Mougiakakos D

    Acute myeloid leukemia (AML) represents the most common acute leukemia among adults. Despite recent progress in diagnosis and treatment, long-term outcome remains unsatisfactory. The success of allogeneic stem cell transplantation underscores the immunoresponsive nature of AML, creating the basis for further exploiting immunotherapies. However, emerging evidence suggests that AML, similar to other malignant entities, employs a variety of mechanisms to evade immunosurveillance. In light of this, T-cell inhibitory myeloid-derived suppressor cells (MDSC) are gaining interest as key facilitators of immunoescape. Accumulation of CD14+HLA-DRlow monocytic MDSCs has been described in newly diagnosed AML patients, and deciphering the underlying mechanisms could help to improve anti-AML immunity. Here, we report that conventional monocytes readily take-up AML-derived extracellular vesicles (EV) and subsequently undergo MDSC differentiation. They acquired an CD14+HLA-DRlow phenotype, expressed the immunomodulatory indoleamine-2,3-dioxygenase, and upregulated expression of genes characteristic for MDSCs, such as S100A8/9 and cEBPβ. The Akt/mTOR pathway played a critical role in the AML-EV-induced phenotypical and functional transition of monocytes. Generated MDSCs displayed a glycolytic switch, which rendered them more susceptible toward glycolytic inhibitors. Furthermore, palmitoylated proteins on the AML-EV surface activated Toll-like receptor 2 as the initiating event of Akt/mTOR-dependent induction of MDSC. Therefore, targeting protein palmitoylation in AML blasts could block MDSC accumulation to improve immune responses. SIGNIFICANCE: These findings indicate that targeting protein palmitoylation in AML could interfere with the leukemogenic potential and block MDSC accumulation to improve immunity.

    Pubmed
  • Evidence for liver and peripheral immune cells secreting tumor-suppressive extracellular vesicles in melanoma patients.

    EBioMedicine. 2020;62():

    Lee JH, Eberhardt M, Blume K, Vera J, Baur AS

    BACKGROUND: Before and after surgery melanoma patients harbor elevated levels of extracellular vesicles in plasma (pEV), suppressing tumor cell activity. However, due to technical reasons and lack of cell-specific biomarkers, their cellular origin remains obscure.

    METHODS: We mimicked the interaction of tumor cells with liver cells and PBMC in vitro, and compared newly secreted EV-associated miRNAs and protein factors with those detected in melanoma patient`s pEV.

    FINDINGS: Our results suggest that pEV from melanoma patients are secreted in part by residual or relapsing tumor cells, but also by liver and peripheral blood mononuclear cells (PBMC). Our approach identified factors that were seemingly associated either with tumor cell activity, or the counteracting immune system, including liver cells. Notably, the presence/absence of these factors correlated with the clinical stage and tumor relapse.

    INTERPRETATION: Our study may provide new insights into the innate immune defense against tumor cells and implies that residual tumor cells could be more active than previously thought. In addition we provide some preliminary evidence that pEV marker patterns could be used to predict cancer relapse.

    Pubmed
  • Long-term, open-label extension study of the efficacy and safety of epicutaneous immunotherapy for peanut allergy in children: PEOPLE 3-year results.

    J Allergy Clin Immunol. 2020;146(4): 863-874

    Fleischer DM, Shreffler WG, Campbell DE, Green TD, Anvari S, Assa'ad A, Bégin P, Beyer K, Bird JA, Brown-Whitehorn T, Byrne A, Chan ES, Cheema A, Chinthrajah S, Chong HJ, Davis CM, Ford LS, Gagnon R, Greenhawt M, Hourihane JO, Jones SM, Kim EH, Lange L, Lanser BJ, Leonard S, Mahler V, Maronna A, Nowak-Wegrzyn A, Oriel RC, O'Sullivan M, Petroni D, Pongracic JA, Prescott SL, Schneider LC, Smith P, Staab D, Sussman G, Wood R, Yang WH, Lambert R, Peillon A, Bois T, Sampson HA

    BACKGROUND: The PEPITES (Peanut EPIT Efficacy and Safety) trial, a 12-month randomized controlled study of children with peanut allergy and 4 to 11 years old, previously reported the safety and efficacy of epicutaneous immunotherapy (EPIT) for peanut allergy (250 μg, daily epicutaneous peanut protein; DBV712 250 μg).

    OBJECTIVE: We sought to assess interim safety and efficacy of an additional 2 years of EPIT from the ongoing (5-year treatment) PEOPLE (PEPITES Open-Label Extension) study.

    METHODS: Subjects who completed PEPITES were offered enrollment in PEOPLE. Following an additional 2 years of daily DBV712 250 μg, subjects who had received DBV712 250 μg in PEPITES underwent month-36 double-blind, placebo-controlled food challenge with an optional month-38 sustained unresponsiveness assessment.

    RESULTS: Of 213 eligible subjects who had received DBV712 250 μg in PEPITES, 198 (93%) entered PEOPLE, of whom 141 (71%) had assessable double-blind, placebo-controlled food challenge at month 36. At month 36, 51.8% of subjects (73 of 141) reached an eliciting dose of ≥1000 mg, compared with 40.4% (57 of 141) at month 12; 75.9% (107 of 141) demonstrated increased eliciting dose compared with baseline; and 13.5% (19 of 141) tolerated the full double-blind, placebo-controlled food challenge of 5444 mg. Median cumulative reactive dose increased from 144 to 944 mg. Eighteen subjects underwent an optional sustained unresponsiveness assessment; 14 of those (77.8%) maintained an eliciting dose of ≥1000 mg at month 38. Local patch-site skin reactions were common but decreased over time. There was no treatment-related epinephrine use in years 2 or 3. Compliance was high (96.9%), and withdrawals due to treatment-related adverse events were low (1%).

    CONCLUSIONS: These results demonstrate that daily EPIT treatment for peanut allergy beyond 1 year leads to continued response from a well-tolerated, simple-to-use regimen.

    Pubmed
  • Dermal fillers do not induce upregulation of NLRP3 inflammasomes or expression of inflammatory cytokines in granulomas.

    J Cosmet Dermatol. 2020;19(11): 2838-2844

    Reinholz M, Clanner-Engelshofen BM, Heppt MV, Marsela E, Kawakami Y, Wiest LG, French LE, Stolz W, Gauglitz GG

    BACKGROUND: Filling materials have increasingly been used in aesthetics over the last decades. Understanding the pathophysiology of granuloma formation as a very relevant unwanted side effect of filler application may be essential to help avoid these adverse events.

    AIMS: Our aim was to investigate the role of the inflammasome in the formation of filler granuloma, as a central column of the innate immune response.

    METHODS: RPMI 1640 medium was used for growth of THP-1 cells and the induction of THP-1 macrophages. Sonication was applied in order to crush the acrylic particles of the filler. ELISA was the method of analysis for the specific cytokines. Biopsy specimens of filler granuloma were analyzed by various immunohistochemical methods. GraphPad Prism 5 software was used for the statistical data analysis.

    RESULTS: Neither was the sensor NALP3 overexpressed, nor could an elevated expression of cleaved IL-1β, IL-18, or IFN-γ be detected. Furthermore, no increased expression of IL-8 or IL-1β was detectable in vitro.

    CONCLUSION: No increased inflammasome activation could be observed; however, filler granulomas were infiltrated with granulocytes and macrophages. Therefore, we speculate that an unspecific immune response might be the key player in the formation of filler granuloma.

    Pubmed
  • Risk Prediction Models for Melanoma: A Systematic Review on the Heterogeneity in Model Development and Validation.

    Int J Environ Res Public Health. 2020;17(21):

    Kaiser I, Pfahlberg AB, Uter W, Heppt MV, Veierød MB, Gefeller O

    The rising incidence of cutaneous melanoma over the past few decades has prompted substantial efforts to develop risk prediction models identifying people at high risk of developing melanoma to facilitate targeted screening programs. We review these models, regarding study characteristics, differences in risk factor selection and assessment, evaluation, and validation methods. Our systematic literature search revealed 40 studies comprising 46 different risk prediction models eligible for the review. Altogether, 35 different risk factors were part of the models with nevi being the most common one (n = 35, 78%); little consistency in other risk factors was observed. Results of an internal validation were reported for less than half of the studies (n = 18, 45%), and only 6 performed external validation. In terms of model performance, 29 studies assessed the discriminative ability of their models; other performance measures, e.g., regarding calibration or clinical usefulness, were rarely reported. Due to the substantial heterogeneity in risk factor selection and assessment as well as methodologic aspects of model development, direct comparisons between models are hardly possible. Uniform methodologic standards for the development and validation of risk prediction models for melanoma and reporting standards for the accompanying publications are necessary and need to be obligatory for that reason.

    Pubmed
  • Overdiagnosis of melanoma - causes, consequences and solutions.

    J Dtsch Dermatol Ges. 2020;18(11): 1236-1243

    Kutzner H, Jutzi TB, Krahl D, Krieghoff-Henning EI, Heppt MV, Hekler A, Schmitt M, Maron RCR, Fröhling S, von Kalle C, Brinker TJ

    Malignant melanoma is the skin tumor that causes most deaths in Germany. At an early stage, melanoma is well treatable, so early detection is essential. However, the skin cancer screening program in Germany has been criticized because although melanomas have been diagnosed more frequently since introduction of the program, the mortality from malignant melanoma has not decreased. This indicates that the observed increase in melanoma diagnoses be due to overdiagnosis, i.e. to the detection of lesions that would never have created serious health problems for the patients. One of the reasons is the challenging distinction between some benign and malignant lesions. In addition, there may be lesions that are biologically equivocal, and other lesions that are classified as malignant according to current criteria, but that grow so slowly that they would never have posed a threat to patient's life. So far, these "indolent" melanomas cannot be identified reliably due to a lack of biomarkers. Moreover, the likelihood that an in-situ melanoma will progress to an invasive tumor still cannot be determined with any certainty. When benign lesions are diagnosed as melanoma, the consequences are unnecessary psychological and physical stress for the affected patients and incurred therapy costs. Vice versa, underdiagnoses in the sense of overlooked melanomas can adversely affect patients' prognoses and may necessitate more intense therapies. Novel diagnostic options could reduce the number of over- and underdiagnoses and contribute to more objective diagnoses in borderline cases. One strategy that has yielded promising results in pilot studies is the use of artificial intelligence-based diagnostic tools. However, these applications still await translation into clinical and pathological routine.

    Pubmed
  • Artificial Intelligence and Its Effect on Dermatologists' Accuracy in Dermoscopic Melanoma Image Classification: Web-Based Survey Study.

    J Med Internet Res. 2020;22(9):

    Maron RC, Utikal JS, Hekler A, Hauschild A, Sattler E, Sondermann W, Haferkamp S, Schilling B, Heppt MV, Jansen P, Reinholz M, Franklin C, Schmitt L, Hartmann D, Krieghoff-Henning E, Schmitt M, Weichenthal M, von Kalle C, Fröhling S, Brinker TJ

    BACKGROUND: Early detection of melanoma can be lifesaving but this remains a challenge. Recent diagnostic studies have revealed the superiority of artificial intelligence (AI) in classifying dermoscopic images of melanoma and nevi, concluding that these algorithms should assist a dermatologist's diagnoses.

    OBJECTIVE: The aim of this study was to investigate whether AI support improves the accuracy and overall diagnostic performance of dermatologists in the dichotomous image-based discrimination between melanoma and nevus.

    METHODS: Twelve board-certified dermatologists were presented disjoint sets of 100 unique dermoscopic images of melanomas and nevi (total of 1200 unique images), and they had to classify the images based on personal experience alone (part I) and with the support of a trained convolutional neural network (CNN, part II). Additionally, dermatologists were asked to rate their confidence in their final decision for each image.

    RESULTS: While the mean specificity of the dermatologists based on personal experience alone remained almost unchanged (70.6% vs 72.4%; P=.54) with AI support, the mean sensitivity and mean accuracy increased significantly (59.4% vs 74.6%; P=.003 and 65.0% vs 73.6%; P=.002, respectively) with AI support. Out of the 10% (10/94; 95% CI 8.4%-11.8%) of cases where dermatologists were correct and AI was incorrect, dermatologists on average changed to the incorrect answer for 39% (4/10; 95% CI 23.2%-55.6%) of cases. When dermatologists were incorrect and AI was correct (25/94, 27%; 95% CI 24.0%-30.1%), dermatologists changed their answers to the correct answer for 46% (11/25; 95% CI 33.1%-58.4%) of cases. Additionally, the dermatologists' average confidence in their decisions increased when the CNN confirmed their decision and decreased when the CNN disagreed, even when the dermatologists were correct. Reported values are based on the mean of all participants. Whenever absolute values are shown, the denominator and numerator are approximations as every dermatologist ended up rating a varying number of images due to a quality control step.

    CONCLUSIONS: The findings of our study show that AI support can improve the overall accuracy of the dermatologists in the dichotomous image-based discrimination between melanoma and nevus. This supports the argument for AI-based tools to aid clinicians in skin lesion classification and provides a rationale for studies of such classifiers in real-life settings, wherein clinicians can integrate additional information such as patient age and medical history into their decisions.

    Pubmed
  • Cantharidin as an Alternative Treatment for Genital Warts: A Case Monitored With Optical Coherence Tomography.

    Acta Derm Venereol. 2020;100(16):

    Ruini C, Clanner-Engelshofen BM, Heppt M, Herzinger T, Sárdy M, Ruzicka T, French LE, Reinholz M

    Pubmed
  • Fasten the seat belt: Increasing safety of CAR T-cell therapy.

    Exp Dermatol. 2020;29(11): 1039-1045

    Simon B, Uslu U

    After the recent success and approvals of chimeric antigen receptor (CAR) T cells in haematological malignancies, its efficacy is currently evaluated in a broad spectrum of tumor entities including melanoma. However, severe and potentially life-threatening side effects like cytokine release syndrome, neurologic toxicities, and the competing risk of morbidity and mortality from the treatment itself are still a major limiting factor in the current CAR T-cell landscape. In addition, especially in solid tumors, the lack of ideal target antigens to avoid on-target/off-tumor toxicities also restricts its use. While various groups are working on strategies to boost CAR T-cell efficacy, mechanisms to increase engineered T-cell safety should not move out of focus. Thus, the aim of this article is to summarize and to discuss current and potential future strategies and mechanisms to increase CAR T-cell safety in order to enable the wide use of this promising approach in melanoma and other tumor entities.

    Pubmed
  • Cryopreservation impairs 3-D migration and cytotoxicity of natural killer cells.

    Nat Commun. 2020;11(1):

    Mark C, Czerwinski T, Roessner S, Mainka A, Hörsch F, Heublein L, Winterl A, Sanokowski S, Richter S, Bauer N, Angelini TE, Schuler G, Fabry B, Voskens CJ

    Natural killer (NK) cells are important effector cells in the immune response to cancer. Clinical trials on adoptively transferred NK cells in patients with solid tumors, however, have thus far been unsuccessful. As NK cells need to pass stringent safety evaluation tests before clinical use, the cells are cryopreserved to bridge the necessary evaluation time. Standard degranulation and chromium release cytotoxicity assays confirm the ability of cryopreserved NK cells to kill target cells. Here, we report that tumor cells embedded in a 3-dimensional collagen gel, however, are killed by cryopreserved NK cells at a 5.6-fold lower rate compared to fresh NK cells. This difference is mainly caused by a 6-fold decrease in the fraction of motile NK cells after cryopreservation. These findings may explain the persistent failure of NK cell therapy in patients with solid tumors and highlight the crucial role of a 3-D environment for testing NK cell function.

    Pubmed
  • Harnessing the Complete Repertoire of Conventional Dendritic Cell Functions for Cancer Immunotherapy.

    Pharmaceutics. 2020;12(7):

    Amon L, Hatscher L, Heger L, Dudziak D, Lehmann CHK

    The onset of checkpoint inhibition revolutionized the treatment of cancer. However, studies from the last decade suggested that the sole enhancement of T cell functionality might not suffice to fight malignancies in all individuals. Dendritic cells (DCs) are not only part of the innate immune system, but also generals of adaptive immunity and they orchestrate the de novo induction of tolerogenic and immunogenic T cell responses. Thus, combinatorial approaches addressing DCs and T cells in parallel represent an attractive strategy to achieve higher response rates across patients. However, this requires profound knowledge about the dynamic interplay of DCs, T cells, other immune and tumor cells. Here, we summarize the DC subsets present in mice and men and highlight conserved and divergent characteristics between different subsets and species. Thereby, we supply a resource of the molecular players involved in key functional features of DCs ranging from their sentinel function, the translation of the sensed environment at the DC:T cell interface to the resulting specialized T cell effector modules, as well as the influence of the tumor microenvironment on the DC function. As of today, mostly monocyte derived dendritic cells (moDCs) are used in autologous cell therapies after tumor antigen loading. While showing encouraging results in a fraction of patients, the overall clinical response rate is still not optimal. By disentangling the general aspects of DC biology, we provide rationales for the design of next generation DC vaccines enabling to exploit and manipulate the described pathways for the purpose of cancer immunotherapy in vivo. Finally, we discuss how DC-based vaccines might synergize with checkpoint inhibition in the treatment of malignant diseases.

    Pubmed
  • Editorial: Harnessing the Participation of Dendritic Cells in Immunity and Tolerance.

    Front Immunol. 2020;11():

    Boscardin SB, Dudziak D, Münz C, Rosa DS

    Pubmed
  • Subsets of CD1c+ DCs: Dendritic Cell Versus Monocyte Lineage.

    Front Immunol. 2020;11():

    Heger L, Hofer TP, Bigley V, de Vries IJM, Dalod M, Dudziak D, Ziegler-Heitbrock L

    Currently three bona fide dendritic cell (DC) types are distinguished in human blood. Herein we focus on type 2 DCs (DC2s) and compare the three defining markers CD1c, CD172, and CD301. When using CD1c to define DC2s, a CD14+ and a CD14- subset can be detected. The CD14+ subset shares features with monocytes, and this includes substantially higher expression levels for CD64, CD115, CD163, and S100A8/9. We review the current knowledge of these CD1c+CD14+ cells as compared to the CD1c+CD14- cells with respect to phenotype, function, transcriptomics, and ontogeny. Here, we discuss informative mutations, which suggest that two populations have different developmental requirements. In addition, we cover subsets of CD11c+CD8- DC2s in the mouse, where CLEC12A+ESAMlow cells, as compared to the CLEC12A-ESAMhigh subset, also express higher levels of monocyte-associated markers CD14, CD3, and CD115. Finally, we summarize, for both man and mouse, the data on lower antigen presentation and higher cytokine production in the monocyte-marker expressing DC2 subset, which demonstrate that the DC2 subsets are also functionally distinct.

    Pubmed
  • Impact of Plasma Membrane Domains on IgG Fc Receptor Function.

    Front Immunol. 2020;11():

    Kara S, Amon L, Lühr JJ, Nimmerjahn F, Dudziak D, Lux A

    Lipid cell membranes not only represent the physical boundaries of cells. They also actively participate in many cellular processes. This contribution is facilitated by highly complex mixtures of different lipids and incorporation of various membrane proteins. One group of membrane-associated receptors are Fc receptors (FcRs). These cell-surface receptors are crucial for the activity of most immune cells as they bind immunoglobulins such as immunoglobulin G (IgG). Based on distinct mechanisms of IgG binding, two classes of Fc receptors are now recognized: the canonical type I FcγRs and select C-type lectin receptors newly referred to as type II FcRs. Upon IgG immune complex induced cross-linking, these receptors are known to induce a multitude of cellular effector responses in a cell-type dependent manner, including internalization, antigen processing, and presentation as well as production of cytokines. The response is also determined by specific intracellular signaling domains, allowing FcRs to either positively or negatively modulate immune cell activity. Expression of cell-type specific combinations and numbers of receptors therefore ultimately sets a threshold for induction of effector responses. Mechanistically, receptor cross-linking and localization to lipid rafts, i.e., organized membrane microdomains enriched in intracellular signaling proteins, were proposed as major determinants of initial FcR activation. Given that immune cell membranes might also vary in their lipid compositions, it is reasonable to speculate, that the cell membrane and especially lipid rafts serve as an additional regulator of FcR activity. In this article, we aim to summarize the current knowledge on the interplay of lipid rafts and IgG binding FcRs with a focus on the plasma membrane composition and receptor localization in immune cells, the proposed mechanisms underlying this localization and consequences for FcR function with respect to their immunoregulatory capacity.

    Pubmed
  • Maturation of Monocyte-Derived DCs Leads to Increased Cellular Stiffness, Higher Membrane Fluidity, and Changed Lipid Composition.

    Front Immunol. 2020;11():

    Lühr JJ, Alex N, Amon L, Kräter M, Kubánková M, Sezgin E, Lehmann CHK, Heger L, Heidkamp GF, Smith AS, Zaburdaev V, Böckmann RA, Levental I, Dustin ML, Eggeling C, Guck J, Dudziak D

    Dendritic cells (DCs) are professional antigen-presenting cells of the immune system. Upon sensing pathogenic material in their environment, DCs start to mature, which includes cellular processes, such as antigen uptake, processing and presentation, as well as upregulation of costimulatory molecules and cytokine secretion. During maturation, DCs detach from peripheral tissues, migrate to the nearest lymph node, and find their way into the correct position in the net of the lymph node microenvironment to meet and interact with the respective T cells. We hypothesize that the maturation of DCs is well prepared and optimized leading to processes that alter various cellular characteristics from mechanics and metabolism to membrane properties. Here, we investigated the mechanical properties of monocyte-derived dendritic cells (moDCs) using real-time deformability cytometry to measure cytoskeletal changes and found that mature moDCs were stiffer compared to immature moDCs. These cellular changes likely play an important role in the processes of cell migration and T cell activation. As lipids constitute the building blocks of the plasma membrane, which, during maturation, need to adapt to the environment for migration and DC-T cell interaction, we performed an unbiased high-throughput lipidomics screening to identify the lipidome of moDCs. These analyses revealed that the overall lipid composition was significantly changed during moDC maturation, even implying an increase of storage lipids and differences of the relative abundance of membrane lipids upon maturation. Further, metadata analyses demonstrated that lipid changes were associated with the serum low-density lipoprotein (LDL) and cholesterol levels in the blood of the donors. Finally, using lipid packing imaging we found that the membrane of mature moDCs revealed a higher fluidity compared to immature moDCs. This comprehensive and quantitative characterization of maturation associated changes in moDCs sets the stage for improving their use in clinical application.

    Pubmed
  • Editorial: Sentinel CLECs at Immunological Decision Nodes.

    Front Immunol. 2020;11():

    Hoober JK, van Vliet SJ, Dudziak D, Eggink LL

    Pubmed
  • Human Fcγ-receptor IIb modulates pathogen-specific versus self-reactive antibody responses in lyme arthritis.

    Elife. 2020;9():

    Danzer H, Glaesner J, Baerenwaldt A, Reitinger C, Lux A, Heger L, Dudziak D, Harrer T, Gessner A, Nimmerjahn F

    Pathogen-specific antibody responses need to be tightly regulated to generate protective but limit self-reactive immune responses. While loss of humoral tolerance has been associated with microbial infections, the pathways involved in balancing protective versus autoreactive antibody responses in humans are incompletely understood. Studies in classical mouse model systems have provided evidence that balancing of immune responses through inhibitory receptors is an important quality control checkpoint. Genetic differences between inbred mouse models and the outbred human population and allelic receptor variants not present in mice; however, argue for caution when directly translating these findings to the human system. By studying Borrelia burgdorferi infection in humanized mice reconstituted with human hematopoietic stem cells from donors homozygous for a functional or a non-functional FcγRIIb allele, we show that the human inhibitory FcγRIIb is a critical checkpoint balancing protective and autoreactive immune responses, linking infection with induction of autoimmunity in the human immune system.

    Pubmed
  • Nutrition status in patients with wounds: a cross-sectional analysis of

    50 patients with chronic leg ulcers or acute wounds

    Eur J Dermatol. 2019;29(6): 619-626

    Renner R, Garibaldi MD, Benson S, Ronicke M, Erfurt-Berge C

    Background: The possible impact of nutritional status on healing and course of disease in patients with chronic wounds is widely suggested, however, most data are based on small groups of patients with no control group and minor afflictions. Clear diagnostic strategies are missing. Objectives: To analyse in detail the nutritional status of chronic wound patients relative to healthy controls based on a large patient population. Material and Methods: We screened a group of 50 patients for their nutritional status based on body mass index (BMI), the Mini-Nutritional Assessment (MNA), and Nutritional Risk Screening (NRS), as well as additional laboratory investigations. Twenty-five patients suffered from chronic venous leg ulcers and were compared with a matching control group of 25 patients with acute surgical wounds. Results: Patients with chronic venous leg ulcers showed significantly higher BMI, hyperhomo-cysteinaemia, and higher levels of serum copper but significantly lower levels of vitamin B6, B9 and C, as well as a significantly lower level of zinc. Vitamin D deficiency was present in both groups, however, severe vitamin D deficiency was present only in the leg ulcer group. Mobility was significantly reduced in patients with leg ulcers. Conclusion: Ulcer patients are often obese but suffer from qualitative malnutrition, including a lack of vitamin D, which might be explained by reduced mobility and being housebound. Hypoalbuminaemia, as a sign of protein deficiency, was observed significantly more often in patients with chronic leg ulcers, irrespective of wound area or wound duration.

    Pubmed
  • NF-kappa B activation triggers NK-cell stimulation by monocyte-derived

    dendritic cells

    Ther Adv Med Oncol. 2019;11():

    Bosch NC, Voll RE, Voskens CJ, Gross S, Seliger B, Schuler G, Schaft N, Doerrie J

    Background: In therapeutic cancer vaccination, monocyte-derived dendritic cells (moDCs) efficiently activate specific T-cell responses; however, optimizing the activation of innate immune cells could support and improve the antitumor effects. A major disadvantage of moDCs matured with the standard cytokine cocktail (consisting of IL-1 beta, IL-6, TNF alpha, and PGE(2)) is their inability to secrete IL-12p70. IL-12 prominently activates natural killer (NK) cells, which are crucial in innate antitumor immunity, as they act as helper cells for the induction of a cytotoxic T lymphocyte (CTL) response and are also able to directly kill the tumor. Methods: Previously we have shown that triggering the NF-kappa B pathway in moDCs by transfection of mRNA encoding constitutively active IKK beta (caIKK beta) led to IL-12p70 secretion and improved the dendritic cells' capability to activate and expand CTLs with a memory-like phenotype. In this study, we examined whether such dendritic cells could activate autologous NK cells. Results: moDCs matured with the standard cytokine cocktail followed by transfection with the caIKK beta-RNA were able to activate autologous NK cells, detected by the upregulation of CD54, CD69, and CD25 on the NK cells, their ability to secrete IFN gamma, and their high lytic activity. Moreover, the ability of NK-cell activation was not diminished by simultaneous T-cell activation. Conclusion: The capacity of caIKK beta-DCs to activate both the adaptive and innate immune response indicates an enhanced potential for clinical efficacy.

    Pubmed
  • GMP-compliant human monocyte-derived dendritic cells for cancer

    vaccination generated by using the Quantum (R) hollow fiber bioreactor

    system

    Ann Oncol. 2019;30(): 14-14

    Uslu U, Erdmann M, Wiesinger M, Schuler G, Schuler-Thurner B

    Pubmed
  • [Prevalence of an association between coeliac disease and vitiligo].

    Hautarzt. 2019;70(12): 960-963

    Henker J, Hartmann A

    Coeliac disease and vitiligo are immune-mediated disorders that are often associated with other immune-mediated disorders. In a prospective study we included 174 patients with vitiligo between the ages of 3 and 79 years (mean 38.2 years) to investigate whether there is an increased risk for coeliac disease in patients with vitiligo. We determined immunoglobulin A and IgA- and IgG-antibodies against tissue transglutaminase, while also optionally measuring blood count, ferritin, and endomysial-IgA-antibodies. In 3 of 174 (1.7%) vitiligo patients, coeliac disease was diagnosed serologically and by duodenal biopsy. Assuming a coeliac disease prevalence of less than 0.0033%, the incidence is statistically significant. In two other patients with vitiligo, coeliac disease was already known and confirmed with biopsy. If these two patients are included in the calculation, 2.8% (5 von 176) of vitiligo patients have coeliac disease. This value is statistically significant even with a higher coeliac disease prevalence of 0.01. Thus, it is recommended that celiac-disease-specific antibodies also be determined during routine blood workup in vitiligo patients. In case of positive results, a gastroduodenoscopy with biopsy of the small intestine is recommended for diagnosis confirmation. If celiac disease is unlikely, a trial of gluten-free diet for a specific time should nevertheless be discussed with individuals affected by vitiligo because repigmentation appears possible.

    Pubmed
  • Gene expression and promoter methylation of angiogenic and lymphangiogenic factors as prognostic markers in melanoma.

    Mol Oncol. 2019;13(6): 1433-1449

    Monteiro AC, Muenzner JK, Andrade F, Rius FE, Ostalecki C, Geppert CI, Agaimy A, Hartmann A, Fujita A, Schneider-Stock R, Jasiulionis MG

    The high mortality rate of melanoma is broadly associated with its metastatic potential. Tumor cell dissemination is strictly dependent on vascularization; therefore, angiogenesis and lymphangiogenesis play an essential role in metastasis. Hence, a better understanding of the players of tumor vascularization and establishing them as new molecular biomarkers might help to overcome the poor prognosis of melanoma patients. Here, we further characterized a linear murine model of melanoma progression and showed that the aggressiveness of melanoma cells is closely associated with high expression of angiogenic factors, such as Vegfc, Angpt2, and Six1, and that blockade of the vascular endothelial growth factor pathway by the inhibitor axitinib abrogates their tumorigenic potential in vitro and in the in vivo chicken chorioallantoic membrane assay. Furthermore, analysis of The Cancer Genome Atlas data revealed that the expression of the angiogenic factor ANGPT2 (P-value = 0.044) and the lymphangiogenic receptor VEGFR-3 (P-value = 0.002) were independent prognostic factors of overall survival in melanoma patients. Enhanced reduced representation bisulfite sequencing-based methylome profiling revealed for the first time a link between abnormal VEGFC, ANGPT2, and SIX1 gene expression and promoter hypomethylation in melanoma cells. In patients, VEGFC (P-value = 0.031), ANGPT2 (P-value < 0.001), and SIX1 (P-value = 0.009) promoter hypomethylation were independent prognostic factors of shorter overall survival. Hence, our data suggest that these angio- and lymphangiogenesis factors are potential biomarkers of melanoma prognosis. Moreover, these findings strongly support the applicability of our melanoma progression model to unravel new biomarkers for this aggressive human disease.

    Pubmed
  • Peripheral PD-1+CD56+ T-cell frequencies correlate with outcome in stage IV melanoma under PD-1 blockade.

    PLoS ONE. 2019;14(8):

    Bochem J, Zelba H, Amaral T, Spreuer J, Soffel D, Eigentler T, Wagner NB, Uslu U, Terheyden P, Meier F, Garbe C, Pawelec G, Weide B, Wistuba-Hamprecht K

    Immune checkpoint blockade with anti-PD-1 antibodies is showing great promise for patients with metastatic melanoma and other malignancies, but despite good responses by some patients who achieve partial or complete regression, many others still do not respond. Here, we sought peripheral blood T-cell biomarker candidates predicting treatment outcome in 75 stage IV melanoma patients treated with anti-PD-1 antibodies. We investigated associations with clinical response, progression-free survival (PFS) and overall survival (OS). Univariate analysis of potential biological confounders and known biomarkers, and a multivariate model, was used to determine statistical independence of associations between candidate biomarkers and clinical outcomes. We found that a lower than median frequency of peripheral PD-1+CD56+ T-cells was associated with longer OS (p = 0.004), PFS (p = 0.041) and superior clinical benefit (p = 0.009). However, neither frequencies of CD56-CD4+ nor CD56-CD8+ T-cells, nor of the PD-1+ fraction within the CD4 or CD8 subsets was associated with clinical outcome. In a multivariate model with known confounders and biomarkers only the M-category (HR, 3.11; p = 0.007) and the frequency of PD-1+CD56+ T-cells (HR, 2.39; p = 0.028) were identified as independent predictive factors for clinical outcome under PD-1 blockade. Thus, a lower than median frequency of peripheral blood PD-1+CD56+ T-cells prior to starting anti-PD-1 checkpoint blockade is associated with superior clinical response, longer PFS and OS of stage IV melanoma patients.

    Pubmed
  • Innate extracellular vesicles from melanoma patients suppress β-catenin in tumor cells by miRNA-34a.

    Life Sci Alliance. 2019;2(2):

    Lee JH, Dindorf J, Eberhardt M, Lai X, Ostalecki C, Koliha N, Gross S, Blume K, Bruns H, Wild S, Schuler G, Vera J, Baur AS

    Upon tumor development, new extracellular vesicles appear in circulation. Our knowledge of their relative abundance, function, and overall impact on cancer development is still preliminary. Here, we demonstrate that plasma extracellular vesicles (pEVs) of non-tumor origin are persistently increased in untreated and post-excision melanoma patients, exhibiting strong suppressive effects on the proliferation of tumor cells. Plasma vesicle numbers, miRNAs, and protein levels were elevated two- to tenfold and detected many years after tumor resection. The vesicles revealed individual and clinical stage-specific miRNA profiles as well as active ADAM10. However, whereas pEV from patients preventing tumor relapse down-regulated β-catenin and blocked tumor cell proliferation in an miR-34a-dependent manner, pEV from metastatic patients lost this ability and stimulated β-catenin-mediated transcription. Cancer-induced pEV may constitute an innate immune mechanism suppressing tumor cell activity including that of residual cancer cells present after primary surgery.

    Pubmed
  • Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors.

    Eur J Cancer. 2019;106(): 12-23

    Moreira A, Loquai C, Pföhler C, Kähler KC, Knauss S, Heppt MV, Gutzmer R, Dimitriou F, Meier F, Mitzel-Rink H, Schuler G, Terheyden P, Thoms KM, Türk M, Dummer R, Zimmer L, Schröder R, Heinzerling L

    AIM: To characterise clinical presentation, laboratory and histopathologic characteristics and assess the treatment and outcome of neuromuscular side-effects of checkpoint therapy.

    METHODS: The side-effect registry and the institutional database from ten skin cancer centres were queried for reports on myositis and neuromuscular side-effects induced by checkpoint inhibitors. In total, 38 patients treated with ipilimumab, tremelimumab, nivolumab and pembrolizumab for metastatic skin cancer were evaluated and characterised.

    RESULTS: Myositis was the most frequent neuromuscular adverse event. In 32% of cases, myositis was complicated by concomitant myocarditis. Furthermore, cases of isolated myocarditis, myasthenia gravis, polymyalgia rheumatica, radiculoneuropathy and asymptomatic creatine kinase elevation were reported. The onset of side-effects ranged from the first week of treatment to 115 weeks after the start of therapy. Most of the cases were severe (49% grade III-IV Common Terminology Criteria for Adverse Events), and there were two fatalities (5%) due to myositis and myositis with concomitant myocarditis. Only half of the cases (50%) completely resolved, whereas the rest was either ongoing or had sequelae. Steroids were given in 80% of the resolved cases and in 40% of the unresolved cases.

    CONCLUSION: Immune-mediated neuromuscular side-effects of checkpoint inhibitors greatly vary in presentation and differ from their idiopathic counterparts. These side-effects can be life threatening and may result in permanent sequelae. Occurrence of these side-effects must be taken into consideration for patient information, especially when considering adjuvant immunotherapy with anti-programmed cell-death protein 1 (PD-1) antibodies and monitoring, which should include regular surveillance of creatine kinase.

    Pubmed
  • Age as key factor for pattern, timing, and extent of distant metastasis in patients with cutaneous melanoma: A study of the German Central Malignant Melanoma Registry.

    J Am Acad Dermatol. 2019;80(5): 1299-1307.e7

    Gassenmaier M, Keim U, Leiter U, Eigentler TK, Röcken M, Gesierich A, Moritz RKC, Heinzerling L, Tüting T, Wollina U, Garbe C

    BACKGROUND: Melanoma incidence rates rise as people age, but the impact of aging on distant metastasis is unclear.

    OBJECTIVE: To investigate how timing, pattern, and extent of distant metastasis is influenced by age.

    METHODS: Analysis of a single-center cohort of 1457 patients of the German Central Malignant Melanoma Registry with prospectively documented follow-up. Findings were compared with those for 1682 patients from 5 different institutions. All patients presented initially with stage IA to IIC and developed distant metastasis in their further disease course.

    RESULTS: The number of metastatic sites decreased with increasing age at melanoma diagnosis (P < .001). The rate of stage M1d disease decreased from 50.2% in patients aged 50 years or younger to 30.1% in patients older than 70 years, and the rate of stage M1b disease increased from 5.8% to 21.5%. The rate of lung metastases remained stable in all investigated age groups (P = .54). Distant metastases occurred earlier and were more synchronized in patients older than 70 years than in patients aged 50 years or younger. An age-dependent decrease in metastatic sites and stable rate of lung metastasis were found and confirmed by data on the multi-institutional cohort.

    LIMITATIONS: The study was not population based.

    CONCLUSION: Pattern, timing, and extent of distant metastasis change as people age. These findings may be considered when treating patients with melanoma of different ages.

    Pubmed
  • Sequence-dependent cross-resistance of combined radiotherapy plus BRAFV600E inhibition in melanoma.

    Eur J Cancer. 2019;109(): 137-153

    Shannan B, Matschke J, Chauvistré H, Vogel F, Klein D, Meier F, Westphal D, Bruns J, Rauschenberg R, Utikal J, Forschner A, Berking C, Terheyden P, Dabrowski E, Gutzmer R, Rafei-Shamsabadi D, Meiss F, Heinzerling L, Zimmer L, Livingstone E, Váraljai R, Hoewner A, Horn S, Klode J, Stuschke M, Scheffler B, Marchetto A, Sannino G, Grünewald TGP, Schadendorf D, Jendrossek V, Roesch A

    INTRODUCTION: Treatment of patients with metastatic melanoma is hampered by drug-resistance and often requires combination with radiotherapy as last-resort option. However, also after radiotherapy, clinical relapses are common.

    METHODS & RESULTS: Our preclinical models indicated a higher rate of tumour relapse when melanoma cells were first treated with BRAFV600E inhibition (BRAFi) followed by radiotherapy as compared to the reverse sequence. Accordingly, retrospective follow-up data from 65 stage-IV melanoma patients with irradiated melanoma brain metastases confirmed a shortened duration of local response of mitogen-activated protein kinase (MAPK)-inhibitor-pretreated compared with MAPK-inhibitor-naïve intracranial metastases. On the molecular level, we identified JARID1B/KDM5B as a cellular marker for cross-resistance between BRAFi and radiotherapy. JARID1Bhigh cells appeared more frequently under upfront BRAFi as compared with upfront radiation. JARID1B favours cell survival by transcriptional regulation of genes controlling cell cycle, DNA repair and cell death.

    CONCLUSION: The level of cross-resistance between combined MAPK inhibition and radiotherapy is dependent on the treatment sequence. JARID1B may represent a novel therapy-overarching resistance marker.

    Pubmed
  • Prediction of melanoma evolution in melanocytic nevi via artificial intelligence: A call for prospective data.

    Eur J Cancer. 2019;119(): 30-34

    Sondermann W, Utikal JS, Enk AH, Schadendorf D, Klode J, Hauschild A, Weichenthal M, French LE, Berking C, Schilling B, Haferkamp S, Fröhling S, von Kalle C, Brinker TJ

    Recent research revealed the superiority of artificial intelligence over dermatologists to diagnose melanoma from images. However, 30-50% of all melanomas and more than half of those in young patients evolve from initially benign lesions. Despite its high relevance for melanoma screening, neither clinicians nor computers are yet able to reliably predict a nevus' oncologic transformation. The cause of this lies in the static nature of lesion presentation in the current standard of care, both for clinicians and algorithms. The status quo makes it difficult to train algorithms (and clinicians) to precisely assess the likelihood of a benign skin lesion to transform into melanoma. In addition, it inhibits the precision of current algorithms since 'evolution' image features may not be part of their decision. The current literature reveals certain types of melanocytic nevi (i.e. 'spitzoid' or 'dysplastic' nevi) and criteria (i.e. visible vasculature) that, in general, appear to have a higher chance to transform into melanoma. However, owing to the cumulative nature of oncogenic mutations in melanoma, a more fine-grained early morphologic footprint is likely to be detectable by an algorithm. In this perspective article, the concept of melanoma prediction is further explored by the discussion of the evolution of melanoma, the concept for training of such a nevi classifier and the implications of early melanoma prediction for clinical practice. In conclusion, the authors believe that artificial intelligence trained on prospective image data could be transformative for skin cancer diagnostics by (a) predicting melanoma before it occurs (i.e. pre-in situ) and (b) further enhancing the accuracy of current melanoma classifiers. Necessary prospective images for this research are obtained via free mole-monitoring mobile apps.

    Pubmed
  • Checkpoint Inhibitors.

    Dtsch Arztebl Int. 2019;116(8): 119-126

    Heinzerling L, De Toni EN, Schett G, Hundorfean G, Zimmer L

    BACKGROUND: Treatment with checkpoint inhibitors such as anti-programmed death-1 (anti-PD-1), anti-PD-ligand 1 (anti-PD-L1), and anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) antibodies can prolong the survival of cancer patients, but it also induces autoimmune side effects in 86-96% of patients by activating the immune system. In 17-59% of patients, these are severe or even life-threatening.

    METHODS: This review is based on pertinent articles retrieved by a search in PubMed and on an evaluation of a side-effect registry.

    RESULTS: Checkpoint-inhibitor-induced autoimmune side effects manifest themselves in all organ systems, most commonly as skin lesions (46-62%), autoimmune colitis (22-48%), autoimmune hepatitis (7-33%), and endocrinopathies (thyroiditis, hypophysitis, adrenalitis, diabetes mellitus; 12-34%). Rarer side effects include pneumonitis (3-8%), nephritis (1-7%), cardiac side effects including cardiomyositis (5%), and neurological side effects (1-5%). Severe (sometimes lethal) side effects arise in 17-21%, 20-28%, and 59% of patients undergoing anti-PD-1 and anti- CTLA-4 antibody treatment and the approved combination therapy, respectively. With proper monitoring, however, these side effects can be recognized early and, usually, treated with success. Endocrine side effects generally require long-term hormone substitution. Patients who have stopped taking checkpoint inhibitors because of side effects do not show a poorer response of their melanoma or shorter survival in comparison to patients who continue to take checkpoint inhibitors.

    CONCLUSION: The complex management of checkpoint-inhibitor-induced side effects should be coordinated in experienced centers. The creation of an interdisciplinary "tox team" with designated experts for organ-specific side effects has proven useful. Prospective registry studies based on structured documentation of side effects in routine clinical practice are currently lacking and urgently needed.

    Pubmed
  • Chronic hand eczema in Germany: 5-year follow-up data from the CARPE registry.

    Contact Dermatitis. 2019;80(1): 45-53

    Apfelbacher CJ, Ofenloch RF, Weisshaar E, Molin S, Bauer A, Mahler V, Heinrich A, von Kiedrowski R, Schmitt J, Elsner P, Diepgen TL

    The CARPE registry was set up in 2009 to prospectively investigate the management of patients with chronic hand eczema (CHE).To report comprehensive follow-up data from the CARPE registry.We investigated sociodemographic and clinical characteristics, provision of medical care, physician-assessed outcomes, and patient-reported outcomes (PROs). Data were collected between 2009 and 2016, with up to 5 years of follow-up, and are reported descriptively.Overall, 1281 patients were included in the registry (53.7% female). Mean age was 47.0 years. Of the patients, 793 and 231 completed the 2-year follow-up and 5-year follow-up, respectively. At baseline, 5.4% had changed or given up their job because of CHE, the average duration of CHE was 6.1 years, and, in 22.4%, the CHE was severe according to physician global assessment. Systemic treatment (alitretinoin, acitretin, and methotrexate) was prescribed at least once to 39.0% of the patients during the course of the follow-up. Disease severity, quality of life and treatment satisfaction improved over time, and the proportion of patients receiving systemic treatments decreased.Under continued dermatological care, substantial improvements in disease severity and PROs over time was achieved during the course of the CARPE registry, even in patients with long-standing and severe hand eczema.

    Pubmed
  • Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management.

    ESMO Open. 2019;4(3):

    Heinzerling L, Eigentler TK, Fluck M, Hassel JC, Heller-Schenck D, Leipe J, Pauschinger M, Vogel A, Zimmer L, Gutzmer R

    The inhibition of the mitogen-activated protein kinases signalling pathway through combined use of BRAF and MEK inhibitors (BRAFi+MEKi) represents an established therapeutic option in patients with BRAF-mutated, advanced melanoma. These efficient therapies are well tolerated with mostly moderate and reversible side effects and a discontinuation rate due to adverse events of 11.5%-15.7%. Median duration of therapy ranges between 8.8 and 11.7 months. Based on data from confirmatory trials, safety profiles of three BRAFi+MEKi combinations were reviewed, that is, dabrafenib plus trametinib, vemurafenib plus cobimetinib and encorafenib plus binimetinib. Many adverse events are class effects, such as cutaneous, gastrointestinal, ocular, cardiac and musculoskeletal events; some adverse events are substance associated. Fever (dabrafenib) and photosensitivity (vemurafenib) are the most common and clinically prominent examples. Other adverse events are less frequent and the association to one substance is less strong such as anaemia, facial paresis (encorafenib), neutropenia (dabrafenib), skin rash, QTc prolongation and increased liver function tests (vemurafenib). This narrative review provides recommendations for monitoring, adverse event evaluation and management focusing on the clinically relevant side effects of the three regimens.

    Pubmed
  • Generation of an Oncolytic Herpes Simplex Virus 1 Expressing Human MelanA.

    Front Immunol. 2019;10():

    Boscheinen JB, Thomann S, Knipe DM, DeLuca N, Schuler-Thurner B, Gross S, Dörrie J, Schaft N, Bach C, Rohrhofer A, Werner-Klein M, Schmidt B, Schuster P

    Robust anti-tumor immunity requires innate as well as adaptive immune responses. We have shown that plasmacytoid dendritic cells develop killer cell-like activity in melanoma cell cocultures after exposure to the infectious but replication-deficient herpes simplex virus 1 (HSV-1) d106S. To combine this innate effect with an enhanced adaptive immune response, the gene encoding human MelanA/MART-1 was inserted into HSV-1 d106S via homologous recombination to increase direct expression of this tumor antigen. Infection of Vero cells using this recombinant virus confirmed MelanA expression by Western blotting, flow cytometry, and immunofluorescence. HSV-1 d106S-MelanA induced expression of the transgene in fibroblast and melanoma cell lines not naturally expressing MelanA. Infection of a melanoma cell line with CRISPR-Cas9-mediated knockout of MelanA confirmed de novo expression of the transgene in the viral context. Dependent on MelanA expression, infected fibroblast and melanoma cell lines induced degranulation of HLA-matched MelanA-specific CD8+ T cells, followed by killing of infected cells. To study infection of immune cells, we exposed peripheral blood mononuclear cells and in vitro-differentiated macrophages to the parental HSV-1 d106S, resulting in expression of the transgene GFP in CD11c+ cells and macrophages. These data provide evidence that the application of MelanA-encoding HSV-1 d106S could enhance adaptive immune responses and re-direct MelanA-specific CD8+ T cells to tumor lesions, which have escaped adaptive immune responses via downregulation of their tumor antigen. Hence, HSV-1 d106S-MelanA harbors the potential to induce innate immune responses in conjunction with adaptive anti-tumor responses by CD8+ T cells, which should be evaluated in further studies.

    Pubmed
  • Arming T Cells with a gp100-Specific TCR and a CSPG4-Specific CAR Using

    Combined DNA- and RNA-Based Receptor Transfer

    Cancers. 2019;11(5):

    Simon B, Harrer DC, Schuler-Thurner B, Schuler G, Uslu U

    Tumor cells can develop immune escape mechanisms to bypass T cell recognition, e.g., antigen loss or downregulation of the antigen presenting machinery, which represents a major challenge in adoptive T cell therapy. To counteract these mechanisms, we transferred not only one, but two receptors into the same T cell to generate T cells expressing two additional receptors (TETARs). We generated these TETARs by lentiviral transduction of a gp100-specific T cell receptor (TCR) and subsequent electroporation of mRNA encoding a second-generation CSPG4-specific chimeric antigen receptor (CAR). Following pilot experiments to optimize the combined DNA- and RNA-based receptor transfer, the functionality of TETARs was compared to T cells either transfected with the TCR only or the CAR only. After transfection, TETARs clearly expressed both introduced receptors on their cell surface. When stimulated with tumor cells expressing either one of the antigens or both, TETARs were able to secrete cytokines and showed cytotoxicity. The confirmation that two antigen-specific receptors can be functionally combined using two different methods to introduce each receptor into the same T cell opens new possibilities and opportunities in cancer immunotherapy. For further evaluation, the use of these TETARs in appropriate animal models will be the next step towards a potential clinical use in cancer patients.

    Pubmed
  • Enhancing lentiviral transduction to generate melanoma-specific human T

    cells for cancer immunotherapy

    J Immunol Methods. 2019;472(): 55-64

    Simon B, Harrer DC, Thirion C, Schuler-Thurner B, Schuler G, Uslu U

    Introduction of a tumor antigen-specific T cell receptor (TCR) into patient-derived lymphocytes has already exhibited promising results for the treatment of melanoma and other malignancies in clinical trials. However, insufficient or unsuccessful ex vivo manufacturing of engineered T cells due to low expansion and/or transduction rate can still be observed in some patients. Thus, we isolated human CD8(+) T cells from healthy donors and equipped them with a gp100-specific TCR using a lentiviral construct in combination with a novel chemical lentiviral transduction enhancer (Lentiboost) to increase the rate of transduced cells. Following experiments to determine the ideal multiplicity of infection (MOI) and to analyze the efficacy of the transduction enhancer using a GFP-encoding lentivirus, we analyzed in the next step the transduction rate, cell count, and functionality of gp100 TCR-transduced T cells, i.e. antigen-specific cytokine secretion and lyric capacity. In order to increase the number of transduced cells, antigen-specific stimulation was performed, either once for 1 week (1st activation) or twice for another week (2nd activation). In general, each cycle of antigen-specific stimulation resulted in expansion of TCR-positive cells, while no further significant increase of transduced cells was observed after 2nd activation. Cytokine production pattern of transduced cells after antigen encounter, however, revealed significant antigen-specific secretion of TNF and IFN gamma after the 1st as well as the 2nd activation. Furthermore, TCR T cells, either activated once or twice, showed significant cytotoxicity towards antigen-positive tumor cells. Taken together, these results show that it is feasible to transduce human T cells using a lentiviral construct in combination with this novel lentiviral transduction enhancer, which shows potential in the growing field of cancer immunotherapy.

    Pubmed
  • Panniculitis Under Successful Targeted Inhibition of the MAPK/ERK

    Signaling Pathway in a Patient With BRAF V600E-mutated Spindle Cell

    Oncocytoma of the Pituitary Gland

    Anticancer Res. 2019;39(7): 3955-3959

    Sollfrank L, Lettmaier S, Erdmann M, Uslu U

    Background: Spindle cell oncocytoma (SCO) is a rare non-neuroendocrine neoplasm of the pituitary gland. In general, surgical excision and radiation therapy is performed. However, local recurrences are frequently seen, requiring repeated surgical and radio-oncological interventions. Thus, mutational analysis of the tumor and targeted therapy may represent a valuable therapy option in these patients. Case Report: A 38-year-old female patient with past medical history of 6 surgeries (two transsphenoidal and four transcranial), radiation therapy, and chemoradiation therapy due to several recurrences of a SCO, presented for follow-up imaging. MRI of the brain showed growth of a tumor in the right parasellar region consistent with a new local recurrence, which due to its size and location was considered to be not resectable. Molecular analysis of a previously surgically removed tumor showed a BRAF V600E mutation and thus, combined targeted inhibition of the MAPK/ERK signaling pathway using a BRAF inhibitor and a MEK inhibitor was started. Due to drug-induced panniculitis, MEK inhibitor had to be stopped and BRAF inhibitor only was continued, which was well tolerated by the patient. Subsequent imaging revealed tumor regression already four weeks after therapy initiation and no disease progression has been observed to date. Conclusion: A SCO patient with BRAF V600E mutation was successfully treated using targeted inhibition of the MAPK/ERK signaling pathway. Under therapy, tumor regression was observed and the patient has been free of progressive disease for more than two years now. Thus, mutational analysis and targeted inhibition may offer an effective treatment option for SCO patients, while potential side-effects to this therapy, like observed in our case, can occur and needs to be adequately treated.

    Pubmed
  • Senescence markers: Predictive for response to checkpoint inhibitors

    Int J Cancer. 2019;144(5): 1147-1150

    Moreira A, Gross S, Kirchberger MC, Erdmann M, Schuler G, Heinzerling L

    Recent studies suggest that the age-related remodeling of the immune system, known as immunosenescence, could impact the efficacy of immune checkpoint inhibitors in leukemia or nonsmall cell lung cancer. We investigated whether senescence markers can predict response to checkpoint inhibitor therapy in melanoma patients. The peripheral blood of patients with newly diagnosed, untreated metastatic melanoma was analyzed by flow cytometry to correlate the frequency of senescence markers with clinical response as measured by RECIST after 12 weeks of treatment with immune checkpoint inhibitors. The loss of surface markers CD27 and CD28 or the expression of Tim-3 and CD57 on T cells was associated with resistance to checkpoint inhibitor blockade, presenting these phenotypes as possible predictive biomarkers for checkpoint inhibitor therapy. Immunosenescence seems to impact on the response to checkpoint inhibitor therapy in melanoma patients. Thus, lymphocyte phenotyping for senescence markers, with the introduction of immunosenescence panels, could be predictive for checkpoint inhibitor response.

    Pubmed
  • Eosinophilic polymorphic and pruritic eruption associated with radiotherapy: case report and overview of disease characteristics.

    Clin Exp Dermatol. 2019;44(5): 567-569

    Loebelenz L, Schliep S, Woerl P, Uslu U

    Click for the corresponding questions to this CME article.

    Pubmed
  • Engulfment of mast cell secretory granules on skin inflammation boosts dendritic cell migration and priming efficiency.

    J Allergy Clin Immunol. 2019;143(5): 1849-1864.e4

    Dudeck J, Froebel J, Kotrba J, Lehmann CHK, Dudziak D, Speier S, Nedospasov SA, Schraven B, Dudeck A

    BACKGROUND: Mast cells (MCs) are best known as key effector cells of allergic reactions, but they also play an important role in host defense against pathogens. Despite increasing evidence for a critical effect of MCs on adaptive immunity, the underlying mechanisms are poorly understood.

    OBJECTIVE: Here we monitored MC intercellular communication with dendritic cells (DCs), MC activation, and degranulation and tracked the fate of exocytosed mast cell granules (MCGs) during skin inflammation.

    METHODS: Using a strategy to stain intracellular MCGs in vivo, we tracked the MCG fate after skin inflammation-induced MC degranulation. Furthermore, exogenous MCGs were applied to MC-deficient mice by means of intradermal injection. MCG effects on DC functionality and adaptive immune responses in vivo were assessed by combining intravital multiphoton microscopy with flow cytometry and functional assays.

    RESULTS: We demonstrate that dermal DCs engulf the intact granules exocytosed by MCs on skin inflammation. Subsequently, the engulfed MCGs are actively shuttled to skin-draining lymph nodes and finally degraded inside DCs within the lymphoid tissue. Most importantly, MCG uptake promotes DC maturation and migration to skin-draining lymph nodes, partially through MC-derived TNF, and boosts their T-cell priming efficiency. Surprisingly, exogenous MCGs alone are sufficient to induce a prominent DC activation and T-cell response.

    CONCLUSION: Our study highlights a unique feature of peripheral MCs to affect lymphoid tissue-borne adaptive immunity over distance by modifying DC functionality through delivery of granule-stored mediators.

    Pubmed
  • Nachwuchs für die Dermatologie begeistern: Die DDG auf dem Bundeskongress der Bundesvertretung der Medizinstudierenden in Deutschland e. V.

