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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

  • 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

  • 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.


  • 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.

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

    Br J Dermatol. 2023;188(2):

    Berking C

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • [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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

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

    Rheumatology (Oxford). 2023;():

    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: MicroRNAs (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 psoriatic arthritis (PsA) is currently unknown. We aimed to search for circulating miRNA signatures associated with PsO and PsA patients.

    METHODS: Expression of miRNAs was analyzed by 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 analyzed in 48 samples (PsA, PsO, controls: each N = 16). For validation, 17 selected miRNAs were measured in the total population.

    RESULTS: 141 patients and controls were analyzed (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). 17 top candidates from discovery were assessed in the validation phase, 9 of them discriminated PsA and PsO from controls (AUC ≥0.70, all p< 0.05). Four miRNAs (miR-19b-3p, miR-21-5p, miR-92a-3p and let-7b-5p) were significantly different regulated between PsO and PsA. A combination of these miRNAs increased 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, 5 of them previously reported to be involved in bone and cartilage metabolism, indicating intimate association of psoriatic inflammation and bone/cartilage changes.

  • 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

  • VEXAS syndrome mimicking lupus-like disease.

    Rheumatology (Oxford). 2023;():

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

  • 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.

  • 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.

  • 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.

  • SCLE manifestation after mRNA COVID-19 vaccination.

    J Eur Acad Dermatol Venereol. 2022;36(4): e261-e263

    Rechtien L, Erfurt-Berge C, Sticherling M

  • 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

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • 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.

  • 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

  • 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

  • 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.

  • Annual Health Care Utilization and Costs for Treatment of Cutaneous and Anogenital Warts Among a Commercially Insured Population in the US, 2017-2019 Reply

    JAMA Dermatol. 2022;():

    Heppt MV, Steeb T, Berking C

  • 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

  • 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.

  • [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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • 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.

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

    Eur J Immunol. 2022;():

    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.

  • 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.

  • 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.

  • Guidelines for mouse and human DC generation.

    Eur J Immunol. 2022;():

    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.

  • [The UV Protection Alliance in Germany-Purpose and goals].

    Ophthalmologe. 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.

  • Atypical Mycobacteriosis During TNF Blockade.

    Dtsch Arztebl Int. 2022;119(21):

    Kaufmann MD, Erfurt-Berge C, Wörl P

  • 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.

  • Guidelines for mouse and human DC functional assays.

    Eur J Immunol. 2022;():

    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.

  • 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

  • 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.

  • 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

  • [The UV Protection Alliance in Germany -Timeline of the development of the contents].

    Ophthalmologe. 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

  • 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

  • [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.

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

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

    Eur J Immunol. 2022;():

    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.

  • 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.

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

    J Cancer Educ. 2022;():

    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.

  • 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.

  • 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

  • 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.

  • 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.

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

    Eur J Immunol. 2022;():

    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.

  • 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.

  • [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.

  • 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.

  • 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.

  • [Wound treatment without curative intention: position paper of the Initiative Chronische Wunden (ICW) e. V.]

    Hautarzt. 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • [Position paper of the Initiative Chronische Wunde (ICW) e. V. on the nomenclature of debridement in chronic wounds].

    Hautarzt. 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.

  • 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

  • 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

  • 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.

  • 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

  • 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.

  • 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.

  • "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

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • 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


    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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.


    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

  • 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.

  • 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.

  • [3D whole body scans in dermatology-a new era in clinical practice and research?]

    Hautarzt. 2022;73(7): 575-579

    Sitaru S, Kaczmarczyk R, Erdmann M, Biedermann T, Zink A

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • [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.

  • Association of Fabry Disease and Psoriasis - therapeutically significant?

    J Dtsch Dermatol Ges. 2021;19 Suppl 2(): 85-85

    Sollfrank L, Sticherling M

  • 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.

  • 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

  • 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.

  • 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.


    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

  • 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.

  • 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.

  • 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.

  • 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

  • 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

  • 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

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • [Talking about vaccinations-also relevant for dermatology?]

    Hautarzt. 2021;72(2):

    Sticherling M

  • 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

  • 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.

  • 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.

  • 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

  • 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

  • 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.

  • 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

  • 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.

  • 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.

  • [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.

  • Onkologische Systemtherapie bis zum bitteren Ende?

    J Dtsch Dermatol Ges. 2021;19(9): 1259-1260

    Berking C

  • Spectrum of peristomal Dermatoses

    J Dtsch Dermatol Ges. 2021;19 Suppl 2(): 137-137

    Dietmaier L, Summa S, Erfurt-Berge C

  • 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.