    J Dtsch Dermatol Ges. 2019;17(2):

    Hüning S, Rode S, Nashan D, Emmert S, Uslu U

    Pubmed
  • Eosinophil-cationic protein - a novel liquid prognostic biomarker in

    melanoma

    BMC Cancer. 2019;19():

    Krueckel A, Moreira A, Froehlich W, Schuler G, Heinzerling L

    BackgroundThe role of eosinophils in cancer is not yet completely understood, but patients with eosinophilia show a trend towards longer survival in several types of cancer, including melanoma. However, eosinophil count at initial diagnosis of metastatic melanoma does not predict survival. Since eosinophil cationic protein (ECP) mediates anticancer effects, such as tissue remodelling and cytotoxic activity, we investigated this marker as an early prognostic marker in metastatic melanoma.MethodsSerum of 56 melanoma patients was collected at the time of diagnosis of metastatic disease. ECP levels as measured by ELISA were correlated with overall survival (OS) in patients before systemic therapy with immunotherapy or chemotherapy. Statistical analyses were performed using the Log-Rank (Mantel-Cox) test.ResultsThe median OS for patients with high serum ECP above 12.2ng/ml was 12months (n=39), compared to 28months for patients with ECP below this threshold (n=17; p=0.0642). In patients with cutaneous melanoma, excluding patients with uveal and mucosal melanoma, the survival difference was even more striking (p=0.0393). ECP's effect size on OS was observed independently of the consecutive therapy. ECP levels were not correlated with LDH levels.ConclusionECP seems to be a novel prognostic serum marker for the outcome of melanoma patients, which is independent of LDH and easy to perform in clinical practice. The striking negative prognostic value of high ECP level is unanticipated and can guide patient management.

    Pubmed
  • Clinical-Scale Production of CAR-T Cells for the Treatment of Melanoma

    Patients by mRNA Transfection of a CSPG4-Specific CAR under Full GMP

    Compliance

    Cancers (Basel). 2019;11(8):

    Wiesinger M, Maerz J, Kummer M, Schuler G, Doerrie J, Schuler-Thurner B, Schaft N

    Chimeric antigen receptor (CAR)-T cells already showed impressive clinical regressions in leukemia and lymphoma. However, the development of CAR-T cells against solid tumors lags behind. Here we present the clinical-scale production of CAR-T cells for the treatment of melanoma under full GMP compliance. In this approach a CAR, specific for chondroitin sulfate proteoglycan 4 (CSPG4) is intentionally transiently expressed by mRNA electroporation for safety reasons. The clinical-scale protocol was optimized for: (i) expansion of T cells, (ii) electroporation efficiency, (iii) viability, (iv) cryopreservation, and (v) potency. Four consistency runs resulted in CAR-T cells in clinically sufficient numbers, i.e., 2.4 x 10(9) CAR-expressing T cells, starting from 1.77x10(8)PBMCs, with an average expansion of 13.6x, an electroporation efficiency of 88.0% CAR-positive cells, a survival of 74.1% after electroporation, and a viability of 84% after cryopreservation. Purity was 98.7% CD3(+) cells, with 78.1% CD3(+)/CD8(+) T cells and with minor contaminations of 1.2% NK cells and 0.6% B cells. The resulting CAR-T cells were tested for cytolytic activity after cryopreservation and showed antigen-specific and very efficient lysis of tumor cells. Although our work is descriptive rather than investigative in nature, we expect that providing this clinically applicable protocol to generate sufficient numbers of mRNA-transfected CAR-T cells will help in moving the field of adoptive cell therapy of cancer forward.

    Pubmed
  • CSPG4-Specific CAR T Cells for High-Risk Childhood B Cell Precursor Leukemia.

    Int J Mol Sci. 2019;20(11):

    Harrer DC, Schuler G, Doerrie J, Schaft N

    The advent of CD19-specific chimeric antigen receptor (CAR) T cells has proven to be a powerful asset in the arsenal of cancer immunotherapy of acute lymphoblastic leukemia and certain B cell lymphomas. However, a sizable portion of patients treated with CD19-CAR T cells relapse with CD19-negative cancer cells, necessitating the quest for back-up antigens. Chondroitin sulfate proteoglycan 4 (CSPG4) expression has been reported on leukemic blasts bearing the ill-fated MLL 11q23 rearrangement. We aimed at exploring the use of CSPG4-specific CAR T cells against mixed-lineage leukemia (MLL)-rearranged leukemic blasts, using the precursor B cell leukemia cell line KOPN8 (MLL-MLLT1 translocation) as a model. First, we confirmed CSPG4 expression on KOPN8 cells. Bulk T cells electroporated with mRNA encoding a CSPG4-specific CAR upregulated activation markers and secreted the Th1 cytokines TNF and IFNγ in an antigen-specific manner upon co-culture with KOPN8 cells. More importantly, CSPG4-specific CAR T cells evinced specific degranulation towards KOPN8 cells and specifically lysed KOPN8 target cells in chromium lysis experiments. CSPG4 is a well-established CAR target in cutaneous melanoma. Here, we provide proof-of-principle data for the use of CSPG4-specific CAR T cells against MLL-translocated leukemias.

    Pubmed
  • Characterization of tanning behavior assessed via online survey:

    Attitudes, habits, and preventive measures with focus on sunscreen use

    Photodermatol Photoimmunol Photomed. 2019;35(4): 268-274

    Schneiderbanger CK, Schuler G, Heinzerling L, Kirchberger MC

    Background/purpose Incidence of melanoma is increasing globally. Exposure to ultraviolet radiation (UVR) as important risk factor for developing skin cancer can be influenced by tanning behavior. Only a few studies are available concerning sun tanning behavior and protective measures. Methods An online survey was distributed via social media to assess tanning habits and examine associated demographic and behavioral factors. Results In total, 403 questionnaires were distributed, and mean age of respondents was 32. Having a tanned skin, feeling warm and relaxed were the most common motivations for tanning. The use of sunscreen varied and seemed to depend on the occasion of UVR exposure, constantly applied during vacation and during tanning, less commonly applied in daily life and during work. Avoiding painful solar dermatitis was more important as motivation for the use of sunscreen than skin cancer prevention. Skin aging as reason for the use of sunscreen was especially important for females younger than 26 years. The most common applied sun protection factor was 16-49. The main reason opposing the use of sunscreen was a too laborious usage, which was significantly associated with male. Beauty was the only association related to tanned skin the majority (62%) agreed with. Conclusion The motivation for tanning and reasons for avoiding sunscreen strongly varies. Knowledge about these factors could be used for improving campaigns with respect to target groups. Clarifying the appropriate application of sunscreen, developing convenient sunscreen formulations and providing information about UVR-induced skin aging could lead to an increased usage of sunscreen and therefore to an improved UVR protection.

    Pubmed
  • Detection and Characterization of Circulating Tumor Cells in Patients

    with Merkel Cell Carcinoma

    Clin Chem. 2019;65(3): 462-472

    Riethdorf S, Hildebrandt L, Heinzerling L, Heitzer E, Fischer N, Bergmann S, Mauermann O, Waldispuehl-Geigl J, Coith C, Schoen G, Peine S, Schuler G, Speicher MR, Moll I, Pantel K

    BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with increasing incidence and high mortality rates. MCC has recently become the subject of immune checkpoint therapy, but reliable biomarkers for estimating prognosis, risk stratification, and prediction of response are missing.

    METHODS: Circulating tumor cells (CTCs) were detected in peripheral blood from patients with MCC by use of the CellSearch (R) system. Moreover, CTCs of selected cases were characterized for Merkel cell polyomavirus (MCPyV), chromosomal aberrations, and programed death ligand 1 (PD-L1) production.

    RESULTS: Fifty-one patients were tested at first blood draw (baseline), and 16 patients had 2 or 3 consecutive measurements to detect CTCs. At baseline, >= 1 CTC (range, 1-790), >1, or >= 5 CTCs/7.5 mL were detected in 21 (41%), 17 (33%), and 6 (12%) patients, respectively. After a median follow-up of 21.1 months for 50 patients, detection of CTCs correlated with overall survival (>= 1, P = 0.030; >1, P = 0.020; and >= 5 CTCs/7.5 mL, P = 0.0001). In multivariate Cox regression analysis, the detection of >= 5 CTCs/7.5 mL adjusted to age and sex compared to that of <5 was associated with a reduced overall survival (P = 0.001, hazard ratio = 17.8; 95% CI, 4.0 -93.0). MCPyV DNA and genomic aberrations frequently found in MCC tissues could also be detected in single CTCs. Analyzed CTCs were PD-L1 negative or only weakly positive.

    CONCLUSIONS: The presence of CTCs is a prognostic factor of impaired clinical outcome, with the potential to monitor the progression of the disease in real time. Molecular characterization of CTCs might provide new insights into the biology of MCC. (c) 2018 American Association for Clinical Chemistry

    Pubmed
  • Curatopes Melanoma: A Database of Predicted T-cell Epitopes from Overly

    Expressed Proteins in Metastatic Cutaneous Melanoma

    Cancer Res. 2019;79(20): 5452-5456

    Lischer C, Eberhardt M, Jaitly T, Schinzel C, Schaft N, Dorrie J, Schuler G, Vera J

    Therapeutic anticancer vaccination has been adapted as an immunotherapy in several solid tumors. However, the selection of promising candidates from the total quantity of possible epitopes poses a challenge to clinicians and bioinformaticians alike, and very few epitopes have been tested in experimental or clinical settings to validate their efficacy. Here, we present a comprehensive database of predicted nonmutated peptide epitopes derived from genes that are overly expressed in a group of 32 melanoma biopsies compared with healthy tissues and that were filtered against expression in a curated list of survival-critical tissues. We hypothesize that these "self-tolerant" epitopes have two desirable properties: they do not depend on mutations, being immediately applicable to a large patient collective, and they potentially cause fewer autoimmune reactions. To support epitope selection, we provide an aggregated score of expected therapeutic efficiency as a shortlist mechanism. The database has applications in facilitating epitope selection and trial design and is freely accessible at www.curatopes.com.

    Significance: A database is presented that predicts and scores antitumor T-cell epitopes, with a focus on tolerability and avoidance of severe autoimmunity, offering a supplementary epitope set for further investigation in immunotherapy.

    Pubmed
  • S2k guidelines for the treatment of psoriasis in children and adolescents - Short version part 2.

    J Dtsch Dermatol Ges. 2019;17(9): 959-973

    Eisert L, Augustin M, Bach S, Dittmann M, Eiler R, Fölster-Holst R, Gerdes S, Hamm H, Höger P, Horneff G, von Kiedrowski R, Philipp S, Pleimes M, Schlaeger M, Schuster V, Staubach P, Weberschock T, Werner RN, Nast A, Sticherling M

    The present guidelines are aimed at residents and board-certified physicians in the fields of dermatology, pediatrics, pediatric dermatology and pediatric rheumatology as well as policymakers and insurance funds. They were developed by dermatologists and pediatric dermatologists in collaboration with pediatric rheumatologists using a formal consensus process (S2k). The guidelines highlight topics such as disease severity, quality of life, treatment goals as well as problems associated with off-label drug therapy in children. Trigger factors and diagnostic aspects are discussed. The primary focus is on the various topical, systemic and UV-based treatment options available and includes recommendations for use and treatment algorithms. Other aspects addressed herein include vaccinations in children and adolescents with psoriasis as well as various disease subtypes such as guttate psoriasis, diaper psoriasis, pustular psoriasis and psoriatic arthritis. Finally, we also provide recommendations for imaging studies and the diagnostic workup to rule out tuberculosis prior to initiating systemic treatment. Note: This article constitutes part 2 of the Sk2 guidelines for the treatment of psoriasis in children and adolescents. Part 1 was published in last month's issue. It contained introductory remarks and addressed aspects of diagnosis and topical treatment.

    Pubmed
  • S2k guidelines for the treatment of psoriasis in children and adolescents - Short version part 1.

    J Dtsch Dermatol Ges. 2019;17(8): 856-870

    Eisert L, Augustin M, Bach S, Dittmann M, Eiler R, Fölster-Holst R, Gerdes S, Hamm H, Höger P, Horneff G, von Kiedrowski R, Philipp S, Pleimes M, Schläger M, Schuster V, Staubach P, Weberschock T, Werner RN, Nast A, Sticherling M

    The present guidelines are aimed at residents and board-certified physicians in the fields of dermatology, pediatrics, pediatric dermatology and pediatric rheumatology as well as policymakers and insurance funds. They were developed by dermatologists and pediatric dermatologists in collaboration with pediatric rheumatologists using a formal consensus process (S2k). The guidelines highlight topics such as disease severity, quality of life, treatment goals as well as problems associated with off-label drug therapy in children. Trigger factors and diagnostic aspects are discussed. The primary focus is on the various topical, systemic and UV-based treatment options available and includes recommendations for use and treatment algorithms. Other aspects addressed herein include vaccinations in children and adolescents with psoriasis as well as various disease subtypes such as guttate psoriasis, diaper psoriasis, pustular psoriasis and psoriatic arthritis. Finally, we also provide recommendations for imaging studies and the diagnostic workup to rule out tuberculosis prior to initiating systemic treatment. Note: This article constitutes part 1 of the Sk2 guidelines for the treatment of psoriasis in children and adolescents. Part 2 will be published in the next issue. It contains chapters on UV therapy, systemic treatment, tonsillectomy and antibiotics, vaccinations, guttate psoriasis, psoriatic arthritis, complementary medicine, as well as imaging studies and diagnostic workup to rule out tuberculosis prior to systemic treatment.

    Pubmed
  • Disease interception with interleukin-17 inhibition in high-risk psoriasis patients with subclinical joint inflammation-data from the prospective IVEPSA study.

    Arthritis Res Ther. 2019;21(1):

    Kampylafka E, Simon D, d'Oliveira I, Linz C, Lerchen V, Englbrecht M, Rech J, Kleyer A, Sticherling M, Schett G, Hueber AJ

    BACKGROUND: A specific subset of psoriasis patients is characterized by subclinical inflammatory changes. These patients frequently present with arthralgia and have a higher risk to develop psoriatic arthritis (PsA). We hypothesized that IL-17A inhibition in this subset of patients can intercept the link between skin and joint disease and resolves pain and inflammatory changes.

    METHODS: Psoriasis, but no PsA, patients were included in the open prospective exploratory Interception in very early PsA (IVEPSA) study. Patients had to have nail or scalp involvement or a high psoriasis area severity index (PASI) (> 6) as well as inflammatory or erosive changes in MRI or CT. Patients received treatment with the anti-interleukin (IL)-17A antibody secukinumab over 24 weeks. Clinical assessments of skin and joint disease were done at baseline and after 12 and 24 weeks, MRI and CT at baseline and after 24 weeks.

    RESULTS: Twenty patients were included, 85% of them reporting arthralgia and 40% had tender joints at the examination. Eighty-three percent had at least one inflammatory lesion in the MRI, most of them synovitis/enthesitis. Skin disease (PASI: p < 0.002; BSA: p < 0.003) and arthralgia (VAS pain: p < 0.003) significantly improved after 24 weeks. Total PsAMRIS (p = 0.005) and synovitis subscore (p = 0.008) also significantly improved. Erosions and enthesiophytes did not progress, while bone mass in the distal radius significantly (p = 0.020) increased after 24 weeks.

    CONCLUSIONS: These data suggest that very early disease interception in PsA is possible leading to a comprehensive decline in skin symptoms, pain, and subclinical inflammation. IVEPSA therefore provides rationale for future early interventions with the concept to prevent the onset of PsA in high-risk individuals.

    TRIAL REGISTRATION: Trial registry name PSARTROS; trial registry number: NCT02483234; June 26, 2015.

    Pubmed
  • Multiple Dermal Abscesses by Trichophyton rubrum in an Immunocompromised Patient.

    Front Med (Lausanne). 2019;6():

    Toussaint F, Sticherling M

    We report the case of a 52-year-old man who presented with a 10 year history of multiple nodules with purulent drainage on the upper extremities. Several attempts of treatment with oral antibiotics had been unsuccessful. A skin biopsy specimen showed a dermal abscess with branched septate hyphae. A mycological culture of pus and of the biopsy specimen revealed Trichophyton rubrum. Deeper dermatophytosis presenting as dermal abscesses is a rare disease which occurs normally in immunocompromised conditions. Our patient was on immunosuppressive therapy with methylprednisolone and azathioprine because of inflammatory demyelinating polyneuropathy and presented with extensive abscesses. In cases of dermal abscesses it is important to not only consider bacterial but also fungal infections as underlying cause.

    Pubmed
  • Systemische Sklerodermie - die dermatologische Sicht.

    J Dtsch Dermatol Ges. 2019;17(7): 716-729

    Sticherling M

    Pubmed
  • [Sclerosing skin diseases].

    Internist (Berl). 2019;60(8): 783-791

    Sticherling M

    Sclerosing skin manifestations are more a symptom than a diagnosis and must therefore be meticulously clarified. Systemic scleroderma as a multiorgan disease must be distinguished from localized scleroderma or morphea because in addition to a different clinical picture they have a different prognosis and necessitate other therapeutic procedures. Rare sclerosing skin diseases with implications for internal medicine are eosinophilic fasciitis, Buschke's scleredema adultorum, scleromyxedema and nephrogenic systemic fibrosis.

    Pubmed
  • [50-year-old woman with cold-associated attacks of white discoloration of individual fingers : Preparation for the specialist examination: part 51].

    Hautarzt. 2019;70(Suppl 1): 93-96

    Sticherling M

    Pubmed
  • S2k-Leitlinie zur Therapie der Psoriasis bei Kindern und Jugendlichen - Kurzfassung Teil 2.

    J Dtsch Dermatol Ges. 2019;17(9): 959-974

    Eisert L, Augustin M, Bach S, Dittmann M, Eiler R, Fölster-Holst R, Gerdes S, Hamm H, Höger P, Horneff G, von Kiedrowski R, Philipp S, Pleimes M, Schlaeger M, Schuster V, Staubach P, Weberschock T, Werner RN, Nast A, Sticherling M

    Pubmed
  • S2k-Leitlinie zur Therapie der Psoriasis bei Kindern und Jugendlichen - Kurzfassung Teil 1.

    J Dtsch Dermatol Ges. 2019;17(8): 856-870

    Eisert L, Augustin M, Bach S, Dittmann M, Eiler R, Fölster-Holst R, Gerdes S, Hamm H, Höger P, Horneff G, von Kiedrowski R, Philipp S, Pleimes M, Schlaeger M, Schuster V, Staubach P, Weberschock T, Werner RN, Nast A, Sticherling M

    Pubmed
  • PU.1 controls fibroblast polarization and tissue fibrosis.

    Nature. 2019;566(7744): 344-349

    Wohlfahrt T, Rauber S, Uebe S, Luber M, Soare A, Ekici A, Weber S, Matei AE, Chen CW, Maier C, Karouzakis E, Kiener HP, Pachera E, Dees C, Beyer C, Daniel C, Gelse K, Kremer AE, Naschberger E, Stürzl M, Butter F, Sticherling M, Finotto S, Kreuter A, Kaplan MH, Jüngel A, Gay S, Nutt SL, Boykin DW, Poon GMK, Distler O, Schett G, Distler JHW, Ramming A

    Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix, which induces scarring and organ failure. By contrast, a hallmark feature of fibroblasts in arthritis is degradation of the extracellular matrix because of the release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms that drive these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts remain unknown. Here we identify the transcription factor PU.1 as an essential regulator of the pro-fibrotic gene expression program. The interplay between transcriptional and post-transcriptional mechanisms that normally control the expression of PU.1 expression is perturbed in various fibrotic diseases, resulting in the upregulation of PU.1, induction of fibrosis-associated gene sets and a phenotypic switch in extracellular matrix-producing pro-fibrotic fibroblasts. By contrast, pharmacological and genetic inactivation of PU.1 disrupts the fibrotic network and enables reprogramming of fibrotic fibroblasts into resting fibroblasts, leading to regression of fibrosis in several organs.

    Pubmed
  • Analyses of association of psoriatic arthritis and psoriasis vulgaris with functional NCF1 variants.

    Rheumatology (Oxford). 2019;58(5): 915-917

    Löhr S, Ekici AB, Uebe S, Büttner C, Köhm M, Behrens F, Böhm B, Sticherling M, Schett G, Simon D, Mössner R, Nimeh A, Oji V, Assmann G, Rech J, Holmdahl R, Burkhardt H, Reis A, Hüffmeier U

    Pubmed
  • Topische Therapie bei Psoriasis vulgaris - ein Behandlungspfad.

    J Dtsch Dermatol Ges. 2019;17 Suppl 4(): 3-14

    Körber A, Wilsmann-Theis D, Augustin M, von Kiedrowski R, Mrowietz U, Rosenbach T, Meller S, Pinter A, Sticherling M, Gerdes S, PsoNet Förderverein

    Pubmed
  • Centrosomal protein TRIM43 restricts herpesvirus infection by regulating

    nuclear lamina integrity

    NAT. MICROBIOL. 2019;4(1): 164-+

    Full F, van Gent M, Sparrer KMJ, Chiang C, Zurenski MA, Scherer M, Brockmeyer NH, Heinzerling L, Stürzl M, Korn K, Stamminger T, Ensser A, Gack MU

    Tripartite motif (TRIM) proteins mediate antiviral host defences by either directly targeting viral components or modulating innate immune responses. Here we identify a mechanism of antiviral restriction in which a TRIM E3 ligase controls viral replication by regulating the structure of host cell centrosomes and thereby nuclear lamina integrity. Through RNAi screening we identified several TRIM proteins, including TRIM43, that control the reactivation of Kaposi's sarcoma-associated herpesvirus. TRIM43 was distinguished by its ability to restrict a broad range of herpesviruses and its profound upregulation during herpesvirus infection as part of a germline-specific transcriptional program mediated by the transcription factor DUX4. TRIM43 ubiquitinates the centrosomal protein pericentrin, thereby targeting it for proteasomal degradation, which subsequently leads to alterations of the nuclear lamina that repress active viral chromatin states. Our study identifies a role of the TRIM43-pericentrin-lamin axis in intrinsic immunity, which may be targeted for therapeutic intervention against herpesviral infections.

    Pubmed
  • Dendritic Cells Control Regulatory T Cell Function Required for Maintenance of Intestinal Tissue Homeostasis.

    J Immunol. 2019;203(11): 3068-3077

    Hilpert C, Sitte S, Arnold H, Lehmann CHK, Dudziak D, Mattner J, Voehringer D

    Dendritic cells (DCs) together with regulatory T cells (Tregs) are essential mediators of immune homeostasis. Disruption of function or frequency of either cell type can lead to fatal autoimmunity. We previously described that mice constitutively lacking DCs (∆DC) develop autoimmunity characterized by reduced body weight, autoantibodies, and pronounced intestinal inflammation. In this study, we show that lack of DCs leads to an altered gene expression profile in peripheral but not thymic Tregs with increased expression of inhibitory receptors. The suppressive function of Tregs from ΔDC mice was impaired in T cell cocultures. In a model of transfer colitis, Tregs from ∆DC mice were only functional in the presence of DCs in recipient mice. Lack of MHC class II on DCs also resulted in upregulation of inhibitory receptors on Tregs, reduced body weight, and elevated serum IgA levels. Further analysis of the IgA response revealed an expansion of IgA+ germinal center B cells and plasma cells in mesenteric lymph nodes and more IgA-coated commensal bacteria in feces of ∆DC mice. Thus, we show a critical role for DCs to establish intestinal homeostasis by regulating Treg function for prevention of spontaneous inflammation.

    Pubmed
  • Transcriptional control of dendritic cell development and functions.

    Int Rev Cell Mol Biol. 2019;349(): 55-151

    Amon L, Lehmann CHK, Baranska A, Schoen J, Heger L, Dudziak D

    Dendritic cells (DCs) are major regulators of adaptive immunity, as they are not only capable to induce efficient immune responses, but are also crucial to maintain peripheral tolerance and thereby inhibit autoimmune reactions. DCs bridge the innate and the adaptive immune system by presenting peptides of self and foreign antigens as peptide MHC complexes to T cells. These properties render DCs as interesting target cells for immunomodulatory therapies in cancer, but also autoimmune diseases. Several subsets of DCs with special properties and functions have been described. Recent achievements in understanding transcriptional programs on single cell level, together with the generation of new murine models targeting specific DC subsets, advanced our current understanding of DC development and function. Thus, DCs arise from precursor cells in the bone marrow with distinct progenitor cell populations splitting the monocyte populations and macrophage populations from the DC lineage, which upon lineage commitment can be separated into conventional cDC1, cDC2, and plasmacytoid DCs (pDCs). The DC populations harbor intrinsic programs enabling them to react for specific pathogens in dependency on the DC subset, and thereby orchestrate T cell immune responses. Similarities, but also varieties, between human and murine DC subpopulations are challenging, and will require further investigation of human specimens under consideration of the influence of the tissue micromilieu and DC subset localization in the future.

    Pubmed
  • CSPG4 as Target for CAR-T-Cell Therapy of Various Tumor Entities-Merits and Challenges.

    Int J Mol Sci. 2019;20(23):

    Harrer DC, Dörrie J, Schaft N

    Targeting cancer cells using chimeric-antigen-receptor (CAR-)T cells has propelled adoptive T-cell therapy (ATT) to the next level. A plentitude of durable complete responses using CD19-specific CAR-T cells in patients suffering from various lymphoid malignancies resulted in the approval by the food and drug administration (FDA) of CD19-directed CAR-T cells for the treatment of acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). A substantial portion of this success in hematological malignancies can be traced back to the beneficial properties of the target antigen CD19, which combines a universal presence on target cells with no detectable expression on indispensable host cells. Hence, to replicate response rates achieved in ALL and DLBCL in the realm of solid tumors, where ideal target antigens are scant and CAR-T cells are still lagging behind expectations, the quest for appropriate target antigens represents a crucial task to expedite the next steps in the evolution of CAR-T-cell therapy. In this review, we want to highlight the potential of chondroitin sulfate proteoglycan 4 (CSPG4) as a CAR-target antigen for a variety of different cancer entities. In particular, we discuss merits and challenges associated with CSPG4-CAR-T cells for the ATT of melanoma, leukemia, glioblastoma, and triple-negative breast cancer.

    Pubmed
  • Gastrointestinal: Eruptive seborrheic keratoses: sign of Leser-Trélat in gastric adenocarcinoma.

    J Gastroenterol Hepatol. 2019;34(12):

    Kirchberger MC

    Pubmed
  • Influenza vaccination and myocarditis among patients receiving immune

    checkpoint inhibitors

    J. Immunother. Cancer. 2019;7():

    Awadalla M, Golden DLA, Mahmood SS, Alvi RM, Mercaldo ND, Hassan MZO, Banerji D, Rokicki A, Mulligan C, Murphy SPT, Jones-O'Connor M, Cohen JV, Heinzerling LM, Armanious M, Sullivan RJ, Damrongwatanasuk R, Chen CL, Gupta D, Kirchberger MC, Moslehi JJ, Shah SP, Ganatra S, Thavendiranathan P, Rizvi MA, Sahni G, Lyon AR, Tocchetti CG, Mercurio V, Thuny F, Ederhy S, Mahmoudi M, Lawrence DP, Groarke JD, Nohria A, Fradley MG, Reynolds KL, Neilan TG

    BackgroundInfluenza vaccination (FV) is recommended for patients with cancer. Recent data suggested that the administration of the FV was associated with an increase in immune-related adverse events (irAEs) among patients on immune checkpoint inhibitors (ICIs). Myocarditis is an uncommon but serious complication of ICIs and may also result from infection with influenza. There are no data testing the relationship between FV and the development of myocarditis on ICIs.MethodsPatients on ICIs who developed myocarditis (n=101) (cases) were compared to ICI-treated patients (n=201) without myocarditis (controls). A patient was defined as having the FV if they were administered the FV from 6months prior to start of ICI to anytime during ICI therapy. Alternate thresholds for FV status were also tested. The primary comparison of interest was the rate of FV between cases and controls. Patients with myocarditis were followed for major adverse cardiac events (MACE), defined as the composite of cardiogenic shock, cardiac arrest, hemodynamically significant complete heart block and cardiovascular death.ResultsThe FV was administered to 25% of the myocarditis cases compared to 40% of the non-myocarditis ICI-treated controls (p=0.01). Similar findings of lower rates of FV administration were noted among myocarditis cases when alternate thresholds were tested. Among the myocarditis cases, those who were vaccinated had 3-fold lower troponin levels when compared to unvaccinated cases (FV vs. No FV: 0.12 [0.02, 0.47] vs. 0.40 [0.11, 1.26] ng/ml, p=0.02). Within myocarditis cases, those administered the FV also had a lower rate of other irAEs when compared to unvaccinated cases (36 vs. 55% p=0.10) including lower rates of pneumonitis (12 vs. 36%, p=0.03). During follow-up (175 [IQR 89, 363] days), 47% of myocarditis cases experienced a MACE. Myocarditis cases who received the FV were at a lower risk of cumulative MACE when compared to unvaccinated cases (24 vs. 59%, p=0.002).ConclusionThe rate of FV among ICI-related myocarditis cases was lower than controls on ICIs who did not develop myocarditis. In those who developed myocarditis related to an ICI, there was less myocardial injury and a lower risk of MACE among those who were administered the FV.

    Pubmed
  • Rhinophyma-Like Cutaneous Leishmaniasis due to Leishmania aethiopica

    Treated Successfully with Liposomal Amphotericin B

    Am J Trop Med Hyg. 2019;100(2): 231-232

    Kirchberger MC, Schliep S, Bogdan C

    Pubmed
  • Influence on contact allergy of immune-mediated skin diseases such as

    psoriasis

    Br J Dermatol. 2019;180(2): 256-257

    Erfurt-Berge C

    Pubmed
  • Quality of life assessment in family members of patients with chronic

    wounds

    Eur J Dermatol. 2019;29(5): 484-489

    Erfurt-Berge C, Ronicke M, Richter-Schmidinger T, Walther F, Renner R

    Background: Familial caregivers are often directly involved in treatment of patients with chronic wounds, however, less is known about their personal impairment, and specific support is lacking for these important members of the therapeutic team regarding wound care. Objectives: The aim of this study was to investigate the influence of wound care provided by family members on their quality of life, and to create a suitable questionnaire to describe the affected personal aspects. Materials and methods: A five-part questionnaire, named ELWA, was created by the authors and answered by 30 familial caregivers of 30 respective patients with chronic leg ulcers. Results: One third of the caregivers reported receiving no medical advice about detailed wound care at all. A lack of information regarding details of the disease correlated with personal strain. Additional costs, anxiety, frustration, and reduced sparetime activities were among the top-rated factors affecting quality of life of family members. Conclusion: The results from this newly created questionnaire point out the needs of familial caregivers of patients with chronic wounds and may help to establish individual support. Implementation of clinical treatment strategies is planned through multicentre application.

    Pubmed
  • Long-term efficacy of interventions for actinic keratosis: protocol for a systematic review and network meta-analysis.

    Syst Rev. 2019;8(1):

    Steeb T, Heppt MV, Becker L, Kohl C, French LE, Berking C

    BACKGROUND: Actinic keratoses (AK) are common precancerous lesions of the skin due to cumulative sun exposure. A variety of interventions are available for the treatment; however, the majority of randomised controlled trials (RCTs) and meta-analyses focus on short-term efficacy outcomes. This network meta-analysis aims to investigate the long-term (> 12 months) efficacy of interventions for AK.

    METHODS: To identify relevant studies, we will perform a systematic literature research in MEDLINE, Embase, and CENTRAL and hand-search pertinent trial registers. Two authors will independently screen titles and abstracts for eligibility. We will include RCTs with an inter-individual (parallel arm) design. The study population includes patients with a clinical or histopathologic diagnosis of AK. Eligibility will be restricted to the following interventions: surgical approaches, cryosurgery, ablative laser treatment, topical drug treatment with 5-fluorouracil, imiquimod, ingenol mebutate, diclofenac, or photodynamic therapy. As outcomes, we will consider the following endpoints: (1) the participant complete clearance rate, (2) the participant partial clearance rate, (3) the lesion-specific clearance, (4) the mean lesion reduction per patient, and (5) the number of withdrawals due to adverse events after at least 12 months after the end of treatment. Monotherapy or placebo will serve as a comparison. Estimates of effects from individual studies will be pooled using a random-effects model. Heterogeneity will be evaluated based on I2 and chi-square test. The risk of bias will be estimated with the Cochrane Risk of Bias Tool by two review authors independently. The quality of evidence of the outcomes will be assessed with the GRADE approach. A network meta-analysis will be performed to combine direct and indirect evidence from the included RCTs.

    DISCUSSION: The potential of interventions to achieve a sustained clearance of AK has not been assessed to date. To investigate the long-term efficacy of interventions is important as the natural disease course is highly variable and relapses occur frequently even after initial lesion clearance. This review will help to set a framework for clinical decision making in patients with AK.

    SYSTEMATIC REVIEW REGISTRATION: CRD42018095903 (PROSPERO).

    Pubmed
  • Harmonisation of Outcome Parameters and Evaluation (HOPE) for actinic keratosis: protocol for the development of a core outcome set.

    Trials. 2019;20(1):

    Heppt MV, Steeb T, Schmitz L, Garbe C, French LE, Leiter U, Berking C

    BACKGROUND: Actinic keratoses (AK) are common skin lesions that can progress to invasive squamous cell carcinoma of the skin. A variety of lesion- or field-targeted treatment options exist and their efficacy has been demonstrated in numerous randomised controlled trials (RCTs). However, the reported endpoints are highly heterogeneous, making it difficult to assess and compare distinct treatment options and to reach an evidence-based choice of therapy.

    METHODS: A systematic literature search will be conducted to analyse which endpoints are reported in RCTs. The focus will be on effectiveness, tolerability, cosmesis, and patient satisfaction. The reported endpoints of these studies, as well as their frequency and data collection times, will be documented in a standardised way to generate a comprehensive list of reported endpoints. In order to complete the identified outcomes in the literature search, focus groups on affected patients and structured interviews with board-certified dermatologists will be conducted to identify both patient- and practice-relevant endpoints. After the identification phase, the evaluation of the endpoints follows. In a two-stage Delphi procedure, experts including patient representatives will evaluate the endpoints in a standardised and transparent manner. A final face-to-face consensus meeting will be conducted after the last Delphi round in which a final list of core outcomes will be consented.

    DISCUSSION: The development of a standardised endpoint set for the treatment of AK will contribute to improving the comparability of therapeutic options. Our catalogue will enhance the synthesis of evidence for the future by reducing heterogeneity in outcomes between RCTs and hence contribute to improving the quality of research, evidence-based and patient-centred treatment.

    TRIAL REGISTRATION: Core Outcome Measures for Effectiveness ( COMET ) database. Registered in December 2018.

    Pubmed
  • Comparison of guidelines for the management of patients with high-risk and advanced cutaneous squamous cell carcinoma - a systematic review.

    J Eur Acad Dermatol Venereol. 2019;33 Suppl 8(): 25-32

    Heppt MV, Steeb T, Berking C, Nast A

    The management of high-risk cutaneous squamous cell carcinoma (cSCC) can be a challenge as evidence from high quality clinical trials is rare. Guideline developers are challenged to provide practical and useful guidance for clinicians even in the absence of good evidence. In order to compare treatment recommendations for high-risk and advanced cSCC among national and international guidelines and to extract the most precise guidance provided, a systematic search was carried out in guideline databases Medline and Embase with a cutoff of 4 March 2019. Treatment recommendations for predefined clinical scenarios were extracted from selected guidelines and compared qualitatively. Five guidelines published from 2015 to 2018 were included. Excision of high-risk tumours with margin assessment was recommended in all guidelines. A safety margin of at least 6 mm was suggested in four guidelines. There was no clear recommendation to perform a sentinel lymph node biopsy in any guideline. Lymph node dissection was uniformly recommended in the presence of nodal disease. Treatment for metastatic cSCC was poorly characterized and restricted to the use of chemotherapy and epidermal growth factor receptor inhibitors. Recommendations for the management of high-risk and advanced cSCC were limited. We propose that guidelines should be updated to reflect recent advances in checkpoint blockade for metastatic cSCC.

    Pubmed
  • Photodynamic therapy 'to go' - a strengths, weaknesses, opportunities and threats analysis.

    J Eur Acad Dermatol Venereol. 2019;33(12): e447-e449

    Heppt MV, Steeb T, Berking C

    Pubmed
  • Skin Cancer Smartphone Applications for German-speaking Patients: Review and Content Analysis Using the Mobile App Rating Scale.

    Acta Derm Venereol. 2019;99(11): 1043-1044

    Steeb T, Wessely A, French LE, Heppt MV, Berking C

    Pubmed
  • Sensitivity and specificity of standardised allergen extracts in skin

    prick test for diagnoses of IgE-mediated respiratory allergies

    Clin. Transl. Allergy. 2019;9():

    Wagner N, Rudert M

    Background: Skin prick tests (SPTs) are essential for the diagnosis of IgE-mediated allergy and are influenced by extract quality, biological potency and concentration of allergen.

    Methods: In this open multicentre study 431 patients, aged 18-64 years were enrolled. Patients had a history of IgE-mediated allergy and a sensitisation (previous positive SPT of any manufacturer) against at least one of the investigated allergens: 6-grass pollen, house dust mite, birch and mugwort pollen. In our study, these allergens were tested in five concentrations each. To establish the optimal trade-off between sensitivity and specificity, the area under the receiver operating characteristic (ROC) curve was estimated by comparing the outcome of the SPT with three methods referred to as 'reference methods' (specific IgE, clinical case history and a previous SPT).

    Results: For all allergens and reference methods, the area under the ROC curves were highly significant (p < 0.001). Specific IgE reference method resulted in the largest area under the curve (AUC) for all allergens (0.80-0.90) followed by previous SPT (0.70-0.87) and case history (0.65-0.74). Sensitivity of SPT increased with increasing concentration and specificity decreased. For all allergens, compared to specific IgE, the highest sensitivity (specificity at least 80%) was observed for the SPT solution of 50,000 Standardised Units (SU)/mL (grass pollen, birch pollen, house dust mite and mugwort).

    Conclusion: In this study, with a large number of patients, it was demonstrated that clinical case history, previous SPT and specific IgE measurement could all be used as reference methods for the assessment of sensitivity/specificity of SPT solutions. The comparison of SPT with specific IgE resulted in the largest AUC. The highest sensitivity was observed for the SPT solution of 50,000 SU/mL. Trial registration EudraCT: 2006-005304-14.

    Pubmed
  • RNA Sequencing of Collecting Duct Renal Cell Carcinoma Suggests an Interaction between miRNA and Target Genes and a Predominance of Deregulated Solute Carrier Genes.

    Cancers. 2019;12(1):

    Wach S, Taubert H, Weigelt K, Hase N, Köhn M, Misiak D, Hüttelmaier S, Stöhr CG, Kahlmeyer A, Haller F, Vera J, Hartmann A, Wullich B, Lai X

    Collecting duct carcinoma (CDC) is a rare renal cell carcinoma subtype with a very poor prognosis. There have been only a few studies on gene expression analysis in CDCs. We compared the gene expression profiles of two CDC cases with those of eight normal tissues of renal cell carcinoma patients. At a threshold of |log2fold-change| ≥ 1, 3349 genes were upregulated and 1947 genes were downregulated in CDCs compared to the normal samples. Pathway analysis of the deregulated genes revealed that cancer pathways and cell cycle pathways were most prominent in CDCs. The most upregulated gene was keratin 17, and the most downregulated gene was cubilin. Among the most downregulated genes were four solute carrier genes (SLC3A1, SLC9A3, SLC26A7, and SLC47A1). The strongest negative correlations between miRNAs and mRNAs were found between the downregulated miR-374b-5p and its upregulated target genes HIST1H3B, HK2, and SLC7A11 and between upregulated miR-26b-5p and its downregulated target genes PPARGC1A, ALDH6A1, and MARC2. An upregulation of HK2 and a downregulation of PPARGC1A, ALDH6A1, and MARC2 were observed at the protein level. Survival analysis of the cancer genome atlas (TCGA) dataset showed for the first time that low gene expression of MARC2, cubilin, and SLC47A1 and high gene expression of KRT17 are associated with poor overall survival in clear cell renal cell carcinoma patients. Altogether, we identified dysregulated protein-coding genes, potential miRNA-target interactions, and prognostic markers that could be associated with CDC.

    Pubmed
  • Beyond corticotherapy: how to manage severe immune adverse events that

    do not respond to corticotherapy?

    J Transl Med. 2019;17():

    Amaral T, Berking C, Loquai C, Heinzerling L, Zimmer L, Ugurel S, Garbe C, Eigentler T

    Pubmed
  • A convolutional neural network trained with dermoscopic images performed on par with 145 dermatologists in a clinical melanoma image classification task.

    Eur J Cancer. 2019;111(): 148-154

    Brinker TJ, Hekler A, Enk AH, Klode J, Hauschild A, Berking C, Schilling B, Haferkamp S, Schadendorf D, Fröhling S, Utikal JS, von Kalle C, Collaborators , Ludwig-Peitsch W, Sirokay J, Heinzerling L, Albrecht M, Baratella K, Bischof L, Chorti E, Dith A, Drusio C, Giese N, Gratsias E, Griewank K, Hallasch S, Hanhart Z, Herz S, Hohaus K, Jansen P, Jockenhöfer F, Kanaki T, Knispel S, Leonhard K, Martaki A, Matei L, Matull J, Olischewski A, Petri M, Placke JM, Raub S, Salva K, Schlott S, Sody E, Steingrube N, Stoffels I, Ugurel S, Sondermann W, Zaremba A, Gebhardt C, Booken N, Christolouka M, Buder-Bakhaya K, Bokor-Billmann T, Enk A, Gholam P, Hänßle H, Salzmann M, Schäfer S, Schäkel K, Schank T, Bohne AS, Deffaa S, Drerup K, Egberts F, Erkens AS, Ewald B, Falkvoll S, Gerdes S, Harde V, Hauschild A, Jost M, Kosova K, Messinger L, Metzner M, Morrison K, Motamedi R, Pinczker A, Rosenthal A, Scheller N, Schwarz T, Stölzl D, Thielking F, Tomaschewski E, Wehkamp U, Weichenthal M, Wiedow O, Bär CM, Bender-Säbelkampf S, Horbrügger M, Karoglan A, Kraas L, Faulhaber J, Géraud C, Guo Z, Koch P, Linke M, Maurier N, Müller V, Thomas B, Utikal JS, Alamri ASM, Baczako A, Berking C, Betke M, Haas C, Hartmann D, Heppt MV, Kilian K, Krammer S, Lapczynski NL, Mastnik S, Nasifoglu S, Ruini C, Sattler E, Schlaak M, Wolff H, Achatz B, Bergbreiter A, Drexler K, Ettinger M, Haferkamp S, Halupczok A, Hegemann M, Dinauer V, Maagk M, Mickler M, Philipp B, Wilm A, Wittmann C, Gesierich A, Glutsch V, Kahlert K, Kerstan A, Schilling B, Schrüfer P

    BACKGROUND: Recent studies have demonstrated the use of convolutional neural networks (CNNs) to classify images of melanoma with accuracies comparable to those achieved by board-certified dermatologists. However, the performance of a CNN exclusively trained with dermoscopic images in a clinical image classification task in direct competition with a large number of dermatologists has not been measured to date. This study compares the performance of a convolutional neuronal network trained with dermoscopic images exclusively for identifying melanoma in clinical photographs with the manual grading of the same images by dermatologists.

    METHODS: We compared automatic digital melanoma classification with the performance of 145 dermatologists of 12 German university hospitals. We used methods from enhanced deep learning to train a CNN with 12,378 open-source dermoscopic images. We used 100 clinical images to compare the performance of the CNN to that of the dermatologists. Dermatologists were compared with the deep neural network in terms of sensitivity, specificity and receiver operating characteristics.

    FINDINGS: The mean sensitivity and specificity achieved by the dermatologists with clinical images was 89.4% (range: 55.0%-100%) and 64.4% (range: 22.5%-92.5%). At the same sensitivity, the CNN exhibited a mean specificity of 68.2% (range 47.5%-86.25%). Among the dermatologists, the attendings showed the highest mean sensitivity of 92.8% at a mean specificity of 57.7%. With the same high sensitivity of 92.8%, the CNN had a mean specificity of 61.1%.

    INTERPRETATION: For the first time, dermatologist-level image classification was achieved on a clinical image classification task without training on clinical images. The CNN had a smaller variance of results indicating a higher robustness of computer vision compared with human assessment for dermatologic image classification tasks.

    Pubmed
  • Deep learning outperformed 136 of 157 dermatologists in a head-to-head dermoscopic melanoma image classification task.

    Eur J Cancer. 2019;113(): 47-54

    Brinker TJ, Hekler A, Enk AH, Klode J, Hauschild A, Berking C, Schilling B, Haferkamp S, Schadendorf D, Holland-Letz T, Utikal JS, von Kalle C, Collaborators , Ludwig-Peitsch W, Sirokay J, Heinzerling L, Albrecht M, Baratella K, Bischof L, Chorti E, Dith A, Drusio C, Giese N, Gratsias E, Griewank K, Hallasch S, Hanhart Z, Herz S, Hohaus K, Jansen P, Jockenhöfer F, Kanaki T, Knispel S, Leonhard K, Martaki A, Matei L, Matull J, Olischewski A, Petri M, Placke JM, Raub S, Salva K, Schlott S, Sody E, Steingrube N, Stoffels I, Ugurel S, Zaremba A, Gebhardt C, Booken N, Christolouka M, Buder-Bakhaya K, Bokor-Billmann T, Enk A, Gholam P, Hänßle H, Salzmann M, Schäfer S, Schäkel K, Schank T, Bohne AS, Deffaa S, Drerup K, Egberts F, Erkens AS, Ewald B, Falkvoll S, Gerdes S, Harde V, Hauschild A, Jost M, Kosova K, Messinger L, Metzner M, Morrison K, Motamedi R, Pinczker A, Rosenthal A, Scheller N, Schwarz T, Stölzl D, Thielking F, Tomaschewski E, Wehkamp U, Weichenthal M, Wiedow O, Bär CM, Bender-Säbelkampf S, Horbrügger M, Karoglan A, Kraas L, Faulhaber J, Geraud C, Guo Z, Koch P, Linke M, Maurier N, Müller V, Thomas B, Utikal JS, Alamri ASM, Baczako A, Berking C, Betke M, Haas C, Hartmann D, Heppt MV, Kilian K, Krammer S, Lapczynski NL, Mastnik S, Nasifoglu S, Ruini C, Sattler E, Schlaak M, Wolff H, Achatz B, Bergbreiter A, Drexler K, Ettinger M, Haferkamp S, Halupczok A, Hegemann M, Dinauer V, Maagk M, Mickler M, Philipp B, Wilm A, Wittmann C, Gesierich A, Glutsch V, Kahlert K, Kerstan A, Schilling B, Schrüfer P

    BACKGROUND: Recent studies have successfully demonstrated the use of deep-learning algorithms for dermatologist-level classification of suspicious lesions by the use of excessive proprietary image databases and limited numbers of dermatologists. For the first time, the performance of a deep-learning algorithm trained by open-source images exclusively is compared to a large number of dermatologists covering all levels within the clinical hierarchy.

    METHODS: We used methods from enhanced deep learning to train a convolutional neural network (CNN) with 12,378 open-source dermoscopic images. We used 100 images to compare the performance of the CNN to that of the 157 dermatologists from 12 university hospitals in Germany. Outperformance of dermatologists by the deep neural network was measured in terms of sensitivity, specificity and receiver operating characteristics.

    FINDINGS: The mean sensitivity and specificity achieved by the dermatologists with dermoscopic images was 74.1% (range 40.0%-100%) and 60% (range 21.3%-91.3%), respectively. At a mean sensitivity of 74.1%, the CNN exhibited a mean specificity of 86.5% (range 70.8%-91.3%). At a mean specificity of 60%, a mean sensitivity of 87.5% (range 80%-95%) was achieved by our algorithm. Among the dermatologists, the chief physicians showed the highest mean specificity of 69.2% at a mean sensitivity of 73.3%. With the same high specificity of 69.2%, the CNN had a mean sensitivity of 84.5%.

    INTERPRETATION: A CNN trained by open-source images exclusively outperformed 136 of the 157 dermatologists and all the different levels of experience (from junior to chief physicians) in terms of average specificity and sensitivity.

    Pubmed
  • Sustainable responses in metastatic melanoma patients with/without brain

    metastases after immunotherapy induced CR.

    J Clin Oncol. 2019;37(15):

    Dimitriou F, Ramelyte E, Allayous C, Gerard CL, Kaehler KC, Toussaint F, Schaefer S, Hassel JC, Heinzerling L, Hauschild A, Michielin O, Lebbe C, Braun RP, Dummer R, Mangana J

    Pubmed
  • Adverse events 2.0-Let us get SERIOs New reporting for adverse event

    outcomes needed in the era of immunooncology

    Eur J Cancer. 2019;112(): 29-31

    Heinzerling L, Ascierto PA, Dummer R, Gogas H, Grob JJ, Lebbe C, Long GV, McArthur G, Moslehi JJ, Neilan TG, Ribas A, Robert C, Schadendorf D, Wolchok JD, Hauschild A

    Pubmed
  • Quality, Rather Than Quantity, of Life Is the Crucial Criterion Reply

    Dtsch Arztebl Int. 2019;116(20): 363-364

    Heinzerling L

    Pubmed
  • c-Rel is a cell cycle modulator in human melanoma cells

    Exp Dermatol. 2019;28(2): 121-128

    Priebe MK, Dewert N, Amschler K, Erpenbeck L, Heinzerling L, Schoen MP, Seitz CS, Lorenz VN

    Melanoma progression and resistance to therapy are associated with faulty regulation of signalling molecules including the central transcription factor NF-kappa B. Increased expression of the c-Rel subunit of NF-kappa B has been described in progressing melanoma, though mechanistic implications of this upregulation remain unclear. To elucidate the functional role of c-Rel in melanoma biology, we have assessed its expression in human melanoma as well as in melanoma cell lines. Suppression of c-Rel expression in four melanoma cell lines resulted in reduced growth and altered cell cycle regulation, namely G2/M and polyploid phase induction. Moreover, mitotic spindle morphology was profoundly altered in three of the cell lines with a predominance of monopolar structures. These findings suggest that c-Rel is involved in G2/M phase regulation, prevention of polyploidy and, consequently, chromosomal stability. Our results highlight a novel tumor-promoting function of c-Rel in human melanoma cells through governing cell cycle regulation.

    Pubmed
  • Age as a Key Factor in the Pattern, Extent and timing Process of Distant

    Metastasis in Patients with malignant Melanoma. A Study by the German

    Central Register of Malignant Melanoma

    J Dtsch Dermatol Ges. 2019;17(): 163-163

    Gassenmaier M, Leiter U, Eigentler T, Roecken M, Keim U, Gesierich A, Moritz R, Heinzerling L, Tueting T, Wollina U, Garbe C

    Pubmed
  • Association of an initial Exanthem with Vemurafenib and Cobimetinib for

    a better Therapeutic Success in metastatic Melanoma Patients

    J Dtsch Dermatol Ges. 2019;17(): 54-55

    Kaehler K, Bohne AS, Gutzmer R, Satzger I, Meier F, Reinhardt L, Zimmer L, Schadendorf D, Heppt M, Gesierich A, Thoms KM, Utikal J, Hassel J, Loquai C, Pfoehler C, Heinzerling L, Kaatz M, Goeppner D, Pflugfelder A, Ugurel S

    Pubmed
  • Myocarditis in the Setting of Cancer Therapeutics Proposed Case

    Definitions for Emerging Clinical Syndromes in Cardio-Oncology

    Circulation. 2019;140(1): 80-91

    Bonaca MP, Olenchock BA, Salem JE, Wiviott SD, Ederhy S, Cohen A, Stewart GC, Choueiri TK, Di Carli M, Allenbach Y, Kumbhani DJ, Heinzerling L, Amiri-Kordestani L, Lyon AR, Thavendiranathan P, Padera R, Lichtman A, Liu PP, Johnson DB, Moslehi J

    Recent developments in cancer therapeutics have improved outcomes but have also been associated with cardiovascular complications. Therapies harnessing the immune system have been associated with an immune-mediated myocardial injury described as myocarditis. Immune checkpoint inhibitors are one such therapy with an increasing number of case and cohort reports describing a clinical syndrome of immune checkpoint inhibitor-associated myocarditis. Although the full spectrum of immune checkpoint inhibitor-associated cardiovascular disease still needs to be fully defined, described cases of myocarditis range from syndromes with mild signs and symptoms to fatal events. These observations in the clinical setting stand in contrast to outcomes from randomized clinical trials in which myocarditis is a rare event that is investigator reported and lacking in a specific case definition. The complexities associated with diagnosis, as well as the heterogeneous clinical presentation of immune checkpoint inhibitor-associated myocarditis, have made ascertainment and identification of myocarditis with high specificity challenging in clinical trials and other data sets, limiting the ability to better understand the incidence, outcomes, and predictors of these rare events. Therefore, establishing a uniform definition of myocarditis for application in clinical trials of cancer immunotherapies will enable greater understanding of these events. We propose an operational definition of cancer therapy-associated myocarditis that may facilitate case ascertainment and report and therefore may enhance the understanding of the incidence, outcomes, and risk factors of this novel clinical syndrome.

    Pubmed
  • Predicting the response of uveal melanoma to immunotherapy with MRI assessments

    Cancer Immunol Res. 2019;7 Suppl S(2):

    Moreira A, Saake M, Schuler G, Heinzerling L

    Pubmed
  • Intratumoral RNA-based TLR-7/-8 and RIG-I agonist CV8102 alone and in

    combination with anti-PD-1 in a Phase I dose-escalation and expansion

    trial in patients with advanced solid tumors

    Cancer Res. 2019;79(13):

    Eigentler T, Krauss J, Schreiber J, Weishaupt C, Terheyden P, Heinzerling L, Mohr P, Weide B, Gutzmer R, Becker JC, Kiecker F, Daehling A, Funkner F, Heidenreich R, Kays SK, Klinkhardt U, Scheel B, Schoenborn-Kellenberger O, Seibel T, Stosnach C, Strack T, Gnad-Vogt U

    Pubmed
  • ECP as prognostic Marker for Melanoma

    J Dtsch Dermatol Ges. 2019;17(): 27-28

    Moreira A, Krueckel A, Schuler G, Utikal J, Heinzerling L

    Pubmed
  • Mycophenolate Mofetil for the Treatment of Ipilimumab-induced Autoimmune

    Colitis in Patients with metastatic Melanoma

    J Dtsch Dermatol Ges. 2019;17(): 31-31

    Naoum C, Majenka P, Loquai C, Kaehler K, Heinzerling L, Dudda M, Hassel J

    Pubmed
  • Neurological side effects of checkpoint inhibitors

    Nervenarzt. 2019;90(2): 138-147

    Knauss S, Roque LG, Huehnchen P, Heinzerling L, Boehmerle W, Endres M

    Background. In recent years the treatment of many tumor entities has been revolutionized by the use of modern immunotherapies with checkpoint inhibitors; however, good response rates are contrasted by many immune-mediated side effects. Neurological immune-mediated side effects are rare but often severe complications of checkpoint inhibitor treatment.

    Method. Asystematic search in the PubMed and Web of Sciences databases was carried out for case reports and studies on neurological side effects during checkpoint inhibitor treatment.

    Results. A total of 42articles on neurological side effects of checkpoint inhibitors with a total of 85 reported cases could be identified. The most frequently reported neurological side effects were myopathies, neuropathies, diseases of the neuromuscular endplates and encephalitides. Among those, encephalitides and myopathies with accompanying myocarditis were associated with the highest morbidity and mortality.

    Conclusion. Against the background of arapidly increasing use of checkpoint inhibitors, this article provides an overview of currently available reports on the clinical courses of neurological side effects. Controlled studies on the treatment of neurological side effects are lacking. From case studies it can be assumed that early steroid treatment increases the probability of acomplete remission of neurological symptoms. Typical symptom constellations must therefore be rapidly recognized and an immunosuppressive treatment must be initiated.

    Pubmed
  • Characterization of Patients with inoperable malignant Stage IIIB-D

    Melanoma

    J Dtsch Dermatol Ges. 2019;17(): 63-64

    Zaremba A, Weishaupt C, Glutsch V, Schilling B, Loquai C, Rafei-Shamsabadi D, Meiss F, Gutzmer R, Haferkamp S, Kaehler K, Moreira A, Heinzerling L, Thoms KM, Kiecker F, Pfoehler C, Ugurel S, Roesch A, Zimmer L, Schadendorf D, Livingstone E

    Pubmed
  • Major Adverse Cardiac Events and the Timing and Dose of Corticosteroids in Immune Checkpoint Inhibitor-Associated Myocarditis

    Circulation. 2019;140 Suppl 1():

    Zhang LL, Zlotoff DA, Awadalla M, Nohria A, Mahmood SS, Hassan M, Thuny F, Zubiri L, Murphy S, Alvi RM, Rokicki A, Mulligan C, Jones-O'Connor M, Heinzerling L, Barac A, Forrestal B, Yang EH, Chen CL, Gupta D, Kirchberger MC, Shah S, Coelho-Filho OR, Rizvi M, Sahni G, Mandawat A, Tocchetti CG, Mercurio V, Mahmoudi M, Lawrence DP, Ganatra S, Ederhy S, Groarke JD, Lyon A, Thavendiranathan P, Sullivan RJ, Cohen J, Reynolds K, Fradley MG, Neilan TG

    Pubmed
  • Dendritic cell vaccination in metastatic uveal melanoma as compassionate

    treatment: Immunological and clinical responses.

    J Clin Oncol. 2019;37(15):

    Moreira A, Gross S, Uslu U, Doerrie J, Kummer M, Schliep S, Sponagl F, Lischer C, Erdmann M, Heinzerling L, Schuler G, Schuler-Thurner B

    Pubmed
  • HAND FUNCTION IS IMPAIRED IN PATIENTS WITH RHEUMATOID ARTHRITIS,

    PSORIATIC ARTHRITIS, AND PSORIASIS COMPARED TO HEALTHY CONTROLS

    Ann Rheum Dis. 2019;78(): 2126-2126

    Liphardt AM, Liehr S, Manger E, Bieniek L, Kleyer A, Simon D, Tascilar K, Sticherling M, Rech J, Schett G, Hueber A

    Pubmed
  • Psoriatic Arthritis - Epidemiology, Incidence Rate in Psoriasis Patients, Comorbidity Profiles and Risk Factor Analysis

    Arthritis Rheumatol. 2019;71 Suppl 10():

    Rech J, Sticherling M, Biermann M, Haeberle B, Reinhardt M

    Pubmed
  • Association analyses of functional NCF1 variants in psoriatic arthritis

    and psoriasis vulgaris

    Eur J Hum Genet. 2019;27(): 125-125

    Hueffmeier UD, Loehr S, Ekici AB, Uebe S, Koehm M, Behrens F, Boehm B, Sticherling M, Schett G, Moessner R, Nimeh A, Assmann G, Rech J, Oji V, Holmdahl R, Burkhardt H, Reis A

    Pubmed
  • Interleukin 17 Blockade in Psoriasis Patients with Subclinical Joint

    Inflammation- Prospective Open Study to Influence the Course of the

    Disease by means of Secukinumab

    J Dtsch Dermatol Ges. 2019;17(): 127-128

    Kampylafka E, Oliveira I, Linz C, Lerchen V, Englbrecht M, Simon D, Rech J, Kleyer A, Schett G, Sticherling M, Hueber AJ

    Pubmed
  • The transfection of natural killer T cells with a tumor-antigen specific

    chimeric antigen receptor (CAR) for melanoma immunotherapy

    Exp Dermatol. 2019;28(3): E56-E57

    Simon B, Wiesinger M, Maerz J, Wistuba-Hamprecht K, Weide B, Schuler-Thurner B, Schuler G, Doerrie J, Uslu U

    Pubmed
  • Clonality of CD4+ Blood T Cells Predicts Longer Survival With CTLA4 or PD-1 Checkpoint Inhibition in Advanced Melanoma.

    Front Immunol. 2019;10():

    Arakawa A, Vollmer S, Tietze J, Galinski A, Heppt MV, Bürdek M, Berking C, Prinz JC

    Recognition of cancer antigens drives the clonal expansion of cancer-reactive T cells, which is thought to contribute to restricted T-cell receptor (TCR) repertoires in tumor-infiltrating lymphocytes (TILs). To understand how tumors escape anti-tumor immunity, we investigated tumor-associated T-cell repertoires of patients with advanced melanoma and after blockade of the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PD-1). TCR Vβ-gene spectratyping allowed us to quantify restrictions of T-cell repertoires and, further, diversities of T-cell clones. In this study, we show that the blood TCR repertoires were variably restricted in CD4+ and extensively restricted in CD8+ T cells of patients with advanced melanoma, and contained clones in both T-cell fractions prior to the start of immunotherapy. A greater diversification especially of CD4+ blood T-cell clones before immunotherapy showed statistically significant correlations with long-term survival upon CTLA4 or PD-1 inhibition. Analysis of TILs and corresponding blood available in one patient indicated that blood clonality may at least partially be related to the clonal expansion in the tumor microenvironment. In patients who developed severe immune-related adverse events (IrAEs), CD4+ and CD8+ TCR spectratypes became more restricted during anti-CTLA4 treatment, suggesting that newly expanded oligoclonal T-cell responses may contribute to IrAEs. This study reveals diverse T-cell clones in the blood of melanoma patients prior to immunotherapy, which may reflect the extent to which T cells are able to react against melanoma and potentially control melanoma progression. Therefore, the T-cell clonality in the circulation may have predictive value for antitumor responses from checkpoint inhibition.

    Pubmed
  • Non-invasive monitoring of subclinical and clinical actinic keratosis of face and scalp under topical treatment with ingenol mebutate gel 150 mcg/g by means of reflectance confocal microscopy and optical coherence tomography: New perspectives and comparison of diagnostic techniques.

    J Biophotonics. 2019;12(7):

    Ruini C, Hartmann D, Bastian M, Ruzicka T, French LE, Berking C, von Braunmühl T

    Actinic keratosis (AK) corresponds to the earliest stage of in situ squamous cell carcinoma and arises on chronically sun-exposed skin. Around the clinically evident AKs, the apparently healthy epidermis may contain different grades of atypia that can be detected by noninvasive imaging techniques such as reflectance confocal microscopy (RCM) and optical coherence tomography (OCT). Subclinical actinic keratosis (sAK) has captured increasing interest as a potential target of field therapies. The aim of this study was to evaluate in vivo the changes in the field cancerization undergoing treatment with topical ingenol mebutate by combining RCM and OCT. Twenty patients with field cancerization of the face and scalp were treated with ingenol mebutate gel (150 mcg/g) for three consecutive days on an area of 25 cm2 containing at least two AKs, two sAKs and two apparently healthy sites. About 120 lesions were evaluated through clinical investigation and clinical, dermoscopical, RCM and OCT images at day 0, 4, 14 and 56 based on the diagnostic criteria for AKs. Main pathological features improved in both AKs and sAKs, in particular the epidermal thickness measured by OCT and the epidermal atypia graded by RCM. Local skin reactions (LSR) arose predominantly in the lesional area compared with healthy skin. A complete clearance was detected in 58% for AKs, and in 55% and 72% for sAKs measured by RCM and OCT, respectively. Both OCT and RCM allow the morphological representation of field cancerization including subclinical lesions and provide complementary information. Ingenol mebutate is effective not only in clinically evident but also in sAKs. The differences in LSR highlight the potential selectivity of the treatment.

    Pubmed
  • Quality, Readability, and Understandability of German Booklets Addressing Melanoma Patients.

    J Cancer Educ. 2019;34(4): 760-767

    Brütting J, Reinhardt L, Bergmann M, Schadendorf D, Weber C, Tilgen W, Berking C, Meier F, NVKH

    Booklets are the preferably used form among patient education materials and are often handed out during medical consultations in dermatological oncology settings. However, little is known about how beneficial they are and whether they correspond to essential quality characteristics. To assess the quality, readability, and understandability of currently freely available booklets written in German addressing melanoma patients (MP). Melanoma booklets in accordance with predefined criteria were searched and analyzed. Three reviewers independently assessed their quality and understandability by applying the DISCERN tool and PEMAT-P. The Flesch Reading Ease Score (FRES) was calculated to determine readability. Nine booklets addressing MP were analyzed. The overall median DISCERN score was 3.6 (interquartile range (IQR) 2.9-4.1), median PEMAT-P score was 91% (IQR 83-94.5), and median FRES was 43 (IQR 33.5-47.5), indicating a medium quality, a high application of understandability elements, but low readability in at least half of the booklets. Incomplete reporting on treatments and insufficient meta-information caused the main quality deficits. There is a need of content and didactic revision of German booklets for MP to raise their quality and to make them beneficial and understandable for more patients. An adaption in accordance with evidence-based criteria and an even stronger involvement of MP in assessment and development of patient education material are considered to be the best approaches.

    Pubmed
  • Sources of information and support for melanoma patients: differences between patients' and clinicians' preferences.

    J Dtsch Dermatol Ges. 2019;17(6): 652-654

    Brütting J, Bergmann M, Schadendorf D, Weber C, Tilgen W, Berking C, Meier F, NVKH

    Pubmed
  • Unmet information needs of patients with melanoma in Germany.

    Melanoma Res. 2019;29(2): 196-204

    Brütting J, Bergmann M, Garzarolli M, Rauschenberg R, Weber C, Berking C, Tilgen W, Schadendorf D, Meier F, on behalf of the NVKH supporting group

    There is a scarcity of available data on unmet information needs (UINs) of melanoma patients (MPs) from Germany and of MPs with clinical stage IV. In a multicenter cross-sectional survey, we explored the UINs of 529 MPs by applying a standardized questionnaire. Subgroup differences in scope and contents of UINs were determined by univariate analyses. Predictors of the presence of UINs were identified by binary logistic regression. Overall, 55% of MPs reported UINs. Most MPs felt poorly or not informed about psychosocial support (24-31%). In MPs currently receiving medical treatment [odds ratio (OR): 1.9; P=0.017], MPs aging of at least 55 years (OR: 1.7; P=0.029), and in MPs who generally had a high need for information on their condition (OR: 2.4; P=0.001), the presence of UINs was significantly more likely than in post-treatment MPs, MPs more than 55 years of age, and those whose general information need was low. Most UINs concerned treatment-related information and were reported by MPs with tumor progression. Presence and scope of UINs did not differ significantly between metastatic and nonmetastatic MPs (57 vs. 53%; P=0.436). We highlighted differences in the presence, scope, and contents of UINs between MP subgroups, which should be considered when educating them in medical consultations and providing information via media. In particular, MPs felt insufficiently informed about psychosocial support and desired more treatment information.

    Pubmed
  • Local interventions for actinic keratosis in organ transplant recipients: a systematic review.

    Br J Dermatol. 2019;180(1): 43-50

    Heppt MV, Steeb T, Niesert AC, Zacher M, Leiter U, Garbe C, Berking C

    Actinic keratosis (AK) in organ transplant recipients (OTRs) has a high risk of progressing to invasive squamous cell carcinoma of the skin. Thus, early and consequent treatment of AKs is warranted in OTRs.To summarize the current evidence for nonsystemic treatments of AKs in OTRs.We performed a systematic literature search in MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) and hand-searched pertinent trial registers up to 22 August 2018. Randomized controlled trials (RCTs) evaluating nonsystemic interventions for AKs in OTRs were included. The risk of bias was estimated using the Cochrane Risk of Bias Tool.Of 663 records initially identified, eight RCTs with 242 OTRs were included in a qualitative synthesis. Most studies evaluated methyl aminolaevulinate photodynamic therapy (MAL-PDT), followed by ablative fractional laser (AFXL) and diclofenac sodium 3% in hyaluronic acid, imiquimod 5% cream and 5-fluorouracil 5% cream (5-FU). MAL-PDT showed the highest rates of participant complete clearance (40-76·4%), followed by imiquimod (27·5-62·1%), diclofenac (41%) and 5-FU (11%). Similar results were observed for lesion-specific clearance rates. Treatment with AFXL alone revealed low lesion clearance (5-31%). Local skin reactions were most intense in participants treated with a combination of AFXL and daylight MAL-PDT. There were no therapy-related transplant rejections or worsening of graft function in any trial. The overall risk of bias was high.Limited evidence is available for the treatment of AKs in OTRs. MAL-PDT is currently the best-studied intervention. Lesion-specific regimens may not be sufficient to achieve disease control. Field-directed regimens are preferable in this high-risk population.

    Pubmed
  • Cryosurgery combined with topical interventions for actinic keratosis: a systematic review and meta-analysis.

    Br J Dermatol. 2019;180(4): 740-748

    Heppt MV, Steeb T, Ruzicka T, Berking C

    Actinic keratoses (AKs) are early in situ carcinomas of the skin caused by cumulative sun exposure. Cryosurgery is an easy and practicable lesion-directed approach for treatment of isolated lesions.To investigate whether an upfront combination of cryosurgery with a topical intervention is superior to cryosurgery alone for treatment of AK.We performed a systematic literature search in MEDLINE, Embase and CENTRAL and hand searched pertinent trial registers for eligible randomized controlled trials until 17 July 2018. Results from individual studies were pooled using a random effects model. The risk of bias was estimated with the Cochrane Risk of Bias Tool and the quality of evidence of the outcomes with the GRADE approach.Out of 1758 records initially identified, nine studies with a total sample size of 1644 patients were included. Cryosurgery in combination with a topical approach showed significantly higher participant complete clearance rates than monotherapy [risk ratio (RR) 1·74, 95% confidence interval (CI) 1·25-2·43, I = 73%, eight studies]. The participant partial clearance rate was not statistically different (RR 1·64, 95% CI 0·88-3·03, I = 77%, three studies). The number of patients who completed the study protocol and did not withdraw due to adverse events was equal in both groups (RR 0·98, 95% CI 0·95-1·01, I = 75%, seven studies). The studies were estimated to have high risk for selective reporting bias.Our results suggest the superiority of a combination regimen for AK clearance, with equal tolerability. This study highlights the importance of a field-directed approach in patients with multiple AKs or field cancerization.

    Pubmed
  • Conceptual, statistical and clinical interpretation of results from: Cryosurgery combined with topical interventions for actinic keratosis: reply from the authors.

    Br J Dermatol. 2019;181(2): 424-425

    Heppt MV, Steeb T, Berking C

    Pubmed
  • Efficacy of photodynamic therapy combined with topical interventions for the treatment of actinic keratosis: a meta-analysis.

    J Eur Acad Dermatol Venereol. 2019;33(5): 863-873

    Heppt MV, Steeb T, Leiter U, Berking C

    BACKGROUND: Photodynamic therapy (PDT) is a highly effective treatment option for patients with actinic keratoses (AK). However, efficacy can be reduced by insufficient illumination or hyperkeratotic nature of lesions.

    OBJECTIVES: To investigate if PDT combined with a topical intervention is superior to monotherapy in terms of efficacy and tolerability.

    METHODS: A systematic literature research was conducted in Medline, Embase and CENTRAL. Pertinent trial registers were hand-searched for eligible randomized controlled trials (RCTs) until 20 August 2018. Results were pooled using a random effects model to calculate relative risks (RR) or mean differences. The risk of bias was assessed with the Cochrane Risk of Bias Tool. The quality of evidence was estimated for each outcome of interest according to GRADE.

    RESULTS: Out of 1800 references initially identified, 10 RCTs with a total sample size of n = 277 were included. Four studies investigated a combination of PDT with imiquimod cream, three with 5-fluorouracil cream and one each with ingenol mebutate gel, tazarotene gel and calcipotriol ointment, respectively. Patients treated with a combination showed higher participant complete (RR 1.63; 95% CI 1.15-2.33; P = 0.007) and partial clearance rates (RR 1.19; 95% CI 0.84-1.67; P = 0.33). Similarly, the lesion-specific clearance was higher for PDT plus topical intervention compared to monotherapy (RR 1.48; 95% CI 1.04-2.11; P = 0.03). A subgroup analysis was performed for PDT combined with imiquimod, revealing an increased participant complete clearance rate compared to monotherapy (RR 1.57, 95% CI 1.09-2.25, P = 0.02). PDT-induced pain and local skin reactions after treatment were poorly reported. The studies were estimated at high risk for performance and detection bias.

    CONCLUSION: The combination of PDT with another topical drug intervention does improve AK clearance rates compared to either monotherapy alone. This study highlights that the sequential application of two field-directed treatments represents an efficient approach in patients with multiple AK and field cancerization.

    Pubmed
  • Patient Attitudes and Their Awareness Towards Skin Cancer-Related Apps: Cross-Sectional Survey.

    JMIR mHealth uHealth. 2019;7(7):

    Steeb T, Wessely A, Mastnik S, Brinker TJ, French LE, Niesert AC, Berking C, Heppt MV

    BACKGROUND: In the emerging era of digitalization and electronic health, skin cancer-related apps represent useful tools to support dermatologic consultation and examination. Yet, little is known about how patients perceive the value of such apps.

    OBJECTIVE: The aim of this study was to investigate patient attitudes and their awareness toward skin cancer-related apps.

    METHODS: A cross-sectional study including 200 patients from the oncological outpatient unit was conducted at the University Hospital (LMU Munich, Germany) between September and December 2018. Patients were asked to complete a self-administered questionnaire on the popularity and usefulness of health-related and skin cancer-related apps. A descriptive analysis was performed with the expression of categorical variables as frequencies and percentages. For continuous variables, the median and range were indicated. Contingency tables and chi-square tests were performed to investigate associations between sociodemographic data and selected items of the questionnaire.

    RESULTS: A total of 98.9% (195/197) of patients had never used skin cancer-related apps or could not remember. In 49.7% (93/187) of cases, patients were unsure about the usefulness of skin cancer apps, whereas 42.6% (78/183) thought that skin cancer apps could supplement or support the professional skin examination performed by a physician. However, 47.9% (90/188) were interested in acquiring more information by their dermatologists about skin cancer apps. Young age (P=.002), male gender (P=.02), a previous history of melanoma (P=.004), and higher educational level (P=.002) were significantly associated with a positive attitude. Nevertheless, 55.9% (105/188) preferred a printed patient brochure on skin cancer to downloading and using an app.

    CONCLUSIONS: The experience and knowledge of skin cancer-related apps was surprisingly low in this population, although there was a high general interest in more information about such apps. Printed patient brochures were the preferred information source.

    Pubmed
  • The myelin protein PMP2 is regulated by SOX10 and drives melanoma cell invasion.

    Pigment Cell Melanoma Res. 2019;32(3): 424-434

    Graf SA, Heppt MV, Wessely A, Krebs S, Kammerbauer C, Hornig E, Strieder A, Blum H, Bosserhoff AK, Berking C

    The transcription factor sex determining region Y-box 10 (SOX10) plays a key role in the development of melanocytes and glial cells from neural crest precursors. SOX10 is involved in melanoma initiation, proliferation, invasion, and survival. However, specific mediators which impart its oncogenic properties remain widely unknown. To identify target genes of SOX10, we performed RNA sequencing after ectopic expression of SOX10 in human melanoma cells. Among nine differentially regulated genes, peripheral myelin protein 2 (PMP2) was consistently upregulated in several cell lines. Direct regulation of PMP2 by SOX10 was shown by chromatin immunoprecipitation, electrophoretic mobility shift, and luciferase reporter assays. Moreover, a coregulation of PMP2 by SOX10 and early growth response 2 in melanoma cells was found. Phenotypical investigation demonstrated that PMP2 expression can increase melanoma cell invasion. As PMP2 protein was detected only in a subset of melanoma cell lines, it might contribute to melanoma heterogeneity.

    Pubmed
  • Patient Attitude towards Videodermatoscopy for the Detection of Skin Cancer: A Cross-Sectional Study.

    Oncology Research and Treatment. 2019;42(6): 319-325

    Steeb T, Wessely A, Niesert AC, Ruzicka T, von Braunmühl T, Berking C, Heppt MV

    BACKGROUND: Videodermatoscopy (VD) is a useful device for supporting dermatologists in the distinction between benign and malignant lesions. However, only few patients have access to VD in daily practice.

    OBJECTIVES: To investigate patient attitudes towards VD.

    METHOD: A cross-sectional study was conducted between May and June 2018. Patients were asked to complete a self-administered questionnaire on the popularity of VD. Descriptive analysis was performed including contingency tables and χ2 tests to investigate associations between sociodemographic data and the popularity of VD.

    RESULTS: A total of 61.2% (123/201) of the patients had not heard of VD at the time of assessment or were unsure. Of the 38.8% of patients (78/201) who already knew of VD, 64.1% (50/78) reported that they had already been investigated by VD; 57.5% (111/193) were willing to pay an extra fee for VD. A high level of education and private insurance status had a statistically significant association with the popularity of VD (p = 0.036 and p = 0.026, respectively).

    CONCLUSIONS: There was a strong information deficit, especially in patients with lower education and statutory health insurance. Nevertheless, the willingness to pay an extra fee for a VD-assisted skin examination was high. Dermatologists should actively offer and inform their patients about VD when performing skin cancer screening.

    Pubmed
  • Laser-assisted photodynamic therapy for actinic keratosis: A systematic review and meta-analysis.

    J Am Acad Dermatol. 2019;80(4): 947-956

    Steeb T, Schlager JG, Kohl C, Ruzicka T, Heppt MV, Berking C

    Photodynamic therapy (PDT) is an effective intervention for actinic keratosis and field cancerization. Ablative fractional lasers may facilitate the delivery of photosensitizers and thereby improve the effects of PDT.To summarize the current evidence on the efficacy and safety of laser-assisted PDT.We performed a systematic literature research in Medline, Embase, and the Cochrane Central Register of Controlled Trials and hand-searched pertinent trial registers for eligible randomized controlled trials. Results from individual studies were pooled by using a random-effects model. The risk of bias was estimated with the Cochrane Risk of Bias Tool, and the quality of evidence of the outcomes was assessed with the Grading of Recommendations, Assessment, Development, and Evaluation approach.Of 817 records initially identified, 7 randomized controlled trials were included in the qualitative analysis and 4 were included in the meta-analysis. Laser-assisted PDT showed significantly higher clearance rates than did PDT monotherapy (risk ratio, 1.33; 95% confidence interval, 1.24-1.42; I = 25%; P < .01). There was no difference in pain intensity between laser-assisted PDT and other interventions (mean difference, 0.31; 95% confidence interval, -0.12 to 0.74; I = 0%; P = .16). The included studies showed a high risk of bias.The clinical heterogeneity of included studies.Laser-assisted PDT is more efficient but not more painful than PDT or laser treatment only.

    Pubmed
  • Superior skin cancer classification by the combination of human and artificial intelligence.

    Eur J Cancer. 2019;120(): 114-121

    Hekler A, Utikal JS, Enk AH, Hauschild A, Weichenthal M, Maron RC, Berking C, Haferkamp S, Klode J, Schadendorf D, Schilling B, Holland-Letz T, Izar B, von Kalle C, Fröhling S, Brinker TJ, Collaborators , Schmitt L, Peitsch WK, Hoffmann F, Becker JC, Drusio C, Jansen P, Klode J, Lodde G, Sammet S, Schadendorf D, Sondermann W, Ugurel S, Zader J, Enk A, Salzmann M, Schäfer S, Schäkel K, Winkler J, Wölbing P, Asper H, Bohne AS, Brown V, Burba B, Deffaa S, Dietrich C, Dietrich M, Drerup KA, Egberts F, Erkens AS, Greven S, Harde V, Jost M, Kaeding M, Kosova K, Lischner S, Maagk M, Messinger AL, Metzner M, Motamedi R, Rosenthal AC, Seidl U, Stemmermann J, Torz K, Velez JG, Haiduk J, Alter M, Bär C, Bergenthal P, Gerlach A, Holtorf C, Karoglan A, Kindermann S, Kraas L, Felcht M, Gaiser MR, Klemke CD, Kurzen H, Leibing T, Müller V, Reinhard RR, Utikal J, Winter F, Berking C, Eicher L, Hartmann D, Heppt M, Kilian K, Krammer S, Lill D, Niesert AC, Oppel E, Sattler E, Senner S, Wallmichrath J, Wolff H, Gesierich A, Giner T, Glutsch V, Kerstan A, Presser D, Schrüfer P, Schummer P, Stolze I, Weber J, Drexler K, Haferkamp S, Mickler M, Stauner CT, Thiem A

    BACKGROUND: In recent studies, convolutional neural networks (CNNs) outperformed dermatologists in distinguishing dermoscopic images of melanoma and nevi. In these studies, dermatologists and artificial intelligence were considered as opponents. However, the combination of classifiers frequently yields superior results, both in machine learning and among humans. In this study, we investigated the potential benefit of combining human and artificial intelligence for skin cancer classification.

    METHODS: Using 11,444 dermoscopic images, which were divided into five diagnostic categories, novel deep learning techniques were used to train a single CNN. Then, both 112 dermatologists of 13 German university hospitals and the trained CNN independently classified a set of 300 biopsy-verified skin lesions into those five classes. Taking into account the certainty of the decisions, the two independently determined diagnoses were combined to a new classifier with the help of a gradient boosting method. The primary end-point of the study was the correct classification of the images into five designated categories, whereas the secondary end-point was the correct classification of lesions as either benign or malignant (binary classification).

    FINDINGS: Regarding the multiclass task, the combination of man and machine achieved an accuracy of 82.95%. This was 1.36% higher than the best of the two individual classifiers (81.59% achieved by the CNN). Owing to the class imbalance in the binary problem, sensitivity, but not accuracy, was examined and demonstrated to be superior (89%) to the best individual classifier (CNN with 86.1%). The specificity in the combined classifier decreased from 89.2% to 84%. However, at an equal sensitivity of 89%, the CNN achieved a specificity of only 81.5% INTERPRETATION: Our findings indicate that the combination of human and artificial intelligence achieves superior results over the independent results of both of these systems.

    Pubmed
  • Deep neural networks are superior to dermatologists in melanoma image classification.

    Eur J Cancer. 2019;119(): 11-17

    Brinker TJ, Hekler A, Enk AH, Berking C, Haferkamp S, Hauschild A, Weichenthal M, Klode J, Schadendorf D, Holland-Letz T, von Kalle C, Fröhling S, Schilling B, Utikal JS

    BACKGROUND: Melanoma is the most dangerous type of skin cancer but is curable if detected early. Recent publications demonstrated that artificial intelligence is capable in classifying images of benign nevi and melanoma with dermatologist-level precision. However, a statistically significant improvement compared with dermatologist classification has not been reported to date.

    METHODS: For this comparative study, 4204 biopsy-proven images of melanoma and nevi (1:1) were used for the training of a convolutional neural network (CNN). New techniques of deep learning were integrated. For the experiment, an additional 804 biopsy-proven dermoscopic images of melanoma and nevi (1:1) were randomly presented to dermatologists of nine German university hospitals, who evaluated the quality of each image and stated their recommended treatment (19,296 recommendations in total). Three McNemar's tests comparing the results of the CNN's test runs in terms of sensitivity, specificity and overall correctness were predefined as the main outcomes.

    FINDINGS: The respective sensitivity and specificity of lesion classification by the dermatologists were 67.2% (95% confidence interval [CI]: 62.6%-71.7%) and 62.2% (95% CI: 57.6%-66.9%). In comparison, the trained CNN achieved a higher sensitivity of 82.3% (95% CI: 78.3%-85.7%) and a higher specificity of 77.9% (95% CI: 73.8%-81.8%). The three McNemar's tests in 2 × 2 tables all reached a significance level of p < 0.001. This significance level was sustained for both subgroups.

    INTERPRETATION: For the first time, automated dermoscopic melanoma image classification was shown to be significantly superior to both junior and board-certified dermatologists (p < 0.001).

    Pubmed
  • Systematic outperformance of 112 dermatologists in multiclass skin cancer image classification by convolutional neural networks.

    Eur J Cancer. 2019;119(): 57-65

    Maron RC, Weichenthal M, Utikal JS, Hekler A, Berking C, Hauschild A, Enk AH, Haferkamp S, Klode J, Schadendorf D, Jansen P, Holland-Letz T, Schilling B, von Kalle C, Fröhling S, Gaiser MR, Hartmann D, Gesierich A, Kähler KC, Wehkamp U, Karoglan A, Bär C, Brinker TJ, Collabrators , Schmitt L, Peitsch WK, Hoffmann F, Becker JC, Drusio C, Jansen P, Klode J, Lodde G, Sammet S, Schadendorf D, Sondermann W, Ugurel S, Zader J, Enk A, Salzmann M, Schäfer S, Schäkel K, Winkler J, Wölbing P, Asper H, Bohne AS, Brown V, Burba B, Deffaa S, Dietrich C, Dietrich M, Drerup KA, Egberts F, Erkens AS, Greven S, Harde V, Jost M, Kaeding M, Kosova K, Lischner S, Maagk M, Messinger AL, Metzner M, Motamedi R, Rosenthal AC, Seidl U, Stemmermann J, Torz K, Velez JG, Haiduk J, Alter M, Bär C, Bergenthal P, Gerlach A, Holtorf C, Karoglan A, Kindermann S, Kraas L, Felcht M, Gaiser MR, Klemke CD, Kurzen H, Leibing T, Müller V, Reinhard RR, Utikal J, Winter F, Berking C, Eicher L, Hartmann D, Heppt M, Kilian K, Krammer S, Lill D, Niesert AC, Oppel E, Sattler E, Senner S, Wallmichrath J, Wolff H, Giner T, Glutsch V, Kerstan A, Presser D, Schrüfer P, Schummer P, Stolze I, Weber J, Drexler K, Haferkamp S, Mickler M, Stauner CT, Thiem A

    BACKGROUND: Recently, convolutional neural networks (CNNs) systematically outperformed dermatologists in distinguishing dermoscopic melanoma and nevi images. However, such a binary classification does not reflect the clinical reality of skin cancer screenings in which multiple diagnoses need to be taken into account.

    METHODS: Using 11,444 dermoscopic images, which covered dermatologic diagnoses comprising the majority of commonly pigmented skin lesions commonly faced in skin cancer screenings, a CNN was trained through novel deep learning techniques. A test set of 300 biopsy-verified images was used to compare the classifier's performance with that of 112 dermatologists from 13 German university hospitals. The primary end-point was the correct classification of the different lesions into benign and malignant. The secondary end-point was the correct classification of the images into one of the five diagnostic categories.

    FINDINGS: Sensitivity and specificity of dermatologists for the primary end-point were 74.4% (95% confidence interval [CI]: 67.0-81.8%) and 59.8% (95% CI: 49.8-69.8%), respectively. At equal sensitivity, the algorithm achieved a specificity of 91.3% (95% CI: 85.5-97.1%). For the secondary end-point, the mean sensitivity and specificity of the dermatologists were at 56.5% (95% CI: 42.8-70.2%) and 89.2% (95% CI: 85.0-93.3%), respectively. At equal sensitivity, the algorithm achieved a specificity of 98.8%. Two-sided McNemar tests revealed significance for the primary end-point (p < 0.001). For the secondary end-point, outperformance (p < 0.001) was achieved except for basal cell carcinoma (on-par performance).

    INTERPRETATION: Our findings show that automated classification of dermoscopic melanoma and nevi images is extendable to a multiclass classification problem, thus better reflecting clinical differential diagnoses, while still outperforming dermatologists at a significant level (p < 0.001).

    Pubmed
  • Pathologist-level classification of histopathological melanoma images with deep neural networks.

    Eur J Cancer. 2019;115(): 79-83

    Hekler A, Utikal JS, Enk AH, Berking C, Klode J, Schadendorf D, Jansen P, Franklin C, Holland-Letz T, Krahl D, von Kalle C, Fröhling S, Brinker TJ

    BACKGROUND: The diagnosis of most cancers is made by a board-certified pathologist based on a tissue biopsy under the microscope. Recent research reveals a high discordance between individual pathologists. For melanoma, the literature reports 25-26% of discordance for classifying a benign nevus versus malignant melanoma. Deep learning was successfully implemented to enhance the precision of lung and breast cancer diagnoses. The aim of this study is to illustrate the potential of deep learning to assist human assessment for a histopathologic melanoma diagnosis.

    METHODS: Six hundred ninety-five lesions were classified by an expert histopathologist in accordance with current guidelines (350 nevi and 345 melanomas). Only the haematoxylin and eosin stained (H&E) slides of these lesions were digitalised using a slide scanner and then randomly cropped. Five hundred ninety-five of the resulting images were used for the training of a convolutional neural network (CNN). The additional 100 H&E image sections were used to test the results of the CNN in comparison with the original class labels.

    FINDINGS: The total discordance with the histopathologist was 18% for melanoma (95% confidence interval [CI]: 7.4-28.6%), 20% for nevi (95% CI: 8.9-31.1%) and 19% for the full set of images (95% CI: 11.3-26.7%).

    INTERPRETATION: Even in the worst case, the discordance of the CNN was about the same compared with the discordance between human pathologists as reported in the literature. Despite the vastly reduced amount of data, time necessary for diagnosis and cost compared with the pathologist, our CNN archived on-par performance. Conclusively, CNNs indicate to be a valuable tool to assist human melanoma diagnoses.

    Pubmed
  • Comparing artificial intelligence algorithms to 157 German dermatologists: the melanoma classification benchmark.

    Eur J Cancer. 2019;111(): 30-37

    Brinker TJ, Hekler A, Hauschild A, Berking C, Schilling B, Enk AH, Haferkamp S, Karoglan A, von Kalle C, Weichenthal M, Sattler E, Schadendorf D, Gaiser MR, Klode J, Utikal JS

    BACKGROUND: Several recent publications have demonstrated the use of convolutional neural networks to classify images of melanoma at par with board-certified dermatologists. However, the non-availability of a public human benchmark restricts the comparability of the performance of these algorithms and thereby the technical progress in this field.

    METHODS: An electronic questionnaire was sent to dermatologists at 12 German university hospitals. Each questionnaire comprised 100 dermoscopic and 100 clinical images (80 nevi images and 20 biopsy-verified melanoma images, each), all open-source. The questionnaire recorded factors such as the years of experience in dermatology, performed skin checks, age, sex and the rank within the university hospital or the status as resident physician. For each image, the dermatologists were asked to provide a management decision (treat/biopsy lesion or reassure the patient). Main outcome measures were sensitivity, specificity and the receiver operating characteristics (ROC).

    RESULTS: Total 157 dermatologists assessed all 100 dermoscopic images with an overall sensitivity of 74.1%, specificity of 60.0% and an ROC of 0.67 (range = 0.538-0.769); 145 dermatologists assessed all 100 clinical images with an overall sensitivity of 89.4%, specificity of 64.4% and an ROC of 0.769 (range = 0.613-0.9). Results between test-sets were significantly different (P < 0.05) confirming the need for a standardised benchmark.

    CONCLUSIONS: We present the first public melanoma classification benchmark for both non-dermoscopic and dermoscopic images for comparing artificial intelligence algorithms with diagnostic performance of 145 or 157 dermatologists. Melanoma Classification Benchmark should be considered as a reference standard for white-skinned Western populations in the field of binary algorithmic melanoma classification.

    Pubmed
  • Möglichkeiten und Grenzen von prognostischen Gensignaturen im frühen Melanom.

    J Dtsch Dermatol Ges. 2019;17(8): 769-770

    Heppt MV, Berking C

    Pubmed
  • Phototoxicity of BRAF Inhibitors and their Attenuation by Antioxidants

    J Dtsch Dermatol Ges. 2019;17 Suppl 5(): 28-29

    Heppt M, Clanner-Engelshofen B, Marsela E, Wessely A, Kammerbauer C, Przybilla B, French L, Berking C, Reinholz M

    Pubmed
  • Interim Analysis of the Efficacy and Safety of Dabrafenib and Trametinib in Patients with metastatic Melanoma in daily clinical Practice (COMBI-r)

    J Dtsch Dermatol Ges. 2019;17 Suppl 5(): 72-73

    Berking C, Livingstone E, Weichenthal M, Leiter-Stoeppke U, Wittmann K, Eigentler T, Mohr P, Kiecker F, Loquai C, Debus D, Gutzmer R

    Pubmed
  • Granulomatous Hepatitis with partial Liver Failure after Immunocombination Therapy with Ipilimumab and Nivolumab in metastatic Melanoma

    J Dtsch Dermatol Ges. 2019;17 Suppl 5(): 35-35

    Haas C, Ruini C, Mastnik S, Berking C

    Pubmed
  • Primary biliary Cholangitis as a rare Side Effect of Immune Checkpoint Blockade in metastatic Melanoma

    J Dtsch Dermatol Ges. 2019;17 Suppl 5(): 80-80

    Ruini C, Haas C, Berking C

    Pubmed
  • Diversity of CD4 blood T-cell clonality predicts longer survival with CTLA4 or PD-1 checkpoint inhibition in advanced melanoma

    Eur J Immunol. 2019;49 Suppl 1(): 177-177

    Arakawa A, Vollmer S, Tietze J, Buerdek M, Heppt M, Berking C, Prinz JC

    Pubmed
  • Inhibition of the Neural Crest-Transcription Factor SOX10 leads to Cell Cycle Arrest and Apoptosis in Uveal Melanoma Cells

    J Dtsch Dermatol Ges. 2019;17 Suppl 5(): 51-52

    Wessely A, Kammerbauer C, Berking C, Heppt M

    Pubmed
  • New HOPE for actinic keratosis - Development of a Core Outcome P138 set for Harmonization of Outcome Parameter and Evaluation of actinic Keratosis Studies

    J Dtsch Dermatol Ges. 2019;17 Suppl 5(): 83-84

    Steeb T, Berking C, Schmitz L, Leiter-Stoeppke U, Heppt M

    Pubmed
  • Final Analysis of DeCOG-SLT Trial: No Survival Benefit for Complete Lymph Node Dissection in Patients With Melanoma With Positive Sentinel Node.

    J Clin Oncol. 2019;37(32): 3000-3008

    Leiter U, Stadler R, Mauch C, Hohenberger W, Brockmeyer NH, Berking C, Sunderkötter C, Kaatz M, Schatton K, Lehmann P, Vogt T, Ulrich J, Herbst R, Gehring W, Simon JC, Keim U, Verver D, Martus P, Garbe C, German Dermatologic Cooperative Oncology Group

    PURPOSE: We have previously reported on the 3-year results of the phase III German Dermatologic Cooperative Oncology Group trial (DeCOG; ClinicalTrials.gov identifier: NCT02434107) comparing distant metastasis-free survival (DMFS), recurrence-free survival (RFS), and overall survival (OS) in patients with positive sentinel lymph-node biopsy who were randomly assigned to complete lymph node dissection (CLND) or observation. Here, we report the final analysis with 72 months of median follow up.

    PATIENTS AND METHODS: The multicenter randomized phase III trial included patients with cutaneous melanoma of the trunk and extremities who were randomly assigned (1:1) to undergo CLND or observation. DMFS was analyzed as the primary end point, and RFS, OS, and recurrences in the regional lymph node basin were secondary end points. The analysis was by intention to treat. Disease and survival information were collected quarterly.

    RESULTS: From January 2006 to December 2014, 5,547 patients were screened to identify 1,256 with metastases in the sentinel lymph node (SLN). Of these, 483 (39%) were included: 241 in the observation arm and 242 in the CLND arm. In the final analysis, median follow up was 72 months (interquartile range, 67-77 months). No significant treatment-related difference was seen in the 5-year DMFS between the observation and CLND arms (67.6% v 64.9%, respectively; hazard ratio [HR], 1.08; P = .87). The 5-year RFS and OS also showed no difference (HR, 1.01 and 0.99, respectively). Grade 3 and 4 adverse effects occurred in 32 patients (13%) in the CLND arm; lymphedema (n = 20) and delayed wound healing (n = 5) were most common and no serious adverse events were reported.

    CONCLUSION: The final results of the German Dermatologic Cooperative Oncology Group trial with a median follow up of 72 months showed higher event rates, but similar HRs compared with those at the 3-year analysis. These results confirm that immediate CLND in SLN-positive patients is not superior to observation in terms of DMFS, RFS, or OS and support not recommending CLND in patients with SLN metastasis.

    Pubmed
  • Diversity of CD4(+) blood T-cell clonality predicts longer survival with CTLA4 or PD-1 checkpoint inhibition in advanced melanoma

    Exp Dermatol. 2019;28(3): E54-E54

    Arakawa A, Vollmer S, Tietze J, Galinski A, Heppt MV, Berking C, Prinz JC

    Pubmed
  • The myelin protein PMP2 is regulated by SOX10 and drives melanoma cell

    invasion

    Exp Dermatol. 2019;28(3): E94-E94

    Heppt MV, Graf S, Wessely A, Krebs S, Kammerbauer C, Hornig E, Strieder A, Blum H, Bosserhoff AK, Berking C

    Pubmed
  • Interim analysis of phase 2 results for Cemiplimab, a human monoclonal antibody to programmed death-1 (PD-1), in patients with locally advanced cutaneous squamous cell carcinoma

    J Dtsch Dermatol Ges. 2019;17 Suppl 3(): 161-162

    Migden MR, Berking C, Chang ALS, Eigentler TK, Hauschild A, Hernandez-Aya L, Khushalani NI, Lewis KD, Meier F, Modi B, Rischin D, Schadendorf D, Schmults CD, Ulrich C, Booth J, Li S, Mohan K, Stankevich E, Lowy I, Fury MG

    Pubmed
  • Impact of radiation, systemic therapy and treatment sequencing on survival of patients with melanoma brain metastases.

    Eur J Cancer. 2019;110(): 11-20

    Rauschenberg R, Bruns J, Brütting J, Daubner D, Lohaus F, Zimmer L, Forschner A, Zips D, Hassel JC, Berking C, Kaehler KC, Utikal J, Gutzmer R, Terheyden P, Meiss F, Rafei-Shamsabadi D, Kiecker F, Debus D, Dabrowski E, Arnold A, Garzarolli M, Kuske M, Beissert S, Löck S, Linn J, Troost EGC, Meier F

    BACKGROUND: Combining stereotactic radiosurgery (SRS) and active systemic therapies (STs) achieved favourable survival outcomes in patients with melanoma brain metastases (MBMs) in retrospective analyses. However, several aspects of this treatment strategy remain poorly understood. We report on the overall survival (OS) of patients with MBM treated with a combination of radiotherapy (RT) and ST as well as the impact of the v-Raf murine sarcoma viral oncogene homolog B (BRAF)-V600 mutation (BRAFmut) status, types of RT and ST and their sequence.

    PATIENTS AND METHODS: Data of 208 patients treated with SRS or whole brain radiation therapy (WBRT) and either immunotherapy (IT) or targeted therapy (TT) within a 6-week interval to RT were analysed retrospectively. OS was calculated from RT to death or last follow-up. Univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic features associated with OS.

    RESULTS: The median follow-up was 7.3 months. 139 patients received IT, 67 received TT and 2 received IT and TT within 6 weeks to RT (WBRT 45%; SRS 55%). One-year Kaplan-Meier OS rates were 69%, 65%, 33% and 18% (P < .001) for SRS with IT, SRS with TT, WBRT with IT and WBRT with TT, respectively. Patients with a BRAFmut receiving IT combined with RT experienced higher OS rates (88%, 65%, 50% and 18%). TT following RT or started before and continued thereafter was associated with improved median OS compared with TT solely before RT (12.2 [95% confidence interval {CI} 9.3-15.1]; 9.8 [95% CI 6.9-12.6] versus 5.1 [95% CI 2.7-7.5]; P = .03).

    CONCLUSION: SRS and IT achieved the highest OS rates. A BRAFmut appears to be a favourable prognostic factor for OS. For the combination of RT and TT, the sequence appears to be crucial. Combinations of WBRT and ST achieved unprecedentedly high OS rates and warrant further studies.

    Pubmed
  • Inhibition of the neural crest transcription factor SOX10 leads to cell cycle arrest and apoptosis in uveal melanoma cells

    Exp Dermatol. 2019;28(3): E91-E91

    Wessely A, Heppt MV, Kammerbauer C, Berking C

    Pubmed
  • Actinic Keratosis and Cutaneous Squamous Cell Carcinoma

    Dtsch Arztebl Int. 2019;116(37): 616-+

    Gutzmer R, Wiegand S, Koelbl O, Wermker K, Hepp M, Berking C

    Background: Cutaneous squamous cell carcinoma (cSCC) and its precursors, actinic keratoses (AK), are common. Physicians of multiple specialties are confronted with their treatment.

    Methods: This review is based on publications retrieved by a selective search in PubMed, as well as on the German guidelines on AK and cSCC, skin cancer prevention, and surgery with histologic guidance.

    Results: Local treatments for AK include lesional cryotherapy, curettage, and laser ablation as well as field-directed treatments with topical agents, e.g., diclofenac plus hyaluronic acid, imiquimod, 5-fluorouracil, ingenol mebutate, and photodynamic therapy. These treatments can be administered in various sequences or combinations, depending on individual factors and the stage of the disease. The gold standard of treatment for cSCC is histologically confirmed complete resection; radiotherapy is an alternative. Locally uncontrollable or metastatic disease is treated with systemic drugs. The use of various chemotherapeutic agents, EGFR-directed therapies, and the PD-I inhibitor cemiplimab, either singly or in combination, has been described in uncontrolled trials and case series. Cemiplimab has a reported response rate of 47% and was recently approved for the treatment of advanced cSCC.

    Conclusion: There are many options for the treatment of AK and cSCC that must be considered in the interdisciplinary care of these entities.

    Pubmed
  • Successful Treatment of Genital Warts with Ingenol Mebutate Monitored

    with Optical Coherence Tomography and Reflectance Confocal Microscopy

    Ann Dermatol. 2019;31(4): 434-437

    Reinholz M, Clanner-Engelshofen BM, Heppt MV, Hirai Y, Ruzicka T, Berking C, von Braunmuehl T

    Ingenol mebutate (IM) is approved for the treatment of actinic keratosis and induces cell death in precancerous lesions. The efficacy of IM in the treatment of genital warts was investigated in a therapy-refractory patient. The 74-year-old male was treated with IM gel for three consecutive days. Treatment course and efficacy were evaluated by clinical inspection and non-invasive diagnostics namely optical coherence tomography (OCT) and reflectance confocal microscopy (RCM). Within 24 to 48 hours IM induced a strong local inflammatory reaction. One week later a complete response was observed. OCT and RCM showed a strong reaction after treatment with erosions, swelling of cells, and a subepidermal dark band in representative lesions. IM has the advantage of a short treatment period in contrast to other topical treatments and shows a promising clinical outcome. Larger studies are needed to validate the data.

    Pubmed
  • Phase Ib/II study (SENSITIZE) assessing safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical outcome of domatinostat in combination with pembrolizumab in patients with advanced melanoma refractory/non-responding to prior checkpoint inhibitor therapy

    Ann Oncol. 2019;30 Suppl 5():

    Hassel JC, Berking C, Eigentler T, Gutzmer R, Ascierto PA, Schilling B, Hermann F, Bartz R, Schadendorf D

    Pubmed
  • Primary analysis of phase 2 results of cemiplimab, a human monoclonal anti-PD-1, in patients (pts) with locally advanced cutaneous squamous cell carcinoma (IaCSCC).

    J Clin Oncol. 2019;37 Suppl S(15):

    Migden MR, Khushalani NI, Chang ALS, Rischin D, Schmults CD, Hernandez-Aya LF, Meier FE, Schadendorf D, Guminski AD, Hauschild A, Wong DJL, Daniels GA, Berking C, Jankovic V, Stankevich E, Booth J, Li SY, Lowy I, Fury MG, Lewis KD

    Pubmed
  • Melanoma (vol 392, pg 971, 2018)

    Lancet. 2019;393(10173): 746-746

    Schadendorf D, van Akkooi ACJ, Berking C

    Pubmed
  • Multicentric Sentinel Healthcare Research Project of Skin Cancer Centers

    in Nuremberg, Erlangen, Regensburg and Wuerzburg

    J Dtsch Dermatol Ges. 2019;17(): 68-68

    Enzelsberger K, Debus D, Schultz E, Haferkamp S, Hegemann MV, Stolze I, Erdmann M, Schellerer V

    Pubmed
  • Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition).

    Eur J Immunol. 2019;49(10): 1457-1973

    Cossarizza A, Chang HD, Radbruch A, Acs A, Adam D, Adam-Klages S, Agace WW, Aghaeepour N, Akdis M, Allez M, Almeida LN, Alvisi G, Anderson G, Andrä I, Annunziato F, Anselmo A, Bacher P, Baldari CT, Bari S, Barnaba V, Barros-Martins J, Battistini L, Bauer W, Baumgart S, Baumgarth N, Baumjohann D, Baying B, Bebawy M, Becher B, Beisker W, Benes V, Beyaert R, Blanco A, Boardman DA, Bogdan C, Borger JG, Borsellino G, Boulais PE, Bradford JA, Brenner D, Brinkman RR, Brooks AES, Busch DH, Büscher M, Bushnell TP, Calzetti F, Cameron G, Cammarata I, Cao X, Cardell SL, Casola S, Cassatella MA, Cavani A, Celada A, Chatenoud L, Chattopadhyay PK, Chow S, Christakou E, Čičin-Šain L, Clerici M, Colombo FS, Cook L, Cooke A, Cooper AM, Corbett AJ, Cosma A, Cosmi L, Coulie PG, Cumano A, Cvetkovic L, Dang VD, Dang-Heine C, Davey MS, Davies D, De Biasi S, Del Zotto G, Dela Cruz GV, Delacher M, Della Bella S, Dellabona P, Deniz G, Dessing M, Di Santo JP, Diefenbach A, Dieli F, Dolf A, Dörner T, Dress RJ, Dudziak D, Dustin M, Dutertre CA, Ebner F, Eckle SBG, Edinger M, Eede P, Ehrhardt GRA, Eich M, Engel P, Engelhardt B, Erdei A, Esser C, Everts B, Evrard M, Falk CS, Fehniger TA, Felipo-Benavent M, Ferry H, Feuerer M, Filby A, Filkor K, Fillatreau S, Follo M, Förster I, Foster J, Foulds GA, Frehse B, Frenette PS, Frischbutter S, Fritzsche W, Galbraith DW, Gangaev A, Garbi N, Gaudilliere B, Gazzinelli RT, Geginat J, Gerner W, Gherardin NA, Ghoreschi K, Gibellini L, Ginhoux F, Goda K, Godfrey DI, Goettlinger C, González-Navajas JM, Goodyear CS, Gori A, Grogan JL, Grummitt D, Grützkau A, Haftmann C, Hahn J, Hammad H, Hämmerling G, Hansmann L, Hansson G, Harpur CM, Hartmann S, Hauser A, Hauser AE, Haviland DL, Hedley D, Hernández DC, Herrera G, Herrmann M, Hess C, Höfer T, Hoffmann P, Hogquist K, Holland T, Höllt T, Holmdahl R, Hombrink P, Houston JP, Hoyer BF, Huang B, Huang FP, Huber JE, Huehn J, Hundemer M, Hunter CA, Hwang WYK, Iannone A, Ingelfinger F, Ivison SM, Jäck HM, Jani PK, Jávega B, Jonjic S, Kaiser T, Kalina T, Kamradt T, Kaufmann SHE, Keller B, Ketelaars SLC, Khalilnezhad A, Khan S, Kisielow J, Klenerman P, Knopf J, Koay HF, Kobow K, Kolls JK, Kong WT, Kopf M, Korn T, Kriegsmann K, Kristyanto H, Kroneis T, Krueger A, Kühne J, Kukat C, Kunkel D, Kunze-Schumacher H, Kurosaki T, Kurts C, Kvistborg P, Kwok I, Landry J, Lantz O, Lanuti P, LaRosa F, Lehuen A, LeibundGut-Landmann S, Leipold MD, Leung LYT, Levings MK, Lino AC, Liotta F, Litwin V, Liu Y, Ljunggren HG, Lohoff M, Lombardi G, Lopez L, López-Botet M, Lovett-Racke AE, Lubberts E, Luche H, Ludewig B, Lugli E, Lunemann S, Maecker HT, Maggi L, Maguire O, Mair F, Mair KH, Mantovani A, Manz RA, Marshall AJ, Martínez-Romero A, Martrus G, Marventano I, Maslinski W, Matarese G, Mattioli AV, Maueröder C, Mazzoni A, McCluskey J, McGrath M, McGuire HM, McInnes IB, Mei HE, Melchers F, Melzer S, Mielenz D, Miller SD, Mills KHG, Minderman H, Mjösberg J, Moore J, Moran B, Moretta L, Mosmann TR, Müller S, Multhoff G, Muñoz LE, Münz C, Nakayama T, Nasi M, Neumann K, Ng LG, Niedobitek A, Nourshargh S, Núñez G, O'Connor JE, Ochel A, Oja A, Ordonez D, Orfao A, Orlowski-Oliver E, Ouyang W, Oxenius A, Palankar R, Panse I, Pattanapanyasat K, Paulsen M, Pavlinic D, Penter L, Peterson P, Peth C, Petriz J, Piancone F, Pickl WF, Piconese S, Pinti M, Pockley AG, Podolska MJ, Poon Z, Pracht K, Prinz I, Pucillo CEM, Quataert SA, Quatrini L, Quinn KM, Radbruch H, Radstake TRDJ, Rahmig S, Rahn HP, Rajwa B, Ravichandran G, Raz Y, Rebhahn JA, Recktenwald D, Reimer D, Reis E Sousa C, Remmerswaal EBM, Richter L, Rico LG, Riddell A, Rieger AM, Robinson JP, Romagnani C, Rubartelli A, Ruland J, Saalmüller A, Saeys Y, Saito T, Sakaguchi S, Sala-de-Oyanguren F, Samstag Y, Sanderson S, Sandrock I, Santoni A, Sanz RB, Saresella M, Sautes-Fridman C, Sawitzki B, Schadt L, Scheffold A, Scherer HU, Schiemann M, Schildberg FA, Schimisky E, Schlitzer A, Schlosser J, Schmid S, Schmitt S, Schober K, Schraivogel D, Schuh W, Schüler T, Schulte R, Schulz AR, Schulz SR, Scottá C, Scott-Algara D, Sester DP, Shankey TV, Silva-Santos B, Simon AK, Sitnik KM, Sozzani S, Speiser DE, Spidlen J, Stahlberg A, Stall AM, Stanley N, Stark R, Stehle C, Steinmetz T, Stockinger H, Takahama Y, Takeda K, Tan L, Tárnok A, Tiegs G, Toldi G, Tornack J, Traggiai E, Trebak M, Tree TIM, Trotter J, Trowsdale J, Tsoumakidou M, Ulrich H, Urbanczyk S, van de Veen W, van den Broek M, van der Pol E, Van Gassen S, Van Isterdael G, van Lier RAW, Veldhoen M, Vento-Asturias S, Vieira P, Voehringer D, Volk HD, von Borstel A, von Volkmann K, Waisman A, Walker RV, Wallace PK, Wang SA, Wang XM, Ward MD, Ward-Hartstonge KA, Warnatz K, Warnes G, Warth S, Waskow C, Watson JV, Watzl C, Wegener L, Weisenburger T, Wiedemann A, Wienands J, Wilharm A, Wilkinson RJ, Willimsky G, Wing JB, Winkelmann R, Winkler TH, Wirz OF, Wong A, Wurst P, Yang JHM, Yang J, Yazdanbakhsh M, Yu L, Yue A, Zhang H, Zhao Y, Ziegler SM, Zielinski C, Zimmermann J, Zychlinsky A

    These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.

    Pubmed
  • Non-magnetic chromatographic separation of colloidally metastable superparamagnetic iron oxide nanoparticles and suspension cells.

    J Chromatogr B Analyt Technol Biomed Life Sci. 2019;1122-1123(): 83-89

    Mühlberger M, Janko C, Unterweger H, Band J, Schreiber E, Lehmann C, Dudziak D, Lee G, Alexiou C, Tietze R

    For magnetic control of cells for biomedical applications such as targeting of immune cells to tumors, cells must be magnetizable. For that, cells are incubated with superparamagnetic iron oxide nanoparticles (SPIONs) to take them up and thus become magnetizable. When using adherent cells, non-ingested SPIONs can be easily removed by rinsing of the particles regardless of their colloidal stability in cell culture medium. However, if suspension cells such as T cells are to be loaded with SPIONs, established methods to separate excess nanoparticles from cells are based on physicochemical parameters such as density, size or magnetizability. Thus, colloidal stability of the particles is of great importance, since only colloidally stable SPIONs can be completely separated from the cells due to their physicochemical differences. Aggregates of colloidally meta- or unstable particles cannot, however, be separated from cells due to their overlapping sizes and densities. Thus, development of an alternative method for the separation of nanoparticle aggregates from suspension cells is urgently needed. Here, we present an affinity chromatographic separation method based on immunohistochemical properties of the respective cells. A desthiobiotinylated antibody against a cellular surface antigen (here CD90.2 receptor on EL4 T cells) is immobilized on a streptavidin agarose column optimized for cell purification. Subsequently the column is loaded with the particle/cell suspension so that the cells bind to the column. After removing the particles by washing, the cells can be gently eluted with biotin solution under physiological conditions. This allows >95% of the excess iron concentration to be removed while maintaining cell viability.

    Pubmed
  • Functionalization Of T Lymphocytes With Citrate-Coated Superparamagnetic Iron Oxide Nanoparticles For Magnetically Controlled Immune Therapy.