  • 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.

  • 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

  • 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

  • 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.

  • 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

  • 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.

  • 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

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • B-cells in psoriasis?

    Exp Dermatol. 2021;30(3): E80-E80

    Banki S, Heusinger J, Herter-Kermann T, Sticherling M

  • 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.

  • 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

  • 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

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.


  • 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

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • 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.

  • 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

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • "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.

  • 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

  • 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

  • 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.

  • 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)

  • 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.

  • 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

  • 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.

  • 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.


  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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

  • 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

  • [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.

  • 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

  • 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.

  • 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

  • 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.

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • 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.

  • 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

  • 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.


    J Immunother Cancer. 2021;9 Suppl 1(): A17-A17

    Arakawa A, Vollmer S, Tietze J, Galinski A, Heppt MV, Berking C, Prinz JC

  • 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.

  • 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

  • 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.

  • 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.


    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

  • 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

  • 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.

  • 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.

  • 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

  • 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.

  • 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.

  • 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

  • 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.

  • 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.

  • 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

  • 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.

  • 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.

  • 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

  • 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.

  • 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

  • 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

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • Multiple thoracic Erosions after Vacation in Tunisia

    J Dtsch Dermatol Ges. 2021;19 Suppl 2(): 111-111

    Meder C, Sticherling M

  • 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.

  • 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.

  • [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.

  • 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

  • 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

  • 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.

  • 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

  • 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.

  • 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.

  • 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

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • Mesenchymal-Like Migration Strategies of Immune Cells in a 3D


    Biophys J. 2020;118(3): 600A-600A

    Czerwinski T, Mark C, Roessner S, Bosch-Voskens C, Bhattacharjee T, Angelini TE, Fabry B

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • 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

  • 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

  • [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.

  • 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.

  • 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

  • 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

  • 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

  • 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.

  • 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.

  • 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.

  • [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

  • 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.

  • 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

  • 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

  • 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

  • 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.

  • 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.

  • Editorial: Harnessing the Participation of Dendritic Cells in Immunity and Tolerance.

    Front Immunol. 2020;11():

    Boscardin SB, Dudziak D, Münz C, Rosa DS

  • 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.

  • 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.

  • 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

  • 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

  • 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

  • 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

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • [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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • Editorial: Sentinel CLECs at Immunological Decision Nodes.

    Front Immunol. 2020;11():

    Hoober JK, van Vliet SJ, Dudziak D, Eggink LL

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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

  • [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.

  • 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.

  • 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

  • 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

  • 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

  • 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.

  • 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.

  • 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

  • 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

  • Sinus Pericranii.

    Dtsch Arztebl Int. 2020;116(8): 136-136

    Heppt F, Meder C, Wagner N

  • [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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • [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.

  • 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.

  • 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

  • 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.


    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

  • 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

  • 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.

  • 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).

  • 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.

  • 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.

  • 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.

  • 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

  • [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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • 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.

  • 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.


    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

  • 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.

  • 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.

  • 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.

  • 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.

  • [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.

  • 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.

  • 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.

  • 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.


    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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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

  • 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

  • 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

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • 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


    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

  • 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.

  • 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.

  • 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

  • Melanoma (vol 392, pg 971, 2018)

    Lancet. 2019;393(10173): 746-746

    Schadendorf D, van Akkooi ACJ, Berking C

  • 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.

  • 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

  • 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.

  • 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

  • GMP-compliant human monocyte-derived dendritic cells for cancer

    vaccination generated by using the Quantum (R) hollow fiber bioreactor


    Ann Oncol. 2019;30(): 14-14

    Uslu U, Erdmann M, Wiesinger M, Schuler G, Schuler-Thurner B

  • 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.

  • [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.

  • 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.

  • 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.

  • Characterization of Patients with inoperable malignant Stage IIIB-D


    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

  • 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.

  • 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

  • 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.

  • 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.

  • 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

  • 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

  • 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.

  • [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.

  • 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.

  • 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

  • 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

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • Quality, Rather Than Quantity, of Life Is the Crucial Criterion Reply

    Dtsch Arztebl Int. 2019;116(20): 363-364

    Heinzerling L

  • 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

  • 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

  • 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.

  • 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.

  • 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



    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

  • 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.

  • 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

  • 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

  • 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.

  • 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.