    Int J Nanomedicine. 2019;14(): 8421-8432

    Mühlberger M, Janko C, Unterweger H, Friedrich RP, Friedrich B, Band J, Cebulla N, Alexiou C, Dudziak D, Lee G, Tietze R

    Purpose: Immune activation with T cell tumor infiltration is beneficial for the prognosis of patients suffering from solid cancer. Depending on their immune status, solid tumors can be immunologically classified into three groups: "hot" tumors are infiltrated with T lymphocytes, "cold" tumors are not infiltrated and "immune excluded" tumors are only infiltrated in the peripheral tumor tissue. Checkpoint inhibitors provide new therapeutic options for "hot" tumors by triggering the immune response of T cells. In order to enable this for cold tumors as well, T cells must be enriched in the tumor. Therefore, we use the principle of magnetic targeting to guide T cells loaded with citrate-coated superparamagnetic iron oxide nanoparticles (SPIONCitrate) to the tumor by an externally applied magnetic field.

    Methods: SPIONCitrate were produced by alkaline coprecipitation of iron(II) and iron(III) chloride and in situ coating with sodium citrate. The concentration-dependent cytocompatibility of the particles was determined by flow cytometry and blood stability assays. Atomic emission spectroscopy was used for the quantification of the particle uptake into T lymphocytes. The attractability of the loaded cells was observed by live-cell imaging in the presence of an externally applied magnetic field.

    Results: SPIONCitrate displayed good cytocompatibility to T cells and did not show any sign of aggregation in blood. Finally, SPIONCitrate-loaded T cells were strongly attracted by a small external magnet.

    Conclusion: T cells can be "magnetized" by incorporation of SPIONCitrate for magnetic targeting. The production of the particle-cell hybrid system is straightforward, as the loading process only requires basic laboratory devices and the loading efficiency is sufficient for cells being magnetically controllable. For these reasons, SPIONCitrate are potential suitable candidates for magnetic T cell targeting.

    Pubmed
  • Combination therapies to improve DC-based treatment of melanoma

    Eur J Immunol. 2019;49 Suppl 2(): 21-21

    Seretis A, Cappellano G, Bellmann L, Schachtl-Riess J, Steindl R, Prokopi N, Ortner-Tobider D, Komenda K, Tripp C, Brinckerhoff CE, Luehr J, Amon L, Lehmann C, Dudziak D, Stoitzner P

    Pubmed
  • Antigen targeting of Fc receptors induces strong and functional relevant T cell responses in vivo independent of ITAM signaling but dependent on dendritic cell subsets

    Eur J Immunol. 2019;49 Suppl 1(): 42-42

    Lehmann C, Baranska A, Heidkamp GF, Amon L, Seeling M, Soulat D, Krug AB, Ravetch JV, Leusen JHW, Nimmerjahn F, Dudziak D

    Pubmed
  • Antigen targeting of Fc receptors induces strong and functional relevant T cell responses in vivo independent of ITAM signaling but dependent on dendritic cell subsets

    Eur J Immunol. 2019;49 Suppl 2(): 13-14

    Lehmann C, Baranska A, Heidkamp GF, Amon L, Seeling M, Soulat D, Krug AB, Ravetch JV, Leusen JHW, Nimmerjahn F, Dudziak D

    Pubmed
  • Induction of anti-tumor responses via antigen targeting of dendritic cells in vivo

    Eur J Immunol. 2019;49 Suppl 1(): 273-274

    Amon L, Lehmann C, Baranska A, Heidkamp G, Heger L, Luehr J, Hofmann A, Nimmerjahn F, Dudziak D

    Pubmed
  • Functionalization of T lymphocytes for magnetically controlled immune

    therapy: Selection of suitable superparamagnetic iron oxide

    nanoparticles

    J MAGN MAGN MATER. 2019;473(): 61-67

    Muehlberger M, Janko C, Unterweger H, Schreiber E, Band J, Lehmann C, Dudziak D, Lee G, Alexiou C, Tietze R

    According to the World Health Organization, cancer is the second most important cause of death in Europe. Due to its manifold manifestations, it is not possible to treat all patients according to a uniform scheme. However, all solid tumors have one thing in common: independent of the tumor's molecular subgroup and the treatment protocol, the immune status of the tumor, especially the amount of tumor infiltrating lymphocytes (TILs), is important for the patient's clinical outcome - the higher the number of TILs, the better the outcome. For this reason it seems desirable to increase the number of TILs.

    One way to accumulate T cells in the tumor area is to make them magnetizable and attract them with an external magnetic field. Magnetization can be achieved by superparamagnetic iron oxide nanoparticles (SPIONs) which can be bound to the cells' surface or internalized into the cells.

    For this study, SPIONs with different coatings were synthesized and incubated with immortalized mouse T lymphocytes. SPIONs only stabilized with lauric acid (LA) coated in situ or afterwards showed high toxicity. Addition of an albumin layer increased the biocompatibility but reduced cellular uptake. To increase the cellular uptake the albumin coated particles were aminated, leading to both higher uptake and toxicity, dependent on the degree of amination. In the presence of an externally applied magnetic field, T cells loaded with selected types and amounts of SPIONs were guidable.

    With this promising pilot study we already can demonstrate that it is possible to attract SPION bearing T cells by an external magnet.

    To sum up, biocompatibility and uptake of SPIONs by T cells are opposing events. Thus, for the functionalization of T cells with SPIONs the balance between uptake and toxicity must be evaluated carefully.

    Pubmed
  • Systems biology-based investigation of cooperating microRNAs as monotherapy or adjuvant therapy in cancer.

    Nucleic Acids Res. 2019;47(15): 7753-7766

    Lai X, Eberhardt M, Schmitz U, Vera J

    MicroRNAs (miRNAs) are short, noncoding RNAs that regulate gene expression by suppressing mRNA translation and reducing mRNA stability. A miRNA can potentially bind many mRNAs, thereby affecting the expression of oncogenes and tumor suppressor genes as well as the activity of whole pathways. The promise of miRNA therapeutics in cancer is to harness this evolutionarily conserved mechanism for the coordinated regulation of gene expression, and thus restoring a normal cell phenotype. However, the promiscuous binding of miRNAs can provoke unwanted off-target effects, which are usually caused by high-dose single-miRNA treatments. Thus, it is desirable to develop miRNA therapeutics with increased specificity and efficacy. To achieve that, we propose the concept of miRNA cooperativity in order to exert synergistic repression on target genes, thus lowering the required total amount of miRNAs. We first review miRNA therapies in clinical application. Next, we summarize the knowledge on the molecular mechanism and biological function of miRNA cooperativity and discuss its application in cancer therapies. We then propose and discuss a systems biology approach to investigate miRNA cooperativity for the clinical setting. Altogether, we point out the potential of miRNA cooperativity to reduce off-target effects and to complement conventional, targeted, or immune-based therapies for cancer.

    Pubmed
  • Isobornyl acrylate- contact allergen in continuous glucose sensor system

    Allergy. 2019;74(): 502-502

    Wagner N, Elsbergen L, Feustel J

    Pubmed
  • Trauma as a Trigger Factor for the First clinical Manifestation of

    cutaneous Leishmaniasis

    J Dtsch Dermatol Ges. 2019;17(): 210-210

    Hiernickel J, Bogdan C, Erfurt-Berge C

    Pubmed
  • Unilateral, intermittent, pulsating Swelling of the Forehead

    J Dtsch Dermatol Ges. 2019;17(): 61-61

    Heppt F, Meder C, Wagner N

    Pubmed
  • Human Synovia Contains Trefoil Factor Family (TFF) Peptides 1-3 Although Synovial Membrane Only Produces TFF3: Implications in Osteoarthritis and Rheumatoid Arthritis.

    Int J Mol Sci. 2019;20(23):

    Popp J, Schicht M, Garreis F, Klinger P, Gelse K, Sesselmann S, Tsokos M, Etzold S, Stiller D, Claassen H, Paulsen F

    OBJECTIVE: Trefoil factor family peptide 3 (TFF3) has been shown to support catabolic functions in cases of osteoarthritis (OA). As in joint physiology and diseases such as OA, the synovial membrane (SM) of the joint capsule also plays a central role. We analyze the ability of SM to produce TFF compare healthy SM and its secretion product synovial fluid (SF) with SM and SF from patients suffering from OA or rheumatoid arthritis (RA).

    METHODS: Real-time PCR and ELISA were used to measure the expression of TFFs in healthy SM and SM from patients suffering from OA or RA. For tissue localization, we investigated TFF1-3 in differently aged human SM of healthy donors by means of immunohistochemistry, real-time PCR and Western blot.

    RESULTS: Only TFF3 but not TFF1 and -2 was expressed in SM from healthy donors as well as cases of OA or RA on protein and mRNA level. In contrast, all three TFFs were detected in all samples of SF on the protein level. No significant changes were observed for TFF1 at all. TFF2 was significantly upregulated in RA samples in comparison to OA samples. TFF3 protein was significantly downregulated in OA samples in comparison to healthy samples and cases of RA significantly upregulated compared to OA. In contrast, in SM TFF3 protein was not significantly regulated.

    CONCLUSION: The data demonstrate the production of TFF3 in SM. Unexpectedly, SF contains all three known TFF peptides. As neither articular cartilage nor SM produce TFF1 and TFF2, we speculate that these originate with high probability from blood serum.

    Pubmed
  • Autophagic degradation of lamins facilitates the nuclear egress of herpes simplex virus type 1.

    J Cell Biol. 2019;218(2): 508-523

    Turan A, Grosche L, Krawczyk A, Mühl-Zürbes P, Drassner C, Düthorn A, Kummer M, Hasenberg M, Voortmann S, Jastrow H, Dörrie J, Schaft N, Kraner M, Döhner K, Sodeik B, Steinkasserer A, Heilingloh CS

    Dendritic cells (DCs) are crucial for the induction of potent antiviral immune responses. In contrast to immature DCs (iDCs), mature DCs (mDCs) are not permissive for infection with herpes simplex virus type 1 (HSV-1). Here, we demonstrate that HSV-1 infection of iDCs and mDCs induces autophagy, which promotes the degradation of lamin A/C, B1, and B2 in iDCs only. This in turn facilitates the nuclear egress of progeny viral capsids and thus the formation of new infectious particles. In contrast, lamin protein levels remain stable in HSV-1-infected mDCs due to an inefficient autophagic flux. Elevated protein levels of KIF1B and KIF2A in mDCs inhibited lamin degradation, likely by hampering autophagosome-lysosome fusion. Therefore, in mDCs, fewer progeny capsids were released from the nuclei into the cytosol, and fewer infectious virions were assembled. We hypothesize that inhibition of autophagic lamin degradation in mDCs represents a very powerful cellular counterstrike to inhibit the production of progeny virus and thus viral spread.

    Pubmed
  • Impairment of Taste and Smell in Psoriasis- another Cause of Impaired

    Calorie Intake?

    J Dtsch Dermatol Ges. 2019;17(): 127-127

    Gruenthaler V, Rueter P, Zopf Y, Sticherling M

    Pubmed
  • Non-professional phagocytosis: a general feature of normal tissue cells.

    Sci Rep. 2019;9(1):

    Seeberg JC, Loibl M, Moser F, Schwegler M, Büttner-Herold M, Daniel C, Engel FB, Hartmann A, Schlötzer-Schrehardt U, Goppelt-Struebe M, Schellerer V, Naschberger E, Ganzleben I, Heinzerling L, Fietkau R, Distel LV

    Non-professional phagocytosis by cancer cells has been described for decades. Recently, non-professional phagocytosis by normal tissue cells has been reported, which prompted us to take a closer look at this phenomenon. Non-professional phagocytosis was studied by staining cultured cells with live-cell staining dyes or by staining paraffin-embedded tissues by immunohistochemistry. Here, we report that each of 21 normal tissue cell lines from seven different organs was capable of phagocytosis, including ex vivo cell cultures examined before the 3rd passage as well as the primary and virus-transformed cell lines. We extended our analysis to an in vivo setting, and we found the occurrence of non-professional phagocytosis in healthy skin biopsies immediately after resection. Using dystrophin immunohistochemistry for membrane staining, human post-infarction myocardial tissue was assessed. We found prominent signs of non-professional phagocytosis at the transition zone of healthy and infarcted myocardia. Taken together, our findings suggest that non-professional phagocytosis is a general feature of normal tissue cells.

    Pubmed
  • Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study.

    J Immunother Cancer. 2019;7(1):

    Heppt MV, Amaral T, Kähler KC, Heinzerling L, Hassel JC, Meissner M, Kreuzberg N, Loquai C, Reinhardt L, Utikal J, Dabrowski E, Gesierich A, Pföhler C, Terheyden P, Thoms KM, Zimmer L, Eigentler TK, Kirchberger MC, Stege HM, Meier F, Schlaak M, Berking C

    BACKGROUND: Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear.

    METHODS: Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression.

    RESULTS: The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5 months (range 9.0-65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0-65.0). The median PFS was 3.0 months (95% CI 2.4-3.6). The median OS was estimated to 16.1 months (95% CI 12.9-19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007).

    CONCLUSIONS: The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.

    Pubmed
  • C-reactive protein as an early marker of immune-related adverse events.

    J Cancer Res Clin Oncol. 2019;145(10): 2625-2631

    Abolhassani AR, Schuler G, Kirchberger MC, Heinzerling L

    PURPOSE: Immune checkpoint inhibitors (ICIs) are effective against a wide variety of cancers. However, they also induce a plethora of unique immune-related adverse events (irAEs). Since for many organ systems symptoms can be unspecific, differential diagnosis with progression of disease or infection may be difficult. C-reactive protein (CRP) has been suggested as a marker for infection. The purpose of this study was to evaluate the diagnostic value of CRP in differentiating infectious causes from autoimmune side effects induced by ICIs.

    METHODS: In order to investigate the role of CRP in irAEs, we screened our patient data base. Only events with full infectious workup were included. In total 88 events of irAEs in 37 melanoma patients were analyzed. CRP levels before and during irAEs were evaluated. Statistical analyses were conducted using the Chi-square test for categorical variables.

    RESULTS: At the onset of irAE, CRP rose in 93% of cases to a mean of 52.7 mg/L (CI 35.1-70.3) from 8.4 mg/L at baseline (normal < 5 mg/L) (P < 0.0001). Other causes of CRP elevation including infectious diseases were excluded, and procalcitonin (PCT) levels were normal in 92% of events. Importantly, in 42% of cases CRP elevations preceded clinical symptoms.

    CONCLUSION: CRP elevation can predict the onset of irAEs in patients treated with ICIs in the absence of infectious disease.

    Pubmed
  • Checkpoint inhibitor-induced eosinophilic fasciitis following high eosinophilia associated with complete response.

    Rheumatology (Oxford). 2019;58(10): 1875-1877

    Toussaint F, Hammon M, Erdmann M, Moreira A, Kirchberger MC, Schuler G, Schett G, Heinzerling L

    Pubmed
  • Limited Effect of Anti-PD-1 in advanced Skin Tumors of Patients with

    hemato-oncological Primary Disease: A retrospective multi-center Study

    of ADO

    J Dtsch Dermatol Ges. 2019;17(): 6-6

    Leiter-Stoeppke U, Loquai C, Meier F, Rafei-Shamsabadi D, Hassel J, Glutsch V, Sirokay J, Schlecht N, Ruebben A, Gutzmer R, Kaehler K, Gambichler T, Schatton K, Pfoehler C, Franklin C, Terheyden P, Haferkamp S, Mohr P, Heinzerling L, Meiwes A, Keim U, Becker JC, Bischof L, Livingstone E, Schadendorf D, Ugurel S

    Pubmed
  • A phase I dose-escalation and expansion trial of intratumorally

    administered CV8102, alone and in combination with anti-PD-1 in patients

    with advanced solid tumours

    Ann Oncol. 2019;30(): 191-+

    Krauss J, Eigentler T, Schreiber J, Weishaupt C, Terheyden P, Heinzerling L, Mohr P, Weide B, Ochsenreither S, Gutzmer R, Becker JC, Kiecker F, Funkner F, Heidenreich R, Kays SK, Klinkhardt U, Gnad-Vogt US, Scheel B, Schoenborn-Kellenberger O, Seibel T

    Pubmed
  • Lipase Elevations and Diabetes under Checkpoint Inhibition - Experience

    in 80 Patients

    J Dtsch Dermatol Ges. 2019;17(): 9-9

    Weihkopf D, Satzger I, Zimmer L, Eigentler T, Haessel J, Heinzerling L, Herbst R, Kahler K, Loquai C, Meier F, Pfoehler C, Ruini C, Schultz E, Thoms KM, Utikal J, Gutzmer R

    Pubmed
  • A phase I dose escalation and expansion study of intratumorally

    administered CV8102 as a single-agent or in combination with anti-PD-1

    antibodies in patients with advanced solid tumors

    J. Immunother. Cancer. 2019;7():

    Eigentler T, Krauss J, Schreiber J, Weishaupt C, Terheyden P, Heinzerling L, Mohr P, Weide B, Ochsenreither S, Becker J, Bauernfeind FG, Brossart P, Funkner F, Heidenreich R, Kays SK, Muth A, Seibel T, Scheel B, Schoenborn-Kellenberger O, Stosnach C, Daehling A, Strack T, Korolkiewicz R, Gnad-Vogt U

    Pubmed
  • Vaccination with dendritic Cells for metastasized Uveal Melanoma:

    immunological and clinical Responses

    J Dtsch Dermatol Ges. 2019;17(): 18-19

    Moreira A, Gross S, Uslu U, Doerrie J, Kummer M, Schliep S, Sponagl F, Lischer C, Erdmann M, Heinzerling L, Schuler G, Schuler-Thurner B

    Pubmed
  • Successful Treatment of a primary cutaneous aggressive epidermotropic

    CD8+T-cell Lymphoma with Nivolumab

    J Dtsch Dermatol Ges. 2019;17(): 19-19

    Toussaint F, Erdmann M, Grosch E, Schuler G, Schliep S, Heinzerling L

    Pubmed
  • Blood eosinophilia is an on-treatment biomarker in patients undergoing

    vaccination with dendritic cells that correlates with long-term patient

    outcome

    J Dtsch Dermatol Ges. 2019;17(): 25-25

    Moreira A, Vass V, Erdmann M, Sponagl F, Schuler G, Schuler-Thurner B

    Pubmed
  • Noonan Syndrome with multiple Lentigines (Leopard Syndrome) - Case

    Description of a 45-year-old Patient

    J Dtsch Dermatol Ges. 2019;17(): 108-108

    Sponagl F, Sticherling M, Seybold H, Erdmann M, Wagner N

    Pubmed
  • Do Patients with Lower Limb Melanoma have an increased Risk of a "false

    negative" Sentinel Node Biopsy?

    J Dtsch Dermatol Ges. 2019;17(): 64-64

    Braun L, Schellerer V, Schuler G, Goeol J, Erdmann M

    Pubmed
  • Dyspnoea under Immunotherapy for Patients with Melanoma: Pneumonia,

    Pulmonary Embolism, Pneumonitis or Myocarditis?

    J Dtsch Dermatol Ges. 2019;17(): 148-149

    Koeceroglu I, Bosch-Voskens C, Erdmann M

    Pubmed
  • Systemic sclerosis - the dermatological perspective.

    J Dtsch Dermatol Ges. 2019;17(7): 716-728

    Sticherling M

    Systemic scleroderma/systemic sclerosis (SSc) is an inflammatory connective tissue disease clinically characterized by two major subtypes: limited and diffuse SSc. While both conditions present with Raynaud's phenomenon (paroxysmal digital ischemia), diffuse SSc is associated with rapid disease progression and early - prognostically relevant - involvement of internal organs. Treatment is challenging. In addition to general lifestyle modifications, measures include treatments aimed at improving circulation as well as immunosuppressive and immunomodulatory drugs. However, these agents are effective only in terms of slowing disease progression.

    Pubmed
  • Skin and Soft Tissue Infections Caused by Mycobacterium chelonae: More Common Than Expected?

    Acta Derm Venereol. 2019;99(10): 889-893

    Uslu U, Böhm O, Heppt F, Sticherling M

    Mycobacterium chelonae is a rapidly growing non-tuberculous mycobacterium, which causes infections of the human skin and soft tissue. Despite an increasing incidence of such infections, patients are often misdiagnosed. We report here 5 patients with cutaneous and/or soft tissue infection due to M. chelonae who were diagnosed and treated at our centre. Two of the 5 patients were on immunosuppressive treatment. While clinical presentations differed in each patient, all had a long history of skin lesions. In addition to careful history-taking, tissue biopsies were obtained for mycobacterial culture and histopathological examination. Culture-directed antibiotic therapy was initiated, which resulted in a slow, but continuous, healing of the lesions. In summary, M. chelonae infections are still relatively rare, but should be considered in both immunocompromised and immunocompetent patients with prolonged skin lesions resistant to standard antibiotic treatment. For diagnosis, tissue analysis for mycobacterial culture and histopathological examination, and once diagnosed, adequate antibiotic treatment, is needed.

    Pubmed
  • Differential expression of toll like receptors and antibiotic peptides

    by human keratinocytes

    Exp Dermatol. 2019;28(3): E20-E21

    Heusinger J, Herter-Kermann T, Sticherling M

    Pubmed
  • First real-world insights on benefit of apremilast treatment in patients

    with moderate to severe psoriasis after switching from fumaric acid

    esters from the APART Study - an interim analysis

    J Dtsch Dermatol Ges. 2019;17(): 123-123

    Mrowietz U, Ertner K, Sticherling M, Grosse V, Popp G, Roemmler-Zehrer J, Lampl M, Helget U, Gomez NN

    Pubmed
  • Disseminated Pustules in a 3 Year Old Boy

    J Dtsch Dermatol Ges. 2019;17(): 174-174

    Grosch E, Koeceroglu MI, Schliep S, Kiesewetter F, Sticherling M, Voskens CJ

    Pubmed
  • Multiple dermal Abscesses by Trichophyton rubrum in an immunosuppressed

    Patients

    J Dtsch Dermatol Ges. 2019;17(): 136-137

    Toussaint F, Sticherling M

    Pubmed
  • Psoriasis in children: a single center analysis

    J Dtsch Dermatol Ges. 2019;17(): 107-107

    Heppt F, Raap J, Sticherling M

    Pubmed
  • Alopecia areata- Clinical Picture and Therapy Response of Heterogeneous

    Disease

    J Dtsch Dermatol Ges. 2019;17(): 113-113

    Busch D, Sticherling M

    Pubmed
  • Dermatomyositis- a rare, but important Disease between Dermatology and

    Internal Medicine

    J Dtsch Dermatol Ges. 2019;17(): 127-127

    Sell S, Sticherling M

    Pubmed
  • The Art of Making Moulages - a hidden Art?

    J Dtsch Dermatol Ges. 2019;17(): 79-79

    Sticherling M, Groenhardt K, Saake M

    Pubmed
  • Dermatological Moulages in Germany- Comparison of Two Representative

    Collections

    J Dtsch Dermatol Ges. 2019;17(): 110-110

    Sticherling M

    Pubmed
  • Pruritus in Psoriasis - Correlation to the Severity of the clinical

    appearance of the Skin?

    J Dtsch Dermatol Ges. 2019;17(): 181-181

    Achterberg F, Kremer A, Sticherling M

    Pubmed
  • Automated Good Manufacturing Practice-compliant generation of human

    monocyte-derived dendritic cells from a complete apheresis product using

    a hollow-fiber bioreactor system overcomes a major hurdle in the

    manufacture of dendritic cells for cancer vaccines

    Cytotherapy. 2019;21(11): 1166-1178

    Uslu U, Erdmann M, Wiesinger M, Schuler G, Schuler-Thurner B

    Background: Although dendritic cell (DC)-based cancer vaccines represent a promising treatment strategy, its exploration in the clinic is hampered due to the need for Good Manufacturing Practice (GMP) facilities and associated trained staff for the generation of large numbers of DCs. The Quantum bioreactor system offered by Terumo BCT represents a hollow-fiber platform integrating GMP-compliant manufacturing steps in a closed system for automated cultivation of cellular products. In the respective established protocols, the hollow fibers are coated with fibronectin and trypsin is used to harvest the final cell product, which in the case of DCs allows processing of only one tenth of an apheresis product. Materials and Results: We successfully developed a new protocol that circumvents the need for fibronectin coating and trypsin digestion, and makes the Quantum bioreactor system now suitable for generating large numbers of mature human monocyte-derived DCs (Mo-DCs) by processing a complete apheresis product at once. To achieve that, it needed a step-by-step optimization of DC-differentiation, e.g., the varying of media exchange rates and cytokine concentration until the total yield (% of input CD14(+) monocytes), as well as the phenotype and functionality of mature Mo-DCs, became equivalent to those generated by our established standard production of Mo-DCs in cell culture bags. Conclusions: By using this new protocol for the Food and Drug Administration-approved Quantum system, it is now possible for the first time to process one complete apheresis to automatically generate large numbers of human Mo-DCs, making it much more feasible to exploit the potential of individualized DC-based immunotherapy.

    Pubmed
  • Towards a pro-resolving concept in systemic lupus erythematosus

    Semin Immunopathol. 2019;41(6): 681-697

    Boeltz S, Hagen M, Knopf J, Mahajan A, Schick M, Zhao Y, Erfurt-Berge C, Rech J, Munoz LE, Herrmann M

    Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with prominent chronic inflammatory aspects. SLE most often affects women (9:1) in childbearing age. The multifactorial nature of the etiopathogenesis of SLE involves a deficient clearance of dead and dying cells. This is supported by the occurrence of autoantibodies directed against autoantigens modified in dying and dead cells (dsDNA, high mobility group box 1 protein, apoptosis-associated chromatin modifications, e.g., histones H3-K27-me3; H2A/H4 AcK8,12,16; and H2B-AcK12) that are deposited in various tissues, including skin, kidneys, joints, muscles, and brain. The subsequent hyperinflammatory response often leads to irreparable tissue damage and organ destruction. In healthy individuals, dead and dying cells are rapidly removed by macrophages in an anti-inflammatory manner, referred to as efferocytosis. In SLE, extensive and prolonged cell death (apoptosis, necrosis, neutrophil extracellular trap (NET) formation) leads to autoantigens leaking out of the not cleared cell debris. These neo-epitopes are subsequently presented to B cells by follicular dendritic cells in the germinal centers of secondary lymphoid tissues conditioning the break of self-tolerance. Activation of autoreactive B cells and subsequent production of autoantibodies facilitate the formation of immune complexes (ICs) fueling the inflammatory response and leading to further tissue damage. ICs may also be ingested by phagocytes, which then produce further pro-inflammatory cytokines. These processes establish a vicious circle that leads to sustained inflammation. This review highlights the cell death-related events in SLE, the protagonists involved in SLE pathogenesis, the resolution of inflammation in various tissues affected in SLE, and explores strategies for intervention to restore hemostasis in a hyperinflammatory state.

    Pubmed
  • Prediction of melanoma evolution in melanocytic nevi via artificial

    intelligence: A call for prospective data (vol 119, pg 30, 2019)

    Eur J Cancer. 2019;123(): 171-171

    Sondermann W, Utikal JS, Enk AH, Schadendorf D, Klode J, Hauschild A, Weichenthal M, French LE, Berking C, Schilling B, Haferkamp S, Froehling S, von Kalle C, Brinker TJ

    Pubmed
  • LATE GADOLINIUM ENHANCEMENT IN PATIENTS WITH MYOCARDITIS FROM IMMUNE CHECKPOINT INHIBITORS

    J Am Coll Cardiol. 2019;73 Suppl 1(9): 675-675

    Zhang LL, Awadalla M, Mahmood SS, Groarke JD, Nohria A, Liu SY, Hassan MZO, Cohen JV, Jones-O'Connor M, Murphy SPT, Heinzerling LM, Sahni G, Chen CL, Gupta D, Moslehi JJ, Ganatra S, Ederhy S, Thuny F, Lyon AR, Tocchetti CG, Rizvi MA, Thavendiranathan P, Fradley MG, Neilan TG, Int ICI Myocarditis Cohort Study

    Pubmed
  • [Concentrations of testosterone, estrone and estrone sulfate in peripheral blood of donkey stallions in relation to season].

    Tierarztl Prax Ausg G Grosstiere Nutztiere. 2019;47(5): 294-297

    Schuler G, Bernhardt-Welte AW, Failing K, Hoffmann B

    OBJECTIVE: To assess testicular endocrine function in the male donkey (Equus asinus) during the course of the year.

    MATERIAL AND METHODS: In 5 miniature and 4 standard donkey stallions, peripheral blood concentrations of testosterone (T), estrone (E1) and estrone sulfate (E1S) were determined using radioimmunoassay.

    RESULTS: There was a highly significant influence of the season (p < 0.0001) on the course of all 3 steroids. Values were low in November until January and high in April, May and June. As delineated by the measurement of E1 the breed also had an effect on the expression of seasonality. Mean T concentration (X̅g × SF ± 1) was 1.58 × 1.20 ± 1 ng/ml, values ranged between 0.39 and 5.95 ng/ml, which is approximately double the plasma T concentrations observed in horse stallions. As in horse stallions, E1 levels were only slightly above the detection limit of the assay (0.10-0.17 ng/ml). Mean E1S concentration amounted to 0.91 ± 0.23 ng/ml, values ranged between 0.34-1.36 ng/ml and taking peak levels into account measured approximately 300-fold lower than in the horse stallion.

    CONCLUSIONS: The data obtained confirm that the donkey belongs to the group of long day breeders. Irrespective of the close phylogenetical relationship the course of E1S concentrations reveals distinct differences between horse and donkey.

    CLINICAL RELEVANCE: Even between closely related species established reference values for sex steroids cannot be transferred without verification.

    Pubmed
  • CT radiomics differentiates levels of radiosensitivity in tumor subvolumes in head and neck cancer

    Strahlenther Onkol. 2019;195(12): 1128-1128

    Bogowicz M, Bogowicz M, Pavic M, Riesterer O, Finazzi T, Schuler GH, Holz-Sapra E, Rudofsky L, Glatz S, Basler L, Spaniol M, Hullner M, Guckenberger M, Tanadini-Lang S

    Pubmed
  • IFN-gamma-induced PD-L1 expression in melanoma depends on p53 expression.

    J Exp Clin Cancer Res. 2019;38(1):

    Thiem A, Hesbacher S, Kneitz H, di Primio T, Heppt MV, Hermanns HM, Goebeler M, Meierjohann S, Houben R, Schrama D

    BACKGROUND: Immune checkpoint inhibition and in particular anti-PD-1 immunotherapy have revolutionized the treatment of advanced melanoma. In this regard, higher tumoral PD-L1 protein (gene name: CD274) expression is associated with better clinical response and increased survival to anti-PD-1 therapy. Moreover, there is increasing evidence that tumor suppressor proteins are involved in immune regulation and are capable of modulating the expression of immune checkpoint proteins. Here, we determined the role of p53 protein (gene name: TP53) in the regulation of PD-L1 expression in melanoma.

    METHODS: We analyzed publicly available mRNA and protein expression data from the cancer genome/proteome atlas and performed immunohistochemistry on tumors with known TP53 status. Constitutive and IFN-ɣ-induced PD-L1 expression upon p53 knockdown in wildtype, TP53-mutated or JAK2-overexpressing melanoma cells or in cells, in which p53 was rendered transcriptionally inactive by CRISPR/Cas9, was determined by immunoblot or flow cytometry. Similarly, PD-L1 expression was investigated after overexpression of a transcriptionally-impaired p53 (L22Q, W23S) in TP53-wt or a TP53-knockout melanoma cell line. Immunoblot was applied to analyze the IFN-ɣ signaling pathway.

    RESULTS: For TP53-mutated tumors, an increased CD274 mRNA expression and a higher frequency of PD-L1 positivity was observed. Interestingly, positive correlations of IFNG mRNA and PD-L1 protein in both TP53-wt and -mutated samples and of p53 and PD-L1 protein suggest a non-transcriptional mode of action of p53. Indeed, cell line experiments revealed a diminished IFN-ɣ-induced PD-L1 expression upon p53 knockdown in both wildtype and TP53-mutated melanoma cells, which was not the case when p53 wildtype protein was rendered transcriptionally inactive or by ectopic expression of p53L22Q,W23S, a transcriptionally-impaired variant, in TP53-wt cells. Accordingly, expression of p53L22Q,W23S in a TP53-knockout melanoma cell line boosted IFN-ɣ-induced PD-L1 expression. The impaired PD-L1-inducibility after p53 knockdown was associated with a reduced JAK2 expression in the cells and was almost abrogated by JAK2 overexpression.

    CONCLUSIONS: While having only a small impact on basal PD-L1 expression, both wildtype and mutated p53 play an important positive role for IFN-ɣ-induced PD-L1 expression in melanoma cells by supporting JAK2 expression. Future studies should address, whether p53 expression levels might influence response to anti-PD-1 immunotherapy.

    Pubmed
  • Induction of ALP and MMP9 activity facilitates invasive behavior in heterogeneous human BMSC and HNSCC 3D spheroids.

    FASEB J. 2019;33(11): 11884-11893

    Wessely A, Waltera A, Reichert TE, Stöckl S, Grässel S, Bauer RJ

    Mesenchymal stem cells (MSCs) are multipotent progenitor cells capable of differentiating into adipocytic, osteogenic, chondrogenic, and myogenic lineages. There is growing evidence that MSCs home into the tumor microenvironment attracted by a variety of signals such as chemokines, growth factors, and cytokines. Tumor-homing stem cells may originate from bone marrow-derived MSCs (BMSCs) or adipose tissue-derived MSCs. Recent scientific data suggest that MSCs in combination with tumor cells can either promote or inhibit tumorigenic behavior. In head and neck squamous cell carcinoma (HNSCC), BMSCs are reported to be enriched with a potential negative role. Here, we evaluated the effect of BMSCs from 4 different donors in combination with 4 HNSCC cell lines in a 3-dimensional multicellular spheroid model. Heterogeneous combinations revealed an up-regulation of gene and protein expression of osteogenic markers runt-related transcription factor 2 (RUNX2) and alkaline phosphatase (ALP) together with a substantial secretion of matrix metalloproteinase 9. Moreover, heterogenous BMSC/tumor spheroids showed increased invasion compared with homogenous spheroids in a Boyden chamber invasion assay. Furthermore, inhibition of ALP resulted in a substantially decreased spreading of heterogeneous spheroids on laminin-rich matrix. In summary, our data suggest a prometastatic effect of BMSCs combined with HNSCC.-Wessely, A., Waltera, A., Reichert, T. E., Stöckl, S., Grässel, S., Bauer, R. J. Induction of ALP and MMP9 activity facilitates invasive behavior in heterogeneous human BMSC and HNSCC 3D-spheroids.

    Pubmed
  • Teledermatology: Comparison of Store-and-Forward Versus Live Interactive Video Conferencing.

    J Med Internet Res. 2018;20(10): e11871

    Brinker TJ, Hekler A, von Kalle C, Schadendorf D, Esser S, Berking C, Zacher MT, Sondermann W, Grabe N, Steeb T, Utikal JS, French LE, Enk AH

    A decreasing number of dermatologists and an increasing number of patients in Western countries have led to a relative lack of clinicians providing expert dermatologic care. This, in turn, has prolonged wait times for patients to be examined, putting them at risk. Store-and-forward teledermatology improves patient access to dermatologists through asynchronous consultations, reducing wait times to obtain a consultation. However, live video conferencing as a synchronous service is also frequently used by practitioners because it allows immediate interaction between patient and physician. This raises the question of which of the two approaches is superior in terms of quality of care and convenience. There are pros and cons for each in terms of technical requirements and features. This viewpoint compares the two techniques based on a literature review and a clinical perspective to help dermatologists assess the value of teledermatology and determine which techniques would be valuable in their practice.

    Pubmed
  • How to MEK the best of uveal melanoma: A systematic review on the efficacy and safety of MEK inhibitors in metastatic or unresectable uveal melanoma.

    Eur J Cancer. 2018;103(): 41-51

    Steeb T, Wessely A, Ruzicka T, Heppt MV, Berking C

    BRAF and MEK inhibitors have demonstrated significant survival benefits for patients with cutaneous melanoma. However, their use for uveal melanoma (UM) is less established. The aim of this systematic review was to summarise the current evidence on the efficacy and safety of MEK inhibitors in metastatic UM.We performed a systematic literature search in MEDLINE, Embase and the Cochrane Library CENTRAL from 1946 through 17 April 2018. Abstracts of oncologic conferences, trial registers and reference lists were handsearched for relevant publications. The risk of bias was assessed with the Cochrane Risk of Bias Tool.Of 590 records identified, six studies met the eligibility criteria and were included in the qualitative synthesis. Data were available for selumetinib ± dacarbazine (n = 3), trametinib ± AKT inhibitor (n = 2) and binimetinib plus sotrastaurin (n = 1) from three open-label phase II, two open-label phase I and one placebo-controlled phase III trial. The overall response rate was available in five studies and ranged from 0 to 14% with an average of 2.5%. The median progression-free survival ranged from 3.1 weeks to 16 weeks. Data on overall survival and 1-year survival rates were not consistently reported. Severe treatment-related adverse events were observed most commonly for the combination use of selumetinib plus dacarbazine (62%) and binimetinib plus sotrastaurin (75%).UM is little responsive to MEK inhibition, regardless of the inhibiting agent and combination partner. Our results do not support the use of MEK inhibitors in UM. Novel treatment options are urgently needed in this patient population.

    Pubmed
  • Skin Cancer Classification Using Convolutional Neural Networks: Systematic Review.

    J Med Internet Res. 2018;20(10): e11936

    Brinker TJ, Hekler A, Utikal JS, Grabe N, Schadendorf D, Klode J, Berking C, Steeb T, Enk AH, von Kalle C

    State-of-the-art classifiers based on convolutional neural networks (CNNs) were shown to classify images of skin cancer on par with dermatologists and could enable lifesaving and fast diagnoses, even outside the hospital via installation of apps on mobile devices. To our knowledge, at present there is no review of the current work in this research area.This study presents the first systematic review of the state-of-the-art research on classifying skin lesions with CNNs. We limit our review to skin lesion classifiers. In particular, methods that apply a CNN only for segmentation or for the classification of dermoscopic patterns are not considered here. Furthermore, this study discusses why the comparability of the presented procedures is very difficult and which challenges must be addressed in the future.We searched the Google Scholar, PubMed, Medline, ScienceDirect, and Web of Science databases for systematic reviews and original research articles published in English. Only papers that reported sufficient scientific proceedings are included in this review.We found 13 papers that classified skin lesions using CNNs. In principle, classification methods can be differentiated according to three principles. Approaches that use a CNN already trained by means of another large dataset and then optimize its parameters to the classification of skin lesions are the most common ones used and they display the best performance with the currently available limited datasets.CNNs display a high performance as state-of-the-art skin lesion classifiers. Unfortunately, it is difficult to compare different classification methods because some approaches use nonpublic datasets for training and/or testing, thereby making reproducibility difficult. Future publications should use publicly available benchmarks and fully disclose methods used for training to allow comparability.

    Pubmed
  • Quality assessment of German websites on immunotherapy for melanoma patients

    J Dtsch Dermatol Ges. 2018;16 Suppl 1(): 23-24

    Steeb T, Bruetting J, Reinhardt L, Meier F, Berking C

    Pubmed
  • Natural Killer (NK) cells switch between mesenchymal and amoeboid migration in adhesive vs. non-adhesive 3D environments.

    Mol Biol Cell. 2018;29(26):

    Czerwinski TL, Mark CW, Mainka A, Bosch-Voskens C, Roessner S, Bhattacharjee T, Angelini TE, Fabry B

    Pubmed
  • The Role and Function of the Neural Crest Transcription Factor SOX10 in Uveal Melanoma

    J Dtsch Dermatol Ges. 2018;16 Suppl 6(): 18-19

    Wessely A, Heppt M, Kammerbauer C, Berking C

    Pubmed
  • Systemische Therapien des Ulcus cruris (vol 16, pg 873, 2018)

    J Dtsch Dermatol Ges. 2018;16(9): 1170-1170

    Dissemond J, Erfurt-Berge C, Goerge T, Kroger K, Funke-Lorenz C, Reich-Schupke S

    Pubmed
  • Non-celiac gluten/wheat sensitivity (NCGS)-a currently undefined disorder without validated diagnostic criteria and of unknown prevalence: Position statement of the task force on food allergy of the German Society of Allergology and Clinical Immunology (D

    Allergo J Int. 2018;27(5): 147-151

    Reese I, Schäfer C, Kleine-Tebbe J, Ahrens B, Bachmann O, Ballmer-Weber B, Beyer K, Bischoff SC, Blümchen K, Dölle S, Enck P, Enninger A, Huttegger I, Lämmel S, Lange L, Lepp U, Mahler V, Mönnikes H, Ockenga J, Otto B, Schnadt S, Szépfalusi Z, Treudler R, Wassmann-Otto A, Zuberbier T, Werfel T, Worm M

    Within the last decade, non-celiac gluten/wheat sensitivity (NCGS) has been increasingly discussed not only in the media but also among medical specialties. The existence and the possible triggers of NCGS are controversial. Three international expert meetings which proposed recommendations for NCGS were not independently organized and only partially transparent regarding potential conflicts of interest of the participants. The present position statement reflects the following aspects about NCGS from an allergist's and nutritionist's point of view: (A) Validated diagnostic criteria and/or reliable biomarkers are still required. Currently, this condition is frequently self-diagnosed, of unknown prevalence and non-validated etiology. (B) Gluten has not been reliably identified as an elicitor of NCGS because of high nocebo and placebo effects. Double-blind, placebo-controlled provocation tests are of limited value for the diagnosis of NCGS and should be performed in a modified manner (changed relation of placebo and active substance). (C) Several confounders hamper the assessment of subjective symptoms during gluten-reduced or gluten-free diets. Depending on the selection of food items, e.g., an increased vegetable intake with soluble fibers, diets may induce physiological digestive effects and can modify gastrointestinal transit times independent from the avoidance of gluten. (D) A gluten-free diet is mandatory in celiac disease based on scientific evidence. However, a medically unjustified avoidance of gluten may bear potential disadvantages and risks. (E) Due to a lack of diagnostic criteria, a thorough differential diagnostic work-up is recommended when NCGS is suspected. This includes a careful patient history together with a food-intake and symptom diary, if necessary an allergy diagnostic workup and a reliable exclusion of celiac disease. We recommend such a structured procedure since a medically proven diagnosis is required before considering the avoidance of gluten.

    Pubmed
  • Indications and Use of Isotretinoin in Facial Plastic Surgery.

    Facial Plast Surg. 2018;34(1): 75-81

    Heppt MV, Kirchberger MC, Ruzicka T, Berking C, Heppt WJ

    Isotretinoin is a first generation retinoid with pleiotropic effects on keratinocyte differentiation, proliferation, and activity of sebaceous glands. For years, there has been intense debate on whether the use of isotretinoin combined with cosmetic or surgical procedures is safe and potentially more efficient than either therapy alone. Due to delays in wound healing and keloid formation, conservative recommendations were not to combine isotretinoin with any plastic surgery or local treatment at 6 to 12 months after discontinuation of the drug. However, there is increasing evidence that a combination approach is not only safe, but may also provide excellent cosmetic outcomes in acne scars, sebaceous gland hyperplasia, and thick-skinned patients undergoing facial plastic surgery. In particular, low-dose regimens of isotretinoin may offer advantages over standard dosage treatments because of better tolerability and safety in long-term use adjunct with surgical interventions. In this article, the authors aim to summarize the current evidence on the use of isotretinoin in facial plastic surgery and to share their experience from selected patients.

    Pubmed
  • Unusual presentation of a cutaneous metastasis in the face arising from gastric cancer: a case report.

    SAGE Open Med Case Rep. 2018;6():

    Kirchberger MC

    A well-known example of gastrointestinal cancers metastasizing to the skin is Sister Mary Joseph's nodule, which usually presents as a cutaneous nodule on the umbilicus. In this case, a 91-year-old man was referred to our dermatology clinic for a rapidly growing 3 cm × 2 cm ulcerative nodule at his chin. Biopsy showed skin metastasis originating from a gastric adenocarcinoma. The subcutaneous and cutaneous manifestation of gastric cancer is very rare and associated with a poor prognosis and widespread metastatic disease as presented in this case. However, skin metastasis may be the first clinically apparent sign of underlying systemic malignancy and therefore immediate clarification in case of uncertainty is recommended.

    Pubmed
  • The siRNA-mediated downregulation of PD-1 alone or simultaneously with CTLA-4 shows enhanced in vitro CAR-T-cell functionality for further clinical development towards the potential use in immunotherapy of melanoma.

    Exp Dermatol. 2018;27(7): 769-778

    Simon B, Harrer DC, Schuler-Thurner B, Schaft N, Schuler G, Dörrie J, Uslu U

    Chimeric antigen receptor (CAR)-T cells have been used successfully for cancer immunotherapy. While substantial tumor regression was observed in leukaemia and lymphoma, CAR therapy of solid tumors needs further improvement. A major obstacle to the efficiency of engineered T cells is posed by triggering of inhibitory receptors, for example programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), leading to an impaired antitumor activity. To boost CAR-T-cell function, we co-electroporated T cells with both, mRNA encoding a CAR specific for chondroitin sulphate proteoglycan 4 (CSPG4) and small-interfering RNAs (siRNAs) to downregulate PD-1 (siPD-1) and CTLA-4 (siCTLA-4). Flow cytometry revealed that activation-induced upregulation of both PD-1 and CTLA-4 was suppressed when compared to CAR-T cells electroporated with negative control siRNA. The siRNA transfection showed no influence on CAR expression of engineered T cells. Functionality assays were performed using PD-L1- and CD80-transfected melanoma cells endogenously expressing CSPG4. CAR-T cells transfected with siPD-1 alone showed improvement in cytokine secretion. Additionally, CAR-T cells transfected with either siPD-1 alone or together with siCTLA-4 exhibited a significantly increased cytotoxicity. No or only little effects were observed when CAR-T cells were co-transfected with siCTLA-4 only. Taken together, it is feasible to optimize CAR-T cells by co-transfection of CAR-encoding mRNA and siRNAs to downregulate inhibitory receptors. Our in vitro data indicate an improvement of the functionality of these CAR-T cells, suggesting that this strategy could represent a novel method to enhance CAR-T-cell immunotherapy of cancer.

    Pubmed
  • The genetic basis for most patients with pustular skin disease remains elusive.

    Br J Dermatol. 2018;178(3): 740-748

    Mössner R, Wilsmann-Theis D, Oji V, Gkogkolou P, Löhr S, Schulz P, Körber A, Christoph-Prinz J, Renner R, Schäkel K, Vogelsang L, Peters KP, Philipp S, Reich K, Ständer H, Jacobi A, Weyergraf A, Kingo K, Kõks S, Gerdes S, Steinz K, Schill T, Griewank KG, Müller M, Frey S, Ebertsch L, Uebe S, Sticherling M, Sticht H, Hüffmeier U

    BACKGROUND: Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP).

    OBJECTIVES: To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN.

    METHODS: Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype-phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort.

    RESULTS: The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers.

    CONCLUSIONS: The identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease-causing genetic factors outside IL36RN.

    Pubmed
  • Clinical outcome of concomitant vs interrupted BRAF inhibitor therapy during radiotherapy in melanoma patients.

    Br J Cancer. 2018;118(6): 785-792

    Hecht M, Meier F, Zimmer L, Polat B, Loquai C, Weishaupt C, Forschner A, Gutzmer R, Utikal JS, Goldinger SM, Geier M, Hassel JC, Balermpas P, Kiecker F, Rauschenberg R, Dietrich U, Clemens P, Berking C, Grabenbauer G, Schadendorf D, Grabbe S, Schuler G, Fietkau R, Distel LV, Heinzerling L

    This corrects the article DOI: 10.1038/bjc.2017.85.

    Pubmed
  • Willingness to pay for a cure of low-risk melanoma patients in Germany.

    PLoS ONE. 2018;13(5):

    Augustin M, Blome C, Forschner A, Gutzmer R, Hauschild A, Heinzerling L, Livingstone E, Loquai C, Schadendorf D, Utikal J, Wagner T, Wilden S, Kähler KC

    Malignant melanoma is potentially life-threatening but in most cases curable if detected early. Willingness to pay (WTP) is a preference-based construct that reflects burden of disease by assessment of the monetary value for a hypothetical cure from disease. Since WTP (directly as total amount of money) has not been assessed so far in patients with low risk melanoma, it was interesting to gain insights in this patient population and then, in a second step, compare it directly with the WTP of their treating dermato-oncologists. WTP was assessed in 125 patients with low-risk melanoma and additionally in 105 treating physicians, asking for the one-time and continuous payments they would be willing to make for a sustainable cure, both as absolute sums and as percentages of monthly income. The median WTP based on one-time payment was €10,000 for patients and €100,000 for physicians; relative numbers were 100% versus 300% of monthly income. For continuous monthly payments, WTP was €500 for patients and €1000 for physicians, relative numbers 25% and 50% of income, respectively. Even after controlling for income differences, there was a significantly higher WTP in physicians for all four questions. Compared to patients with chronic skin diseases such as vitiligo, rosacea, atopic eczema and psoriasis, patients with low-risk melanoma showed a significantly higher WTP. Our data suggest that there is a relevant burden of disease even in patients with low-risk tumors. Higher WTP of physicians underlines the prevalence of differences in disease perception.

    Pubmed
  • Ipilimumab in metastatic melanoma patients with pre-existing autoimmune disorders.

    Cancer Immunol Immunother. 2018;67(5): 825-834

    Kähler KC, Eigentler TK, Gesierich A, Heinzerling L, Loquai C, Meier F, Meiss F, Pföhler C, Schlaak M, Terheyden P, Thoms KM, Ziemer M, Zimmer L, Gutzmer R, German Dermatologic Cooperative Oncology Group (DeCOG)

    BACKGROUND: Ipilimumab and programmed death (PD) 1-antibodies are effective treatment options in metastatic melanoma. The safety and efficacy of ipilimumab in patients with pre-existing autoimmune disorders (AD) has only been evaluated in a selected number of patients.

    METHODS: We performed a retrospective analysis in 14 German skin cancer centers for patients with metastatic melanoma and pre-existing AD treated with ipilimumab.

    RESULTS: 41 patients with 44 pre-existing AD were treated with ipilimumab (thyroiditis n = 15, rheumatoid n = 11, dermatologic n = 10, Crohn's disease/ulcerative colitis n = 3, neurological n = 2, sarcoidosis n = 2, pancreatitis n = 1). 3 out of 41 patients had two AD, 11 patients required immunosuppressants at the time of induction of ipilimumab. 12 patients (29.2%) experienced a flare of their pre-existing AD, mainly patients with rheumatoid or dermatologic diseases. Additional immune-related adverse events (irAEs) occurred in 12 patients (29.2%). In 23 patients (56%) neither a change of their AD nor additional irAEs were observed. Objective responses were seen in five patients (one complete remission, four partial remissions, 12.1%).

    CONCLUSION: This is the largest series of patients with pre-existing AD and treatment with ipilimumab reported. Flares of pre-existing AD were observed but manageable. Response rates and occurrence of new irAEs were comparable to previous trials. Thus, in this patient subgroup, ipilimumab can be a treatment option after a thorough discussion of pros and cons and taking severity and activity of the preexisting AD into account.

    Pubmed
  • Acral lentiginous melanoma: a skin cancer with unfavourable prognostic features. A study of the German central malignant melanoma registry (CMMR) in 2050 patients.

    Br J Dermatol. 2018;178(2): 443-451

    Teramoto Y, Keim U, Gesierich A, Schuler G, Fiedler E, Tüting T, Ulrich C, Wollina U, Hassel JC, Gutzmer R, Goerdt S, Zouboulis C, Leiter U, Eigentler TK, Garbe C

    BACKGROUND: Acral lentiginous melanoma (ALM) is one of the four major subtypes in cutaneous melanoma (CM). Although ALM has a poorer prognosis than other CM subtypes, the prognostic factors associated with ALM have only been verified in small-sized cohorts because of the low incidence of ALM worldwide.

    OBJECTIVES: To investigate the clinical characteristics of ALM and to evaluate their prognostic values based on a large dataset from the Central Malignant Melanoma Registry (CMMR) of the German Dermatologic Society.

    METHODS: The Kaplan-Meier method was used to estimate the potential influence of clinical and histological parameters on ALM disease-specific survival (DSS) curves, which were compared using the log-rank test. A Cox proportional hazards model was used to identify independent prognostic factors for DSS.

    RESULTS: In total, 2050 patients with ALM were identified from 58 949 patients with CM recorded by the CMMR with follow-up data. In multivariate analyses, age (P = 0·006), ulceration (P = 0·013), tumour thickness (P < 0·001) and tumour spread (P < 0·001) turned out to be significant prognostic factors for DSS in ALM whereas sex, nevus association and level of invasion were not independent factors.

    CONCLUSIONS: ALM has the same prognostic factors as other subtypes of melanoma. Unfavourable prognosis probably derives from the delay in diagnosis in comparison with other melanoma subtypes.

    Pubmed
  • Can checkpoint inhibitor therapy improve response to chemotherapy?

    J Cancer Res Clin Oncol. 2018;144(1): 183-185

    Kirchberger MC, Schilling B, Haferkamp S, Bosserhoff A, Schuler G, Heinzerling L

    Pubmed
  • MEK inhibition may increase survival of NRAS-mutated melanoma patients treated with checkpoint blockade: Results of a retrospective multicentre analysis of 364 patients.

    Eur J Cancer. 2018;98(): 10-16

    Kirchberger MC, Ugurel S, Mangana J, Heppt MV, Eigentler TK, Berking C, Schadendorf D, Schuler G, Dummer R, Heinzerling L

    BACKGROUND: Melanoma harbours genetic alterations in genes such as BRAF, NRAS and KIT. Activating NRAS mutations are present in about 20% of melanomas. Even though BRAF mutations can be effectively targeted with specific inhibitors, this approach has proven more challenging in cases of NRAS mutations. Previous reports suggested that immunotherapy might be more successful in NRAS-mutated compared to BRAF-mutated or BRAF/NRAS wildtype melanoma.

    PATIENTS AND METHODS: In this study, overall survival and response to anti-PD-1 (nivolumab, pembrolizumab) and anti-CTLA-4 (ipilimumab) therapy of 364 patients with metastatic melanoma were assessed comparing 236 NRAS-mutated patients with 128 NRAS wildtype patients. Subtyping of NRAS mutation in 211 cases revealed 12 different genotypes of which Q61 mutations were predominant (95%).

    RESULTS: Patients with NRAS mutant melanoma showed similar response rates to checkpoint inhibitor therapy compared to NRAS wildtype patients with 15% versus 13% for ipilimumab (P = 0.731), 21% versus 13% for anti-PD-1 monotherapy (P = 0.210) and 40% versus 39% for ipilimumab and anti-PD-1 therapy in combination or sequence (P = 0.859). Nevertheless, median overall survival of patients with NRAS mutant melanoma was significantly lower with 21 months compared to 33 months in NRAS wildtype melanoma patients (P = 0.034). Therapy with oral MEK inhibitors before or after checkpoint inhibitor therapy showed a trend toward a survival benefit in patients with NRAS mutant melanoma.

    CONCLUSIONS: Immune checkpoint inhibition shows comparable response rates in NRAS-mutated and NRAS wildtype melanoma even though survival is less favourable in case of NRAS mutation. Additional MEK inhibition might improve clinical benefit.

    Pubmed
  • Hypertonicity primes malignant melanoma cells for apoptosis.

    Apoptosis. 2018;23(3-4): 201-209

    Calance DN, Steixner C, Gross S, Schuler-Thurner B, Knoll G, Ehrenschwender M

    The tumor environment critically influences responsiveness of cancer cells to chemotherapies, most of which activate the mitochondria-regulated (intrinsic) apoptotic cascade to kill malignant cells. Especially skin tumors encounter an environment with remarkable biophysical properties. Cutaneous accumulation of Na+ locally establishes osmotic pressure gradients in vivo (hypertonicity or hyperosmotic stress), but whether cutaneous hypertonicity is a factor that modulates the responsiveness of skin cancers to therapeutic apoptosis-induction has thus far not been investigated. Here, we show that hyperosmotic stress lowers the threshold for apoptosis induction in malignant melanoma, the deadliest form of skin cancer. Hypertonic conditions enforce addiction to BCL-2-like proteins to prevent initiation of the mitochondria-regulated (intrinsic) apoptotic pathway. Essentially, hyperosmotic stress primes mitochondria for death. Our work identifies osmotic pressure in the tumor microenvironment as a cell extrinsic factor that modulates responsiveness of malignant melanoma cells to therapy.

    Pubmed
  • Concealed complete response in melanoma patients under therapy with immune checkpoint inhibitors: two case reports.

    J Immunother Cancer. 2018;6(1):

    Schliep S, Agaimy A, Cavallaro A, Kiesewetter F, Schuler G, Heinzerling L

    BACKGROUND: The assessment of tumor size by RECIST using CT scans and MRIs is considered to be standard of care for staging cancer patients. Despite radiologic evidence of widespread disease, we document for the first time that patients were completely free of viable tumor.

    CASE PRESENTATION: Two patients with metastatic melanoma were treated with immune checkpoint inhibitors (ipilimumab/ nivolumab) and progressive metastases were detected on CT-scans performed shortly before histologic examinations. In both patients histologic assessment revealed a complete response with necrotic and scarred lesions free of tumor. One of the patients had started immunotherapy 20 months before with an initial partial response.

    CONCLUSIONS: This phenomenon of a concealed complete response can lead to overtreatment or unnecessary change in treatment. Thus, it is essential to raise awareness for it. Correct identification of responders to immune checkpoint inhibitor therapy is crucial to spare patients immune-mediated side effects and unnecessary as well as expensive treatment. Regression of metastases without decline in size, in these cases manifesting as complete responses, are probably more common than expected and identified to date. Until such responses can be readily identified by new imaging techniques, we recommend liberal biopsies for histologic assessment of progressive metastases in patients during and/or after immune checkpoint inhibitor therapy.

    Pubmed
  • BRAF and MEK Inhibitors Influence the Function of Reprogrammed T Cells: Consequences for Adoptive T-Cell Therapy.

    Int J Mol Sci. 2018;19(1):

    Dörrie J, Babalija L, Hoyer S, Gerer KF, Schuler G, Heinzerling L, Schaft N

    BRAF and MEK inhibitors (BRAFi/MEKi), the standard treatment for patients with BRAFV600 mutated melanoma, are currently explored in combination with various immunotherapies, notably checkpoint inhibitors and adoptive transfer of receptor-transfected T cells. Since two BRAFi/MEKi combinations with similar efficacy are approved, potential differences in their effects on immune cells would enable a rational choice for triple therapies. Therefore, we characterized the influence of the clinically approved BRAFi/MEKi combinations dabrafenib (Dabra) and trametinib (Tram) vs. vemurafenib (Vem) and cobimetinib (Cobi) on the activation and functionality of chimeric antigen receptor (CAR)-transfected T cells. We co-cultured CAR-transfected CD8⁺ T cells and target cells with clinically relevant concentrations of the inhibitors and determined the antigen-induced cytokine secretion. All BRAFi/MEKi reduced this release as single agents, with Dabra having the mildest inhibitory effect, and Dabra + Tram having a clearly milder inhibitory effect than Vem + Cobi. A similar picture was observed for the upregulation of the activation markers CD25 and CD69 on CAR-transfected T cells after antigen-specific stimulation. Most importantly, the cytolytic capacity of the CAR-T cells was significantly inhibited by Cobi and Vem + Cobi, whereas the other kinase inhibitors showed no effect. Therefore, the combination Dabra + Tram would be more suitable for combining with T-cell-based immunotherapy than Vem + Cobi.

    Pubmed
  • Life-threatening Autoimmune Cardiomyopathy Reproducibly Induced in a Patient by Checkpoint Inhibitor Therapy.

    J Immunother. 2018;41(1): 35-38

    Tajmir-Riahi A, Bergmann T, Schmid M, Agaimy A, Schuler G, Heinzerling L

    Checkpoint inhibitors induce a plethora of immune-related adverse events (irAEs) including autoimmune colitis, hepatitis, endocrinopathies, and rarer side effects like neuritis. Here, a case of autoimmune cardiomyopathy (grade 3 CTCAE) and myocarditis under combination therapy with nivolumab plus ipilimumab in a 72-year-old melanoma patient is reported. Treatment induced a partial response for 14 months. However, after 10 infusions the patient developed dyspnea, edema of the legs, ascites and a weight gain of 10 kg because of a decompensated heart insufficiency with a reduced ejection fraction from formerly 48%-50% to 15%. Ischemia and viral infections were ruled out. Histopathology showed hypertrophic myocarditis with interstitial lymphocytes. Prednisolone improved the patient's condition within 3 days, leading to a 25% and 30% ejection fraction after 2 and 8 weeks, respectively, and clinical symptoms subsided completely. Importantly, reinduction of anti-PD1 therapy resulted in a flare of myocarditis. Awareness for potentially life-threatening irAE of checkpoint inhibitors like autoimmune cardiomyopathy and myocarditis is crucial to rapidly initiate adequate treatment.

    Pubmed
  • Prognostic Significance of Remote Myocardium Alterations Assessed by Quantitative Noncontrast T1 Mapping in ST-Segment Elevation Myocardial Infarction.

    JACC Cardiovasc Imaging. 2018;11(3): 411-419

    Reinstadler SJ, Stiermaier T, Liebetrau J, Fuernau G, Eitel C, de Waha S, Desch S, Reil JC, Pöss J, Metzler B, Lücke C, Gutberlet M, Schuler G, Thiele H, Eitel I

    OBJECTIVES: This study assessed the prognostic significance of remote zone native T1 alterations for the prediction of clinical events in a population with ST-segment elevation myocardial infarction (STEMI) who were treated by primary percutaneous coronary intervention (PPCI) and compared it with conventional markers of infarct severity.

    BACKGROUND: The exact role and incremental prognostic relevance of remote myocardium native T1 mapping alterations assessed by cardiac magnetic resonance (CMR) after STEMI remains unclear.

    METHODS: We included 255 consecutive patients with STEMI who were reperfused within 12 h after symptom onset. CMR core laboratory analysis was performed to assess left ventricular (LV) function, standard infarct characteristics, and native T1 values of the remote, noninfarcted myocardium. The primary endpoint was a composite of death, reinfarction, and new congestive heart failure within 6 months (major adverse cardiac events [MACE]).

    RESULTS: Patients with increased remote zone native T1 values (>1,129 ms) had significantly larger infarcts (p = 0.012), less myocardial salvage (p = 0.002), and more pronounced LV dysfunction (p = 0.011). In multivariable analysis, remote zone native T1 was independently associated with MACE after adjusting for clinical risk factors (p = 0.001) or other CMR variables (p = 0.007). In C-statistics, native T1 of remote myocardium provided incremental prognostic information beyond clinical risk factors, LV ejection fraction, and other markers of infarct severity (all p < 0.05). The addition of remote zone native T1 to a model of prognostic CMR parameters (ejection fraction, infarct size, and myocardial salvage index) led to net reclassification improvement of 0.82 (95% confidence interval: 0.46 to 1.17; p < 0.001) and to an integrated discrimination improvement of 0.07 (95% confidence interval: 0.02 to 0.13; p = 0.01).

    CONCLUSIONS: In STEMI patients treated by PPCI, evaluation of remote zone alterations by quantitative noncontrast T1 mapping provided independent and incremental prognostic information in addition to clinical risk factors and traditional CMR outcome markers. Remote zone alterations may thus represent a novel therapeutic target and a useful parameter for optimized risk stratification. (Effect of Conditioning on Myocardial Damage in STEMI [LIPSIA-COND]; NCT02158468).

    Pubmed
  • BRAF and MEK inhibitors change human immune cell phenotype and function; possible consequences for combination therapy

    Exp Dermatol. 2018;27(3): E22-E22

    Hoyer S, Eberlein V, Babalija L, Gerer K, Walter L, Schuler G, Schaft N, Heinzerling L, Doerrie J

    Pubmed
  • Mananging toxicities of immunotherapies - a side effect register for rare and severe side effects of checkpoint Inhibitor therapy

    Oncology Research and Treatment. 2018;41(): 45-45

    Heinzerling L, Schuler G

    Pubmed
  • Patients' and Physicians' Preferences for Systemic Psoriasis Treatments: A Nationwide Comparative Discrete Choice Experiment (PsoCompare).

    Acta Derm Venereol. 2018;98(2): 200-205

    Schaarschmidt ML, Herr R, Gutknecht M, Wroblewska K, Gerdes S, Sticherling M, Augustin M, Peitsch WK

    Systemic antipsoriatic treatment options are increasing rapidly. The aim of this nationwide discrete choice experiment was to compare patients' (n = 222) and physicians' (n = 78) preferences for outcome and process attributes of systemic antipsoriatics using Relative Importance Scores (RIS). Both groups considered Psoriasis Area and Severity Index 90 (PASI 90) to be most important (RIS 21.4 and 20.8, respectively). Moreover, patients were highly concerned about mild and severe adverse events (RIS = 18.2 and 14.2), physicians about severe adverse events (RIS = 14.9) and cost (RIS = 13.8). Compared to physicians, patients worried more about mild adverse events and treatment location, but less about cost and frequency of laboratory tests. Physicians' preferences were influenced by work experience and percentage of biological prescriptions, patients' preferences by age, disease duration and severity. Older and less severely affected patients recruited via a patient organization focused more on safety, but less on efficacy and time until response than did patients from study centres. In conclusion, these differences in trade-offs should be integrated into a shared decision-making.

    Pubmed
  • BRAF Inhibitors and Radiation Do Not Act Synergistically to Inhibit WT and V600E BRAF Human Melanoma.

    Anticancer Res. 2018;38(3): 1335-1341

    Walter L, Heinzerling L

    BACKGROUND/AIM: Recent evidence suggests that melanoma patients treated with BRAF inhibitors experience radiosensitization with an increased frequency of side-effects. This could also imply increased effectiveness when treating melanoma.

    MATERIALS AND METHODS: To test whether the BRAF inhibitors dabrafenib and vemurafenib together with ionizing radiation more effectively inhibit melanoma cells, primary human melanoma tumor cell lines expressing wild-type (WT) or mutant V600E BRAF were analyzed by cell survival, cell death, and cell-cycle testing.

    RESULTS: All melanoma cell lines examined were radioresistant in these assays. BRAF inhibitor treatment alone suppressed cell survival more effectively than radiation in all the mutant V600E BRAF cell lines, and vemurafenib, but not dabrafenib, also inhibited cell survival in the WT BRAF cell lines at clinically relevant concentrations. However, when cells were treated with BRAF inhibitor followed by radiation, there was no increased effect on the suppression of cell survival. Vemurafenib induced more necrosis than radiation in most melanoma cell lines, irrespective of BRAF status, but this effect was not additive with the combination treatment. BRAF inhibitors and radiation had variable, but independent effects on the induction of cell-cycle arrest.

    CONCLUSION: These results suggest that BRAF inhibitors and ionizing radiation do not act synergistically to inhibit the growth of primary human melanoma cells.

    Pubmed
  • Understanding microRNA-mediated immunogenicity of dendritic cells using an integrative approach

    Eur J Immunol. 2018;48(): 3-4

    Lai X, Dreyer FS, Jaitly T, Cantone M, Gerer KF, Schuler G, Doerrie J, Schaft N, Vera J

    Pubmed
  • The simultaneous siRNA-mediated downregulation of PD-1 and CTLA-4 to improve CAR-T cell immunotherapy of melanoma

    Exp Dermatol. 2018;27(3): E52-E53

    Simon B, Harrer D, Schuler-Thurner B, Doerrie J, Schaft N, Schuler G, Uslu U

    Pubmed
  • Comparative analysis of human dendritic cell subpopulations in steady state and inflammation

    Eur J Immunol. 2018;48(): 156-156

    Heger L, Heidkamp G, Lehmann C, Soeder S, Hartmann A, Alexiou C, Schuler G, Purbojo A, Cesnjevar R, Nimmerjahn F, Dudziak D

    Pubmed
  • A web platform for the network analysis of high-throughput data in melanoma and its use to investigate mechanisms of resistance to anti-PD1 immunotherapy.

    Biochim Biophys Acta Mol Basis Dis. 2018;1864(6 Pt B): 2315-2328

    Dreyer FS, Cantone M, Eberhardt M, Jaitly T, Walter L, Wittmann J, Gupta SK, Khan FM, Wolkenhauer O, Pützer BM, Jäck HM, Heinzerling L, Vera J

    Cellular phenotypes are established and controlled by complex and precisely orchestrated molecular networks. In cancer, mutations and dysregulations of multiple molecular factors perturb the regulation of these networks and lead to malignant transformation. High-throughput technologies are a valuable source of information to establish the complex molecular relationships behind the emergence of malignancy, but full exploitation of this massive amount of data requires bioinformatics tools that rely on network-based analyses. In this report we present the Virtual Melanoma Cell, an online tool developed to facilitate the mining and interpretation of high-throughput data on melanoma by biomedical researches. The platform is based on a comprehensive, manually generated and expert-validated regulatory map composed of signaling pathways important in malignant melanoma. The Virtual Melanoma Cell is a tool designed to accept, visualize and analyze user-generated datasets. It is available at: www.vcells.net/melanoma. To illustrate the utilization of the web platform and the regulatory map, we have analyzed a large publicly available dataset accounting for anti-PD1 immunotherapy treatment of malignant melanoma patients.

    Pubmed
  • Myocarditis in Patients Treated With Immune Checkpoint Inhibitors.

    J Am Coll Cardiol. 2018;71(16): 1755-1764

    Mahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, Sullivan RJ, Damrongwatanasuk R, Chen CL, Gupta D, Kirchberger MC, Awadalla M, Hassan MZO, Moslehi JJ, Shah SP, Ganatra S, Thavendiranathan P, Lawrence DP, Groarke JD, Neilan TG

    BACKGROUND: Myocarditis is an uncommon, but potentially fatal, toxicity of immune checkpoint inhibitors (ICI). Myocarditis after ICI has not been well characterized.

    OBJECTIVES: The authors sought to understand the presentation and clinical course of ICI-associated myocarditis.

    METHODS: After observation of sporadic ICI-associated myocarditis cases, the authors created a multicenter registry with 8 sites. From November 2013 to July 2017, there were 35 patients with ICI-associated myocarditis, who were compared to a random sample of 105 ICI-treated patients without myocarditis. Covariates of interest were extracted from medical records including the occurrence of major adverse cardiac events (MACE), defined as the composite of cardiovascular death, cardiogenic shock, cardiac arrest, and hemodynamically significant complete heart block.

    RESULTS: The prevalence of myocarditis was 1.14% with a median time of onset of 34 days after starting ICI (interquartile range: 21 to 75 days). Cases were 65 ± 13 years of age, 29% were female, and 54% had no other immune-related side effects. Relative to controls, combination ICI (34% vs. 2%; p < 0.001) and diabetes (34% vs. 13%; p = 0.01) were more common in cases. Over 102 days (interquartile range: 62 to 214 days) of median follow-up, 16 (46%) developed MACE; 38% of MACE occurred with normal ejection fraction. There was a 4-fold increased risk of MACE with troponin T of ≥1.5 ng/ml (hazard ratio: 4.0; 95% confidence interval: 1.5 to 10.9; p = 0.003). Steroids were administered in 89%, and lower steroids doses were associated with higher residual troponin and higher MACE rates.

    CONCLUSIONS: Myocarditis after ICI therapy may be more common than appreciated, occurs early after starting treatment, has a malignant course, and responds to higher steroid doses.

    Pubmed
  • MYOCARDITIS IN PATIENTS TREATED WITH IMMUNE CHECKPOINT INHIBITORS

    J Am Coll Cardiol. 2018;71(11): 699-699

    Mahmood S, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, Sullivan RJ, Damrongwatanasuk R, Chen C, Gupta D, Kirchberger MC, Moslehi J, Shah S, Ganatra S, Thavendiranathan P, Lawrence DP, Groarke JD, Neilan TG

    Pubmed
  • Ulcerative colitis: yet another paradoxical effect of tumour necrosis factor blockers?

    Br J Dermatol. 2018;178(2): 333-334

    Sticherling M

    Pubmed
  • Crusted Nodules on the Lower Left Arm in a Traveller Returning from South America: A Quiz. Furuncular myiasis.

    Acta Derm Venereol. 2018;98(1): 159-160

    Uslu U, Erdmann M, Schliep S, Sticherling M

    Pubmed
  • Localized Scleroderma of the Head and Face Area: A Retrospective Cross-sectional Study of 96 Patients from 5 German Tertiary Referral Centres.

    Acta Derm Venereol. 2018;98(6): 603-605

    Kreuter A, Mitrakos G, Hofmann SC, Lehmann P, Sticherling M, Krieg T, Lahner N, Tigges C, Hunzelmann N, Moinzadeh P

    Pubmed
  • From relative to absolute Treatment Goals - Correlation of PASI 90 and PASI <=2 in three clinical Studies with Secukinumab

    J Dtsch Dermatol Ges. 2018;16(): 8-8

    Reich K, Bachhuber T, Melzer N, Sieder C, Sticherling M

    Pubmed
  • The outweigh of toxicity versus risk of recurrence for adjuvant interferon therapy: a survey in German melanoma patients and their treating physicians.

    Oncotarget. 2018;9(40): 26217-26225

    Kähler KC, Blome C, Forschner A, Gutzmer R, Hauschild A, Heinzerling L, Livingstone E, Loquai C, Müller-Brenne T, Schadendorf D, Utikal J, Wagner T, Augustin M

    After more than two decades with interferon alfa-2a and 2b (IFN) as the only approved drugs in the adjuvant setting for melanoma, new treatment approaches like immune checkpoint inhibitors and BRAF-MEK inhibitors improve the progression free survival (PFS) and also the overall survival (OS). We compared physicians' preferences ("utilities") for health states associated with IFN therapy to their patients' preferences. Utilities describe a preference for a specific health state on a scale of 0 (as bad as death) to 1.0 (perfect health).

    Setting: We assessed utilities for health states associated with adjuvant IFN using the standard gamble technique in 108 physicians and 130 melanoma patients. Four IFN toxicity scenarios and three outcome scenarios were given to the participants. Both groups were asked for the 5-year disease free survival (DFS) they would need to accept the described IFN-related side effects.

    Results: In both groups, utilities for melanoma relapse were significantly lower than for IFN side effects, showing that toxicity was more acceptable than relapse. Physicians indicated higher utilities for each scenario and needed lower 5-year DFS both in case of mild-to-moderate and severe side effects. Patients were willing to tolerate mild-to-moderate and severe toxicity for a 50% and 75% chance of 5-year DFS, while physicians only required a chance of 40% and 50%, respectively.

    Conclusion: Both physicians and patients rated melanoma recurrence much lower than even severe IFN side effects. In direct comparison, physicians rated cancer-related scenarios more positively and accepted IFN toxicity for an even lower treatment benefit.

    Pubmed
  • Real world experience in low-dose ipilimumab in combination with PD-1 blockade in advanced melanoma patients.

    Oncotarget. 2018;9(48): 28903-28909

    Kirchberger MC, Moreira A, Erdmann M, Schuler G, Heinzerling L

    Dual immune-checkpoint blockade with the anti-PD-1 antibody nivolumab (1 mg/kg) and standard-dose ipilimumab (3 mg/kg) is the mainstay of immunotherapy in advanced melanoma and it is approved since 2016. However, severe side effects (grade 3/4) occur in up to 60% of the patients. Recently, clinical trials have shown similar anti-tumor activity with a more favorable toxicity profile in patients treated with low-dose ipilimumab (1 mg/kg) and standard-dose pembrolizumab (2 mg/kg). In this study we report on the real-world experience of this dosing regime in advanced melanoma patients not eligible for clinical trials. A total of 33 patients with metastatic melanoma (24 with cutaneous and 9 with uveal melanoma) were assessed, retrospectively. Brain metastases were present in 33% of the patients and lactate dehydrogenase was elevated in 70%. Overall response rates were 38% and 0% in cutaneous melanoma and uveal melanoma respectively. Median overall survival was not reached in cutaneous melanoma and was 18 months in uveal melanoma. In 18% of the patients at least one treatment-related severe adverse event was observed. Our observation that the combination of standard dose pembrolizumab and low-dose ipilimumab has a favorable toxicity profile yet anti-tumor activity comparable to the approved standard-dose combination regime in advanced patients not suitable for enrollment in clinical trials is encouraging.

    Pubmed
  • Effective anti-programmed death-1 therapy in a SUFU-mutated patient with Gorlin-Goltz syndrome.

    Br J Dermatol. 2018;179(3): 747-749

    Moreira A, Kirchberger MC, Toussaint F, Erdmann M, Schuler G, Heinzerling L

    We present the case of a 77-year-old male patient with more than 50 basal cell carcinomas on the head and upper trunk. The patient did not respond to several lines of treatment, including surgery, imiquimod, retinoids, itraconazole and therapy with the hedgehog inhibitor vismodegib. The patient responded well to off-label therapy with the anti-programmed death-1 antibody pembrolizumab after four infusions.

    Pubmed
  • Chimeric Antigen Receptors in Different Cell Types: New Vehicles Join the Race.

    Hum Gene Ther. 2018;29(5): 547-558

    Harrer DC, Dörrie J, Schaft N

    Adoptive cellular therapy has evolved into a powerful force in the battle against cancer, holding promise for curative responses in patients with advanced and refractory tumors. Autologous T cells, reprogrammed to target malignant cells via the expression of a chimeric antigen receptor (CAR) represent the frontrunner in this approach. Tremendous clinical regressions have been achieved using CAR-T cells against a variety of cancers both in numerous preclinical studies and in several clinical trials, most notably against acute lymphoblastic leukemia, and resulted in a very recent United States Food and Drug Administration approval of the first CAR-T-cell therapy. In most studies CARs are transferred to conventional αβT cells. Nevertheless, transferring a CAR into different cell types, such as γδT cells, natural killer cells, natural killer T cells, and myeloid cells has yet received relatively little attention, although these cell types possess unique features that may aid in surmounting some of the hurdles CAR-T-cell therapy currently faces. This review focuses on CAR therapy using effectors beyond conventional αβT cells and discusses those strategies against the backdrop of developing a safe, powerful, and durable cancer therapy.

    Pubmed
  • A comparative analysis of articular bone in large cohort of patients with chronic inflammatory diseases of the joints, the gut and the skin.

    Bone. 2018;116(): 87-93

    Simon D, Kleyer A, Englbrecht M, Stemmler F, Simon C, Berlin A, Kocijan R, Haschka J, Hirschmann S, Atreya R, Neurath MF, Sticherling M, Rech J, Hueber AJ, Engelke K, Schett G

    Chronic inflammatory diseases are associated with bone loss. While the occurrence of systemic bone loss is well described in chronic inflammatory diseases, the impact of these conditions on articular bone has not been systematically investigated. Recent refinements in high-resolution CT assessment of the joints now allow the accurate measure of articular bone composition. In this study 476 subjects comprising healthy individuals and patients with anticitrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA), ACPA-negative RA, Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO) and psoriatic arthritis (PsA) were subjected to high-resolution quantitative computed tomography (HR-pQCT) of the hand. Metacarpal heads were assessed for total, trabecular and cortical volumetric bone mineral density (vBMD). Only ACPA+RA, but not the remaining inflammatory diseases (ACPA-RA, CD, UC, PsO, PsA) showed significant (p < 0.001) loss of articular bone affecting both the trabecular and the cortical compartments. Age and body mass index were also associated with articular bone changes, the former with lower, the latter with higher articular bone mass. In multivariate models, presence of ACPA+RA was an independent factor for articular bone loss. Among chronic inflammatory diseases ACPA+RA is the most potent precipitator for articular bone loss pointing out the role of autoimmunity in the development of articular bone disease in the context of chronic inflammatory disease.

    Pubmed
  • Omalizumab treatment in patients with chronic inducible urticaria: A systematic review of published evidence.

    J Allergy Clin Immunol. 2018;141(2): 638-649

    Maurer M, Metz M, Brehler R, Hillen U, Jakob T, Mahler V, Pföhler C, Staubach P, Treudler R, Wedi B, Magerl M

    BACKGROUND: Omalizumab, a recombinant anti-IgE antibody, effectively treats chronic spontaneous urticaria. Evidence is lacking in patients with chronic inducible urticarias (CIndUs), which are frequently H1-antihistamine resistant.

    OBJECTIVE: From the current published literature, we aimed to determine the strength of evidence for omalizumab efficacy and safety in the treatment of CIndUs.

    METHODS: We performed a PubMed search to identify evidence on omalizumab use in the following 9 CIndU subtypes: symptomatic dermographism, cold urticaria, delayed-pressure urticaria, solar urticaria, heat urticaria, vibratory angioedema, cholinergic urticaria, contact urticaria, and aquagenic urticaria.

    RESULTS: Forty-three trials, case studies, case reports, and analyses were identified. Our review indicates that omalizumab has substantial benefits in patients with various CIndUs. The evidence is strongest for symptomatic dermographism, cold urticaria, and solar urticaria. Little/no evidence was available on vibratory angioedema and aquagenic and contact urticaria. Our review supports rapid onset of action demonstrated through early symptom control in most cases, sometimes within 24 hours. Many patients gained complete/partial symptom relief and substantially improved quality of life. Adverse events were generally low, with omalizumab being well tolerated by most patients, including children.

    CONCLUSIONS: A strong body of evidence supports the use of omalizumab in the treatment of patients with therapy-refractory CIndU. More data from randomized controlled studies are warranted.

    Pubmed
  • Hypertonicity-enforced BCL-2 addiction unleashes the cytotoxic potential of death receptors.

    Oncogene. 2018;37(30): 4122-4136

    Sirtl S, Knoll G, Trinh DT, Lang I, Siegmund D, Gross S, Schuler-Thurner B, Neubert P, Jantsch J, Wajant H, Ehrenschwender M

    Attempts to exploit the cytotoxic activity of death receptors (DR) for treating cancer have thus far been disappointing. DR activation in most malignant cells fails to trigger cell death and may even promote tumor growth by activating cell death-independent DR-associated signaling pathways. Overcoming apoptosis resistance is consequently a prerequisite for successful clinical exploitation of DR stimulation. Here we show that hyperosmotic stress in the tumor microenvironment unleashes the deadly potential of DRs by enforcing BCL-2 addiction of cancer cells. Hypertonicity robustly enhanced cytotoxicity of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and other DR ligands in various cancer entities. Initial events in TRAIL DR signaling remained unaffected, but hypertonic conditions unlocked activation of the mitochondrial death pathway and thus amplified the apoptotic signal. Mechanistically, we demonstrate that hyperosmotic stress imposed a BCL-2-addiction on cancer cells to safeguard the integrity of the outer mitochondrial membrane (OMM), essentially exhausting the protective capacity of BCL-2-like pro-survival proteins. Deprivation of these mitochondrial safeguards licensed DR-generated truncated BH3-interacting domain death agonist (tBID) to activate BCL-2-associated X protein (BAX) and initiated mitochondrial outer membrane permeabilization (MOMP). Our work highlights that hyperosmotic stress in the tumor environment primes mitochondria for death and lowers the threshold for DR-induced apoptosis. Beyond TRAIL-based therapies, our findings could help to strengthen the efficacy of other apoptosis-inducing cancer treatment regimens.

    Pubmed
  • Rapid development of cutaneous melanoma metastases after herpes zoster infection in a radiotherapy field.

    Clin Exp Dermatol. 2018;43(1): 94-96

    Uslu U, Schliep S, Erdmann M

    Click for the corresponding questions to this CME article.

    Pubmed
  • Resolution of synovitis and arrest of catabolic and anabolic bone changes in patients with psoriatic arthritis by IL-17A blockade with secukinumab: results from the prospective PSARTROS study.

    Arthritis Res Ther. 2018;20(1):

    Kampylafka E, d'Oliveira I, Linz C, Lerchen V, Stemmler F, Simon D, Englbrecht M, Sticherling M, Rech J, Kleyer A, Schett G, Hueber AJ

    BACKGROUND: Although the effects of interleukin-17A (IL-17A) inhibition on the signs and symptoms of psoriatic arthritis (PsA) are well defined, little is known about its impact of local inflammatory and structural changes in the joints. The PSARTROS study was designed to elucidate the effects of IL-17A inhibition on inflammation and bone changes in joints affected by PsA.

    METHODS: This was a prospective open-label study in 20 patients with active PsA receiving 24 weeks of treatment with the IL-17A inhibitor secukinumab. Magnetic resonance imaging (MRI), power Doppler ultrasound (PDUS), and high-resolution peripheral quantitative computer tomography (HR-pQCT) of the hands were performed at baseline and after 24 weeks to assess synovitis, periarticular inflammation, bone erosion, enthesiophyte formation, and bone structure. Demographic and clinical measures of joint disease (DAPSA and DAS28-ESR), skin disease (PASI and BSA), and composite measures (minimal disease activity, or MDA) were also recorded.

    RESULTS: Treatment with secukinumab led to significant improvement of signs and symptoms of PsA; 46% reached MDA and 52% DAPSA low disease activity. MRI synovitis (P = 0.034) and signal in PDUS (P = 0.030) significantly decreased after 24 weeks of treatment. Bone erosions in MRI and HR-pQCT and enthesiophytes in the HR-pQCT did not show any progression, and structural integrity and functional bone strength remained stable.

    CONCLUSIONS: IL-17 inhibition by secukinumab over 24 weeks led to a significant decrease of synovial inflammation and no progression of catabolic and anabolic bone changes in the joints of patients with PsA.

    TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02483234 , June 26, 2015; retrospectively registered.

    Pubmed
  • CLEC10A Is a Specific Marker for Human CD1c+ Dendritic Cells and Enhances Their Toll-Like Receptor 7/8-Induced Cytokine Secretion.

    Front Immunol. 2018;9():

    Heger L, Balk S, Lühr JJ, Heidkamp GF, Lehmann CHK, Hatscher L, Purbojo A, Hartmann A, Garcia-Martin F, Nishimura SI, Cesnjevar R, Nimmerjahn F, Dudziak D

    Dendritic cells (DCs) are major players for the induction of immune responses. Apart from plasmacytoid DCs (pDCs), human DCs can be categorized into two types of conventional DCs: CD141+ DCs (cDC1) and CD1c+ DCs (cDC2). Defining uniquely expressed surface markers on human immune cells is not only important for the identification of DC subpopulations but also a prerequisite for harnessing the DC subset-specific potential in immunomodulatory approaches, such as antibody-mediated antigen targeting. Although others identified CLEC9A as a specific endocytic receptor for CD141+ DCs, such a receptor for CD1c+ DCs has not been discovered, yet. By performing transcriptomic and flow cytometric analyses on human DC subpopulations from different lymphohematopoietic tissues, we identified CLEC10A (CD301, macrophage galactose-type C-type lectin) as a specific marker for human CD1c+ DCs. We further demonstrate that CLEC10A rapidly internalizes into human CD1c+ DCs upon binding of a monoclonal antibody directed against CLEC10A. The binding of a CLEC10A-specific bivalent ligand (the MUC-1 peptide glycosylated with N-acetylgalactosamine) is limited to CD1c+ DCs and enhances the cytokine secretion (namely TNFα, IL-8, and IL-10) induced by TLR 7/8 stimulation. Thus, CLEC10A represents not only a candidate to better define CD1c+ DCs-due to its high endocytic potential-CLEC10A also exhibits an interesting candidate receptor for future antigen-targeting approaches.

    Pubmed
  • Lenalidomide enhances MOR202-dependent macrophage-mediated effector functions via the vitamin D pathway.

    Leukemia. 2018;32(11): 2445-2458

    Busch L, Mougiakakos D, Büttner-Herold M, Müller MJ, Volmer DA, Bach C, Fabri M, Bittenbring JT, Neumann F, Boxhammer R, Nolting J, Bisht S, Böttcher M, Jitschin S, Hoffmann MH, Balzer H, Beier F, Gezer D, Dudziak D, Gelse K, Hennig FF, Pallasch CP, Spriewald B, Mackensen A, Bruns H

    Macrophages are key mediators of the therapeutic effects exerted by monoclonal antibodies, such as the anti-CD38 antibody MOR202, currently introduced in multiple myeloma (MM) therapy. Therefore, it is important to understand how antibody-mediated effector functions of myeloma-associated macrophages (MAMs) are regulated. Here, we focused on the effects of vitamin D, a known regulator of macrophage effector functions. Consequently, it was the aim of this study to assess whether modulation of the vitamin D pathway alters the tumoricidal activity of MAMs. Here, we demonstrate that MAMs display a defective vitamin D pathway with reduced expression level of CYP27B1 and limited tumoricidal activity which can be restored by the IMiD lenalidomide in vitro. Furthermore, our data indicate that the vitamin D pathway of MAMs from MM patients does recover during an IMiD-containing therapy shown by an improved MOR202-mediated cytotoxic activity of these MAMs against primary MM cells ex vivo. Here, the ex vivo cytotoxic activity could be further enhanced by vitamin D supplementation. These data suggest that vitamin D holds a key role for the effector functions of MAMs and that vitamin D supplementation in IMiD combination trials could further increase the therapeutic efficacy of anti-CD38 antibodies such as MOR202, which remains to be investigated in clinical studies.

    Pubmed
  • Delay in antibiotic therapy results in fatal disease outcome in murine pneumococcal pneumonia.

    Crit Care. 2018;22(1):

    Berger S, Goekeri C, Gupta SK, Vera J, Dietert K, Behrendt U, Lienau J, Wienhold SM, Gruber AD, Suttorp N, Witzenrath M, Nouailles G

    BACKGROUND: Community-acquired pneumonia (CAP) remains a major cause of death worldwide. Mechanisms underlying the detrimental outcome despite adequate antibiotic therapy and comorbidity management are still not fully understood.

    METHODS: To model timely versus delayed antibiotic therapy in patients, mice with pneumococcal pneumonia received ampicillin twice a day starting early (24 h) or late (48 h) after infection. Clinical readouts and local and systemic inflammatory mediators after early and late antibiotic intervention were examined.

    RESULTS: Early antibiotic intervention rescued mice, limited clinical symptoms and restored fitness, whereas delayed therapy resulted in high mortality rates. Recruitment of innate immune cells remained unaffected by antibiotic therapy. However, both early and late antibiotic intervention dampened local levels of inflammatory mediators in the alveolar spaces. Early treatment protected from barrier breakdown, and reduced levels of vascular endothelial growth factor (VEGF) and perivascular and alveolar edema formation. In contrast, at 48 h post infection, increased pulmonary leakage was apparent and not reversed by late antibiotic treatment. Concurrently, levels of VEGF remained high and no beneficial effect on edema formation was evident despite therapy. Moreover, early but not late treatment protected mice from a vast systemic inflammatory response.

    CONCLUSIONS: Our data show that only early antibiotic therapy, administered prior to breakdown of the alveolar-capillary barrier and systemic inflammation, led to restored fitness and rescued mice from fatal streptococcal pneumonia. The findings highlight the importance of identifying CAP patients prior to lung barrier failure and systemic inflammation and of handling CAP as a medical emergency.

    Pubmed
  • Fear of cancer progression in patients with stage IA malignant melanoma.

    Eur J Cancer Care (Engl). 2018;27(5):

    Wagner T, Augustin M, Blome C, Forschner A, Garbe C, Gutzmer R, Hauschild A, Heinzerling L, Livingstone E, Loquai C, Schadendorf D, Terheyden P, Mueller-Brenne T, Kähler KC

    We aimed to determine the prevalence and importance of fear of cancer progression (FoP) in melanoma patients with stage IA tumours to assess psychosocial and demographic factors associated with severity of FoP and to determine the relationship of FoP and quality of life (QoL). One hundred and thirty-six patients with stage IA melanoma completed the short version of the Fear of Progression Questionnaire (FoP-Q-SF), the Hospital Anxiety and Depression Scale (HADS) and the EORTC-QLQ-C30. We found a mean FoP-Q-SF sum score of 30.2 points (±8.4 points SD). In this study, 33% of patients reported high FoP at or above the cutoff-value of 34 points. Higher FoP was found in women (p < 0.01), young (p = 0.03) and employed (p = 0.02) patients. Being confronted with a cancer diagnosis in closely related persons predicted higher FoP (p < 0.01). FoP correlated positively with the HADS anxiety (r = 0.50, p < 0.01) and depression scales (r = 0.26, p < 0.01) and negatively with the EORTC-QLQ-C30 global health state (r = -0.32, p < 0.01). FoP is considerably prevalent in low-risk melanoma patients and associated with reduced QoL, cancer in related persons, women sex and participation in working life. Considerably high levels of FoP, even in patients with low-risk malignancies, underline the need for psychosocial support and psychotherapeutic interventions for melanoma patients.

    Pubmed
  • Genital ulcers as diagnostic clue for acute myeloid leukaemia.

    Int Wound J. 2018;15(5): 845-848

    Schröder SD, Krause SW, Erfurt-Berge C

    Acute myeloid leukaemia is a myeloid neoplasm with an extremely varying clinical appearance. Skin lesions are common for specific subtypes of acute myeloid leukaemia but are often misinterpreted. Here, we present a case of acute myeloid leukaemia in a young woman exhibiting genital ulcerations and gingival erosions.

    Pubmed
  • High volume of polysorbate-containing (Tween® 80) solutions induces false-positive results in intradermal test.

    J Eur Acad Dermatol Venereol. 2018;32(11): 1972-1976

    Wagner N, Podda M

    BACKGROUND: Intradermal test is used to detect causative allergens in IgE-mediated hypersensitivity. The surfactant polysorbate 80 can be added to intradermal test solutions to more reliably dissolve the allergen and ensure a constant bioavailability of the injected allergen. Polysorbate 80 has, however, some histamine-releasing properties which could blur the difference to the histamine-induced wheal. Routinely serving as a control.

    OBJECTIVE: Allergen-free polysorbate 80 containing (0.005%) test solutions were therefore systematically tested at different injection volumes to see whether polysorbate can falsify skin reactions and if yes whether conditions can be identified to avoid this.

    METHODS: In a partly blinded study, 30 patients were tested intracutaneously at the back: each received at three separate sites 0.05 mL of polysorbate-containing solvent, 0.02 mL polysorbate-containing solvent as well as 0.02 mL polysorbate-free solvent. After 15 min, wheal and erythema were documented and planimetrically quantified.

    RESULTS: Unexpectedly 23 of 30 (77%) patients showed false-positive test reactions to the volume of 0.05 mL of the polysorbate-containing solvent whereas the polysorbate-containing solvent with 0.02 mL and the polysorbate-free solvent with 0.02 mL injection volume had no reinforcing effect on skin test reaction.

    CONCLUSIONS: Different volumes of polysorbate-containing solutions, all recommended by manufacturers for intradermal tests, may significantly influence test results. The study shows that a polysorbate 80 used at 0.005% in solvents for intradermal test to provide a better bioavailability of allergens produces false-positive reactivity in a surprising and a hitherto unknown 77% if the 0.05 mL volume is injected. It is, therefore, mandatory to strictly adhere to an intradermal test volume of 0.02 mL as only then falsifying effects of the polysorbate additive are avoided, and comparable test results are ensured.

    Pubmed
  • The involvement of Toll-like receptor 9 in the pathogenesis of erosive autoimmune arthritis.

    J Cell Mol Med. 2018;22(9): 4399-4409

    Fischer A, Abdollahi-Roodsaz S, Böhm C, Niederreiter B, Meyer B, Yau ACY, Lönnblom E, Joosten LAB, Koenders M, Lehmann CHK, Dudziak D, Krönke G, Holmdahl R, Steiner G

    Endogenous nucleic acids and their receptors may be involved in the initiation of systemic autoimmune diseases including rheumatoid arthritis (RA). As the role of the DNA sensing Toll-like receptor (TLR) 9 in RA is unclear, we aimed to investigate its involvement in the pathogenesis of autoimmune arthritis using three different experimental models of RA. The data obtained revealed involvement of TLR9 in the T cell-dependent phase of inflammatory arthritis. In rats with pristane-induced arthritis (PIA), TLR9 inhibition before disease onset reduced arthritis significantly and almost completely abolished bone erosion. Accordingly, serum levels of IL-6, α-1-acid-glycoprotein and rheumatoid factor were reduced. Moreover, in TLR9-/- mice, streptococcal cell wall (SCW)-induced arthritis was reduced in the T cell-dependent phase, whereas T cell-independent serum-transfer arthritis was not affected. Remarkably, while TLR7 expression did not change during in vitro osteoclastogenesis, TLR9 expression was higher in precursor cells than in mature osteoclasts and partial inhibition of osteoclastogenesis was achieved only by the TLR9 antagonist. These results demonstrate a pivotal role for TLR9 in the T cell-dependent phases of inflammatory arthritis and additionally suggest some role during osteoclastogenesis. Hence, endogenous DNA seems to be crucially involved in the pathophysiology of inflammatory autoimmune arthritis.

    Pubmed
  • Patterns of chronic hand eczema: a semantic map analysis of the CARPE registry data.

    Br J Dermatol. 2018;178(1): 229-237

    Cazzaniga S, Apfelbacher C, Diepgen T, Ofenloch RF, Weisshaar E, Molin S, Bauer A, Mahler V, Elsner P, Schmitt J, Ballmer-Weber BK, Spring P, Naldi L, Borradori L, Simon D, CARPE study groups of Germany and Switzerland

    BACKGROUND: Hand eczema has a high incidence and prevalence and has a negative impact on both physical and psychological well-being, with the risk of persistence as a chronic condition. Epidemiological studies on hand eczema provided mainly descriptive and risk analyses, but pattern analyses of variables associated with hand eczema, in particular chronic hand eczema, have not been explored to date.

    OBJECTIVES: To investigate and display the semantics of associations between variables of hand eczema obtained from the Swiss and German registries of chronic hand eczema (CARPE) to dissect patterns and novel links.

    METHODS: This was a cross-sectional study on selected variables from the CARPE registries. Associations between variables were analysed by means of an autoassociative system. A semantic connectivity map was generated by using a maximum spanning tree algorithm.

    RESULTS: Baseline datasets of 1466 patients with chronic hand eczema (Switzerland: 199; Germany: 1267) were analysed. Occupational exposure had the highest impact in the total and country cohorts. We identified two areas of exposure linked to corresponding occupations that clearly demarcated the sexes.

    CONCLUSIONS: This study, using semantic connectivity as a novel method of data analysis, reveals the complexity of features characterizing chronic hand eczema as well as novel association patterns that deserve further investigation.

    Pubmed
  • Factors increasing the risk for a severe reaction in anaphylaxis: An analysis of data from The European Anaphylaxis Registry.

    Allergy. 2018;73(6): 1322-1330

    Worm M, Francuzik W, Renaudin JM, Bilo MB, Cardona V, Scherer Hofmeier K, Köhli A, Bauer A, Christoff G, Cichocka-Jarosz E, Hawranek T, Hourihane JO', Lange L, Mahler V, Muraro A, Papadopoulos NG, Pföhler C, Poziomkowska-Gęsicka I, Ruëff F, Spindler T, Treudler R, Fernandez-Rivas M, Dölle S

    BACKGROUND: Preventive measures to decrease the frequency and intensity of anaphylactic events are essential to provide optimal care for allergic patients. Aggravating factors may trigger or increase the severity of anaphylaxis and therefore need to be recognized and avoided.

    OBJECTIVE: To identify and prioritize factors associated with an increased risk of developing severe anaphylaxis.

    METHODS: Data from the Anaphylaxis Registry (122 centers in 11 European countries) were used in logistic regression models considering existing severity grading systems, elicitors, and symptoms to identify the relative risk of factors on the severity of anaphylaxis.

    RESULTS: We identified higher age and concomitant mastocytosis (OR: 3.1, CI: 2.6-3.7) as the most important predictors for an increased risk of severe anaphylaxis. Vigorous physical exercise (OR: 1.5, CI: 1.3-1.7), male sex (OR: 1.2, CI: 1.1-1.3), and psychological burden (OR: 1.4, CI: 1.2-1.6) were more often associated with severe reactions. Additionally, intake of beta-blockers (OR: 1.9, CI: 1.5-2.2) and ACE-I (OR: 1.28, CI: 1.05, 1.51) in temporal proximity to allergen exposition was identified as an important factor in logistic regression analysis.

    CONCLUSION: Our data suggest it may be possible to identify patients who require intensified preventive measures due to their relatively higher risk for severe anaphylaxis by considering endogenous and exogenous factors.

    Pubmed
  • Prospective study in bullous pemphigoid: association of high serum anti-BP180 IgG levels with increased mortality and reduced Karnofsky score.

    Br J Dermatol. 2018;179(4): 918-924

    Holtsche MM, Goletz S, van Beek N, Zillikens D, Benoit S, Harman K, Walton S, English J, Sticherling M, Chapman A, Levell NJ, Groves R, Williams HC, König IR, Schmidt E, members of the BLISTER Study Group , Günther C, Luger T, Steinbrink K, Wozel G, Akhras V, Alkali A, Anstey A, Antony F, Azam A, Aziz O, Blackford S, Bower C, Buckley D, Charles-Holmes R, Davies K, Dunnill G, Gibbs S, Graham R, Hampton P, Hussain K, Ilchyshyn A, Kaushal G, Layton A, Lewis V, Malhomme H, Nasr I, Ormerod A, Rallan D, Ravenscroft J, Salvary I, Seukeran D, Shipley D, Sterling J, Velangi S, Venning V, Veysey E, Wachsmuth R, Wahie S, Wright A

    BACKGROUND: Bullous pemphigoid (BP) is a subepidermal blistering disease characterized by autoantibodies against the two hemidesmosomal proteins, BP180 (type XVII collagen) and BP230. The multicentre prospective BLISTER (Bullous Pemphigoid Steroids and Tetracyclines) trial randomized 253 patients with BP to compare the benefits and harms between initial treatment with doxycycline or prednisolone.

    OBJECTIVES: To analyse distinct autoantibody profiles for the prediction of the disease course in a well-characterized cohort of BP sera.

    METHODS: One hundred and forty-three patients of the BLISTER trial consented to participate in this serological study. Sera taken at baseline were analysed by (i) indirect immunofluorescence, (ii) anti-BP180 NC16A (16th noncollagenous domain) and anti-BP230 enzyme-linked immunosorbent assay and (iii) immunoblotting with various substrates. Results were then linked with clinical parameters including age, Karnofsky score, number of blisters, related adverse events and mortality.

    RESULTS: Disease activity correlated with immunoglobulin (Ig)G anti-BP180 levels but not with levels of anti-BP230 IgG and anti-BP180 IgE. High levels of both anti-BP180 IgG and anti-BP230 IgG were associated with a low Karnofsky score. The presence of anti-BP230 IgG was more frequent in older patients. Those with higher total IgE serum levels suffered from fewer adverse events. Higher IgG anti-BP180 levels were associated with an increased 1-year mortality rate.

    CONCLUSIONS: Analysis of the autoantibody profile is not only of diagnostic relevance but may also be helpful in predicting the course of the disease.

    Pubmed
  • Simultaneous quantification of bone erosions and enthesiophytes in the joints of patients with psoriasis or psoriatic arthritis - effects of age and disease duration.

    Arthritis Res Ther. 2018;20(1):

    Simon D, Kleyer A, Faustini F, Englbrecht M, Haschka J, Berlin A, Kraus S, Hueber AJ, Kocijan R, Sticherling M, Rech J, Schett G

    BACKGROUND: Comprehensive simultaneous quantification of bone erosion and enthesiophytes in the joints of patients with psoriatic arthritis (PsA) has not been performed. Herein, we aimed to compare the extent of bone erosion and enthesiophytes in patients with PsA, psoriasis (PSO) and healthy controls, assess the influence of age and disease duration on the development of erosions and enthesiophytes and define their impact on physical function.

    METHODS: Patients with PsA or with PSO and controls were analysed by high-resolution peripheral quantitative computed tomography (HR-pQCT). The extent of bone erosions and enthesiophytes was assessed and plotted according to different categories of age, duration of PSO and duration of PsA, respectively. In addition, demographic and disease-specific data, including physical function (health assessment questionnaire) were collected.

    RESULTS: A total of 203 patients were analysed; 101 had PsA, 55 had PSO and 47 were healthy individuals. Patients with PsA had significantly more and larger erosions (p = 0.002/p = 0.003) and enthesiophytes (p < 0.001) compared to patients with PSO and healthy controls. Patients with PSO and healthy controls did not differ in erosions, while enthesiophytes were more frequent in patients with PSO than in healthy controls. Bone erosions, but not enthesiophytes, showed strong age-dependency in all three groups. In contrast, enthesiophytes were mostly influenced by the duration of PSO and PsA and, in contrast to bone erosions, were associated with poorer physical function.

    CONCLUSIONS: Bone erosions are age-dependent, enhanced in PsA and increase with disease duration. Enthesiophytes are less age-dependent, are enhanced in both PSO and PsA and strongly influenced by disease duration. Enthesiophytes impact physical function in PsA suggesting the need for early therapeutic interventions to prevent damage.

    Pubmed
  • The p.Arg435His Variation of IgG3 With High Affinity to FcRn Is Associated With Susceptibility for Pemphigus Vulgaris-Analysis of Four Different Ethnic Cohorts.

    Front Immunol. 2018;9():

    Recke A, Konitzer S, Lemcke S, Freitag M, Sommer NM, Abdelhady M, Amoli MM, Benoit S, El-Chennawy F, Eldarouti M, Eming R, Gläser R, Günther C, Hadaschik E, Homey B, Lieb W, Peitsch WK, Pföhler C, Robati RM, Saeedi M, Sárdy M, Sticherling M, Uzun S, Worm M, Zillikens D, Ibrahim S, Vidarsson G, Schmidt E, German AIBD Genetic Study Group , Kreuter A, Zouboulis CC, Däschlein G, Steinbrink K, Kunz M, Hunzelmann N, Goetze S

    IgG3 is the IgG subclass with the strongest effector functions among all four IgG subclasses and the highest degree of allelic variability among all constant immunoglobulin genes. Due to its genetic position, IgG3 is often the first isotype an antibody switches to before IgG1 or IgG4. Compared with the other IgG subclasses, it has a reduced half-life which is probably connected to a decreased affinity to the neonatal Fc receptor (FcRn). However, a few allelic variants harbor an amino acid replacement of His435 to Arg that reverts the half-life of the resulting IgG3 to the same level as the other IgG subclasses. Because of its functional impact, we hypothesized that the p.Arg435His variation could be associated with susceptibility to autoantibody-mediated diseases like pemphigus vulgaris (PV) and bullous pemphigoid (BP). Using a set of samples from German, Turkish, Egyptian, and Iranian patients and controls, we were able to demonstrate a genetic association of the p.Arg435His variation with PV risk, but not with BP risk. Our results suggest a hitherto unknown role for the function of IgG3 in the pathogenesis of PV.

    Pubmed
  • HIV Activates the Tyrosine Kinase Hck to Secrete ADAM Protease-Containing Extracellular Vesicles.

    EBioMedicine. 2018;28(): 151-161

    Lee JH, Ostalecki C, Zhao Z, Kesti T, Bruns H, Simon B, Harrer T, Saksela K, Baur AS

    Pubmed
  • Whither systems medicine?

    Exp Mol Med. 2018;50(3):

    Apweiler R, Beissbarth T, Berthold MR, Blüthgen N, Burmeister Y, Dammann O, Deutsch A, Feuerhake F, Franke A, Hasenauer J, Hoffmann S, Höfer T, Jansen PL, Kaderali L, Klingmüller U, Koch I, Kohlbacher O, Kuepfer L, Lammert F, Maier D, Pfeifer N, Radde N, Rehm M, Roeder I, Saez-Rodriguez J, Sax U, Schmeck B, Schuppert A, Seilheimer B, Theis FJ, Vera J, Wolkenhauer O

    New technologies to generate, store and retrieve medical and research data are inducing a rapid change in clinical and translational research and health care. Systems medicine is the interdisciplinary approach wherein physicians and clinical investigators team up with experts from biology, biostatistics, informatics, mathematics and computational modeling to develop methods to use new and stored data to the benefit of the patient. We here provide a critical assessment of the opportunities and challenges arising out of systems approaches in medicine and from this provide a definition of what systems medicine entails. Based on our analysis of current developments in medicine and healthcare and associated research needs, we emphasize the role of systems medicine as a multilevel and multidisciplinary methodological framework for informed data acquisition and interdisciplinary data analysis to extract previously inaccessible knowledge for the benefit of patients.

    Pubmed
  • MiR-205-5p and miR-342-3p cooperate in the repression of the E2F1 transcription factor in the context of anticancer chemotherapy resistance.

    Theranostics. 2018;8(4): 1106-1120

    Lai X, Gupta SK, Schmitz U, Marquardt S, Knoll S, Spitschak A, Wolkenhauer O, Pützer BM, Vera J

    High rates of lethal outcome in tumour metastasis are associated with the acquisition of invasiveness and chemoresistance. Several clinical studies indicate that E2F1 overexpression across high-grade tumours culminates in unfavourable prognosis and chemoresistance in patients. Thus, fine-tuning the expression of E2F1 could be a promising approach for treating patients showing chemoresistance. Methods: We integrated bioinformatics, structural and kinetic modelling, and experiments to study cooperative regulation of E2F1 by microRNA (miRNA) pairs in the context of anticancer chemotherapy resistance. Results: We showed that an enhanced E2F1 repression efficiency can be achieved in chemoresistant tumour cells through two cooperating miRNAs. Sequence and structural information were used to identify potential miRNA pairs that can form tertiary structures with E2F1 mRNA. We then employed molecular dynamics simulations to show that among the identified triplexes, miR-205-5p and miR-342-3p can form the most stable triplex with E2F1 mRNA. A mathematical model simulating the E2F1 regulation by the cooperative miRNAs predicted enhanced E2F1 repression, a feature that was verified by in vitro experiments. Finally, we integrated this cooperative miRNA regulation into a more comprehensive network to account for E2F1-related chemoresistance in tumour cells. The network model simulations and experimental data indicate the ability of enhanced expression of both miR-205-5p and miR-342-3p to decrease tumour chemoresistance by cooperatively repressing E2F1. Conclusions: Our results suggest that pairs of cooperating miRNAs could be used as potential RNA therapeutics to reduce E2F1-related chemoresistance.

    Pubmed
  • DISEASE INTERCEPTION IN PSORIASIS PATIENTS WITH SUBCLINICAL JOINT

    INFLAMMATION BY INTERLEUKIN 17 INHIBITION WITH SECUKINUMAB - DATA FROM A

    PROSPECTIVE OPEN LABEL STUDY

    Ann Rheum Dis. 2018;77(): 199-199

    Kamoylafka E, Oliveira ID, Linz C, Lerchen V, Englbrecht M, Simon D, Sticherling M, Rech J, Kleyer A, Schett G, Hueber AJ

    Pubmed
  • Ex vivo expanded NK Cells from Melanoma Patients receive their Migration

    in a 3D Model and lyse autologous Melanoma Cells

    J Dtsch Dermatol Ges. 2018;16(): 52-52

    Rossner S, Czerwinski T, Mark C, Gross S, Karg M, Bosch J, Schuler-Thurner B, Fabry B, Schuler G, Bosch-Voskens C

    Pubmed
  • TILGen: A Program to Investigate Immune Targets in Breast Cancer Patients - First Results on the Influence of Tumor-Infiltrating Lymphocytes

    Breast Care (Basel). 2018;13(1): 8-14

    Wuerfel F, Erber R, Huebner H, Hein A, Lux MP, Jud S, Kremer A, Kranich H, Mackensen A, Haeberle L, Hack CC, Rauh C, Wunderle M, Gass P, Rabizadeh S, Brandl AL, Langemann H, Volz B, Nabieva N, Schulz-Wendtland R, Dudziak D, Beckmann MW, Hartmann A, Fasching PA, Ruebner M

    Background: Despite advancements in the treatment of primary and metastatic breast cancer, many patients lack a durable response to these treatments. Patients with triplenegative breast cancer (TNBC) and human epidermal growth factor receptor 2(HER2)-positive breast cancer who do not have a pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) have a very poor prognosis. Tumor-infiltrating lymphocytes (TILs) have been identified as a predictive marker for pCR after NACT in TNBC and HER2-positive breast cancer. These patient populations could also be suitable for novel treatment strategies including neoepitope-based therapies. This work analyses the effect of TILs on the pCR in neoadjuvantly treated patients in the TILGen study and presents the procedures aimed at establishing neoepitope-based therapies in this study. Methods: Neoadjuvantly treated HER2positive and TNBC patients were eligible for the presented analysis concerning the association between TILs and pCR. A total of 146 patients could be identified within the TILGen study. TILs were evaluated as percentage of stromal tumor tissue in core biopsies at primary diagnosis. The phenotype 'lymphocyte-predominant breast cancer' (LPBC) was associated with pCR by logistic regression adjusted for estrogen receptor status, progesterone receptor status, HER2 status, age at diagnosis, and grading. Results: LPBC was seen in 24 (16.4%) patients. In this patient group, 66.7% achieved a pCR, while the pCR rate was 32.8% in patients with a low TIL count. The adjusted odds ratio was 6.60 (95% confidence interval 2.02-21.56; p < 0.01). Conclusion: TILs are a strong predictor of pCR in TNBC and HER2-positive breast cancer patients. Implications for the use of this information including the effect on prognosis might help to identify patients most likely to benefit from a neoepitope-based therapy approach. (C) 2018 S. Karger GmbH, Freiburg

    Pubmed
  • The Generation of CAR-Transfected Natural Killer T Cells for the Immunotherapy of Melanoma.