  • 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

  • The myelin protein PMP2 is regulated by SOX10 and drives melanoma cell


    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

  • 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.

  • 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.

  • Multiple dermal Abscesses by Trichophyton rubrum in an immunosuppressed


    J Dtsch Dermatol Ges. 2019;17(): 136-137

    Toussaint F, Sticherling M

  • 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

  • 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

  • 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

  • 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

  • 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.

  • 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

  • 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

  • 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.

  • 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.

  • Psoriasis in children: a single center analysis

    J Dtsch Dermatol Ges. 2019;17(): 107-107

    Heppt F, Raap J, Sticherling M

  • Alopecia areata- Clinical Picture and Therapy Response of Heterogeneous


    J Dtsch Dermatol Ges. 2019;17(): 113-113

    Busch D, Sticherling M

  • 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

  • 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

  • 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

  • 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.

  • 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

  • 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.

  • 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).

  • Dermatomyositis- a rare, but important Disease between Dermatology and

    Internal Medicine

    J Dtsch Dermatol Ges. 2019;17(): 127-127

    Sell S, Sticherling M

  • 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

  • Systemische Sklerodermie - die dermatologische Sicht.

    J Dtsch Dermatol Ges. 2019;17(7): 716-729

    Sticherling M

  • 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

  • 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

  • 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.

  • 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.

  • 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.

  • Gastrointestinal: Eruptive seborrheic keratoses: sign of Leser-Trélat in gastric adenocarcinoma.

    J Gastroenterol Hepatol. 2019;34(12):

    Kirchberger MC

  • 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).

  • The Art of Making Moulages - a hidden Art?

    J Dtsch Dermatol Ges. 2019;17(): 79-79

    Sticherling M, Groenhardt K, Saake M

  • 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.

  • [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.

  • Functionalization of T lymphocytes for magnetically controlled immune

    therapy: Selection of suitable superparamagnetic iron oxide


    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.

  • 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

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • Dermatological Moulages in Germany- Comparison of Two Representative


    J Dtsch Dermatol Ges. 2019;17(): 110-110

    Sticherling M

  • 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.

  • [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

  • 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.

  • 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

  • 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

  • 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.

  • 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

  • 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.

  • Möglichkeiten und Grenzen von prognostischen Gensignaturen im frühen Melanom.

    J Dtsch Dermatol Ges. 2019;17(8): 769-770

    Heppt MV, Berking C

  • 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

  • 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.

  • 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

  • Isobornyl acrylate- contact allergen in continuous glucose sensor system

    Allergy. 2019;74(): 502-502

    Wagner N, Elsbergen L, Feustel J

  • 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

  • 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

  • Influence on contact allergy of immune-mediated skin diseases such as


    Br J Dermatol. 2019;180(2): 256-257

    Erfurt-Berge C

  • Quality of life assessment in family members of patients with chronic


    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.

  • 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

  • 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.

  • 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.

  • 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

  • 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

  • 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

  • Blood eosinophilia is an on-treatment biomarker in patients undergoing

    vaccination with dendritic cells that correlates with long-term patient


    J Dtsch Dermatol Ges. 2019;17(): 25-25

    Moreira A, Vass V, Erdmann M, Sponagl F, Schuler G, Schuler-Thurner B

  • Eosinophil-cationic protein - a novel liquid prognostic biomarker in


    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.

  • 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.

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • Unilateral, intermittent, pulsating Swelling of the Forehead

    J Dtsch Dermatol Ges. 2019;17(): 61-61

    Heppt F, Meder C, Wagner N

  • 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

  • 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

  • Clinical-Scale Production of CAR-T Cells for the Treatment of Melanoma

    Patients by mRNA Transfection of a CSPG4-Specific CAR under Full GMP


    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.

  • 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.

  • 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.

  • 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

  • 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.


  • 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

  • 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

  • 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.

  • 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

  • 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

  • ECP as prognostic Marker for Melanoma

    J Dtsch Dermatol Ges. 2019;17(): 27-28

    Moreira A, Krueckel A, Schuler G, Utikal J, Heinzerling L

  • 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.

  • 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

  • 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.

  • 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

  • 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).

  • Editorial: Foundations of Theoretical Approaches in Systems Biology.

    Front Genet. 2018;9():

    Marin-Sanguino A, Vera J, Alves R

  • 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.

  • 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

  • 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.

  • 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.

  • 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

  • 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

  • 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.

  • 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.

  • 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

  • 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.

  • 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

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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 tumor