    Int J Mol Sci. 2018;19(8):

    Simon B, Wiesinger M, März J, Wistuba-Hamprecht K, Weide B, Schuler-Thurner B, Schuler G, Dörrie J, Uslu U

    Natural killer T (NKT) cells represent a cell subpopulation that combines characteristics of natural killer (NK) cells and T cells. Through their endogenous T-cell receptors (TCRs), they reveal a pronounced intrinsic anti-tumor activity. Thus, a NKT cell transfected with a chimeric antigen receptor (CAR), which recognizes a tumor-specific surface antigen, could attack tumor cells antigen-specifically via the CAR and additionally through its endogenous TCR. NKT cells were isolated from peripheral blood mononuclear cells (PBMCs), expanded, and electroporated with mRNA encoding a chondroitin sulfate proteoglycan 4 (CSPG4)-specific CAR. The CAR expression on NKT cells and their in vitro functionality were analyzed. A transfection efficiency of more than 80% was achieved. Upon stimulation with melanoma cells, CAR-NKT cells produced cytokines antigen-specifically. Compared with conventional CAR-T cells, cytokine secretion of CAR-NKT cells was generally lower. Specific cytotoxicity, however, was similar with CAR-NKT cells showing a trend towards improved cytotoxicity. Additionally, CAR-NKT cells could kill target cells through their endogenous TCRs. In summary, it is feasible to generate CAR-NKT cells by using mRNA electroporation. Their CAR-mediated cytotoxicity is at least equal to that of conventional CAR-T cells, while their intrinsic cytotoxic activity is maintained. Thus, CAR-NKT cells may represent a valuable alternative to conventional CAR-T cells for cancer immunotherapy.

    Pubmed
  • Disease Interception in Psoriasis Patients with Subclinical Joint

    Inflammation By Interleukin 17 Inhibition with Secukinumab - Data from a

    Prospective Open Label Study

    Arthritis Rheumatol. 2018;70():

    Kampylafka E, Oliveira I, Linz C, Lerchen V, Englbrecht M, Simon D, Sticherling M, Rech J, Kleyer A, Schett G, Hueber AJ

    Pubmed
  • Transcriptional Profiling of Ligand Expression in Cell Specific Populations of the Adult Mouse Forebrain That Regulates Neurogenesis.

    Front Neurosci. 2018;12():

    Azim K, Akkermann R, Cantone M, Vera J, Jadasz JJ, Küry P

    In the adult central nervous system (CNS), the subventricular zone (SVZ) of the forebrain is the largest and most active source of neural stem cells (NSCs) that generates mainly neurons and few glial cells lifelong. A large body of evidence has shed light on the distinct families of signaling ligands (i.e., morphogens, growth factors, secreted molecules that alter signaling pathways) in regulating NSC biology. However, most of the research has focused on the mRNA expression of individual or few signaling ligands and their pathway components in specific cell types of the CNS in the context of neurogenesis. A single unifying study that underlines the expression of such molecules comprehensively in different cell types in spatial contexts has not yet been reported. By using whole genome transcriptome datasets of individual purified cell specific populations of the adult CNS, the SVZ niche, NSCs, glial cells, choroid plexus, and performing a bioinformatic meta-analysis of signaling ligands, their expression in the forebrain was uncovered. Therein, we report that a large plethora of ligands are abundantly expressed in the SVZ niche, largely from the vasculature than from other sources that may regulate neurogenesis. Intriguingly, this sort of analysis revealed a number of ligands with unknown functions in neurogenesis contexts that warrants further investigations. This study therefore serves as a framework for investigators in the field for understanding the expression patterns of signaling ligands and pathways regulating neurogenesis.

    Pubmed
  • Editorial: Foundations of Theoretical Approaches in Systems Biology.

    Front Genet. 2018;9():

    Marin-Sanguino A, Vera J, Alves R

    Pubmed
  • Select Clr-g Expression on Activated Dendritic Cells Facilitates Cognate Interaction with a Minor Subset of Splenic NK Cells Expressing the Inhibitory Nkrp1g Receptor.

    J Immunol. 2018;200(3): 983-996

    Friede ME, Leibelt S, Dudziak D, Steinle A

    Natural killer gene complex-encoded immunomodulatory C-type lectin-like receptors include members of the NKRP1 and C-type lectin-like 2 (CLEC2) gene families, which constitute genetically linked receptor-ligand pairs and are thought to allow for NK cell-mediated immunosurveillance of stressed or infected tissues. The mouse C-type lectin-like receptor Nkrp1g was previously shown to form several receptor-ligand pairs with the CLEC2 proteins Clr-d, Clr-f, and Clr-g, respectively. However, the physiological expression of Nkrp1g and its CLEC2 ligands as well as their functional relevance remained poorly understood. Recently, we demonstrated a gut-restricted expression of Clr-f on intestinal epithelial cells that is spatially matched by Nkrp1g on subsets of intraepithelial lymphocytes. In this study, we investigated expression and ligand interaction of Nkrp1g in the splenic compartment, and found an exclusive expression on a small subset of NK cells that upregulates Nkrp1g after cytokine exposure. Whereas transcripts of Clr-d and Clr-f are virtually absent from the spleen, Clr-g transcripts were abundantly detected throughout different leukocyte populations and hematopoietic cell lines. However, a newly generated anti-Clr-g mAb detected only residual Clr-g surface expression on splenic monocytes, whereas many hematopoietic cell lines brightly display Clr-g. Clr-g surface expression was strongly upregulated on splenic CD8α+ conventional dendritic cells (DCs) and plasmacytoid DCs upon TLR-mediated activation and detectable by Nkrp1g, which dampens NK cell effector functions upon Clr-g engagement. Hence, different to the intestinal tract, in the spleen, Nkrp1g is selectively expressed by a subset of NK cells, thereby potentially allowing for an inhibitory engagement with Clr-g-expressing activated DCs during immune responses.

    Pubmed
  • Bacterial Adherence and Dwelling Probability: Two Drivers of Early Alveolar Infection by Streptococcus pneumoniae Identified in Multi-Level Mathematical Modeling.

    Front Cell Infect Microbiol. 2018;8():

    Santos G, Lai X, Eberhardt M, Vera J

    Pneumococcal infection is the most frequent cause of pneumonia, and one of the most prevalent diseases worldwide. The population groups at high risk of death from bacterial pneumonia are infants, elderly and immunosuppressed people. These groups are more vulnerable because they have immature or impaired immune systems, the efficacy of their response to vaccines is lower, and antibiotic treatment often does not take place until the inflammatory response triggered is already overwhelming. The immune response to bacterial lung infections involves dynamic interactions between several types of cells whose activation is driven by intracellular molecular networks. A feasible approach to the integration of knowledge and data linking tissue, cellular and intracellular events and the construction of hypotheses in this area is the use of mathematical modeling. For this paper, we used a multi-level computational model to analyse the role of cellular and molecular interactions during the first 10 h after alveolar invasion of Streptococcus pneumoniae bacteria. By "multi-level" we mean that we simulated the interplay between different temporal and spatial scales in a single computational model. In this instance, we included the intracellular scale of processes driving lung epithelial cell activation together with the scale of cell-to-cell interactions at the alveolar tissue. In our analysis, we combined systematic model simulations with logistic regression analysis and decision trees to find genotypic-phenotypic signatures that explain differences in bacteria strain infectivity. According to our simulations, pneumococci benefit from a high dwelling probability and a high proliferation rate during the first stages of infection. In addition to this, the model predicts that during the very early phases of infection the bacterial capsule could be an impediment to the establishment of the alveolar infection because it impairs bacterial colonization.

    Pubmed
  • Systemic therapy with calcitonin has positive clinical effects on systemic sclerosis in patients with cutaneous manifestations.

    Eur J Dermatol. 2018;28(3): 364-369

    Uslu U, Streiff L, Sticherling M

    BACKGROUND: Calcitonin gene-related peptide (CGRP) is a vasodilatory neuropeptide that plays an important role in the blood vessels of heart and peripheral circulation, a lack of which may cause vasculopathies.

    OBJECTIVE: In this study, the clinical course of disease, as well as the efficacy, side effects, and patient satisfaction of systemic calcitonin therapy in patients with systemic sclerosis (SSc), was evaluated.

    METHODS: Forty-nine patients received repetitive intravenous calcitonin infusions as first-line treatment. The average number of cycles was 12.2 ± 10.3 over a period of 30 months (each cycle: 100 U/day over 10 days). Clinical examinations, laboratory tests, and organ imaging were performed before the start of, and at regular intervals during therapy in order to evaluate organ manifestations and the clinical course of the disease. In addition, patients' own experiences of the therapy, side effects, and therapy success were evaluated with standardized questionnaires.

    RESULTS: Over the course of the treatment, seven patients experienced improvements in their condition with a considerable reduction in digital ulceration and improved movement (14.3%). Pulmonary function in seven patients improved during the therapy (14.3%). With regards to side effects, nausea (41.7%), headaches (33.3%), fluctuations in blood pressure (29.2%), and flushing (29.2%) were observed. Overall, 45.8% of patients evaluated the therapy as good and 58.3% would undergo further courses of therapy with calcitonin.

    CONCLUSIONS: Systemic calcitonin treatment seems to have positive clinical effects on SSc and contributes to relieving symptoms, especially in patients with cutaneous manifestations. No severe side effects were reported during this study.

    Pubmed
  • Monocyte-Derived signals activate human natural Killer cells in response to Leishmania Parasites

    Front Immunol. 2018;9():

    Messlinger H, Sebald H, Heger L, Dudziak D, Bogdan C, Schleicher U

    Activated natural killer (NK) cells release interferon (IFN)-gamma, which is crucial for the control of intracellular pathogens such as Leishmania. In contrast to experimental murine leishmaniasis, the human NK cell response to Leishmania is still poorly characterized. Here, we investigated the interaction of human blood NK cells with promastigotes of different Leishmania species (Leishmania major, Leishmania mexicana, Leishmania infantum, and Leishmania donovani). When peripheral blood mononuclear cells or purified NK cells and monocytes (all derived from healthy blood donors from Germany without a history of leishmaniasis) were exposed to promastigotes, NK cells showed increased surface expression of the activation marker CD69. The extent of this effect varied depending on the Leishmania species; differences between dermotropic and viscerotropic L. infantum strains were not observed. Upregulation of CD69 required direct contact between monocytes and Leishmania and was partly inhibitable by anti-interleukin (IL)-18. Unexpectedly, IL-18 was undetectable in most of the supernatants (SNs) of monocyte/parasite cocultures. Confocal fluorescence microscopy of non-permeabilized cells revealed that Leishmania-infected monocytes trans-presented IL-18 to NK cells. Native, but not heat-treated SNs of monocyte/Leishmania cocultures also induced CD69 on NK cells, indicating the involvement of a soluble heat-labile factor other than IL-18. A role for the NK cell-activating cytokines IL-1 beta, IL-2, IL-12, IL-15, IL-21, and IFN-alpha/beta was excluded. The increase of CD69 was not paralleled by NK cell IFN-gamma production or enhanced cytotoxicity. However, prior exposure of NK cells to Leishmania parasites synergistically increased their IFN-gamma release in response to IL-12, which was dependent on endogenous IL-18. CD1c(+) dendritic cells were identified as possible source of Leishmania-induced IL-12. Finally, we observed that direct contact between Leishmania and NK cells reduced the expression of CD56 mRNA and protein on NK cells. We conclude that Leishmania activate NK cells via trans-presentation of IL-18 by monocytes and by a monocyte-derived soluble factor. IL-12 is needed to elicit the IFN-gamma-response of NK cells, which is likely to be an important component of the innate control of the parasite.

    Pubmed
  • Extracellular Vesicles in the Plasma of Melanoma Patients under-press

    beta Catenin in Tumor Cells by using miRNA-34a

    J Dtsch Dermatol Ges. 2018;16(): 26-26

    Baur A, Lee JH, Dindorf J, Eberhardt M, Lai X, Ostalecki C, Koliha N, Wild S, Gross S, Schuler G, Vera-Gonzales J

    Pubmed
  • Tumor-suppressing Plasma extracellular Vesicles (pEV) from Melanoma

    Patients are secreted by Liver Cells and PBMC

    J Dtsch Dermatol Ges. 2018;16(): 26-26

    Baur A, Lee JH, Eberhardt M, Blume K, Schuler G, Vera-Gonzales J

    Pubmed
  • Anti-PD-1 Therapy in SUFU mutant Patients with Gorlin-Goltz Syndrome

    J Dtsch Dermatol Ges. 2018;16(): 72-73

    Moreira A, Kirchberger MC, Toussaint F, Erdmann M, Schuler G, Heinzerling L

    Pubmed
  • S2k-Leitlinie zum Gebrauch von Präparationen zur lokalen Anwendung auf der Haut (Topika).

    J Dtsch Dermatol Ges. 2018;16(3): 376-392

    Wohlrab J, Staubach P, Augustin M, Eisert L, Hünerbein A, Nast A, Reimann H, Strömer K, Mahler V

    Diese Leitlinie richtet sich an Assistenz- und Fachärzte der Dermatologie sowie an Kostenträger und politische Entscheidungsgremien. Die Leitlinie wurde im formellen Konsensusverfahren (S2k) von Dermatologen unter Einbindung von Apothekern erstellt. Die Leitlinie stellt allgemeine Aspekte der Pharmakokinetik sowie der regulatorischen Begrifflichkeiten dar. Es werden Empfehlungen zur Indikation von Magistralrezepturen sowie deren Qualitätssicherung gegeben. Die Bedeutung der galenischen Grundlagen und die Problematik bei einer Substitution gegeneinander verschiedener Grundlagen werden dargestellt. Die Leitlinie umfasst Kriterien zur Auswahl einer adäquaten Grundlage sowie spezifische Aspekte zur Therapieplanung. Die Leitlinie gibt Empfehlungen zum Management bei Unverträglichkeiten gegenüber Bestandteilen der Grundlagen oder Hilfsstoffe.

    Pubmed
  • Mastozytose - Pathogenese, Klinik und Therapie.

    J Dtsch Dermatol Ges. 2018;16(1): 42-59

    Wagner N, Staubach P

    The term mastocytosis designates a group of rare disorders characterized by typical skin lesions, frequently associated episodes of anaphylaxis, and clinical symptoms related to the release of various mediators. Dermatologists/allergists are frequently the first to establish the diagnosis. The condition is based on clonal mast cell proliferation, usually in the skin or bone marrow and only rarely in the gastrointestinal tract or other tissues. In general, mastocytosis has a good prognosis in terms of life expectancy. Rare variants - including mast cell leukemia, aggressive mastocytosis, and the exceedingly rare mast cell sarcoma - require cytoreductive therapy. In cases associated with hematological neoplasms, the prognosis depends on the underlying hematologic disorder.

    Pubmed
  • Systemische Therapien des Ulcus cruris.

    J Dtsch Dermatol Ges. 2018;16(7): 873-892

    Dissemond J, Erfurt-Berge C, Goerge T, Kröger K, Funke-Lorenz C, Reich-Schupke S

    Successful management of patients with leg ulcers requires identification of the underlying etiology, with subsequent initiation of causal treatment, if feasible. Supplementary measures of first choice include stage-adjusted wound treatment, usually combined with compression therapy. The significance of systemic drugs has been the subject of controversial debate, depending on the underlying cause of the condition. The present review article is therefore meant to highlight current aspects of systemic drug therapies for the treatment of leg ulcers associated with chronic venous insufficiency, peripheral arterial disease, livedoid vasculopathy, vasculitis, necrobiosis lipoidica, calciphylaxis and pyoderma gangrenosum.

    In summary, the majority of therapeutic options presented herein are used off-label. While systemic drugs are promising options for the more common types of wounds such as venous, mixed or arterial leg ulcers, they do not represent the current standard of treatment. By contrast, systemic agents play a key role in the management of many of the other disorders presented herein. These agents primarily include immunomodulatory and rheological drugs used to expedite wound healing.

    Pubmed
  • Model-Based Phenotypic Signatures Governing the Dynamics of the Stem and Semi-differentiated Cell Populations in Dysplastic Colonic Crypts.

    Bull Math Biol. 2018;80(2): 360-384

    Nikolov S, Santos G, Wolkenhauer O, Vera J

    Mathematical modeling of cell differentiated in colonic crypts can contribute to a better understanding of basic mechanisms underlying colonic tissue organization, but also its deregulation during carcinogenesis and tumor progression. Here, we combined bifurcation analysis to assess the effect that time delay has in the complex interplay of stem cells and semi-differentiated cells at the niche of colonic crypts, and systematic model perturbation and simulation to find model-based phenotypes linked to cancer progression. The models suggest that stem cell and semi-differentiated cell population dynamics in colonic crypts can display chaotic behavior. In addition, we found that clinical profiling of colorectal cancer correlates with the in silico phenotypes proposed by the mathematical model. Further, potential therapeutic targets for chemotherapy resistant phenotypes are proposed, which in any case will require experimental validation.

    Pubmed
  • Can Gamification Contribute to Computer Modeling-Driven Biomedical Research?

    Front Physiol. 2018;9():

    Vera J, Santos G

    Pubmed
  • Antigen targeting of Fc receptors induces strong T cell responses in

    vivo independent of ITAM signaling but dependent on dendritic cell

    subset

    Eur J Immunol. 2018;48(): 24-25

    Lehmann C, Baranska A, Heidkamp G, Seeling M, Soulat D, Krug A, Ravetch J, Leusen J, Nimmerjahn F, Dudziak D

    Pubmed
  • [Type IV contact allergies in the food processing industry: an update].

    Hautarzt. 2018;69(6): 443-448

    Bauer A, Schubert S, Geier J, Mahler V

    BACKGROUND: The food sector is one of the high-risk areas for occupational irritative and allergic contact eczema.

    OBJECTIVES: The present work provides an overview of the main allergens as well as sensitization frequencies and risk in various food industry occupations.

    METHODS: The literature on type IV sensitization in the food sector is summarized.

    RESULTS: The relative risk of developing a work-related eczema in food processing is increased by more than 3 times. The comparison group was calculated on the basis of the proportion of documented cases in the IVDK (Informationsverbund Dermatologischer Kliniken) network per 100,000 working persons in relation to the average of the years 2005 and 2010. For this purpose, the average risk of all patients was set as reference to 1. Bakers, pastry chefs, cooks and meat and fish processors are mainly affected. In addition to irritant contact eczema, allergic contact eczema and protein contact dermatitis often occur. Leading haptens (main allergens) are rubber ingredients, but also disinfectants and compositae.

    CONCLUSION: Only a few contact allergens are responsible for the majority of job-relevant sensitizations in the food industry.

    Pubmed
  • Melanocytes as an emerging key player in niche regulation of limbal stem

    cells

    Invest Ophthalmol Vis Sci. 2018;59(9):

    Schlötzer-Schrehardt U, Polisetti N, Zenkel M, Naschberger E, Heger L, Dudziak D, Stuerzl M, Kruse FE

    Pubmed
  • Dynamic regulation and differential compartmentaliztion of C-type lectin

    receptors in the dendritic cell membrane

    Eur J Immunol. 2018;48(): 5-5

    Luehr J, Eissing N, Heger L, Lehmann C, Heidkamp G, Nimmerjahn F, Balint S, Sezgin E, Eggeling C, Dustin M, Dudziak D

    Pubmed
  • FV03 MEK Inhibitors improved the Survival of NRAS-mutated Melanoma

    Patients by using Checkpoint Inhibitors: Results of a retrospective,

    multicenter Analysis of 364 Patients

    J Dtsch Dermatol Ges. 2018;16(): 4-4

    Kirchberger MC, Ugurel S, Mangana J, Heppt M, Eigentler T, Berking C, Schadendorf D, Schuler G, Dummer R, Heinzerling L

    Pubmed
  • Characterization of Checkpoint Inhibitor-associated Diabetes mellitus -

    Experience in 12 Patients

    J Dtsch Dermatol Ges. 2018;16(): 15-16

    Satzger I, Momma M, Thoms KM, Eigentler T, Schultz E, Loquai C, Zimmer L, Heinzerling L, Kaehler K, Herbst R, Utikal J, Hassel J, Meier F, Pfoehler C, Ruini C, Gutzmer R

    Pubmed
  • Kutane's plasma-cell-rich Pseudolymphoma in histologically complete

    Response under combined Immunotherapy with Talimogene laherparepvec

    (TVEC) and Pembrolizumab

    J Dtsch Dermatol Ges. 2018;16(): 75-75

    Erdmann M, Sponagl F, Kiesewetter F, Schliep S

    Pubmed
  • Expression of Senescence Markers - Is Predictive for Immune Therapy with

    Checkpoint Inhibitors?

    J Dtsch Dermatol Ges. 2018;16(): 75-75

    Moreira A, Gross S, Kirchberger MC, Erdmann M, Schuler G, Heinzerling L

    Pubmed
  • Eosinophilic Fasciitis by Treatment with Checkpoint Inhibitors in

    metastatic Melanoma

    J Dtsch Dermatol Ges. 2018;16(): 76-76

    Toussaint F, Erdmann M, Moreira A, Kirchberger MC, Schuler G, Heinzerling L

    Pubmed
  • From relative to absolute treatment outcomes-Correlation of PASI 90 and

    PASI <= 2 in three clinical trials with secukinumab

    J Am Acad Dermatol. 2018;79(3): AB143-AB143

    Reich K, Bachhuber T, Melzer N, Sieder C, Sticherling M

    Pubmed
  • A matter of perspective: Imputation methods and their effects

    illustrated with the use of data from the PRIME study

    J Am Acad Dermatol. 2018;79(3): AB13-AB13

    Reich K, Bachhuber T, Melzer N, Sieder C, Sticherling M

    Pubmed
  • The Generation of CAR-transfected NKT Cells for the Immunotherapy of

    Melanoma

    J Dtsch Dermatol Ges. 2018;16(): 8-8

    Simon B, Wiesinger M, Marz J, Wistuba-Hamprecht K, Weide B, Schuler-Thurner B, Schuler G, Doerrie J, Uslu U

    Pubmed
  • Neuromuscular Side Effects of Immune Checkpoint Inhibitors

    J Dtsch Dermatol Ges. 2018;16(): 9-10

    Moreira A, Loquai C, Knauss S, Gutzmer R, Dimitriou F, Meier F, Heppt M, Mitzel-Rink H, Schuler G, Terheyden P, Thoms KM, Zimmer L, Dummer R, Pfoehler C, Heinzerling L

    Pubmed
  • Hyponatremia and Nephritis - Rare Side Effects of Checkpoint Inhibitors

    in Patients with metastatic Melanoma

    J Dtsch Dermatol Ges. 2018;16(): 15-15

    Mitzel-Rink H, Hassel J, Berking C, Gutzmer R, Heinzerling L, Majenka P, Meier F, Moreira A, Terheyden P, Thoms KM, Tietze J, Zimmer L, Kaehler K, Loquai C

    Pubmed
  • Influence of previous Radiotherapy on the Success of an immune-oncologic

    Therapy in metastatic Melanoma - a retrospective multicenter Study of

    ADO

    J Dtsch Dermatol Ges. 2018;16(): 28-29

    Knispel S, Zimmer L, Gutzmer R, Heinzerling L, Weishaupt C, Pfoehler C, Gesierich A, Herbst R, Kaehler K, Weide B, Schlaak M, Loquai C, Utikal J, Terheyden P, Kaatz M, Berking C, Kreuter A, Ulrich J, Mohr P, Dippel E, Weichenthal M, Livingstone E, Schadendorf D, Ugurel S

    Pubmed
  • Dry Mouth under Immune Checkpoint Inhibitors: an Analysis of 29 Patients

    from 10 German Skin Cancer Centers

    J Dtsch Dermatol Ges. 2018;16(): 10-11

    Hensen J, Thoms KM, Kaehler K, Gutzmer R, Zimmer L, Zacher M, Alter M, Loquai C, Moreira A, Hassel J, Utikal J

    Pubmed
  • Extracellular vesicles from mature dendritic cells (DC) differentiate monocytes into immature DC.

    Life Sci Alliance. 2018;1(6):

    Schierer S, Ostalecki C, Zinser E, Lamprecht R, Plosnita B, Stich L, Dörrie J, Lutz MB, Schuler G, Baur AS

    During inflammation, murine and human monocytes can develop into dendritic cells (DC), but this process is not entirely understood. Here, we demonstrate that extracellular vesicles (EV) secreted by mature human DC (maDC) differentiate peripheral monocytes into immature DC, expressing a unique marker pattern, including 6-sulfo LacNAc (slan), Zbtb46, CD64, and CD14. While EV from both maDC and immature DC differentiated monocytes similar to GM-CSF/IL-4 stimulation, only maDC-EV produced precursors, which upon maturation stimulus developed into T-cell-activating and IL-12p70-secreting maDC. Mechanistically, maDC-EV induced cell signaling through GM-CSF, which was abundant in EV as were IL-4 and other cytokines and chemokines. When injected into the mouse skin, murine maDC-EV attracted immune cells including monocytes that developed activation markers typical for inflammatory cells. Skin-injected EV also reached lymph nodes, causing a similar immune cell infiltration. We conclude that DC-derived EV likely serve to perpetuate an immune reaction and may contribute to chronic inflammation.

    Pubmed
  • CAR-T cell therapy in melanoma: A future success story?

    Exp Dermatol. 2018;27(12): 1315-1321

    Simon B, Uslu U

    Chimeric antigen receptor (CAR)-T cells are one of the impressive recent success stories of anti-cancer immunotherapy. Especially in haematological malignancies, this treatment strategy has shown promising results leading to the recent approval of two CAR-T cell constructs targeting CD19 in the United States and the European Union. After the huge success in haematological cancers, the next step will be the evaluation of its efficacy in different solid tumors, which is currently investigated in preclinical as well as clinical settings. A commonly examined tumor model in the context of immunotherapy is melanoma, since it is known for its immunogenic features. However, the first results of CAR-T cell therapy in solid tumors did not reveal the same impressive outcomes that were observed in haematological malignancies, as engineered cells need to cope with several challenges. Obstacles include the lack of migration of CAR-T cells from blood vessels to the tumor site as well as the immunosuppressive tumor microenvironment within solid tumors. Another hurdle is posed by the identification of an ideal target antigen to avoid on-target/off-tumor toxicities. Regarding immune escape mechanisms, which can be developed by tumor cells to bypass immune recognition, the observation of antigen loss should also be considered. This article gives an overview of the challenges displayed in CAR-T cell therapy for the use in solid tumors and discusses different new strategies and approaches that deal with these problems in order to improve CAR-T cell therapy, particularly for its use in melanoma.

    Pubmed
  • Risk Factors for Regional and Systemic Metastases in Patients with Sentinel Lymph Node-negative Melanoma.

    Anticancer Res. 2018;38(11): 6571-6577

    Erdmann M, Sigler D, Uslu U, Göhl J, Grützmann R, Schuler G, Schellerer V

    BACKGROUND: Sentinel lymph node status is a strong prognostic factor in melanoma. However, up to 21% of sentinel lymph node-negative patients develop locoregional and distant metastases during follow-up.

    AIM: To analyze risk factors for locoregional and distant metastasis in patients with sentinel lymph node-negative melanoma.

    PATIENTS AND METHODS: A total of 545 patients underwent sentinel lymph node biopsy (SNB) between 2005 and 2013 at our hospital. Data for 449 patients with a negative SNB were analyzed regarding risk factors and development of metastases. Follow-up was performed until 2016.

    RESULTS: A total of 72 SNB-negative patients developed metastases, including 25 (34.7%) distant and 47 (63.3%) locoregional metastases. Locoregional metastases occurred earlier compared to distant metastases (with a mean of 24.2 and 23.5 months for regional lymph node and cutaneous metastases, respectively, vs. 31.4 months for distant metastases). Patients with metastases despite negative SNB had a greater tumor thickness (p=0.001), a higher rate of nodular melanoma (p=0.001), ulceration (p<0.001), and were older (p=0.05) compared to SNB-negative patients without subsequent metastases. Out of SNB-negative patients, 16% developed metastases.

    CONCLUSION: Close clinical follow-up including sonography of the draining lymph node region is mandatory for melanoma patients regardless of SNB status.

    Pubmed
  • Microscopic polyangiitis after alemtuzumab treatment in relapsing-remitting MS.

    Neurol Neuroimmunol Neuroinflamm. 2018;5(5):

    Sauer EM, Schliep S, Manger B, Lee DH, Linker RA

    Pubmed
  • Automated closed-system manufacturing of human monocyte-derived dendritic cells for cancer immunotherapy.

    J Immunol Methods. 2018;463(): 89-96

    Erdmann M, Uslu U, Wiesinger M, Brüning M, Altmann T, Strasser E, Schuler G, Schuler-Thurner B

    Dendritic cell (DC)-based vaccines have been successfully used for immunotherapy of cancer and infections. A major obstacle is the need for high-level class A cleanroom cGMP facilities for DC generation. The CliniMACS Prodigy® (Prodigy) represents a new platform integrating all GMP-compliant manufacturing steps in a closed system for automated production of various cellular products, notably T cells, NK cells and CD34+ cells. We now systematically tested its suitability for producing human mature monocyte-derived DCs (Mo-DCs), and optimized it by directly comparing the Prodigy approach to our established standard production of Mo-DCs from elutriated monocytes in dishes or bags. Upon step-by-step identification of an optimal cell concentration for the Prodigy's CentriCult culture chamber, the total yield (% of input CD14+ monocytes), phenotype, and functionality of mature Mo-DCs were equivalent to those generated by the standard protocol. Technician's labor time was comparable for both methods, but the Prodigy approach significantly reduced hands-on time and high-level clean room resources. In summary, using our optimized conditions for the CliniMACS Prodigy, human Mo-DCs for clinical application can be generated almost automatically in a fully closed system. A significant drawback of the Prodigy approach was, however, that due to the limited size of the CentriCult culture chamber, in contrast to our standard semi-closed elutriation approach, only one fourth of an apheresis could be processed at once.

    Pubmed
  • Emerging functional markers for cancer stem cell-based therapies: Understanding signaling networks for targeting metastasis.

    Semin Cancer Biol. 2018;53(): 90-109

    Marquardt S, Solanki M, Spitschak A, Vera J, Pützer BM

    Metastasis is one of the most challenging issues in cancer patient management, and effective therapies to specifically target disease progression are missing, emphasizing the urgent need for developing novel anti-metastatic therapeutics. Cancer stem cells (CSCs) gained fast attention as a minor population of highly malignant cells within liquid and solid tumors that are responsible for tumor onset, self-renewal, resistance to radio- and chemotherapies, and evasion of immune surveillance accelerating recurrence and metastasis. Recent progress in the identification of their phenotypic and molecular characteristics and interactions with the tumor microenvironment provides great potential for the development of CSC-based targeted therapies and radical improvement in metastasis prevention and cancer patient prognosis. Here, we report on newly uncovered signaling mechanisms controlling CSC's aggressiveness and treatment resistance, and CSC-specific agents and molecular therapeutics, some of which are currently under investigation in clinical trials, gearing towards decisive functional CSC intrinsic or surface markers. One special research focus rests upon subverted regulatory pathways such as insulin-like growth factor 1 receptor signaling and its interactors in metastasis-initiating cell populations directly related to the gain of stem cell- and EMT-associated properties, as well as key components of the E2F transcription factor network regulating metastatic progression, microenvironmental changes, and chemoresistance. In addition, the study provides insight into systems biology tools to establish complex molecular relationships behind the emergence of aggressive phenotypes from high-throughput data that rely on network-based analysis and their use to investigate immune escape mechanisms or predict clinical outcome-relevant CSC receptor signaling signatures. We further propose that customized vector technologies could drastically enhance systemic drug delivery to target sites, and summarize recent progress and remaining challenges. This review integrates available knowledge on CSC biology, computational modeling approaches, molecular targeting strategies, and delivery techniques to envision future clinical therapies designed to conquer metastasis-initiating cells.

    Pubmed
  • Antigen targeting of Fc-receptors induces strong T cell responses in

    vivo independent of ITAM signaling but dependent on dendritic cell

    subsets

    J Immunol. 2018;200(1):

    Lehmann CHK, Baranska A, Heidkamp GF, Heger L, Neubert K, Luehr JJ, Hoffmann A, Reimer KC, Brueckner C, Beck S, Seeling M, Kiessling M, Soulat D, Krug AB, Ravetch JV, Leusen JHW, Nimmerjahn F, Dudziak D

    Pubmed
  • Eosinophil-cationic protein: A novel liquid prognostic biomarker in

    melanoma.

    J Clin Oncol. 2018;36(15):

    Moreira A, Krueckel A, Schuler G, Heinzerling L

    Pubmed
  • Phase I dose-escalation and expansion study of intratumoral CV8102, a

    RNA-based TLR- nd RIG-1 agonist in patients with advanced solid tumors

    Ann Oncol. 2018;29(): 466-466

    Terheyden P, Weishaupt C, Heinzerling L, Klinkhardt U, Krauss J, Mohr P, Kiecker F, Becker JC, Submitter AD, Doener F, Heidenreich R, Scheel B, Schoenborn-Kellenberger O, Seibel T, Gnad-Vogt U

    Pubmed
  • Non-Celiac Gluten-/Wheat Sensitivity (NCGS) - A previously undefined Symptoms with lack of Diagnostic Criteria and unknown Frequency Position Paper of the Working Group Food Allergy of the German Society of Allergology and clinical Immunology (DGAKI)

    Ernahr Umsch. 2018;65(11): M634-M638

    Reese Imke, Schaefer Christiane, Kleine-Tebbe Joerg, Ahrens Birgit, Bachmann Oliver, Ballmer-Weber Barbara, Beyer Kirsten, Bischoff StephanC, Bluemchen Katharina, Doelle Sabine, Enck Paul, Enninger Axel, Huttegger Isidor, Laemmel Sonja, Lange Lars, Lepp Ute, Mahler Vera, Moennikes Hubert, Ockenga Johann, Otto Barbara, Schnadt Sabine, Szepfalusi Zsolt, Treudler Regina, Wassmann-Otto Anja, Zuberbier Torsten, Werfel Thomas, Worm Margitta

    Pubmed
  • Serum levels of miR-320 family members are associated with clinical parameters and diagnosis in prostate cancer patients.

    Oncotarget. 2018;9(12): 10402-10416

    Lieb V, Weigelt K, Scheinost L, Fischer K, Greither T, Marcou M, Theil G, Klocker H, Holzhausen HJ, Lai X, Vera J, Ekici AB, Horninger W, Fornara P, Wullich B, Taubert H, Wach S

    We studied the association of the serum levels of the microRNA family members miR-320a/-b/-c with clinico-pathological data to assess their applicability as diagnostic biomarker in prostate cancer (PCa) patients. The levels of miR-320a/-b/-c in 3 groups were evaluated by qRT-PCR (145 patients with PCa, 31 patients with benign prostatic hyperplasia (BPH) and 19 healthy controls). The levels of the three family members of miR-320 were directly correlated within each group (P < 0.001), but they differed significantly among the three groups (P < 0.001). The serum levels of the miR-320 family members were significantly increased in older patients compared to younger patients (≤ 66 years vs. > 66 years, P ≤ 0.001). In addition, the levels of all three miR-320 family members were significantly different in patients with low tumor stage compared with those with high tumor stage (miR-320a: P = 0.034; miR-320b: P = 0.006; miR-320c: P = 0.007) and in patients with low serum PSA compared with those with high serum PSA (≤ 4 ng vs. > 4 ng; miR-320a: P = 0.003; miR-320b: P = 0.003; miR-320c: P = 0.006). The levels of these miRNAs were inversely correlated with serum PSA levels. Detection in the serum samples of PCa patients with or without PSA relapse revealed higher levels of miR-320a/-b/-c in the group without PSA relapse before/after radical prostatectomy than in that with PCa relapse. In summary, the differences among the PCa/BPH/healthy control groups with respect to miR-320a/-b/-c levels in conjunction with higher levels in patients without a PSA relapse than in those with a relapse suggest the diagnostic potential of these miRNA-320 family members in PCa patients.

    Pubmed
  • Twelve-year survival and immune correlates in dendritic cell-vaccinated melanoma patients.

    JCI Insight. 2017;2(8):

    Gross S, Erdmann M, Haendle I, Voland S, Berger T, Schultz E, Strasser E, Dankerl P, Janka R, Schliep S, Heinzerling L, Sotlar K, Coulie P, Schuler G, Schuler-Thurner B

    BACKGROUND: Reports on long-term (≥10 years) effects of cancer vaccines are missing. Therefore, in 2002, we initiated a phase I/II trial in cutaneous melanoma patients to further explore the immunogenicity of our DC vaccine and to establish its long-term toxicity and clinical benefit after a planned 10-year followup.

    METHODS: Monocyte-derived DCs matured by TNFα, IL-1β, IL-6, and PGE2 and then loaded with 4 HLA class I and 6 class II-restricted tumor peptides were injected intradermally in high doses over 2 years. We performed serial immunomonitoring in all 53 evaluable patients.

    RESULTS: Vaccine-specific immune responses including high-affinity, IFNγ-producing CD4+ and lytic polyfunctional CD8+ T cells were de novo induced or boosted in most patients. Exposure of mature DCs to trimeric soluble CD40 ligand, unexpectedly, did not further enhance such immune responses, while keyhole limpet hemocyanin (KLH) pulsing to provide unspecific CD4+ help promoted CD8+ T cell responses - notably, their longevity. An unexpected 19% of nonresectable metastatic melanoma patients are still alive after 11 years, a survival rate similar to that observed in ipilimumab-treated patients and achieved without any major (>grade 2) toxicity. Survival correlated significantly with the development of intense vaccine injection site reactions, and with blood eosinophilia after the first series of vaccinations, suggesting that prolonged survival was a consequence of DC vaccination.

    CONCLUSIONS: Long-term survival in advanced melanoma patients undergoing DC vaccination is similar to ipilimumab-treated patients and occurs upon induction of tumor-specific T cells, blood eosinophilia, and strong vaccine injection site reactions occurring after the initial vaccinations.

    TRIAL REGISTRATION: ClinicalTrials.gov NCT00053391.

    FUNDING: European Community, Sixth Framework Programme (Cancerimmunotherapy LSHC-CT-2006-518234; DC-THERA LSHB-CT-2004-512074), and German Research Foundation (CRC 643, C1, Z2).

    Pubmed
  • Life-Threatening Atypical Case of Acute Generalized Exanthematous Pustulosis.

    Int Arch Allergy Immunol. 2017;174(2): 108-111

    Tajmir-Riahi A, Wörl P, Harrer T, Schliep S, Schuler G, Simon M

    Antibiotics are known to cause severe cutaneous adverse reactions, such as the rare acute generalized exanthematous pustulosis (AGEP). Unlike Stevens-Johnson syndrome or toxic epidermal necrolysis, AGEP is rarely life-threatening. Systemic involvement is not typical, and if present usually coincides with a mild elevation of the hepatic enzymes and a decrease in renal function. Hence, AGEP is known to have a good prognosis and to be life-threatening only in elderly patients or patients with chronic diseases. Herein, we report a case of AGEP in a young healthy male leading to systemic inflammatory response syndrome and to treatment in an intensive care unit after being treated with 5 different antibiotics. Initial symptoms were not indicative for AGEP and the patient's course of disease led promptly to critical cardiorespiratory symptoms and systemic inflammatory response syndrome. We assume that the administration of the 5 different antibiotics resulted in type IV allergy as well as secondary infection with Enterococcus faecium and Staphylococcus aureus, while the underlying periodontitis also contributed to the severity of this case.

    Pubmed
  • RNA-transfection of γ/δ T cells with a chimeric antigen receptor or an α/β T-cell receptor: a safer alternative to genetically engineered α/β T cells for the immunotherapy of melanoma.

    BMC Cancer. 2017;17(1):

    Harrer DC, Simon B, Fujii SI, Shimizu K, Uslu U, Schuler G, Gerer KF, Hoyer S, Dörrie J, Schaft N

    BACKGROUND: Adoptive T-cell therapy relying on conventional T cells transduced with T-cell receptors (TCRs) or chimeric antigen receptors (CARs) has caused substantial tumor regression in several clinical trials. However, genetically engineered T cells have been associated with serious side-effects due to off-target toxicities and massive cytokine release. To obviate these concerns, we established a protocol adaptable to GMP to expand and transiently transfect γ/δ T cells with mRNA.

    METHODS: PBMC from healthy donors were stimulated using zoledronic-acid or OKT3 to expand γ/δ T cells and bulk T cells, respectively. Additionally, CD8+ T cells and γ/δ T cells were MACS-isolated from PBMC and expanded with OKT3. Next, these four populations were electroporated with RNA encoding a gp100/HLA-A2-specific TCR or a CAR specific for MCSP. Thereafter, receptor expression, antigen-specific cytokine secretion, specific cytotoxicity, and killing of the endogenous γ/δ T cell-target Daudi were analyzed.

    RESULTS: Using zoledronic-acid in average 6 million of γ/δ T cells with a purity of 85% were generated from one million PBMC. MACS-isolation and OKT3-mediated expansion of γ/δ T cells yielded approximately ten times less cells. OKT3-expanded and CD8+ MACS-isolated conventional T cells behaved correspondingly similar. All employed T cells were efficiently transfected with the TCR or the CAR. Upon respective stimulation, γ/δ T cells produced IFNγ and TNF, but little IL-2 and the zoledronic-acid expanded T cells exceeded MACS-γ/δ T cells in antigen-specific cytokine secretion. While the cytokine production of γ/δ T cells was in general lower than that of conventional T cells, specific cytotoxicity against melanoma cell lines was similar. In contrast to OKT3-expanded and MACS-CD8+ T cells, mock-electroporated γ/δ T cells also lysed tumor cells reflecting the γ/δ T cell-intrinsic anti-tumor activity. After transfection, γ/δ T cells were still able to kill MHC-deficient Daudi cells.

    CONCLUSION: We present a protocol adaptable to GMP for the expansion of γ/δ T cells and their subsequent RNA-transfection with tumor-specific TCRs or CARs. Given the transient receptor expression, the reduced cytokine release, and the equivalent cytotoxicity, these γ/δ T cells may represent a safer complementation to genetically engineered conventional T cells in the immunotherapy of melanoma (Exper Dermatol 26: 157, 2017, J Investig Dermatol 136: A173, 2016).

    Pubmed
  • Good Manufacturing Practice-Compliant Production and Lot-Release ofEx VivoExpanded Regulatory T Cells As Basis for Treatment of Patients with Autoimmune and Inflammatory Disorders.

    Front Immunol. 2017;8():

    Wiesinger M, Stoica D, Roessner S, Lorenz C, Fischer A, Atreya R, Neufert CF, Atreya I, Scheffold A, Schuler-Thurner B, Neurath MF, Schuler G, Voskens CJ

    In recent years, the exploration of regulatory T cell (Treg)-based cellular therapy has become an attractive strategy to ameliorate inflammation and autoimmunity in various clinical settings. The main obstacle to the clinical application of Treg in human is their low number circulating in peripheral blood. Therefore,ex vivoexpansion is inevitable. Moreover, isolation of Treg bears the risk of concurrent isolation of unwanted effector cells, which may trigger or deteriorate inflammation upon adoptive Treg transfer. Here, we present a protocol for the GMP-compliant production, lot-release and validation ofex vivoexpanded Tregs for treatment of patients with autoimmune and inflammatory disorders. In the presented production protocol, large numbers of Treg, previously enriched from a leukapheresis product by using the CliniMACS®system, areex vivoexpanded in the presence of anti-CD3/anti-CD28 expander beads, exogenous IL-2 and rapamycin during 21 days. The expanded Treg drug product passed predefined lot-release criteria. These criteria include (i) sterility testing, (ii) assessment of Treg phenotype, (iii) assessment of non-Treg cellular impurities, (iv) confirmation of successful anti-CD3/anti-CD28 expander bead removal after expansion, and (v) confirmation of the biological function of the Treg product. Furthermore, the Treg drug product was shown to retain its stability and suppressive function for at least 1 year after freezing and thawing. Also, dilution of the Treg drug product in 0.9% physiological saline did not affect Treg phenotype and Treg function for up to 90 min. These data indicate that these cells are ready to use in a clinical setting in which a cell infusion time of up to 90 min can be expected. The presented production process has recently undergone on site GMP-conform evaluation and received GMP certification from the Bavarian authorities in Germany. This protocol can now be used for Treg-based therapy of various inflammatory and autoimmune disorders.

    Pubmed
  • Comparison of the Serum Tumor Markers S100 and Melanoma-inhibitory Activity (MIA) in the Monitoring of Patients with Metastatic Melanoma Receiving Vaccination Immunotherapy with Dendritic Cells.

    Anticancer Res. 2017;37(9): 5033-5037

    Uslu U, Schliep S, Schliep K, Erdmann M, Koch HU, Parsch H, Rosenheinrich S, Anzengruber D, Bosserhoff AK, Schuler G, Schuler-Thurner B

    In patients with melanoma, early dissemination via lymphatic and hematogenous routes is frequently seen. Thus, besides clinical follow-up examination and imaging, reliable melanoma-specific serological tumor markers are needed.We retrospectively compared two serum markers for melanoma, S100 and melanoma-inhibitory activity (MIA), for monitoring of patients with metastatic melanoma under either adjuvant or therapeutic vaccination immunotherapy with dendritic cells (DC). Serum was obtained from a total of 100 patients (28 patients in stage III and 72 patients in stage IV, according to the American Joint Committee on Cancer 2002) at regular intervals during therapy, accompanied by follow-up imaging.When relapse was detected, both markers often remained within normal range. In contrast, in patients with metastatic measurable disease receiving therapeutic and not adjuvant DC vaccination, an increase of both markers was a strong indicator for disease progression. When comparing both markers in the whole study population, MIA showed a superior sensitivity to detect disease progression.S100 and MIA are highly sensitive tumor markers for monitoring of patients with melanoma with current metastases, but less sensitive for monitoring of tumor-free patients. In the current study, MIA had a slightly superior sensitivity to detect progressive disease compared to S100 and seems to be more useful in monitoring of patients with metastatic melanoma receiving immunotherapy.

    Pubmed
  • The tanning habits and interest in sunscreen of Google users: what happened in 12 years?

    Photodermatol Photoimmunol Photomed. 2017;33(2): 68-74

    Kirchberger MC, Heppt MV, Eigentler TK, Kirchberger MA, Schuler G, Heinzerling L

    BACKGROUND: The incidence of melanoma has been rising worldwide. One possible reason for this is natural and artificial UV exposure. Only little data on actual consumer statistics from tanning studios and the usage of sunscreen are available. Therefore, it is difficult to describe trends for both and identify the impact of preventive measures.

    METHODS: To gain knowledge about the popularity of 'tanning bed' and 'sunscreen', normalized search volumes for both search queries were obtained from Google Trends for 11 countries between January 2004 and June 2016.

    RESULTS: With few exceptions, worldwide interest in 'tanning bed' has been declining, whereas interest in 'sunscreen' has been increasing. The assessed countries from the Southern Hemisphere showed minor interest in tanning compared to the Northern Hemisphere. Both search queries were observed to fluctuate in a seasonal pattern. Skin cancer prevention measures influence the interest in tanning beds and sunscreen.

    CONCLUSION: Google Trends data can act as a first surrogate marker to evaluate the influence of skin cancer campaigns on the popularity of tanning beds and sunscreen. Fine-tuning of skin cancer campaigns according to seasonal and geographic trends and behaviors may help to maximize their success.

    Pubmed
  • Predictive value of PD-L1 based on mRNA level in the treatment of stage IV melanoma with ipilimumab.

    J Cancer Res Clin Oncol. 2017;143(10): 1977-1984

    Brüggemann C, Kirchberger MC, Goldinger SM, Weide B, Konrad A, Erdmann M, Schadendorf D, Croner RS, Krähenbühl L, Kähler KC, Hafner C, Leisgang W, Kiesewetter F, Dummer R, Schuler G, Stürzl M, Heinzerling L

    INTRODUCTION: PD-L1 is established as a predictive marker for therapy of non-small cell lung cancer with pembrolizumab. Furthermore, PD-L1 positive melanoma has shown more favorable outcomes when treated with anti-PD1 antibodies and dacarbazine compared to PD-L1 negative melanoma. However, the role of PD-L1 expression with regard to response to checkpoint inhibition with anti-CTLA-4 is not clear, yet. In addition, the lack of standardization in the immunohistochemical assessment of PD-L1 makes the comparison of results difficult. In this study, we investigated the PD-L1 gene expression with a new fully automated technique via RT-PCR and correlated the findings with the response to the anti-CTLA-4 antibody ipilimumab.

    MATERIALS AND METHODS: Within a retrospective multi-center trial, PD-L1 gene expression was evaluated in 78 melanoma patients in a total of 111 pre-treatment tumor samples from 6 skin cancer centers and analyzed with regard to response to ipilimumab. For meaningful statistical analysis, the cohort was enriched for responders with 30 responders and 48 non-responders. Gene expression was assessed by quantitative RT-PCR after extracting mRNA from formalin-fixed paraffin embedded tumor tissue and correlated with results from immunohistochemical (IHC) stainings.

    RESULTS AND DISCUSSION: The evaluation of PD-L1 expression based on mRNA level is feasible. Correlation between PD-L1 expression as assessed by IHC and RT-PCR showed varying levels of concordance depending on the antibody employed. RT-PCR should be further investigated to measure PD-L1 expression, since it is a semi-quantitative method with observer-independent evaluation. With this approach, there was no statistical significant difference in the PD-L1 expression between responders and non-responders to the therapy with ipilimumab. The evaluation of PD-L1 expression based on mRNA level is feasible. Correlation between PD-L1 expression as assessed by IHC and RT-PCR showed varying levels of concordance depending on the antibody employed. RT-PCR should be further investigated to measure PD-L1 expression, since it is a semi-quantitative method with observer-independent evaluation. With this approach, there was no statistical significant difference in the PD-L1 expression between responders and non-responders to the therapy with ipilimumab.

    Pubmed
  • Serial or Parallel Metastasis of Cutaneous Melanoma? A Study of the German Central Malignant Melanoma Registry.

    J Invest Dermatol. 2017;137(12): 2570-2577

    Gassenmaier M, Eigentler TK, Keim U, Goebeler M, Fiedler E, Schuler G, Leiter U, Weide B, Grischke EM, Martus P, Garbe C

    For more than a century the Halstedian hypothesis of contiguous metastasis from the primary tumor through the lymphatics to distant sites shaped lymph node surgery for melanoma. We challenge this dogma of serial metastatic dissemination. A single-center series of 2,299 patients with cutaneous metastatic melanoma was investigated to analyze overall survival and distant metastasis-free survival of stage IV patients with or without primary lymphatic metastasis. Results were then compared with those of 2,134 patients from three independent centers of the German Central Malignant Melanoma Registry. A multivariate binary logistic regression model was used to identify risk factors for the initial metastatic pathway. Distant metastasis-free survival (hazard ratio = 1.02; 95% confidence interval = 0.91-1.14; P = 0.76) and overall survival (HR = 1.09; 95% CI = 0.96-1.23; P = 0.177) did not differ between stage IV patients with primary hematogenous or primary lymphatic metastasis. Melanoma localization was the only significant risk factor for the initial metastatic pathway. These findings indicate that regional and distant metastases originate from the primary tumor itself in a rather parallel than serial fashion and could explain the lack of survival benefit associated with immediate complete lymph node dissection in sentinel lymph node-positive melanoma patients.

    Pubmed
  • GM-CSF Monocyte-Derived Cells and Langerhans Cells As Part of the Dendritic Cell Family.

    Front Immunol. 2017;8():

    Lutz MB, Strobl H, Schuler G, Romani N

    Dendritic cells (DCs) and macrophages (Mph) share many characteristics as components of the innate immune system. The criteria to classify the multitude of subsets within the mononuclear phagocyte system are currently phenotype, ontogeny, transcription patterns, epigenetic adaptations, and function. More recently, ontogenetic, transcriptional, and proteomic research approaches uncovered major developmental differences between Flt3L-dependent conventional DCs as compared with Mphs and monocyte-derived DCs (MoDCs), the latter mainly generated in vitro from murine bone marrow-derived DCs (BM-DCs) or human CD14+ peripheral blood monocytes. Conversely, in vitro GM-CSF-dependent monocyte-derived Mphs largely resemble MoDCs whereas tissue-resident Mphs show a common embryonic origin from yolk sac and fetal liver with Langerhans cells (LCs). The novel ontogenetic findings opened discussions on the terminology of DCs versus Mphs. Here, we bring forward arguments to facilitate definitions of BM-DCs, MoDCs, and LCs. We propose a group model of terminology for all DC subsets that attempts to encompass both ontogeny and function.

    Pubmed
  • Survival of metastatic melanoma patients after dendritic cell vaccination correlates with expression of leukocyte phosphatidylethanolamine-binding protein 1/Raf kinase inhibitory protein.

    Oncotarget. 2017;8(40): 67439-67456

    Buschow SI, Ramazzotti M, Reinieren-Beeren IMJ, Heinzerling LM, Westdorp H, Stefanini I, Beltrame L, Hato SV, Ellebaek E, Gross S, Nguyen VA, Weinlich G, Ragoussis J, Baban D, Schuler-Thurner B, Svane IM, Romani N, Austyn JM, De Vries IJM, Schuler G, Cavalieri D, Figdor CG

    Immunotherapy for metastatic melanoma offers great promise but, to date, only a subset of patients have responded. There is an urgent need to identify ways of allocating patients to the most beneficial therapy, to increase survival and decrease therapy-associated morbidity and costs. Blood-based biomarkers are of particular interest because of their straightforward implementation in routine clinical care. We sought to identify markers for dendritic cell (DC) vaccine-based immunotherapy against metastatic melanoma through gene expression analysis of peripheral blood mononuclear cells. A large-scale microarray analysis of 74 samples from two treatment centers, taken directly after the first round of DC vaccination, was performed. We found that phosphatidylethanolamine binding protein 1 (PEBP1)/Raf Kinase inhibitory protein (RKIP) expression can be used to identify a significant proportion of patients who performed poorly after DC vaccination. This result was validated by q-PCR analysis on blood samples from a second cohort of 95 patients treated with DC vaccination in four different centers. We conclude that low PEBP1 expression correlates with poor overall survival after DC vaccination. Intriguingly, this was only the case for expression of PEBP1 after, but not prior to, DC vaccination. Moreover, the change in PEBP1 expression upon vaccination correlated well with survival. Further analyses revealed that PEBP1 expression positively correlated with genes involved in T cell responses but inversely correlated with genes associated with myeloid cells and aberrant inflammation including STAT3, NOTCH1, and MAPK1. Concordantly, PEBP1 inversely correlated with the myeloid/lymphoid-ratio and was suppressed in patients suffering from chronic inflammatory disease.

    Pubmed
  • Eosinophilic count as a biomarker for prognosis of melanoma patients and its importance in the response to immunotherapy.

    Immunotherapy. 2017;9(2): 115-121

    Moreira A, Leisgang W, Schuler G, Heinzerling L

    AIM: The prognostic role of eosinophils in cancer has been controversial. Some entities such as gastrointestinal cancers show a better survival, while others such as Hodgkin's lymphoma a worse survival in patients with eosinophilia. Patients who exhibited an increase in eosinophils upon therapy with ipilimumab or pembrolizumab were shown to survive longer. We wanted to investigate whether eosinophilia is a prognostic marker in metastatic melanoma.

    METHODS: In total, 173 patients with metastatic melanoma from our data base (median age 60 years; n = 86 with immunotherapy, n = 87 without immunotherapy) were analyzed for eosinophil counts and survival over the course of 12 years. Eosinophilic count was detected by peripheral blood smear. The ethical committee had approved this retrospective study.

    RESULTS: Melanoma patients with eosinophilia at any point in their course of disease show a trend toward longer survival independently of their therapy. There is a statistically significant difference for the patients who survive at least 12 months (p < 0.005). In patients with checkpoint inhibitor therapy, survival was significantly prolonged in every patient with eosinophilia (p < 0.05). Furthermore, 69% of the patients treated with immunotherapy experienced at least once an eosinophilia of 5% or greater compared with 46% in the immunotherapy naive-group; for an eosinophilia of 10% values were 30 and 9%, respectively. Interestingly, in patients with more than 20% eosinophils (n = 7) survival was prolonged with a median of 35 months (range 19-60 months) as compared with 16 months (range 1-117 months).

    CONCLUSION: Eosinophilia is a prognostic marker in patients with metastatic melanoma.

    Pubmed
  • Multiepitope tissue analysis reveals SPPL3-mediated ADAM10 activation as a key step in the transformation of melanocytes.

    Sci Signal. 2017;10(470):

    Ostalecki C, Lee JH, Dindorf J, Collenburg L, Schierer S, Simon B, Schliep S, Kremmer E, Schuler G, Baur AS

    The evolution of cancer is characterized by the appearance of specific mutations, but these mutations are translated into proteins that must cooperate to induce malignant transformation. Using a systemic approach with the multiepitope ligand cartography (MELC) technology, we analyzed protein expression profiles (PEPs) in nevi and BRAFV600E-positive superficial spreading melanomas (SSMs) from patient tissues to identify key transformation events. The PEPs in nevi and SSMs differed predominantly in the abundance of specific antigens, but the PEPs of nevi- and melanoma-associated keratinocytes gradually changed during the transformation process. A stepwise change in PEP with similar properties occurred in keratinocytes cocultured with melanoma cells. Analysis of the individual steps indicated that activation of the metalloproteinase ADAM10 by signal peptide peptidase-like 3 (SPPL3) triggered by mutant BRAFV600E was a critical transformation event. SPPL3-mediated ADAM10 activation involved the translocation of SPPL3 and ADAM10 into Rab4- or Rab27-positive endosomal compartments. This endosomal translocation, and hence ADAM10 activation, was inhibited by the presence of the tumor suppressor PTEN. Our findings suggest that systematic tissue antigen analysis could complement whole-genome approaches to provide more insight into cancer development.

    Pubmed
  • Interest in tanning beds and sunscreen in German-speaking countries.

    J Dtsch Dermatol Ges. 2017;15(12): 1192-1198

    Kirchberger MC, Kirchberger LF, Eigentler TK, Reinhard R, Berking C, Schuler G, Heinzerling L, Heppt MV

    BACKGROUND: The growing incidence of nearly all types of skin cancer can be attributed to increased exposure to natural or artificial ultraviolet (UV) radiation. However, there is a scarcity of statistical data on risk behavior or sunscreen use, which would be important for any prevention efforts.

    METHODS: Using the search engine Google® , we analyzed search patterns for the terms Solarium (tanning bed), Sonnencreme (sunscreen), and Sonnenschutz (sun protection) in Germany, Austria, and Switzerland between 2004 and 2016, and compared it to search patterns worldwide. For this purpose, "normalized search volumes" (NSVs) were calculated for the various search queries. The corresponding polynomial functions were then compared with each other over the course of time.

    RESULTS: Since 2001, there has been a marked worldwide decrease in the search queries for tanning bed, whereas those for sunscreen have steadily increased. In German-speaking countries, on the other hand, there have - for years - consistently been more search queries for tanning bed than for sunscreen. There is an annual periodicity of the queries, with the highest NSVs for tanning bed between March and May and those for sunscreen in the summer months around June. In Germany, the city-states of Hamburg and Berlin have particularly high NSVs for tanning bed.

    CONCLUSIONS: Compared to the rest of the world, German-speaking countries show a strikingly unfavorable search pattern. There is still great need for education and prevention with respect to sunscreen use and avoidance of artificial UV exposure.

    Pubmed
  • Block Excision of Iridociliary Tumors Enables Molecular Profiling and Immune Vaccination.

    Ophthalmology. 2017;124(2): 268-270

    Heindl LM, Koch KR, Hermann MM, Merkelbach-Bruse S, Schultheis AM, Wagener S, Büttner R, Mauch C, Schuler-Thurner B, Schuler G, Cursiefen C

    Pubmed
  • Preclinical evaluation of NF-κB-triggered dendritic cells expressing the viral oncogenic driver of Merkel cell carcinoma for therapeutic vaccination.

    Ther Adv Med Oncol. 2017;9(7): 451-464

    Gerer KF, Erdmann M, Hadrup SR, Lyngaa R, Martin LM, Voll RE, Schuler-Thurner B, Schuler G, Schaft N, Hoyer S, Dörrie J

    BACKGROUND: Merkel cell carcinoma (MCC) is a rare but very aggressive skin tumor that develops after integration of a truncated form of the large T-antigen (truncLT) of the Merkel cell polyomavirus (MCV) into the host's genome. Therapeutic vaccination with dendritic cells (DCs) loaded with tumor antigens is an active form of immunotherapy, which intends to direct the immune system towards tumors which express the respective vaccination antigens.

    METHODS: Cytokine-matured monocyte-derived DCs of healthy donors and MCC patients were electroporated with mRNA encoding the truncLT. To permit major histocompatibility complex (MHC) class II next to class I presentation, we used an RNA construct in which the antigen was fused to a DCLamp sequence in addition to the unmodified antigen. To further improve their immunogenicity, the DCs were additionally activated by co-transfection with the constitutively active nuclear factor (NF)-κB activator caIKK. These DCs were used to stimulate autologous CD8+ T-cells or a mixture of CD4+ and CD8+ T-cells. Then the percentage of T-cells, specific for the truncLT, was quantified by interferon (IFN)γ ELISpot assays.

    RESULTS: Both the truncLT and its DCLamp-fusion were detected within the DCs by flow cytometry, albeit the latter required blocking of the proteasome. The transfection with caIKK upregulated maturation markers and induced cytokine production. After 2-3 rounds of stimulation, the T-cells from 11 out of 13 healthy donors recognized the antigen. DCs without caIKK appeared in comparison less potent in inducing such responses. When using cells derived from MCC patients, we could induce responses for 3 out of 5 patients; however, here the caIKK-transfected DCs did not display their superiority.

    CONCLUSION: These results show that optimized DCs are able to induce MCV-antigen-specific T-cell responses. Therapeutic vaccination with such transfected DCs could direct the immune system against MCC.

    Pubmed
  • Factors Influencing Disease Progression in Patients with Head and Neck Melanoma.

    Anticancer Res. 2017;37(7): 3811-3816

    Uslu U, Schuler G, Breuninger H

    BACKGROUND: Histological parameters as well as the status of sentinel lymph node are known to be strong prognostic factors in patients with melanoma.

    PATIENTS AND METHODS: In this study, we retrospectively analyzed 1,384 patients who were diagnosed with head and neck melanoma between 1976 and 2010 regarding prognostic factors [tumor thickness, level of invasion, sentinel lymph node (SLN) status, ulceration, histological subtype, localization, and gender], overall survival, and disease-free survival.

    RESULTS: Patients who developed metastases had a significantly thicker tumor than patients without metastases. Additionally, a thicker tumor was often associated with a higher level of invasion (Clark level). There was no overall survival benefit in patients who underwent SLN dissection when compared to patients who did not (p=0.07). Compared to SLN-negative patients, patients with SLN involvement had a significantly shorter disease-free period (p<0.001) and shorter overall survival time (p<0.001).

    CONCLUSION: In summary, tumor thickness is the most important prognostic factor. SLN dissection does not affect the overall survival of patients with melanoma. However, a positive SLN is a marker for a worse outcome in these patients.

    Pubmed
  • Characterization and Expansion of Autologous GMP-ready Regulatory T Cells for TREG-based Cell Therapy in Patients with Ulcerative Colitis.

    Inflamm Bowel Dis. 2017;23(8): 1348-1359

    Voskens CJ, Fischer A, Roessner S, Lorenz C, Hirschmann S, Atreya R, Neufert C, Atreya I, Neurath MF, Schuler G

    BACKGROUND: A local imbalance between regulatory (Treg) and effector T cells is believed to play a major role in gut-specific inflammation, including ulcerative colitis (UC). Restoration of this balance through an adoptive Treg transfer is an attractive new treatment approach in patients who are refractory to current standard therapies. It was our goal to develop a Good Manufacturing Practices (GMP)-conform protocol for expansion of UC Treg cells as a rational backbone for future studies on Treg therapy in UC.

    METHODS: CD25 blood T cells derived from patients with UC were ex vivo expanded in the presence of IL-2, rapamycin, and anti-CD3/anti-CD28 expander beads using a GMP-conform protocol. Cells were subsequently assessed for stability and function.

    RESULTS: Patient-derived ex vivo rapamycin-expanded GMP-ready CD25 cells were polyclonal, hypomethylated at intron 1 of the FoxP3 locus, and suppressive in carboxyfluorescein succinimidyl ester-dilution assays against autologous peripheral blood-derived and allogeneic colon-derived responder cells. Function was mediated by soluble factors, including toxic granules. In addition to CD4 T cells, suppressive hypermethylated CD8 T-cell subsets were also induced during the expansion process.

    CONCLUSIONS: Patient-derived rapamycin-expanded CD25 cells are stable and functional, and as such, ready to serve in a phase I dose-escalation safety study in UC.

    Pubmed
  • The simultaneous siRNA-mediated downregulation of inhibitory receptors to improve CAR-T cell immunotherapy of melanoma

    J Dtsch Dermatol Ges. 2017;15(): 6-6

    Simon B, Harrer D, Weide B, Schuler G, Schuler-Thurner B, Doerrie J, Schaft N, Uslu U

    Pubmed
  • Sarcoidosis Under Dendritic Cell Vaccination Immunotherapy in Long-term Responding Patients with Metastatic Melanoma.

    Anticancer Res. 2017;37(6): 3243-3248

    Uslu U, Erdmann M, Schliep S, Dörrie J, Schaft N, Schuler G, Schuler-Thurner B

    Sarcoidosis, a chronic inflammatory disorder, results from increased immune responses. Its development can be triggered in patients under immunotherapy, as activation of the immune system in these patients is desired. Since 1997, 249 patients with metastasized cutaneous melanoma (stage III and IV, AJCC 2009) have been treated with dendritic cell (DC)-based vaccines at our hospital. Three out of these patients were diagnosed with sarcoidosis after or during long-term DC vaccination therapy (1.20%). Metastatic disease was initially suspected based on the radiographic manifestation of lung masses or bilateral hilar lymphadenopathy. Histological assessment, however, revealed the appropriate diagnosis. Interestingly, all three patients are long-term responders and have remained free of metastatic or progressive disease for over a period of at least 4 years. In summary, sarcoidosis can occur in patients with cancer who have benefited from DC-based therapeutic vaccination and thus, its development, even with substantial delay, may be associated with successful anticancer immunotherapy.

    Pubmed
  • Ex vivo expanded NK cells up-regulate natural cytotoxicity receptors able to mediate autologous melanoma cell killing

    J Invest Dermatol. 2017;137(10): S229-S229

    Roessner S, Gross S, Karg M, Hamann A, Campana D, Schuler-Thurner B, Bosch J, Schuler G, Voskens CJ

    Pubmed
  • Human lymphoid organ dendritic cell identity is predominantly dictated by ontogeny, not tissue microenvironment

    Eur J Immunol. 2017;47(): 158-159

    Heidkamp GF, Sander J, Lehmann CHK, Heger L, Eissing N, Baranska A, Luehr JJ, Hoffmann A, Reimer KC, Lux A, Soeder S, Hartmann A, Zenk J, Ulas T, McGovern N, Alexiou C, Spriewald B, Mackensen A, Schuler G, Schauf B, Forster A, Repp R, Fasching P, Purbojo A, Cesnjevar R, Ullrich E, Ginhoux F, Schlitzer A, Nimmerjahn F, Schultze JL, Dudziak D

    Pubmed
  • CAR/TCR-transfected gamma/delta T cells for immunotherapy of melanoma

    Exp Dermatol. 2017;26(3): E67-E68

    Harrer DC, Simon B, Fujii S, Shimizu K, Uslu U, Schoch L, Schuler G, Gerer KF, Hoyer S, Doerrie J, Schaft N

    Pubmed
  • Comparative analysis of human dendritic cell subpopulations in steady state and inflammation

    Eur J Immunol. 2017;47(): 70-70

    Heger L, Heidkamp GF, Lehmann CHK, Eissing N, Soeder S, Hartmann A, Zenk J, Alexiou C, Schuler G, Purbojo A, Cesnjevar R, Nimmerjahn F, Dudziak D

    Pubmed
  • RNA-transfection of gamma/delta T cells with a chimeric antigen receptor or an alpha/ss T-cell receptor: a safer alternative to genetically engineered alpha/ss T cells for the immunotherapy of melanoma

    Eur J Immunol. 2017;47(): 10-10

    Harrer D, Simon B, Fujii SI, Kanako S, Uslu U, Schuler G, Gerer KF, Hoyer S, Doerrie J, Schaft N

    Pubmed
  • A systems biology approach to characterize the function of miRNAs in dendritic cell-mediated immunogenicity and therapeutic cancer vaccination

    Eur J Immunol. 2017;47(): 163-163

    Lai X, Dreyer F, Jaitly T, Gerer KF, Schuler G, Doerrie J, Schaft N, Vera J

    Pubmed
  • BRAF and MEK inhibitors influence human immune cell phenotype and function

    Eur J Immunol. 2017;47(): 307-307

    Hoyer S, Eberlein V, Babalija L, Gerer KF, Walter L, Schuler G, Schaft N, Heinzerling L, Doerrie J

    Pubmed
  • The tanning habits and interest in sunscreen of Google Users: What happened in twelve years?

    J Dtsch Dermatol Ges. 2017;15(): 63-64

    Kirchberger M, Heppt M, Eigentler T, Kirchberger M, Schuler G, Heinzerling L

    Pubmed
  • Old Age, nodular Melanoma, Tumor Thickness and Ulceration are Risk Factors for regional and systemic Metastases in Melanoma Patients after negative Sentinel Node Biopsy

    J Dtsch Dermatol Ges. 2017;15 3(): 44-44

    Erdmann M, Dominik S, Gohl J, Grützmann R, Schuler G, Schellerer V

    Pubmed
  • A review of serious adverse effects under treatment with checkpoint inhibitors.

    Curr Opin Oncol. 2017;29(2): 136-144

    Heinzerling L, Goldinger SM

    PURPOSE OF REVIEW: The aim of this article is to raise awareness of physicians for the serious side-effects of immune-checkpoint blocking antibodies. As checkpoint inhibitors can induce severe side-effects and are increasingly being used also in subspecialties besides dermatology and oncology, with less experience with these drugs available, knowledge has to be spread. Early recognition and adequate management is essential.

    RECENT FINDINGS: Recent reports on side-effects document cases of serious side-effects involving all organ systems. These include formerly little referenced and life-threatening side-effects such as cardiotoxicity and neurotoxicity. Furthermore, important additional findings are the inclusion of CMV reactivation in the differential diagnosis or the side-effect profile in special patient populations, that is, in transplant patients, patients with autoimmune disease or previous toxicity to ipilimumab.

    SUMMARY: Checkpoint inhibitor treatment induces a wide range of serious side-effects. However, with prompt diagnosis and adequate treatment these can mostly be safely managed. Documentation and reporting of serious side-effects remains important to share knowledge and thus ensure optimal patient care.

    Pubmed
  • Usage and effectiveness of systemic treatments in adults with severe atopic eczema: First results of the German Atopic Eczema Registry TREATgermany.

    J Dtsch Dermatol Ges. 2017;15(1): 49-59

    Schmitt J, Abraham S, Trautmann F, Stephan V, Fölster-Holst R, Homey B, Bieber T, Novak N, Sticherling M, Augustin M, Kleinheinz A, Elsner P, Weidinger S, Werfel T

    BACKGROUND: The goal of clinical registries is to document the use and effectiveness of therapeutic interventions under real-life conditions. They are an indispensable prerequisite of evidence-based health care.

    METHODS: Initiated in 2011, the German Atopic Dermatitis Registry TREATgermany is the first registry of patients with severe atopic dermatitis worldwide. Adults with severe atopic dermatitis (current/prior systemic antiinflammatory treatment and/or objective SCORAD ≥ 40) are prospectively followed over the course of 24 months. Employed treatment modalities are documented, and validated measuring tools are used to assess clinical disease severity (EASI, objective SCORAD), quality of life (DLQI), symptoms (POEM), global disease severity, as well as patient satisfaction. Herein, we describe the characteristics, therapeutic selection, and effectiveness of systemic antiinflammatory treatments of patients enrolled in the registry until October 2014.

    RESULTS: Overall, 78 individuals (mean age 39 years, 61 % men) were enrolled at five recruitment centers. Patients frequently made use of inpatient and outpatient services. Not only was cyclosporine the most frequently administered systemic treatment, but also the most effective (EASI 50 response rate 51 %; EASI 75 response rate 34 % at 12 weeks). Azathioprine, methotrexate, oral prednisolone, mycophenolate, alitretinoin, and leflunomide were also used in some patients.

    CONCLUSIONS: The present analysis of the German Atopic Dermatitis Registry provides important data with respect to current medical care of adults with severe atopic dermatitis in Germany. It shows the high disease burden, the benefits of current treatment options, and the need for additional effective and safe long-term treatment options.

    Pubmed
  • Influence of TNF-alpha inhibitors and fumaric acid esters on male fertility in psoriasis patients.

    J Eur Acad Dermatol Venereol. 2017;31(11): 1860-1866

    Heppt F, Colsman A, Maronna A, Uslu U, Heppt MV, Kiesewetter F, Sticherling M

    OBJECTIVE: Is there any influence of a therapy with TNF-alpha inhibitors or fumaric acid esters and of disease activity status on male fertility and sperm quality in patients with psoriasis?

    METHODS: In this monocentric, open-label, prospective study, semen samples were collected from patients receiving either TNF-alpha inhibitors or fumaric acid esters for moderate-to-severe plaque psoriasis. Semen was analysed at baseline before onset of the systemic therapy and monitored every 3 months under therapy. Sperm parameters were assessed according to the current WHO definitions.

    RESULTS: In total, 101 semen specimens from 27 patients were obtained. Mean Psoriasis Area and Severity Index (PASI) score at baseline was 11.05. Only 14.8% of patients showed a normozoospermia without any other abnormal seminal values. 85.2% of patients had at least one sperm/seminal abnormality, including two patients showing an azoospermia. Interestingly, 48.1% showed sperm parameters indicative of genital tract inflammation. Therapy with TNF-alpha inhibitors or fumaric acid esters did not have any negative effects on relevant sperm parameters such as mean total sperm number, sperm concentration, total and progressive motility. No major gonadal dysfunction was observed in any patient.

    CONCLUSION: At baseline, many patients with psoriasis showed abnormal semen/sperm parameters and remarkably elevated leukocytes and values of seminal polymorphonuclear elastase, indicating a genital tract inflammation. Thus, genital tract inflammation may represent an important comorbidity of psoriasis, little attention paid to so far. Regarding treatment with TNF-alpha inhibitors or fumaric acid esters, no major negative (side-) effects on sperm quality were observed.

    Pubmed
  • European dermatology forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 2: Scleromyxedema, scleredema and nephrogenic systemic fibrosis.

    J Eur Acad Dermatol Venereol. 2017;31(10): 1581-1594

    Knobler R, Moinzadeh P, Hunzelmann N, Kreuter A, Cozzio A, Mouthon L, Cutolo M, Rongioletti F, Denton CP, Rudnicka L, Frasin LA, Smith V, Gabrielli A, Aberer E, Bagot M, Bali G, Bouaziz J, Braae Olesen A, Foeldvari I, Frances C, Jalili A, Just U, Kähäri V, Kárpáti S, Kofoed K, Krasowska D, Olszewska M, Orteu C, Panelius J, Parodi A, Petit A, Quaglino P, Ranki A, Sanchez Schmidt JM, Seneschal J, Skrok A, Sticherling M, Sunderkötter C, Taieb A, Tanew A, Wolf P, Worm M, Wutte NJ, Krieg T

    The term 'sclerosing diseases of the skin' comprises specific dermatological entities which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present guideline focuses on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, current strategies in the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 2 of this guideline provides clinicians with an overview of the diagnosis and treatment of scleromyxedema, scleredema (of Buschke) and nephrogenic systemic sclerosis (nephrogenic fibrosing dermopathy).

    Pubmed
  • European Dermatology Forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 1: localized scleroderma, systemic sclerosis and overlap syndromes.

    J Eur Acad Dermatol Venereol. 2017;31(9): 1401-1424

    Knobler R, Moinzadeh P, Hunzelmann N, Kreuter A, Cozzio A, Mouthon L, Cutolo M, Rongioletti F, Denton CP, Rudnicka L, Frasin LA, Smith V, Gabrielli A, Aberer E, Bagot M, Bali G, Bouaziz J, Braae Olesen A, Foeldvari I, Frances C, Jalili A, Just U, Kähäri V, Kárpáti S, Kofoed K, Krasowska D, Olszewska M, Orteu C, Panelius J, Parodi A, Petit A, Quaglino P, Ranki A, Sanchez Schmidt JM, Seneschal J, Skrok A, Sticherling M, Sunderkötter C, Taieb A, Tanew A, Wolf P, Worm M, Wutte NJ, Krieg T

    The term 'sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present guideline focuses on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, current strategies in the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 1 of this guideline provides clinicians with an overview of the diagnosis and treatment of localized scleroderma (morphea), and systemic sclerosis including overlap syndromes of systemic sclerosis with diseases of the rheumatological spectrum.

    Pubmed
  • Meeting Report of the Pathogenesis of Pemphigus and Pemphigoid Meeting in Munich, September 2016.

    J Invest Dermatol. 2017;137(6): 1199-1203

    Schmidt E, Spindler V, Eming R, Amagai M, Antonicelli F, Baines JF, Belheouane M, Bernard P, Borradori L, Caproni M, Di Zenzo G, Grando S, Harman K, Jonkman MF, Koga H, Ludwig RJ, Kowalczyk AP, Müller EJ, Nishie W, Pas H, Payne AS, Sadik CD, Seppänen A, Setterfield J, Shimizu H, Sinha AA, Sprecher E, Sticherling M, Ujiie H, Zillikens D, Hertl M, Waschke J

    Autoimmune blistering diseases are a heterogeneous group of about a dozen complex disorders that are characterized by intraepidermal (pemphigus) and subepidermal blistering (pemphigoid diseases and dermatitis herpetiformis). The Pathogenesis of Pemphigus and Pemphigoid Meeting, organized by the Departments of Dermatology in Lübeck and Marburg and the Institute of Anatomy and Cell Biology, Munich, was held in September 2016 in Munich. The meeting brought together basic scientists and clinicians from all continents dedicating their work to autoimmune blistering diseases. Considerable advances have been made in describing incidences and prevalences of these diseases and linking comorbidities with autoantibody reactivities and clinical variants, for example, dipeptidyl peptidase-IV inhibitor-associated noninflammatory bullous pemphigoid. Although new entities are still being described, diagnosis of most autoimmune blistering diseases can now be achieved using standardized and widely available serological test systems. Various experimental mouse models of pemphigus and pemphigoid disease are increasingly being used to understand mechanisms of central and peripheral tolerance and to evaluate more specific treatment approaches for these disorders, such as molecules that target autoreactive T and B cells and anti-inflammatory mediators, that is, dimethyl fumarate, phosphodiesterase 4, and leukotriene B4 inhibitors in pemphigoid disorders, and chimeric antigen receptor T cells in pemphigus. Very recent experimental data about the immunopathology and the determinants of autoantibody formation and keratinocyte susceptibility in pemphigus were discussed. With regard to cellular mechanisms leading to the loss of cell-cell adhesion, new ideas were shared in the field of signal transduction. Major steps were taken to put the various partly contradictory and controversial findings about the effects of pemphigus autoantibodies and other inflammatory mediators into perspective and broaden our view of the complex pathophysiology of this disease. Finally, two investigator-initiated multicenter trials highlighted doxycycline and dapsone as valuable medications in the treatment of bullous pemphigoid.

    Pubmed
  • An open, multicentre, randomized clinical study in patients with bullous pemphigoid comparing methylprednisolone and azathioprine with methylprednisolone and dapsone.

    Br J Dermatol. 2017;177(5): 1299-1305

    Sticherling M, Franke A, Aberer E, Gläser R, Hertl M, Pfeiffer C, Rzany B, Schneider S, Shimanovich I, Werfel T, Wilczek A, Zillikens D, Schmidt E

    BACKGROUND: Current treatment of bullous pemphigoid (BP) is based on the long-term use of topical and/or systemic corticosteroids, which are associated with a high rate of adverse events and increased mortality.

    OBJECTIVES: To study the corticosteroid-sparing potential of azathioprine and dapsone.

    METHODS: This was a prospective, multicentre, randomized, nonblinded clinical trial that compared the efficacy and safety of two parallel groups of patients with BP treated with oral methylprednisolone 0·5 mg kg-1 per day in combination with either azathioprine 1·5-2·5 mg kg-1 per day or dapsone 1·5 mg kg-1 per day. Nine German and Austrian departments of dermatology included 54 patients based on clinical lesions, positive direct immunofluorescence (IF) microscopy and detection of serum autoantibodies by indirect IF microscopy, immunoblotting or enzyme-linked immunosorbent assay. The primary end point was the time until complete tapering of methylprednisolone, and the most important secondary end point was the cumulative corticosteroid dose.

    RESULTS: In eight patients (five azathioprine, three dapsone), methylprednisolone could be discontinued after a median time of 251 days in the azathioprine group and 81 days in the dapsone group. The median cumulative corticosteroid dose was 2·65 g for azathioprine compared with 1·92 g for dapsone (P = 0·06). The median numbers of days when corticosteroids were applied were 148 and 51, respectively (P = 0·24). No significant difference in the number of adverse events was seen between the treatment arms. Four patients (8%) died within the observation period of 12 months.

    CONCLUSIONS: Due to the lower than intended number of patients, the results of the primary and secondary end points were not or only barely significant. Dapsone appeared to have a moderately higher corticosteroid-sparing potential than azathioprine. The combination regimen of either drug with oral methylprednisolone is associated with a relatively low 1-year mortality in this vulnerable patient population.

    Pubmed
  • Effects of structured patient education in adults with atopic dermatitis: Multicenter randomized controlled trial.

    J Allergy Clin Immunol. 2017;140(3): 845-853.e3

    Heratizadeh A, Werfel T, Wollenberg A, Abraham S, Plank-Habibi S, Schnopp C, Sticherling M, Apfelbacher C, Biedermann T, Breuer K, Fell I, Fölster-Holst R, Heine G, Grimm J, Hennighausen L, Kugler C, Reese I, Ring J, Schäkel K, Schmitt J, Seikowski K, von Stebut E, Wagner N, Waßmann-Otto A, Wienke-Graul U, Weisshaar E, Worm M, Gieler U, Kupfer J, Arbeitsgemeinschaft Neurodermitisschulung für Erwachsene (ARNE) Study Group , Brauner K, Dölle S, Ehmann L, Hagmaier U, Eberlein S, Kroth J, Lämmerhirt K, Landleiter R, Lorenz U, Lüdemann A, Matterne U, Mitzel-Rink H, Niebuhr M, Rehberg T, Vogel S, Wichmann K

    BACKGROUND: Atopic dermatitis (AD) is a chronic relapsing skin disease prevalent in 1% to 3% of adults in Western industrialized countries.

    OBJECTIVE: We sought to investigate the effectiveness of educational training in an outpatient setting on coping with the disease, quality of life, symptoms, and severity in adults with AD.

    METHODS: In this German prospective, randomized controlled multicenter study, adult patients with moderate-to-severe AD were educated by referring to a comprehensive 12-hour training manual consented by a multiprofessional study group from different centers (Arbeitsgemeinschaft Neurodermitisschulung für Erwachsene [ARNE]). Patients were randomly allocated to the intervention or waiting control groups. Study visits were performed at baseline and after 1 year (1 year of follow-up). Primary outcomes were defined as a decrease in (1) "catastrophizing cognitions" with respect to itching (Juckreiz-Kognitions-Fragebogen questionnaire), (2) "social anxiety" (Marburger Hautfragebogen questionnaire), (3) subjective burden by symptoms of the disease (Skindex-29 questionnaire), and (4) improvement of disease signs and symptoms assessed by using the SCORAD index at 1 year of follow-up. Data were analyzed on an intention-to-treat basis.

    RESULTS: At 1 year of follow-up, patients from the intervention group (n = 168) showed a significantly better improvement compared with the waiting group (n = 147) in the following defined primary study outcomes: coping behavior with respect to itching (P < .001), quality of life assessed by using the Skindex-29 questionnaire (P < .001), and the SCORAD index (P < .001).

    CONCLUSIONS: This is the first randomized, controlled multicenter study on patient education in adult AD. The ARNE training program shows significant beneficial effects on a variety of psychosocial parameters, as well as AD severity.

    Pubmed
  • Secondary syphilis infection under treatment with ustekinumab.

    Clin Exp Dermatol. 2017;42(7): 836-838

    Uslu U, Heppt F, Sticherling M

    Pubmed
  • Improvement of Joint Inflammation As Assessed By MRI and Power Doppler Ultrasound (PDUS) in an Open Label Study in Patients with Active Psoriatic Arthritis Treated with Secukinumab.

    Arthritis Rheumatol. 2017;69():

    Kampylafka E, Oliveira I, Linz C, Lerchen V, Englbrecht M, Sticherling M, Kleyer A, Rech J, Schett G, Hueber AJ

    Pubmed
  • Fumaric Acid Esters and TNF alpha Inhibitors - Do they affect the Fertility of male Patients with Psoriasis?

    J Dtsch Dermatol Ges. 2017;15(): 77-77

    Heppt F, Colsmann A, Maronna A, Uslu U, Heppt M, Kiesewetter F, Sticherling M

    Pubmed
  • [Specific dermatoses of pregnancy].

    Hautarzt. 2017;68(2): 87-94

    Ambros-Rudolph CM, Sticherling M

    The specific dermatoses of pregnancy represent a heterogeneous group of inflammatory skin diseases related to pregnancy and/or the postpartum period. A clinically relevant classification has been well established over the past 10 years and includes pemphigoid gestationis, polymorphic eruption of pregnancy, intrahepatic cholestasis of pregnancy, and atopic eruption of pregnancy. The hallmark of all four entities is severe pruritus that is accompanied by characteristic skin changes. While some of these dermatoses are distressing only to the mother because of pruritus, others may be associated with significant fetal risks. Early diagnosis and prompt treatment are therefore essential. In this review, we discuss in detail pemphigoid gestationis, polymorphic and atopic eruptions of pregnancy whereas intrahepatic cholestasis of pregnancy is discussed in a separate article (Kremer A, Ständer S, DOI 10.1007/s00105-016-3923-y ). Furthermore, we present a helpful algorithm for diagnosis and management of pruritus in pregnancy.

    Pubmed
  • [Psoriasis capitis and seborrhoic eczema of scalp diseases].

    Hautarzt. 2017;68(6): 457-465

    Sticherling M

    The scalp may be affected by various diseases with equally varying manifestations. Erythema and scaling is often accompanied by agonizing itch. Scalp psoriasis and seborrheic eczema represent the most frequent diseases, which can be differentiated into classical cases; however, overlap and similarities are seen. Sharply demarcated erythematosquamous plaques across the natural hairline in psoriasis are opposed to blurred dark-red erythema and yellowish, greasy scales in seborrheic eczema. Whereas with the latter diffuse alopecia may frequently be found, hair loss is rarely seen in psoriasis and may also be related to therapeutic agents. Treatment is based on acuity as well as extent of disease and individual life quality aspects of the patients. It is mainly based on topical corticosteroids, combined with vitamin D derivatives in psoriasis and antimycotic agents in seborrheic eczema. In severe cases and widespread psoriatic disease, systemic treatment may be necessary, including the classic agents methotrexate, fumarates and ciclosporin as well as biologicals. Systemic treatment of seborrheic eczema is rarely necessary and resides on corticosteroids, antimycotic agents and vitamin A derivatives. In addition, intensive counseling of patients on the necessity of consequent and long-term treatment as well as use of mild skin care products is mandatory.

    Pubmed
  • PASI <= 2 corresponds to PASI 90, irrespective of baseline severity: A post-hoc analysis of the PRIME-study

    J Invest Dermatol. 2017;137(10): S194-S194

    Reich K, Sieder C, Bachhuber T, Melzer N, Sticherling M

    Pubmed
  • Uncommon Presentation of Scleromyxoedema with a Distribution Pattern Mimicking a Photodermatosis.

    Acta Derm Venereol. 2017;97(8): 979-980

    Kirchberger MC, Sticherling M, Erdmann M

    Pubmed
  • Psoriasis in children: a single-centre analysis

    Br J Dermatol. 2017;177(5): E254-E254

    Heppt F, Raap J, Sticherling M

    Pubmed
  • Psoriasis as a Manifestation of an Immune Reconstitution in Two Patients with Hepatitis C Treated with Ledipasvir/Sofosbuvir.

    Acta Derm Venereol. 2017;97(4): 526-527

    Heppt F, Sticherling M

    Pubmed
  • The genetic basis for most patients with pustular skin disease remains elusive

    Br J Dermatol. 2017;177(5): E239-E239

    Hueffmeier U, Loehr S, Schulz P, Koerber A, Prinz JC, Schaekel K, Philipp S, Reich K, Staender H, Jacobi A, Kingo K, Koks S, Gerdes S, Schill T, Griewank KG, Frey S, Steinz K, Uebe S, Sticherling M, Sticht H, Gkogkolou P, Oji V, Wilsmann-Theis D, Moessner R

    Pubmed
  • Secukinumab is superior to fumaric acid esters in treating patients with moderate-to-severe plaque psoriasis who are naive to systemic treatments: results from the randomized controlled PRIME trial.

    Br J Dermatol. 2017;177(4): 1024-1032

    Sticherling M, Mrowietz U, Augustin M, Thaci D, Melzer N, Hentschke C, Kneidl J, Sieder C, Reich K

    BACKGROUND: Secukinumab is a fully human antibody that neutralizes interleukin-17A. It has significant efficacy and a favourable safety profile in moderate-to-severe plaque psoriasis and psoriatic arthritis.

    OBJECTIVES: To compare secukinumab with fumaric acid esters (FAEs) in a randomized controlled trial.

    METHODS: In this 24-week, randomized, open-label, multicentre study with blinded assessment, patients with moderate-to-severe plaque psoriasis, naive to systemic treatments, were randomized to receive secukinumab 300 mg subcutaneously or oral FAEs. The primary end point was ≥ 75% improvement from baseline Psoriasis Area and Severity Index score (PASI 75 response) at week 24, and missing patients were considered responders if they were responders at the time of dropout.

    RESULTS: In total 202 patients were randomized and 200 were treated with at least one dose. Outcomes at week 24 were available for 147 and imputed for 53 patients. Discontinuations were mostly due to adverse events, which occurred more frequently in the FAE group (1·9% vs. 33·0%). At week 24, significantly more patients receiving secukinumab compared with FAEs achieved PASI 75 response (89·5% vs. 33·7%, P < 0·001), PASI 90 response (81·0% vs. 28·4%, P < 0·001) and Dermatology Life Quality Index 0 or 1 response (71·4% vs. 25·3%, P < 0·001).

    CONCLUSIONS: Secukinumab demonstrated superior efficacy to FAEs in patients with psoriasis over a 24-week period.

    Pubmed
  • Doxycycline versus Prednisolone for the initial Treatment of bullous Pemphigoids: a pragmatic prospective randomized Study

    J Dtsch Dermatol Ges. 2017;15(): 74-75

    Schmidt E, Benoit S, Ehrchen J, Glaeser R, Guenther C, Steinbrink K, Sticherling M, van Beek N, Wojnarowska F, Kirtschig G, Mason J, Godec T, Chalmers J, Childs M, Walton S, Harman K, Chapman A, Whitman D, Nunn A, Williams H, BLISTER Team

    Pubmed
  • Fumaric Acid Esters: Patient Characteristics and Duration of Therapy from the PsoBest German Psoriasis Registry

    J Dtsch Dermatol Ges. 2017;15(): 117-117

    Augustin M, Reich K, Spehr C, Rustenbach SJ, Mrowietz U, Radtke MA, Wilsman-Theis D, Sticherling M, Thaci D

    Pubmed
  • Secukinumab Treatment of moderate to severe Plaque Psoriasis in the clinical Routine Care: Baseline Data from the PROSPECT Study on Psoriasis Pre-treatment

    J Dtsch Dermatol Ges. 2017;15(): 138-138

    von Kiedrowski R, Korber A, Kraehn-Senftleben G, Sticherling M, Lange L, Bachhuber T, Kasparek TR, Augustin M, Thaci D, Amon U

    Pubmed
  • Secukinumab is superior to Fumaric Acid Esters in the Treatment of Patients with moderate to severe Plaque Psoriasis without previous Systemic Therapy for Improvement of Skin Symptoms: PASI and IGA mod. 2011-Results of the PRIME Study

    J Dtsch Dermatol Ges. 2017;15(): 143-144

    Reich K, Mrowietz U, Augustin M, Thaci D, Kneidl J, Hentschke C, Simang M, Sieder C, Melzer N, Sticherling M

    Pubmed
  • Secukinumab is superior to Fumaric Acid Esters in the Treatment of Patients with moderate to severe Plaque Psoriasis without prior System Therapy with respect to the Improvement of quality of life: DLQI and SF-36 Results of the PRIME Study

    J Dtsch Dermatol Ges. 2017;15(): 144-145

    Augustin M, Thaci D, Reich K, Mrowietz U, Kneidl J, Hentschke C, Simang M, Sieder C, Melzer N, Sticherling M

    Pubmed
  • Secukinumab is superior to Fumaric Acid Esters in the Treatment of Patients with moderate to severe Plaque Psoriasis with without previous Systemic Therapy for Improvement of Nail Symptoms: NAPSI Results PRIME Study

    J Dtsch Dermatol Ges. 2017;15(): 144-144

    Thaci D, Reich K, Mrowietz U, Augustin M, Kneidl J, Hentschke C, Simang M, Sieder C, Melzer N, Sticherling M

    Pubmed
  • Secukinumab is superior to Fumaric Acid Esters in the Treatment of Patients with moderate to severe Plaque Psoriasis without prior System Therapy with regard to compatibility-related Therapeutic Adherence: Safety Results of the PRIME Study

    J Dtsch Dermatol Ges. 2017;15(): 145-145

    Mrowietz U, Augustin M, Thaci D, Reich K, Kneidl J, Hentschke C, Simang M, Sieder C, Melzer N, Sticherling M

    Pubmed
  • Impairment of gustatory and olfactory senses in plaque psoriasis

    Br J Dermatol. 2017;177(5): E253-E253

    Rueter P, Gruenthaler V, Zopf Y, Sticherling M

    Pubmed
  • Psoriasis - Occurrence and Reality: Disease of the Psoriasis Group

    J Dtsch Dermatol Ges. 2017;15(): 111-112

    Leupolz S, Sticherling M

    Pubmed
  • Hydradenitis suppurativa - new exploration on the famous Disease

    J Dtsch Dermatol Ges. 2017;15(): 111-111

    Oetterich K, Heppt F, Sticherling M

    Pubmed
  • Lungs Ailment - other Comorbidity of the Psoriasis?

    J Dtsch Dermatol Ges. 2017;15(): 112-112

    Moreira A, Sticherling M

    Pubmed
  • Psoriasis vulgaris as Manifestation of Immune Reconstitution in Patients with Hepatitis C under Treatment with Ledipasvir/Sofosbuvir

    J Dtsch Dermatol Ges. 2017;15(): 69-69

    Heppt F, Sticherling M

    Pubmed
  • Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions.

    Cancer Treat Rev. 2017;57(): 36-49

    Hassel JC, Heinzerling L, Aberle J, Bähr O, Eigentler TK, Grimm MO, Grünwald V, Leipe J, Reinmuth N, Tietze JK, Trojan J, Zimmer L, Gutzmer R

    BACKGROUND: Combined immune checkpoint blockade (ICB) provides unprecedented efficacy gains in numerous cancer indications, with PD-1 inhibitor nivolumab plus CTLA-4 inhibitor ipilimumab in advanced melanoma as first-ever approved therapies for combined ICB. However, gains in efficacy must be balanced against a higher frequency and severity of adverse drug reactions (ADR). Because delays in diagnosis and management might result in symptom worsening and further complications, clinicians shall be well trained to identify ADR promptly and monitor patients adequately. This paper reviews safety data assessed by the European Medicines Agency for the anti-PD-1/CTLA-4 combination and provides a literature overview on published case reports for rare ADR with suspected potential underreporting. Incidences and kinetics of immune-related ADR are described. Recommendations for the evaluation and management of ADR are convened by an interdisciplinary expert panel focusing on rare but clinically important side effects arising from combined ICB. Pooled safety data from 1551 patients with advanced melanoma, treated either with 3mg/kg ipilimumab plus 1mg/kg nivolumab (N=407), or nivolumab alone (N=787), or ipilimumab alone (N=357) demonstrate that immune-related ADR occur more frequently for the combination, with a shorter time-to-onset, and tend to be more severe. The majority of events is reversible after systemic use of glucocorticoids, notably methylprednisolone or equivalents; in certain cases of long-lasting and refractory immune toxicities, non-steroidal immunosuppressants may be used, once ICB is interrupted or terminated. Combined ICB has considerable toxicities, therefore close monitoring and high experience in diagnosis and treatment of ADR is necessary.

    Pubmed
  • Ipilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma.

    Eur J Cancer. 2017;75(): 47-55

    Zimmer L, Apuri S, Eroglu Z, Kottschade LA, Forschner A, Gutzmer R, Schlaak M, Heinzerling L, Krackhardt AM, Loquai C, Markovic SN, Joseph RW, Markey K, Utikal JS, Weishaupt C, Goldinger SM, Sondak VK, Zager JS, Schadendorf D, Khushalani NI

    BACKGROUND: The anti-programmed cell death-1 (PD-1) inhibitors pembrolizumab and nivolumab alone or in combination with ipilimumab have shown improved objective response rates and progression-free survival compared to ipilimumab only in advanced melanoma patients. Anti-PD-1 therapy demonstrated nearly equal clinical efficacy in patients who had progressed after ipilimumab or were treatment-naïve. However, only limited evidence exists regarding the efficacy of ipilimumab alone or in combination with nivolumab after treatment failure to anti-PD-therapy.

    PATIENTS AND METHODS: A multicenter retrospective study in advanced melanoma patients who were treated with nivolumab (1 or 3 mg/kg) and ipilimumab (1 mg or 3 mg/kg) or ipilimumab (3 mg/kg) alone after treatment failure to anti-PD-1 therapy was performed. Patient, tumour, pre- and post-treatment characteristics were analysed.

    RESULTS: In total, 47 patients were treated with ipilimumab (ipi-group) and 37 patients with ipilimumab and nivolumab (combination-group) after treatment failure to anti-PD-1 therapy. Overall response rates for the ipi- and the combination-group were 16% and 21%, respectively. Disease control rate was 42% for the ipi-group and 33% for the combination-group. One-year overall survival rates for the ipi- and the combination-group were 54% and 55%, respectively.

    CONCLUSIONS: Ipilimumab should be considered as a viable treatment option for patients with failure to prior anti-PD-1 therapy, including those with progressive disease as best response to prior anti-PD-1. In contrast, the combination of ipilimumab and nivolumab appears significantly less effective in this setting compared to treatment-naïve patients.

    Pubmed
  • Prognostic factors and outcomes in metastatic uveal melanoma treated with programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4 inhibition.

    Eur J Cancer. 2017;82(): 56-65

    Heppt MV, Heinzerling L, Kähler KC, Forschner A, Kirchberger MC, Loquai C, Meissner M, Meier F, Terheyden P, Schell B, Herbst R, Göppner D, Kiecker F, Rafei-Shamsabadi D, Haferkamp S, Huber MA, Utikal J, Ziemer M, Bumeder I, Pfeiffer C, Schäd SG, Schmid-Tannwald C, Tietze JK, Eigentler TK, Berking C

    BACKGROUND: Uveal melanoma (UM) is an ocular malignancy with high potential for metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet shown convincing efficacy in patients with UM. Combined immune checkpoint blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed for UM to date.

    PATIENTS AND METHODS: Patients with metastatic UM treated with either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer centres. Records from 96 cases were analysed for treatment outcomes. Clinical and blood parameters associated with overall survival (OS) or treatment response were identified with multivariate Cox regression and binary logistic regression.

    RESULTS: Eighty-six patients were treated with PD-1 inhibitors only (n = 54 for pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of 4.7%. Median OS was 14 months for pembrolizumab-treated and 10 months for nivolumab-treated patients (p = 0.765). Fifteen patients were treated with combined immune checkpoint blockade with partial response observed in two cases. Median OS was not reached in this group. Multivariate Cox regression identified Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.002), elevated serum levels of lactate dehydrogenase (LDH) (p = 0.002) and C-reactive protein (CRP) (p = 0.001), and a relative eosinophil count (REC) <1.5% (p = 0.002) as independent risk factors for poor survival. Patients with elevated CRP and LDH and a REC <1.5% were at highest risk for disease progression and death (p = 0.001).

    CONCLUSIONS: Blood markers predict survival in metastatic UM treated with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high REC may help identify patients with better prognosis.

    Pubmed
  • Prognostic factors and treatment outcomes in 444 patients with mucosal melanoma.

    Eur J Cancer. 2017;81(): 36-44

    Heppt MV, Roesch A, Weide B, Gutzmer R, Meier F, Loquai C, Kähler KC, Gesierich A, Meissner M, von Bubnoff D, Göppner D, Schlaak M, Pföhler C, Utikal J, Heinzerling L, Cosgarea I, Engel J, Eckel R, Martens A, Mirlach L, Satzger I, Schubert-Fritschle G, Tietze JK, Berking C

    BACKGROUND: Mucosal melanoma (MM) is a rare but diverse cancer entity. Prognostic factors are not well established for Caucasians with MM.

    PATIENTS AND METHODS: We analysed the disease course of 444 patients from 15 German skin cancer centres. Disease progression was determined with the cumulative incidence function. Survival times were estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariate Cox regression analysis.

    RESULTS: Common anatomic sites of primary tumours were head and neck (MMHN, 37.2%), female genital tract (MMFG, 30.4%) and anorectal region (MMAN, 21.8%). MMAN patients showed the highest vertical tumour thickness (p = 0.001), had a more advanced nodal status (p = 0.014) and a higher percentage of metastatic disease (p = 0.001) at diagnosis. Mutations of NRAS (13.8%), KIT (8.6%) and BRAF (6.4%) were evenly distributed across all tumour site groups. Local relapses were observed in 32.4% and most commonly occurred in the MMHN group (p = 0.016). Male gender (p = 0.047), advanced tumour stage (p = 0.001), nodal disease (p = 0.001) and incomplete resection status (p = 0.001) were independent risk factors for disease progression. Overall survival (OS) was highest in the MMFG group (p = 0.030) and in patients without ulceration (p = 0.004). Multivariate risk factors for OS were M stage at diagnosis (p = 0.002) and incomplete resection of the primary tumour (p = 0.001).

    CONCLUSION: In this large series of MM patients in a European population, anorectal MM was associated with the poorest prognosis.

    Pubmed
  • Clinical characteristics and outcome of 60 pediatric patients with malignant melanoma registered with the German Pediatric Rare Tumor Registry (STEP).

    Klin Padiatr. 2017;229(6): 322-328

    Offenmueller S, Leiter U, Bernbeck B, Garbe C, Eigentler T, Borkhardt A, Friedrich Classen C, Corbacioglu S, Dirksen U, Ebetsberger-Dachs G, Heinzerling L, Jorch N, Kuhlen M, Lawlor J, Niggli F, Streiter M, Schneider DT, Brecht I

    Background Malignant melanoma (MM) is a common malignancy in adults while it is rare in children. Thus, information on clinical behavior of pediatric MM is incomplete. Patients The German Pediatric Rare Tumor Registry (STEP) presents a prospective analysis of 60 childhood MM cases diagnosed between June 2006 and December 2014. Method Patients' ages ranged between 0 and 17 years at initial diagnosis (median age 9.6 years). Information on patient's and tumor characteristics was obtained by standardized documentation. Three-year overall survival (OS) and event-free survival (EFS) were estimated by the Kaplan-Meier test. Results Follow-up ranged from 0 to 116 months with a median of 36.5 months, however, univariate analysis was performed for 46 cases with a follow-up > 3 months, only. Cases with spitzoid histotype (40%) did not show a significantly different outcome compared to cases with non-spitzoid MM. Breslow thickness ≤ 2.00 mm was identified in 30% of the cases and 18% were Clark level I to III. Adjuvant therapy was used in 45% of cases. OS at 3 years was 100%, EFS 95.2%. Conclusion We present a series of cases with a high number of spitzoid malignant melanoma and advanced pediatric melanoma, but surprisingly good overall survival rates. Spitzoid and non-spitzoid MM do not differ in clinical behavior and survival.

    Pubmed
  • Prognostic factors and outcomes in metastatic uveal melanoma treated with PD-1 or combined PD-1 / CTLA-4 inhibition

    J Dtsch Dermatol Ges. 2017;15(): 14-14

    Heppt M, Heinzerling L, Kaehler K, Forschner A, Kirchberger M, Loquai C, Meissner M, Meier F, Terheyden P, Schell B, Herbst R, Goeppner D, Kiecker F, Rafei-Shamsabadi D, Haferkamp S, Huber M, Utikal J, Ziemer M, Bumeder I, Pfeiffer C, Schd-Trcka S, Schmid-Tannwald C, Tietze J, Eigentler T, Berking C

    Pubmed
  • The neurotrophin Neuritin1 (cpg15) is involved in melanoma migration, attachment independent growth, and vascular mimicry.

    Oncotarget. 2017;8(1): 1117-1131

    Bosserhoff AK, Schneider N, Ellmann L, Heinzerling L, Kuphal S

    The neurotrophin Neuritin1 (NRN1; cpg15) belongs to the candidate plasticity gene (CPG) family and is expressed in postmitotic-differentiating neurons of the developmental nervous system and neuronal structures associated with plasticity in the brain of human adult.Our newest findings document that NRN1 deregulation could contribute also to disease development and have impact on malignant melanoma. Our analyses displayed the over-expression of NRN1 in melanoma in vitro and in vivo, shown by immunohistochemistry and qRT-PCR on microdissected melanoma tissue; furthermore, soluble NRN1 was detectable in tissue culture supernatant and serum of melanoma patients.To investigate the role of NRN1 in melanoma we performed knockdown, over-expression and recombinant-NRN1-treatment experiments affiliated by functional assays. Our results show that migration, attachment independent growth and vasculogenesis were affected after manipulation of NRN1 on endogenous and extrinsic level. Interestingly, high NRN1 serum levels correlate with low MIA serum levels (< 10ng/ml). Therefore, we speculate that NRN1 could be a marker for early melanoma stages, in particular.In summary, we detected an overexpression of NRN1 in melanoma patient. In functional cell culture experiments we found a correlation between NRN1 expression and the cancerous behavior of melanoma cells.

    Pubmed
  • Fear of progression in patients with low-risk malignant melanoma

    J Dtsch Dermatol Ges. 2017;15(): 48-48

    Wagner T, Augustin M, Blome C, Forschner A, Garbe C, Gutzmer R, Hauschild A, Heinzerling L, Livingstone E, Mueller-Brenne T, Loquai C, Schadendorf D, Terheyden P, Kaehler K

    Pubmed
  • Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity.

    Eur J Cancer. 2017;75(): 24-32

    Gutzmer R, Koop A, Meier F, Hassel JC, Terheyden P, Zimmer L, Heinzerling L, Ugurel S, Pföhler C, Gesierich A, Livingstone E, Satzger I, Kähler KC, German Dermatooncology Group (DeCOG)

    AIM: Programmed cell death protein 1 (PD-1) inhibitors are a common treatment strategy for metastatic melanoma and other tumour entities. Clinical trials usually exclude patients with preexisting autoimmune diseases, thus experience with PD-1 inhibitor (PD-1i) in this patient population is limited.

    PATIENTS AND METHODS: Metastatic melanoma patients with preexisting autoimmune disorders or previous ipilimumab-triggered immune-related adverse events (irAE) undergoing treatment with PD-1i from seven German skin cancer centres were evaluated retrospectively with regard to flare of the preexisting autoimmunity and development of new, not preexisting irAE as well as response to PD-1i therapy.

    RESULTS: In total, 41 patients had either preexisting autoimmunity (n=19, group A, including two patients with additional ipilimumab-triggered autoimmune colitis) or ipilimumab-triggered irAE (n=22, group B). At PD-1i therapy initiation, six patients in group A and two patients in group B required immunosuppressive therapy. In group A, a flare of preexisting autoimmune disorders was seen in 42% of patients, new irAE in 16%. In group B, 4.5% of patients showed a flare of ipilimumab-triggered irAE and 23% new irAE. All flares of preexisting autoimmune disorders or irAE were managed by immunosuppressive and/or symptomatic therapy and did not require termination of PD-1i therapy. tumour responses (32% in group A and 45% in group B) were unrelated to occurrence of autoimmunity.

    CONCLUSION: While preexisting autoimmunity commonly showed a flare during PD-1i therapy, a flare of ipilimumab-triggered irAE was rare. Response rates were above 30% and unrelated to irAE. PD-1i therapy can be considered in patients with autoimmune disorders depending on severity and activity of autoimmunity.

    Pubmed
  • Interleukin-2 and Checkpoint Inhibition as a successful Therapy Sequence for metastatic Melanoma: Case Report and retrospective Analysis in 52 Patients

    J Dtsch Dermatol Ges. 2017;15(): 16-17

    Cosgarea I, Zimmer L, Weide B, Gutzmer R, Heinzerling L, Weishaupt C, Pfoehler C, Gesierich A, Herbst R, Kaehler K, Schlaak M, Loquai C, Utikal J, Kaatz M, Berking C, Kreuter A, Ulrich J, Mohr P, Dippel E, Livingstone E, Weichenthal M, Schadendorf D, Ugurel S

    Pubmed
  • Eosinophilic count as a biomarker for prognosis of melanoma patients

    J Dtsch Dermatol Ges. 2017;15(): 14-15

    Moreira A, Heinzerling L

    Pubmed
  • Can checkpoint inhibitor therapy improve response to chemotherapy?

    J Clin Oncol. 2017;35 15(): -

    Kirchberger MC, Schilling B, Haferkamp S, Bosserhoff A, Schuler G, Heinzerling L

    Pubmed
  • Look-alikes with opposite consequences: Cutaneous Botryomycosis presenting as cutaneous metastases in a patient with a history of metastatic lung cancer

    J Dtsch Dermatol Ges. 2017;15(): 70-71

    Bosch-Voskens C, Woerl P, Kiesewetter F, Schliep S

    Pubmed
  • Identification of Novel STAT6-Regulated Proteins in Mouse B Cells by Comparative Transcriptome and Proteome Analysis.

    J Immunol. 2017;198(9): 3737-3745

    Mokada-Gopal L, Boeser A, Lehmann CHK, Drepper F, Dudziak D, Warscheid B, Voehringer D

    The transcription factor STAT6 plays a key role in mediating signaling downstream of the receptors for IL-4 and IL-13. In B cells, STAT6 is required for class switch recombination to IgE and for germinal center formation during type 2 immune responses directed against allergens or helminths. In this study, we compared the transcriptomes and proteomes of primary mouse B cells from wild-type and STAT6-deficient mice cultured for 4 d in the presence or absence of IL-4. Microarray analysis revealed that 214 mRNAs were upregulated and 149 were downregulated >3-fold by IL-4 in a STAT6-dependent manner. Across all samples, ~5000 proteins were identified by label-free quantitative liquid chromatography/mass spectrometry. A total of 149 proteins was found to be differentially expressed >3-fold between IL-4-stimulated wild-type and STAT6(-/-) B cells (75 upregulated and 74 downregulated). Comparative analysis of the proteome and transcriptome revealed that expression of these proteins was mainly regulated at the transcriptional level, which argues against a major role for posttranscriptional mechanisms that modulate the STAT6-dependent proteome. Nine proteins were selected for confirmation by flow cytometry or Western blot. We show that CD30, CD79b, SLP-76, DEC205, IL-5R?, STAT5, and Thy1 are induced by IL-4 in a STAT6-dependent manner. In contrast, Syk and Fc receptor-like 1 were downregulated. This dataset provides a framework for further functional analysis of newly identified IL-4-regulated proteins in B cells that may contribute to germinal center formation and IgE switching in type 2 immunity.

    Pubmed
  • Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease.

    Nat Immunol. 2017;18(1): 104-113

    Pfeifle R, Rothe T, Ipseiz N, Scherer HU, Culemann S, Harre U, Ackermann JA, Seefried M, Kleyer A, Uderhardt S, Haugg B, Hueber AJ, Daum P, Heidkamp GF, Ge C, Böhm S, Lux A, Schuh W, Magorivska I, Nandakumar KS, Lönnblom E, Becker C, Dudziak D, Wuhrer M, Rombouts Y, Koeleman CA, Toes R, Winkler TH, Holmdahl R, Herrmann M, Blüml S, Nimmerjahn F, Schett G, Krönke G

    The checkpoints and mechanisms that contribute to autoantibody-driven disease are as yet incompletely understood. Here we identified the axis of interleukin 23 (IL-23) and the TH17 subset of helper T cells as a decisive factor that controlled the intrinsic inflammatory activity of autoantibodies and triggered the clinical onset of autoimmune arthritis. By instructing B cells in an IL-22- and IL-21-dependent manner, TH17 cells regulated the expression of ?-galactoside ?2,6-sialyltransferase 1 in newly differentiating antibody-producing cells and determined the glycosylation profile and activity of immunoglobulin G (IgG) produced by the plasma cells that subsequently emerged. Asymptomatic humans with rheumatoid arthritis (RA)-specific autoantibodies showed identical changes in the activity and glycosylation of autoreactive IgG antibodies before shifting to the inflammatory phase of RA; thus, our results identify an IL-23-TH17 cell-dependent pathway that controls autoantibody activity and unmasks a preexisting breach in immunotolerance.

    Pubmed
  • Sweet SIGNs: IgG glycosylation leads the way in IVIG-mediated resolution of inflammation.

    Int Immunol. 2017;29(11): 499-509

    Brückner C, Lehmann C, Dudziak D, Nimmerjahn F

    A hallmark of many chronic inflammatory and autoimmune diseases is that there is an impaired resolution of inflammation and return to the steady state. The infusion of high doses of pooled serum IgG preparations from thousands of donors [intravenous immunoglobulin (IVIG) therapy] has been shown to induce resolution of inflammation in a variety of chronic inflammatory and autoimmune diseases, suggesting that IgG molecules can instruct the immune system to stop inflammatory processes and initiate the return to the steady state. The aim of this review is to discuss how insights into the mechanism of IVIG activity may help to understand the molecular and cellular pathways underlying resolution of inflammation. We will put a special emphasis on pathways dependent on the IgG FC domain and IgG sialylation, as several recent studies have provided new insights into how this glycosylation-dependent pathway modulates innate and adaptive immune responses through different sets of C-type or I-type lectins.

    Pubmed
  • Tumor location determines tissue-specific recruitment of tumor-associated macrophages and antibody-dependent immunotherapy response.

    Sci Immunol. 2017;2(7):

    Lehmann B, Biburger M, Brückner C, Ipsen-Escobedo A, Gordan S, Lehmann C, Voehringer D, Winkler T, Schaft N, Dudziak D, Sirbu H, Weber GF, Nimmerjahn F

    Despite recent advances in activating immune cells to target tumors, the presence of some immune cells, such as tumor-associated macrophages (TAMs) or tumor-associated neutrophils (TANs), may promote rather than inhibit tumor growth. However, it remains unclear how antibody-dependent tumor immunotherapies, such as cytotoxic or checkpoint control antibodies, affect different TAM or TAN populations, which abundantly express activating Fcγ receptors. In this study, we show that the tissue environment determines which cellular effector pathways are responsible for antibody-dependent tumor immunotherapy. Although TAMs derived from Ly6Chighmonocytes recruited by the CCL2-CCR2 axis were critical for tumor immunotherapy of skin tumors, the destruction of lung tumors was CCL2-independent and required the presence of colony-stimulating factor 2-dependent tissue-resident macrophages. Our findings suggest that TAMs may have a dual role not only in promoting tumor growth in certain tissue environments on the one hand but also in contributing to tumor cell destruction during antibody-mediated immunotherapy on the other hand.

    Pubmed
  • Antigen targeting of Fc-receptors induces strong T cell responses in vivo independent of ITAM signaling but dependent on dendritic cell subset

    Eur J Immunol. 2017;47(): 30-30

    Lehmann CHK, Baranska A, Heidkamp GF, Heger L, Neubert K, Luehr JJ, Hoffmann A, Reimer KC, Brueckner C, Beck S, Seeling M, Kiessling M, Soulat D, Krug AB, Ravetch JV, Leusen JHW, Nimmerjahn F, Dudziak D

    Pubmed
  • Antigen targeting of Fc-receptors induces strong T cell responses in vivo independent of ITAM signaling but dependent on dendritic cell subsets

    J Dtsch Dermatol Ges. 2017;15(): 22-23

    Lehmann C, Baranska A, Heidkamp G, Heger L, Neubert K, Luehr J, Hoffmann A, Reimer K, Brueckner C, Beck S, Seeling M, Kiessling M, Soulat D, Krug A, Ravetch J, Leusen J, Nimmerjahn F, Dudziak D

    Pubmed
  • The Influence of MHC Class II on B Cell Defects Induced by Invariant Chain/CD74 N-Terminal Fragments.

    J Immunol. 2017;199(1): 172-185

    Schneppenheim J, Loock AC, Hüttl S, Schweizer M, Lüllmann-Rauch R, Oberg HH, Arnold P, Lehmann CHK, Dudziak D, Kabelitz D, Lucius R, Lennon-Duménil AM, Saftig P, Schröder B

    The invariant chain (CD74) mediates assembly and targeting of MHC class II (MHCII) complexes. In endosomes, CD74 undergoes sequential degradation by different proteases, including cathepsin S (CatS) and the intramembrane protease signal peptide peptidase-like 2a (SPPL2a). In their absence, CD74 N-terminal fragments (NTFs) accumulate. In SPPL2a-/- B cells, such an NTF impairs endosomal trafficking and BCR signal transduction. In mice, this leads to a loss of splenic B cells beyond the transitional stage 1. To gain insight into CD74 determinants and the role of MHCII, we compared B cells from CatS-/- , SPPL2a-/- , and SPPL2a-MHCII double-deficient mice. We assessed differentiation of B cells in bone marrow and spleen and analyzed their endosomal morphology, BCR expression, and signal transduction. We demonstrate that MHCII is dispensable for the B cell phenotype of SPPL2a-/- mice, further supporting a CD74-intrinsic effect. Despite significant vacuolization of endosomal compartments similar to SPPL2a-/- B cells, CatS-/- traditional stage 1 B cells show unimpaired degradation of endocytic cargo, have intact BCR signaling, and do not exhibit any relevant defects in maturation. This could indicate that CD74 NTF-induced structural changes of endosomes are not directly involved in these processes. We further found that the block of CD74 degradation in CatS-/- B cells is incomplete, so that NTF levels are significantly lower than in SPPL2a-/- B cells. This suggests a dose dependency and threshold for the CD74 NTF-associated impairment of B cell signaling and maturation. In addition, different functional properties of the longer, MHCII-bound CD74 NTF could contribute to the milder phenotype of CatS-/- B cells.

    Pubmed
  • CXCR4-SDF1 alpha Blockade Reduces the Severity of Murine Heart Allograft Rejection

    Eur J Immunol. 2017;47(): 16-16

    Fu J, Wahlbuhl M, Wang X, Wilde B, Jing L, Kribben A, Hoyer P, Lehmann CHK, Dudziak D, Witzke O, Hoerning A

    Pubmed
  • DC subset-specific induction of T cell responses upon antigen uptake via Fc? receptors in vivo.

    J Exp Med. 2017;214(5): 1509-1528

    Lehmann CHK, Baranska A, Heidkamp GF, Heger L, Neubert K, Lühr JJ, Hoffmann A, Reimer KC, Brückner C, Beck S, Seeling M, Kießling M, Soulat D, Krug AB, Ravetch JV, Leusen JHW, Nimmerjahn F, Dudziak D

    Dendritic cells (DCs) are efficient antigen-presenting cells equipped with various cell surface receptors for the direct or indirect recognition of pathogenic microorganisms. Interestingly, not much is known about the specific expression pattern and function of the individual activating and inhibitory Fc? receptors (Fc?Rs) on splenic DC subsets in vivo and how they contribute to the initiation of T cell responses. By targeting antigens to select activating and the inhibitory Fc?R in vivo, we show that antigen uptake under steady-state conditions results in a short-term expansion of antigen-specific T cells, whereas under inflammatory conditions especially, the activating Fc?RIV is able to induce superior CD4(+) and CD8(+) T cell responses. Of note, this effect was independent of Fc?R intrinsic activating signaling pathways. Moreover, despite the expression of Fc?RIV on both conventional splenic DC subsets, the induction of CD8(+) T cell responses was largely dependent on CD11c(+)CD8(+) DCs, whereas CD11c(+)CD8(-) DCs were critical for priming CD4(+) T cell responses.

    Pubmed
  • IMPACT OF TOLL-LIKE RECEPTOR 9 IN INFLAMMATORY ARTHRITIS AND OSTEOCLASTOGENESIS

    Ann Rheum Dis. 2017;76(): A86-A86

    Fischer A, Boehm C, Koenders M, van den Berg W, Rothe T, Kroenke G, Dudziak D, Steiner G

    Pubmed
  • The distribution of C-type lectin receptors in the Dendritic cell membrane

    Eur J Immunol. 2017;47(): 19-19

    Luehr JJ, Eissing N, Heidkamp GF, Lehmann CHK, Heger L, Dudziak D

    Pubmed
  • Identification of novel STAT6-regulated proteins in Mouse B cells by comparative transcriptome and proteome analysis

    Eur J Immunol. 2017;47(): 95-95

    Gopal LM, Boeser A, Lehmann CHK, Dudziak D, Warscheid B, Voehringer D

    Pubmed
  • The delivery of antigens to dendritic cells is a potent futureoption for anti-tumor therapies

    J Dtsch Dermatol Ges. 2017;15(): 83-84

    Lehmann C, Heger L, Neubert K, Harzer C, Amon L, Yamazaki S, Heidkamp G, Eissing N, Krug A, Leusen J, Ravetch J, Nimmerjahn F, Dudziak D

    Pubmed
  • Occupational skin diseases: actual state analysis of patient management pathways in 28 European countries.

    J Eur Acad Dermatol Venereol. 2017;31 Suppl 4(): 12-30

    Mahler V, Aalto-Korte K, Alfonso JH, Bakker JG, Bauer A, Bensefa-Colas L, Boman A, Bourke J, Bubaš M, Bulat P, Chaloupka J, Constandt L, Danielsen TE, Darlenski R, Dugonik A, Ettler K, Giménez-Arnau A, Gonçalo M, Johansen JD, John SM, Kieć-Świerczyńska M, Koch P, Kohánka V, Kręcisz B, Larese Filon F, Ljubojević S, Macan J, Marinovic B, Matura M, Mihatsch PW, Mijakoski D, Minov J, Pace J, Pesonen M, Ramada Rodilla JM, Rast H, Reljic V, Salavastru C, Schuster C, Schuttelaar ML, Simon D, Spiewak R, Jurakic Tončić R, Urbanček S, Valiukeviciene S, Weinert P, Wilkinson M, Uter W

    BACKGROUND: Work-related skin diseases (WSD) are caused or worsened by a professional activity. Occupational skin diseases (OSD) need to fulfil additional legal criteria which differ from country to country. OSD range amongst the five most frequently notified occupational diseases (musculoskeletal diseases, neurologic diseases, lung diseases, diseases of the sensory organs, skin diseases) in Europe.

    OBJECTIVE: To retrieve information and compare the current state of national frameworks and pathways to manage patients with occupational skin disease with regard to prevention, diagnosis, treatment and rehabilitation in different European countries.

    METHODS: A questionnaire-based survey of the current situation regarding OSD patient management pathways was carried out with experts on occupational dermatology and/or occupational medicine from 28 European countries contributing to the European Cooperation in Science and Technology (COST) Action TD 1206 (StanDerm) (www.standerm.eu).

    RESULTS: Besides a national health service or a statutory health insurance, most European member states implemented a second insurance scheme specifically geared at occupational diseases [insurance against occupational risks (synonyms: insurance against work accidents and occupational injuries; statutory social accident insurance)]. Legal standards for the assessment of occupationally triggered diseases with a genetic background differ between different countries, however, in most European member states recognition as OSD is possible. In one-third of the countries UV light-induced tumours can be recognized as OSD under specific conditions.

    CONCLUSION: OSD definitions vary between European countries and are not directly comparable, which hampers comparisons between statistics collected in different countries. Awareness of this fact and further efforts for standardization are necessary.

    Pubmed
  • H1-antihistamine-refractory chronic spontaneous urticaria: it's worse than we thought - first results of the multicenter real-life AWARE study.

    Clin Exp Allergy. 2017;47(5): 684-692

    Mäurer M, Staubach P, Raap U, Richter-Huhn G, Bauer A, Ruëff F, Jakob T, Yazdi AS, Mahler V, Wagner N, Lippert U, Hillen U, Schwinn A, Pawlak M, Behnke N, Chaouche K, Chapman-Rothe N

    BACKGROUND: Most data on chronic spontaneous urticaria (CSU) originate from highly selected patient populations treated at specialized centres. Little is known about CSU patient characteristics and the burden of CSU in routine clinical practice. AWARE (A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation) is an ongoing global study designed to assess chronic urticaria in the real-life setting.

    OBJECTIVE: To describe the baseline characteristics of the first 1539 German AWARE patients with H1-antihistamine-refractory CSU.

    METHODS: This prospective non-interventional study included patients (18-75 years) with a diagnosis of H1-antihistamine-refractory CSU for > 2 months. Baseline demographic and disease characteristics, comorbidities, and pharmacological treatments were recorded. Quality of life (QoL) was assessed using the dermatology life quality index (DLQI), chronic urticaria QoL questionnaire (CU-Q2 oL), and angioedema QoL questionnaire (AE-QoL, in cases of angioedema). Previous healthcare resource utilization and sick leave data were collected retrospectively.

    RESULTS: Between March and December 2014, 1539 patients were assessed in 256 sites across Germany. The percentage of females, mean age, and mean body mass index were 70%, 46.3 years, and 27 kg/m2 , respectively. The mean urticaria control test score was 7.9, one in two patients had angioedema, and the most frequent comorbidities were chronic inducible urticaria (CIndU; 24%), allergic rhinitis (18.2%), hypertension (18.1%), asthma (12%), and depression (9.5%). Overall, 57.6% of patients were receiving at least one pharmacological treatment including second-generation H1-antihistamines (46.3%), first-generation H1-antihistamines (9.1%), and corticosteroids (15.8%). The mean DLQI, total CU-Q2 oL, and total AE-QoL scores were 8.3, 36.2, and 46.8, respectively. CSU patients reported frequent use of healthcare resources, including emergency services (29.7%), general practitioners (71.9%), and additional allergists or dermatologists (50.7%).

    CONCLUSIONS AND CLINICAL RELEVANCE: This study reveals that German H1-antihistamine-refractory CSU patients have high rates of uncontrolled disease, angioedema, and comorbid CIndU, are undertreated, have impaired QoL, and rely heavily on healthcare resources.

    Pubmed
  • Contact allergy to preservatives: ESSCA* results with the baseline series, 2009-2012.

    J Eur Acad Dermatol Venereol. 2017;31(4): 664-671

    Giménez-Arnau AM, Deza G, Bauer A, Johnston GA, Mahler V, Schuttelaar ML, Sánchez-Pérez J, Silvestre JF, Wilkinson M, Uter W

    BACKGROUND: Allergic contact dermatitis caused by biocides is common and causes significant patient morbidity.

    OBJECTIVE: To describe the current frequency and pattern of patch test reactivity to biocide allergens included in the baseline series of most European countries.

    METHODS: Data collected by the European Surveillance System on Contact Allergies (ESSCA) network between 2009 and 2012 from 12 European countries were analysed.

    RESULTS: Methylisothiazolinone 0.2% aq. produced the highest prevalence of sensitization during the study period, with an overall prevalence of 4.5%. The mixture methylchloroisothiazolinone /methylisothiazolinone tested at 0.02% aq. followed closely, with 4.1% of positive reactions. Other preservatives with lower rates of sensitization, but still over 1%, include methyldibromo glutaronitrile (MDBGN) 0.5% pet. and iodopropynyl butylcarbamate (IPBC) 0.2% pet. Formaldehyde releasers and parabens yielded less than 1% positive reactions during the study period. Some regional differences in the prevalence of contact allergy to biocides among European countries were observed.

    CONCLUSIONS: Contact allergy to biocides is common throughout Europe, and regional differences could be explained by differences in exposure or characteristics of the population tested. Timely regulatory action for isothiazolinones is required. Although MDBGN is banned from cosmetics products since 2005, sensitization prevalence has not appeared to plateau. IPBC is an emerging allergen with an increasing prevalence over the last few years, and its inclusion in the European baseline series may be appropriate.

    Pubmed
  • Statement of the German Contact Dermatitis Research Group (DKG) and the German Dermatological Society (DDG) on liability issues associated with patch testing using a patient's own materials.

    J Dtsch Dermatol Ges. 2017;15(2): 202-204

    Mahler V, Dickel H, Diepgen TL, Hillen U, Geier J, Kaufmann R, Kreft B, Schnuch A, Szliska C, Bender A

    Pubmed
  • Analysis of the German DRG data for livedoid vasculopathy and calciphylaxis.

    J Eur Acad Dermatol Venereol. 2017;31(11): 1884-1889

    Renner R, Dissemond J, Goerge T, Hoff N, Kröger K, Erfurt-Berge C

    BACKGROUND: Livedoid vasculopathy and calciphylaxis are rare skin disorders. Large cohorts of patients have been missing so far for detailed analysis.

    PATIENTS AND METHODS: Data from diagnosis-related groups (DRGs) of hospitalized cases of livedoid vasculopathy (ntotal = 1357) and calciphylaxis (ntotal = 699) were analysed for the years 2008-2013 concerning sex, age and frequency of diagnosis. To avoid deviations to non-relevant secondary diagnosis and due to changes in ICD-10 indices, we selected the two most recent available years 2013 and 2014 for evaluation of the accompanying diagnoses for both, livedoid vasculopathy (n = 519) and calciphylaxis (n = 324). Those were additionally evaluated as possible comorbidity.

    RESULTS: The male-female ratio for livedoid vasculopathy was 2.1:1. Patients older than 45 years comprehended 74.7% of all patients with peaks between the ages of 45-50 and 70-75. Livedoid vasculopathy patients suffered from cardiovascular and renal diseases. Coding of coagulation disorders was found rarely in our analysis. For calciphylaxis, we calculated a male-female ratio of 1.7:1. Most of the patients were at an age between 65 and 80 years. Diagnosis at an age under 35 years was rare. In general, most calciphylaxis patients showed end-stage renal disease with need of dialysis and presented with the resulting complications.

    CONCLUSIONS: Our data analysis shows relevant comorbidity and cofactors of these rare diseases like livedoid vasculopathy and calciphylaxis in Germany by a large number of cases.

    Pubmed
  • Immune checkpoint blockade can synergize with radiation therapy, even in tumors resistant to checkpoint monotherapy.

    EMBO Mol Med. 2017;9(2): 135-136

    Dörrie J

    Immunotherapy has evolved as a new pillar of cancer treatment during the last decade. The main breakthrough was the development of immune checkpoint blocking (ICB) antibodies, which antagonize inhibitory receptors on T cells and their ligands and thus unleash the cellular immune system against the tumor. ICB showed tremendous effects in several types of cancer. However, only a proportion of the patients suffering from tumors, which are in principle sensitive, benefit from this treatment and other kinds of neoplasia are completely resistant. Great effort is currently being undertaken to distinguish responders from non-responders, and concepts to turn the latter into the former are urgently required. One approach is to combine ICB with already well-established treatment strategies, that is, the other mainstays of cancer therapy such as surgery, radiation therapy (RT), and chemotherapy. Depending on the circumstances, both chemotherapy and RT may act either immune suppressively or immune stimulatingly. In this issue of EMBO Molecular Medicine, Azad etal () show that indeed, pancreatic ductal adenocarcinoma, which is resistant to ICB monotherapy, becomes responsive to this treatment by simultaneous RT or chemotherapy.

    Pubmed
  • Skin symptoms as diagnostic clue for autoinflammatory diseases.

    An Bras Dermatol. 2017;92(1): 72-80

    Moreira A, Torres B, Peruzzo J, Mota A, Eyerich K, Ring J

    Autoinflammatory disorders are immune-mediated diseases with increased production of inflammatory cytokines and absence of detectable autoantibodies. They course with recurrent episodes of systemic inflammation and fever is the most common symptom. Cutaneous manifestations are prevalent and important to diagnosis and early treatment of the syndromes. The purpose of this review is to emphasize to dermatologists the skin symptoms present in these syndromes in order to provide their early diagnosis.

    Pubmed
  • Das Interesse an Solarien und Sonnenschutz im deutschsprachigen Raum.

    J Dtsch Dermatol Ges. 2017;15(12): 1192-1198

    Kirchberger MC, Kirchberger LF, Eigentler TK, Reinhard R, Berking C, Schuler G, Heinzerling L, Heppt MV

    Pubmed
  • Rapid development of bilateral necroses of the upper extremity.

    J Dtsch Dermatol Ges. 2017;15(11): 1163-1165

    Kirchberger MC, Erfurt-Berge C

    Pubmed
  • Minimum standards on prevention, diagnosis and treatment of occupational and work-related skin diseases in Europe - position paper of the COST Action StanDerm (TD 1206).

    J Eur Acad Dermatol Venereol. 2017;31 Suppl 4(): 31-43

    Alfonso JH, Bauer A, Bensefa-Colas L, Boman A, Bubaš M, Constandt L, Crepy MN, Gonçalo M, Macan J, Mahler V, Mijakoski D, Ramada Rodilla JM, Rustemeyer T, Spring P, John SM, Uter W, Wilkinson M, Giménez-Arnau AM

    BACKGROUND: Skin diseases constitute up to 40% of all notified occupational diseases in most European countries, predominantly comprising contact dermatitis, contact urticaria, and skin cancer. While insufficient prevention of work-related skin diseases (WRSD) is a top-priority problem in Europe, common standards for prevention of these conditions are lacking.

    OBJECTIVE: To develop common European standards on prevention and management of WRSD and occupational skin diseases (OSD).

    METHOD: Consensus amongst experts within occupational dermatology was achieved with regard to the definition of minimum evidence-based standards on prevention and management of WRSD/OSD.

    RESULTS: By definition, WRSDs/OSDs are (partially or fully) caused by occupational exposure. The definition of OSD sensu stricto additionally includes diverging national legal requirements, with an impact on registration, prevention, management, and compensation. With the implementation of the classification of WRSD/OSD in the International Classification of Diseases (ICD) 11th Revision in future, a valid surveillance and comparability across countries will be possible. Currently, WRDS and OSD are still under-reported. Depending on legislation and regulations, huge differences exist in notification procedures in Europe, although notification is crucial to prevent chronic and relapsing disease. Facilities for early diagnosis, essential for individual patient management, should be based on existing guidelines and include a multidisciplinary approach. Patch testing is essential if contact dermatitis persists or relapses. Workplace exposure assessment of WRSD/OSD requires full labelling of product ingredients on material safety data sheets helping to identify allergens, irritants and skin carcinogens. Comparable standards in primary, secondary and tertiary prevention must be established in Europe to reduce the burden of WRSD/OSD in Europe.

    CONCLUSION: The adoption of common European standards on prevention of WRSD/OSD will contribute to reduce the incidence of OSD and their socio-economic burden.

    Pubmed
  • Re "International survey on skin patch test procedures, attitudes and interpretation" L.K. Tanno et al., WAOJ (2016) 9:8.

    World Allergy Organ J. 2017;10(1):

    Uter W, Bruze M, Rustemeyer T, Orton D, Mahler V, European Society of Contact Dermatitis

    A previous survey on the practice of diagnostic patch testing among representatives of member societies of the World Allergy Organization (WAO) has, in some countries, not addressed those stakeholders actually involved in patch testing, mainly dermatologists. The need for further standardisation is acknowledged and has been addressed e.g. by publication of a patch test guideline by the European Society of Contact Dermatitis in October 2015.

    Pubmed
  • The α4β1 Homing Pathway Is Essential for Ileal Homing of Crohn's Disease Effector T Cells In Vivo.

    Inflamm Bowel Dis. 2017;23(3): 379-391

    Zundler S, Fischer A, Schillinger D, Binder MT, Atreya R, Rath T, López-Posadas R, Voskens CJ, Watson A, Atreya I, Neufert C, Neurath MF

    BACKGROUND: The precise mechanisms controlling homing of T effector (Teff) cells to the inflamed gut in Crohn's disease (CD) are still unclear, and clinical outcome data from patients with inflammatory bowel disease treated with the anti-α4β7 integrin antibody vedolizumab suggest differences between ulcerative colitis and CD.

    METHODS: Expression of homing molecules was studied with flow cytometry and immunohistochemistry. Their functional role was investigated in in vitro adhesion assays and in a humanized mouse model of T cell homing to the inflamed gut in vivo.

    RESULTS: Despite in vitro blockade of CD Teff adhesion to mucosal vascular addressin cell adhesion molecule-1 (MadCAM-1) and in contrast to previous observations in ulcerative colitis, anti-α4β7 treatment did not result in reduced Teff cell homing to the colon in vivo. However, the integrin α4β1 was expressed in higher levels on Teffs from patients with CD compared with controls, while its expression in the peripheral blood declined, and its expression in the intestine increased during the course of clinical vedolizumab treatment. Consistently, adhesion of CD Teffs to vascular cell adhesion molecule-1 (VCAM-1) was blocked by inhibition of α4 and α4β1 in vitro. Moreover, in vivo homing of CD Teffs to the ileum was reduced by inhibition of α4 and α4β1 integrins, but not α4β7 integrins.

    CONCLUSIONS: Our findings suggest that Teff cell homing to the ileum through the axis α4β1-VCAM-1 is an essential and nonredundant pathway in CD in vivo, possibly affecting efficacy of clinical treatment with antiadhesion compounds.

    Pubmed
  • Genomewide association study identifies GALC as susceptibility gene for mucous membrane pemphigoid.

    Exp Dermatol. 2017;26(12): 1214-1220

    Sadik CD, Bischof J, van Beek N, Dieterich A, Benoit S, Sárdy M, Worm M, Meller S, Gläser R, Zillikens D, Homey B, Setterfield J, Minassian D, Schmidt E, Dart J, MMP study group 2009 - 2014 , Autoimmune Bullous Diseases Study Group , Ibrahim SM, Booth D, Reid E, Carnt N, Gugliemetti S, Shanmuganathan V, Watson M, Saw V, Wilkins M, McCudden V, Ahmad S, Bunce C, Günther C, Hadaschik E, Pföhler C, Schmieder A, Steinbrink K, Sticherling M

    Mucous membrane pemphigoid (MMP) is a rare, chronic and often aggressive subepidermal autoimmune blistering disease potentially affecting several mucous membranes with blisters and secondary erosions and scars. The pathogenesis of MMP is poorly understood, and the contribution of genetic predispositions, other than HLA class II allele variants to MMP, is unknown. The objective of this study is to identify susceptibility genes for MMP in a British cohort of MMP patients. A GWAS was conducted in a British cohort of 106 MMP patients. Publicly available genotypes of 2900 blood donors of the UK Blood Service and of 6740 individuals of the 1958 British Birth Cohort served as control. Subsequently, putative susceptibility genes were independently replicated in a German cohort of 42 MMP patients. The GWAS found 38 SNPs in 28 haploblocks with an odds ratio >2 reaching genomewide significance (P < 5.7 × 10-7 ). Replication confirmed an association of MMP with SNPs in rs17203398 (OR: 3.9), located intronically in the β-galactocerebrosidase gene (GALC) on chromosome 14 and with recessive polymorphisms in rs9936045 (OR: 3.1) in the intergenic region between CASC16 and CHD9 on chromosome 16. The risk of developing MMP is partially genetically determined. SNPs in GALC enhance the risk for MMP, indicating that β-galactocerebrosidase may be involved in the pathogenesis of MMP. Likewise, impacts of polymorphisms in the intergenic region between CASC16 and CHD9 on the activity of neighbouring genes may facilitate the emergence of MMP. The putative role of both polymorphisms requires functional studies in the future.

    Pubmed
  • Rasche Entwicklung bilateraler Nekrosen der oberen Extremität.

    J Dtsch Dermatol Ges. 2017;15(11): 1163-1165

    Kirchberger MC, Erfurt-Berge C

    Pubmed
  • Allergologische und mikrobiologische Gefährdung durch Hautmarkierung bei medizinischen Prozeduren?

    J Dtsch Dermatol Ges. 2017;15(10): 1034-1037

    Maronna A, Psaier S, Erfurt-Berge C, Geier J, Mahler V

    Pubmed
  • Späte Diagnose einer subkutanen Dirofilariose nach einem Mückenstich in Deutschland.

    J Dtsch Dermatol Ges. 2017;15(7): 727-728

    Uslu U, Jahn J, Erdmann M

    Pubmed
  • House dust mite-specific immunotherapy with two licensed vaccines: Outcome under clinical routine conditions.

    Immun Inflamm Dis. 2017;5(2): 132-140

    Mahler V, Klein C, Sager A, Zimmermann J

    INTRODUCTION: House dust mite (HDM) allergens are major causes for the development of allergic diseases. A disease modifying effect and clinical benefit of allergen immunotherapy (AIT) has been demonstrated in a number of clinical trials. Clinical trials, however, are carried out in selected populations under specific conditions based on inclusion and exclusion criteria and may not represent the entire patient population from medical practice. Objective of this study conducted in patients with HDM allergy was to systematically collect information about the benefit of AIT under clinical routine conditions.

    METHODS: In this prospective, multi-center non-interventional study, 220 patients (117 adults, 103 children) with HDM allergy receiving subcutaneous AIT with Depigoid® were monitored for 2 years. Organ-specific key symptoms, health-related quality of life (QoL), and the use of concomitant anti-allergic medication were assessed at baseline and after 12 and 24 months. Effectiveness and tolerability of the AIT was assessed by physicians and patients. Occurrence of adverse events (AEs) was continuously monitored.

    RESULTS: Two hundred and nineteen patients (116 adults, 103 children) were evaluated. A major improvement of the total symptom-score was observed after 24 (12) months in 76% (72%) and 80% (79%) of adults and children, respectively, accompanied by a reduction in concomitant anti-allergic medication and a pronounced improvement in QoL. The effectiveness and tolerability of the AIT was estimated as very good/good by 80-90% of physicians and patients. AEs were observed in 4/117 adults (3.4%) and in 7/103 children (6.8%). Serious AEs were reported in three adults and one child: A grade-II anaphylactic reaction (one adult) controlled by oral antihistamines (no hospitalization) classified as "definitely," three others as not (2) or possibly (1) drug-related.

    CONCLUSIONS: The data collected from 220 patients confirm the efficacy, tolerability/safety, and acceptance of AIT with Depigoid® in adults and children with HDM allergy under routine clinical conditions.

    Pubmed
  • An Interactive Macrophage Signal Transduction Map Facilitates Comparative Analyses of High-Throughput Data.

    J Immunol. 2017;198(5): 2191-2201

    Wentker P, Eberhardt M, Dreyer FS, Bertrams W, Cantone M, Griss K, Schmeck B, Vera J

    Macrophages (Mϕs) are key players in the coordination of the lifesaving or detrimental immune response against infections. The mechanistic understanding of the functional modulation of Mϕs by pathogens and pharmaceutical interventions at the signal transduction level is still far from complete. The complexity of pathways and their cross-talk benefits from holistic computational approaches. In the present study, we reconstructed a comprehensive, validated, and annotated map of signal transduction pathways in inflammatory Mϕs based on the current literature. In a second step, we selectively expanded this curated map with database knowledge. We provide both versions to the scientific community via a Web platform that is designed to facilitate exploration and analysis of high-throughput data. The platform comes preloaded with logarithmic fold changes from 44 data sets on Mϕ stimulation. We exploited three of these data sets-human primary Mϕs infected with the common lung pathogens Streptococcus pneumoniae, Legionella pneumophila, or Mycobacterium tuberculosis-in a case study to show how our map can be customized with expression data to pinpoint regulated subnetworks and druggable molecules. From the three infection scenarios, we extracted a regulatory core of 41 factors, including TNF, CCL5, CXCL10, IL-18, and IL-12 p40, and identified 140 drugs targeting 16 of them. Our approach promotes a comprehensive systems biology strategy for the exploitation of high-throughput data in the context of Mϕ signal transduction. In conclusion, we provide a set of tools to help scientists unravel details of Mϕ signaling. The interactive version of our Mϕ signal transduction map is accessible online at vcells.net/macrophage.

    Pubmed
  • Allergenic and microbiological hazards caused by skin markings during medical procedures?

    J Dtsch Dermatol Ges. 2017;15(10): 1034-1036

    Maronna A, Psaier S, Erfurt-Berge C, Geier J, Mahler V

    Pubmed
  • Proteomic Response of Human Umbilical Vein Endothelial Cells to Histamine Stimulation.

    Proteomics. 2017;17(21):

    Emirbayer PE, Sinha A, Ignatchenko V, Hoyer S, Dörrie J, Schaft N, Pischetsrieder M, Kislinger T

    The histamine receptors (HRs) represent a subclass of G protein-coupled receptors (GPCRs) and comprise four subtypes. Due to their numerous physiological and pathological effects, HRs are popular drug targets for the treatment of allergic reactions or the regulation of gastric acid secretion. Hence, an understanding of the functional selectivity of HR ligands has gained importance. These ligands can bind to specific GPCRs and selectively activate defined pathways. Supporting the activation of a therapeutically necessary pathway without the activation of other signaling cascades can result in drugs with more specific activity and fewer side effects. To evaluate the cellular consequences resulting from receptor binding, comprehensive analyses of cellular protein alterations upon incubation with ligands are required. For this purpose, endothelial cells are treated with histamine, as the endogenous ligand of HRs, to obtain a global overview of its cellular effects. Quantitative proteomics and pathway analyses of histamine-treated and untreated cells reveal enrichment of the nuclear factor-κB and tumor necrosis factor signaling pathways, cytokine-cytokine receptor interactions, complement and coagulation cascades, and acute inflammatory processes upon histamine treatment. This strategy offers the opportunity to monitor HR-mediated signaling in a multidimensional manner.

    Pubmed
  • Targeted label-free quantification of interleukin-8 in PMA-activated U937 cell secretome by nanoLC-ESI-MS/MS-sSRM.

    Proteomics. 2017;17(9):

    Emirbayer PE, Gerer KF, Hoyer S, Pischetsrieder M

    Monocytes are a part of the innate immune system. Their differentiation into macrophages changes their cellular proteome and secretome. Particularly secretome components such as cytokines are crucial for immune response and inflammation in many diseases. Differentiation of human lymphoma cell line U937 can be triggered by phorbol 12-myristate 13-acetate (PMA). Screening of the cytokine release in U937 upon PMA stimulation by cytometric bead array almost exclusively showed interleukin-8 (IL-8). Next, a label-free nanoLC-ESI-MS/MS-sSRM method for quantification of IL-8 in the cell secretome was established and applied to monitor the time kinetics of PMA treatment in different concentrations. Targeted secretome analysis was achieved by scheduled SRM-MS using one proteotypic peptide as precursor ion and four mass transitions. Label-free quantification was performed by external calibration using IL-8 standard. Validation results indicated that the method was suited for the quantification of IL-8 in the secretome. The maximal IL-8 release of 62.4 ng/mL was observed after incubating cells treated by 50 ng/mL PMA for 48 h. The method can now be used for quantification of IL-8 release from different cells under various conditions. Furthermore, it can be easily expanded to other secreted proteins detected by untargeted screening methods.

    Pubmed
  • Intracorneal Hematoma Showing Clinical and Dermoscopic Features of Acral Lentiginous Melanoma.

    Case Rep Dermatol Med. 2017;2017():

    Uslu U, Heppt F, Erdmann M

    Intra- and subcorneal hematoma, a skin alteration seen palmar and plantar after trauma or physical exercise, can be challenging to distinguish from in situ or invasive acral lentiginous melanoma. Thus, careful examination including dermoscopic and histologic assessment may be necessary to make the correct diagnosis. We here present a case of a 67-year-old healthy female patient who presented with a pigmented plantar skin alteration. Differential diagnoses included benign skin lesions, for example, hematoma or melanocytic nevus, and also acral lentiginous melanoma or melanoma in situ. Since clinical and dermoscopic examinations did not rule out a malignant skin lesion, surgical excision was performed and confirmed an intracorneal hematoma. In summary, without adequate physical trigger, it may be clinically and dermoscopically challenging to make the correct diagnosis in pigmented palmar and plantar skin alterations. Thus, biopsy or surgical excision of the skin alteration may be necessary to rule out melanoma.

    Pubmed
  • Unraveling a tumor type-specific regulatory core underlying E2F1-mediated epithelial-mesenchymal transition to predict receptor protein signatures.

    Nat Commun. 2017;8(1):

    Khan FM, Marquardt S, Gupta SK, Knoll S, Schmitz U, Spitschak A, Engelmann D, Vera J, Wolkenhauer O, Pützer BM

    Cancer is a disease of subverted regulatory pathways. In this paper, we reconstruct the regulatory network around E2F, a family of transcription factors whose deregulation has been associated to cancer progression, chemoresistance, invasiveness, and metastasis. We integrate gene expression profiles of cancer cell lines from two E2F1-driven highly aggressive bladder and breast tumors, and use network analysis methods to identify the tumor type-specific core of the network. By combining logic-based network modeling, in vitro experimentation, and gene expression profiles from patient cohorts displaying tumor aggressiveness, we identify and experimentally validate distinctive, tumor type-specific signatures of receptor proteins associated to epithelial-mesenchymal transition in bladder and breast cancer. Our integrative network-based methodology, exemplified in the case of E2F1-induced aggressive tumors, has the potential to support the design of cohort- as well as tumor type-specific treatments and ultimately, to fight metastasis and therapy resistance.Deregulation of E2F family transcription factors is associated with cancer progression and metastasis. Here, the authors construct a map of the regulatory network around the E2F family, and using gene expression profiles, identify tumour type-specific regulatory cores and receptor expression signatures associated with epithelial-mesenchymal transition in bladder and breast cancer.

    Pubmed
  • Transcription factor Sox10 regulates oligodendroglial Sox9 levels via microRNAs.

    Glia. 2017;65(7): 1089-1102

    Reiprich S, Cantone M, Weider M, Baroti T, Wittstatt J, Schmitt C, Küspert M, Vera J, Wegner M

    During development of myelin-forming oligodendrocytes in the central nervous system the two closely related transcription factors Sox9 and Sox10 play essential roles that are partly shared and partly unique. Whereas Sox9 primarily functions during oligodendroglial specification, Sox10 is uniquely required to induce terminal differentiation and myelination. During this process, Sox10 protein levels rise substantially. As this coincides with a reciprocal decrease in Sox9, we postulated that Sox10 influences Sox9 amounts in differentiating oligodendrocytes. Here we show that Sox9 levels are indeed inversely coupled to Sox10 levels such that Sox10 deletion in oligodendroglial cells evokes a reciprocal increase in Sox9. We furthermore provide evidence that this coupling involves upregulation of microRNAs miR335 and miR338 as direct transcriptional targets of Sox10. The two microRNAs in turn recognize the 3'-UTR of Sox9 mRNA and may thereby reduce Sox9 protein levels posttranscriptionally in oligodendroglial cells. Such a mechanism may enable oligodendroglial cells to adapt the ratio of both related Sox proteins in a manner required for successful lineage progression and differentiation. Mathematical modeling furthermore shows that the identified regulatory circuit has the potential to convert a transient stimulus into an irreversible switch of cellular properties and may thus contribute to terminal differentiation of oligodendrocytes.

    Pubmed
  • Allergic contact dermatitis caused by a catheter system containing sodium metabisulfite.

    Contact Dermatitis. 2017;76(3): 186-187

    Grosch E, Mahler V

    Pubmed
  • The current spectrum of contact sensitization in patients with chronic leg ulcers or stasis dermatitis - new data from the Information Network of Departments of Dermatology (IVDK).

    Contact Dermatitis. 2017;77(3): 151-158

    Erfurt-Berge C, Geier J, Mahler V

    BACKGROUND: Patients with lower leg dermatitis, chronic venous insufficiency or chronic leg ulcers have a high prevalence of contact sensitization.

    OBJECTIVES: To identify the current spectrum of contact allergens in these patients.

    PATIENTS AND METHODS: Data of the Information Network of Departments of Dermatology on 5264 patients with the above diagnoses from the years 2003 to 2014 (study group) were compared with data on 4881 corresponding patients from 1994 to 2003 (historical control group) and with a current control group without these diagnoses (n = 55 510).

    RESULTS: Allergic contact dermatitis was diagnosed less frequently in the study group than in the historical control group (25.9% versus 16.9%; p < 0.001), and contact sensitization to most allergens had declined. The allergen spectrum, however, was largely unchanged. Important allergens are Myroxylon pereirae (balsam of Peru) (14.8% positive reactions), fragrance mix I (11.4%), lanolin alcohol (7.8%), colophonium (6.6%), neomycin sulfate (5.0%), cetearyl alcohol (4.4%), oil of turpentine (3.1%), and paraben mix (2.6%). Patch testing with additional series showed sensitization to Amerchol L-101 (9.7%), tert-butyl hydroquinone (8.7%), framycetin sulfate (5.0%), and gentamicin sulfate (3.1%).

    CONCLUSIONS: Topical preparations for treating the above-mentioned conditions should not contain fragrances, Myroxylon pereirae, and colophonium. The special allergen spectrum has to be considered in patch testing.

    Pubmed
  • European Surveillance System on Contact Allergies (ESSCA): results with the European baseline series, 2013/14.

    J Eur Acad Dermatol Venereol. 2017;31(9): 1516-1525

    Uter W, Amario-Hita JC, Balato A, Ballmer-Weber B, Bauer A, Belloni Fortina A, Bircher A, Chowdhury MMU, Cooper SM, Czarnecka-Operacz M, Dugonik A, Gallo R, Giménez-Arnau A, Johansen JD, John SM, Kieć-Świerczyńska M, Kmecl T, Kręcisz B, Larese Filon F, Mahler V, Pesonen M, Rustemeyer T, Sadowska-Przytocka A, Sánchez-Pérez J, Schliemann S, Schuttelaar ML, Simon D, Spiewak R, Valiukeviciene S, Weisshaar E, White IR, Wilkinson SM

    BACKGROUND: Contact allergy is a common condition and can severely interfere with daily life or professional activities. Due to changes in exposures, such as introduction of new substances, new products or formulations and regulatory intervention, the spectrum of contact sensitization changes.

    OBJECTIVE: To evaluate the current spectrum of contact allergy to allergens present in the European baseline series (EBS) across Europe.

    METHODS: Retrospective analysis of data collected by the European Surveillance System on Contact Allergies (ESSCA, www.essca-dc.org) in consecutively patch-tested patients, 2013/14, in 46 departments in 12 European countries.

    RESULTS: Altogether, 31 689 patients were included in the analysis. Compared to a similar analysis in 2004, the prevalence of contact allergy to methylisothiazolinone went up to around 20% in several departments. In comparison, contact allergy to the metals nickel, cobalt and chromium remained largely stable, at 18.1%, 5.9% and 3.2%, respectively, similar to mostly unchanged prevalence with fragrance mix I, II and Myroxylon pereirae (balsam of Peru) at 7.3%, 3.8% and 5.3%, respectively. In the subgroup of departments diagnosing (mainly) patients with occupational contact dermatitis, the prevalence of work-related contact allergies such as epoxy resin or rubber additives was found to be increased, compared to general dermatology departments.

    CONCLUSION: Continuous surveillance of contact allergy based on network data offers the identification of time trends or persisting problems, and thus enables focussing in-depth research (subgroup analyses, exposure analysis) on areas where it is needed.

    Pubmed
  • Patch testing with rubber series in Europe: a critical review and recommendation.

    Contact Dermatitis. 2017;76(4): 195-203

    Warburton KL, Uter W, Geier J, Spiewak R, Mahler V, Crépy MN, Schuttelaar ML, Bauer A, Wilkinson M

    BACKGROUND: Rubber additives constitute an important group of contact allergens, particularly in certain occupations.

    OBJECTIVES: To collect information regarding the current practice of using a 'rubber series' in Europe, and discuss this against the background of evidence concerning the prevalence of allergy in order to derive a recommendation for a 'European rubber series'.

    METHODS: The following were performed: (i) a survey targeting all members of the COST action 'StanDerm' consortium, (ii) analysis of rubber contact allergy data in the database of the European Surveillance System on Contact Allergies, and (iii) a literature review.

    RESULTS: Information from 13 countries was available, from one or several departments of dermatology, and occasionally occupational health. Apart from some substances tested only in single departments, a broad overlap regarding important allergens was evident, but considerable variation existed between departments.

    CONCLUSIONS: An up-to-date 'European rubber series' is recommended, with the exclusion of substances only of historical concern. A 'supplementary rubber series' containing allergens of less proven importance, requiring further analysis, is recommended for departments specializing in occupational contact allergy. These should be continually updated as new evidence emerges.

    Pubmed
  • ADF Winter School-An exciting concept of the Arbeitsgemeinschaft Dermatologische Forschung to connect young scientists and clinician scientists in Dermatology at the top of Germany.

    Exp Dermatol. 2017;26(3): 292-294

    Yazdi AS, Barlin M, Böhm K, Gendrisch F, Ghorbanalipoor S, Häberle S, Hamel A, Hüning S, Hüttner C, Iwanova I, Kanaki T, Kimeswenger S, Lohmann N, Munir S, Muzumdar S, Pereira MP, Peking P, Plesser K, Rendon A, Rentschler M, Schlumprecht C, Smorodchenko A, Stock M, Tillmanns J, Uslu U, Ghoreschi K, Glatz M, Grabbe S, Kunz M, Ludwig R, Scharffetter-Kochanek K, Loser K

    Pubmed
  • THP-1-derived macrophages render lung epithelial cells hypo-responsive to Legionella pneumophila - a systems biology study.

    Sci Rep. 2017;7(1):

    Schulz C, Lai X, Bertrams W, Jung AL, Sittka-Stark A, Herkt CE, Janga H, Zscheppang K, Stielow C, Schulte L, Hippenstiel S, Vera J, Schmeck B

    Immune response in the lung has to protect the huge alveolar surface against pathogens while securing the delicate lung structure. Macrophages and alveolar epithelial cells constitute the first line of defense and together orchestrate the initial steps of host defense. In this study, we analysed the influence of macrophages on type II alveolar epithelial cells during Legionella pneumophila-infection by a systems biology approach combining experimental work and mathematical modelling. We found that L. pneumophila-infected THP-1-derived macrophages provoke a pro-inflammatory activation of neighboring lung epithelial cells, but in addition render them hypo-responsive to direct infection with the same pathogen. We generated a kinetic mathematical model of macrophage activation and identified a paracrine mechanism of macrophage-secreted IL-1β inducing a prolonged IRAK-1 degradation in lung epithelial cells. This intercellular crosstalk may help to avoid an overwhelming inflammatory response by preventing excessive local secretion of pro-inflammatory cytokines and thereby negatively regulating the recruitment of immune cells to the site of infection. This suggests an important but ambivalent immunomodulatory role of macrophages in lung infection.

    Pubmed
  • Corrigendum: Multiplicity of Mathematical Modeling Strategies to Search for Molecular and Cellular Insights into Bacteria Lung Infection.

    Front Physiol. 2017;8():

    Cantone M, Santos G, Wentker P, Lai X, Vera J

    [This corrects the article on p. 645 in vol. 8, PMID: 28912729.].

    Pubmed
  • Multiplicity of Mathematical Modeling Strategies to Search for Molecular and Cellular Insights into Bacteria Lung Infection.

    Front Physiol. 2017;8():

    Cantone M, Santos G, Wentker P, Lai X, Vera J

    Even today two bacterial lung infections, namely pneumonia and tuberculosis, are among the 10 most frequent causes of death worldwide. These infections still lack effective treatments in many developing countries and in immunocompromised populations like infants, elderly people and transplanted patients. The interaction between bacteria and the host is a complex system of interlinked intercellular and the intracellular processes, enriched in regulatory structures like positive and negative feedback loops. Severe pathological condition can emerge when the immune system of the host fails to neutralize the infection. This failure can result in systemic spreading of pathogens or overwhelming immune response followed by a systemic inflammatory response. Mathematical modeling is a promising tool to dissect the complexity underlying pathogenesis of bacterial lung infection at the molecular, cellular and tissue levels, and also at the interfaces among levels. In this article, we introduce mathematical and computational modeling frameworks that can be used for investigating molecular and cellular mechanisms underlying bacterial lung infection. Then, we compile and discuss published results on the modeling of regulatory pathways and cell populations relevant for lung infection and inflammation. Finally, we discuss how to make use of this multiplicity of modeling approaches to open new avenues in the search of the molecular and cellular mechanisms underlying bacterial infection in the lung.

    Pubmed
  • Identification of miRNA-mRNA Modules in Colorectal Cancer Using Rough Hypercuboid Based Supervised Clustering.

    Sci Rep. 2017;7(): 42809

    Paul S, Lakatos P, Hartmann A, Schneider-Stock R, Vera J

    Differences in the expression profiles of miRNAs and mRNAs have been reported in colorectal cancer. Nevertheless, information on important miRNA-mRNA regulatory modules in colorectal cancer is still lacking. In this regard, this study presents an application of the RH-SAC algorithm on miRNA and mRNA expression data for identification of potential miRNA-mRNA modules. First, a set of miRNA rules was generated using the RH-SAC algorithm. The mRNA targets of the selected miRNAs were identified using the miRTarBase database. Next, the expression values of target mRNAs were used to generate mRNA rules using the RH-SAC. Then all miRNA-mRNA rules have been integrated for generating networks. The RH-SAC algorithm unlike other existing methods selects a group of co-expressed miRNAs and mRNAs that are also differentially expressed. In total 17 miRNAs and 141 mRNAs were selected. The enrichment analysis of selected mRNAs revealed that our method selected mRNAs that are significantly associated with colorectal cancer. We identified novel miRNA/mRNA interactions in colorectal cancer. Through experiment, we could confirm that one of our discovered miRNAs, hsa-miR-93-5p, was significantly up-regulated in 75.8% CRC in comparison to their corresponding non-tumor samples. It could have the potential to examine colorectal cancer subtype specific unique miRNA/mRNA interactions.

    Pubmed
  • The AP-1 Transcription Factor c-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages.

    J Immunol. 2017;198(9): 3605-3614

    Hannemann N, Jordan J, Paul S, Reid S, Baenkler HW, Sonnewald S, Bäuerle T, Vera J, Schett G, Bozec A

    Activation of proinflammatory macrophages is associated with the inflammatory state of rheumatoid arthritis. Their polarization and activation are controlled by transcription factors such as NF-?B and the AP-1 transcription factor member c-Fos. Surprisingly, little is known about the role of the AP-1 transcription factor c-Jun in macrophage activation. In this study, we show that mRNA and protein levels of c-Jun are increased in macrophages following pro- or anti-inflammatory stimulations. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment cluster analyses of microarray data using wild-type and c-Jun-deleted macrophages highlight the central function of c-Jun in macrophages, in particular for immune responses, IL production, and hypoxia pathways. Mice deficient for c-Jun in macrophages show an amelioration of inflammation and bone destruction in the serum-induced arthritis model. In vivo and in vitro gene profiling, together with chromatin immunoprecipitation analysis of macrophages, revealed direct activation of the proinflammatory factor cyclooxygenase-2 and indirect inhibition of the anti-inflammatory factor arginase-1 by c-Jun. Thus, c-Jun regulates the activation state of macrophages and promotes arthritis via differentially regulating cyclooxygenase-2 and arginase-1 levels.

    Pubmed
  • A new semisynthetic cardenolide analog 3?-[2-(1-amantadine)- 1-on-ethylamine]-digitoxigenin (AMANTADIG) affects G2/M cell cycle arrest and miRNA expression profiles and enhances proapoptotic survivin-2B expression in renal cell carcinoma cell lines.

    Oncotarget. 2017;8(7): 11676-11691

    Nolte E, Wach S, Silva IT, Lukat S, Ekici AB, Munkert J, Müller-Uri F, Kreis W, Oliveira Simões CM, Vera J, Wullich B, Taubert H, Lai X

    Cardiac glycosides are well known in the treatment of cardiovascular diseases; however, their application as treatment option for cancer patients is under discussion. We showed that the cardiac glycoside digitoxin and its analog AMANTADIG can inhibit the growth of renal cell carcinoma (RCC) cell lines and increase G2/M cell cycle arrest. To identify the signaling pathways and molecular basis of this G2/M arrest, microRNAs were profiled using microRNA arrays. Cardiac glycoside treatment significantly deregulated two microRNAs, miR-2278 and miR-670-5p. Pathway enrichment analysis showed that all cardiac glycoside treatments affected the MAPK and the axon guidance pathway. Within these pathways, three genes, MAPK1, NRAS and RAC2, were identified as in silico targets of the deregulated miRNAs. MAPK1 and NRAS are known regulators of G2/M cell cycle arrest. AMANTADIG treatment enhanced the expression of phosphorylated MAPK1 in 786-O cells. Secondly, we studied the expression of survivin known to be affected by cardiac glycosides and to regulate the G2/M cell phase. AMANTADIG treatment upregulated the expression of the pro-apoptotic survivin-2B variant in Caki-1 and 786-O cells. Moreover, treatment with AMANTADIG resulted in significantly lower survivin protein expression compared to 786-O control cells. Summarizing, treatment with all cardiac glycosides induced G2/M cell cycle arrest and downregulated the miR-2278 and miR-670-5p in microarray analysis. All cardiac glycosides affected the MAPK-pathway and survivin expression, both associated with the G2/M phase. Because cells in the G2/M phase are radio- and chemotherapy sensitive, cardiac glycosides like AMANTADIG could potentially improve the efficacy of radio- and/or chemotherapy in RCCs.

    Pubmed
  • Checkpoint blockade for metastatic melanoma and Merkel cell carcinoma in HIV-positive patients.

    Ann Oncol. 2017;28(12): 3104-3106

    Heppt MV, Schlaak M, Eigentler TK, Kähler KC, Kiecker F, Loquai C, Meier F, Tomsitz D, Brenner N, Niesert AC, Thonke R, Hauschild A, Berking C

    Pubmed
  • Inhibition of FGF receptors for effective treatment of BRAF- and BRAF/MEK inhibitor-resistant melanoma cells

    Exp Dermatol. 2017;26(3): E92-E92

    Graf SA, Strieder A, Meierjohann S, Heppt MV, Kammerbauer C, Berking C

    Pubmed
  • Peripheral myelin protein 2 is a target gene of the transcription factor SOX10 in melanoma and affects tumor cell invasion

    Exp Dermatol. 2017;26(3): E91-E92

    Graf SA, Heppt MV, Krebs S, Kammerbauer C, Hornig E, Strieder A, Blum H, Berking C

    Pubmed
  • Immune checkpoint blockade for unresectable or metastatic uveal melanoma: A systematic review.

    Cancer Treat Rev. 2017;60(): 44-52

    Heppt MV, Steeb T, Schlager JG, Rosumeck S, Dressler C, Ruzicka T, Nast A, Berking C

    The use of immune checkpoint blockade (ICB) for uveal melanoma (UM) is little established. The aim of this review was to provide a comprehensive overview on the efficacy, safety, and tolerability of ICB in patients with UM.We performed a systematic literature research covering MEDLINE, Embase and CENTRAL. Abstracts of pertinent conferences and trial registers were handsearched for relevant studies.Out of 1327 records initially identified, 12 eligible studies were included in the qualitative synthesis. They comprised 7 expanded access or named patient programs (n=162), 4 phase II trials (n=171), and 1 phase Ib trial (sample size unknown), while no randomized controlled trial was found. Ipilimumab monotherapy was assessed at 3mg/kg in 5 trials (n=186) with a response rate of 0 to 5%. Two reports investigated ipilimumab at 10mg/kg (n=45) with radiological responses observed in 0 to 6.5%. The median progression-free survival (PFS) was below 3months and the median overall survival was 5.2-9.8months for ipilimumab monotherapy. Severe immune-related adverse events occurred at a frequency comparable to cutaneous melanoma (6 to 36%). Two studies investigated pembrolizumab (2mg/kg) and nivolumab (3mg/kg) with overall response rates of 30% and 6%, respectively. Data on combined ipilimumab and programmed cell death protein 1 inhibition were available from one expanded access program, but no response was observed with a median PFS of 2.9months.UM is little responsive to ipilimumab regardless of dosage schemes. Sound randomized clinical trials are needed to evaluate the efficacy of combined ICB in patients with UM.

    Pubmed