Publikationen

3-year update on therapy with tebentafusp for metastatic uveal melanoma

J Dtsch Dermatol Ges. 2024;22(3): 485-487

Hassel JC, Berking C

Anti-PD-(L)1 plus BRAF/MEK inhibitors (triplet therapy) after failure of immune checkpoint inhibition and targeted therapy in patients with advanced melanoma.

Eur J Cancer. 2024;202():

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

BACKGROUND: Effective treatment options are limited for patients with advanced melanoma who have progressed on immune checkpoint inhibitors (ICI) and targeted therapies (TT). Preclinical models support the combination of ICI with TT; however, clinical trials evaluating the efficacy of triplet combinations in first-line setting showed limited advantage compared to TT only.

METHODS: We conducted a retrospective, multicenter study, that included patients with advanced melanoma who were treated with BRAF/MEK inhibitors in combination with an anti-PD-(L)1 antibody (triplet therapy) after failure of at least one anti-PD-(L)1-based therapy and one TT in seven major melanoma centers between February 2016 and July 2022.

RESULTS: A total of 48 patients were included, of which 32 patients, 66.7% had brain metastases, 37 patients (77.1%) had three or more metastatic organs and 21 patients (43.8%) had three or more treatment lines. The median follow-up time was 31.4 months (IQR, 22.27-40.45 months). The treatment with triplet therapy resulted in an ORR of 35.4% (n = 17) and a DCR of 47.9% (n = 23). The median DOR was 5.9 months (range, 3.39-14.27 months). Patients treated with BRAF/MEK inhibitors as the last treatment line showed a slightly lower ORR (29.6%) compared to patients who received ICI or chemotherapy last (ORR: 42.9%). Grade 3-4 treatment-related adverse events occurred in 25% of patients (n = 12), with seven patients (14.6%) requiring discontinuation of treatment with both or either drug.

CONCLUSIONS: Triplet therapy has shown activity in heavily pretreated patients with advanced melanoma and may represent a potential treatment regimen after failure of ICI and TT.

Gene network-based and ensemble modeling-based selection of tumor-associated antigens with a predicted low risk of tissue damage for targeted immunotherapy.

J Immunother Cancer. 2024;12(5):

Lischer C, Eberhardt M, Flamann C, Berges J, Güse E, Wessely A, Weich A, Retzlaff J, Dörrie J, Schaft N, Wiesinger M, März J, Schuler-Thurner B, Knorr H, Gupta S, Singh KP, Schuler G, Heppt MV, Koch EAT, van Kleef ND, Freen-van Heeren JJ, Turksma AW, Wolkenhauer O, Hohberger B, Berking C, Bruns H, Vera J

BACKGROUND: Tumor-associated antigens and their derived peptides constitute an opportunity to design off-the-shelf mainline or adjuvant anti-cancer immunotherapies for a broad array of patients. A performant and rational antigen selection pipeline would lay the foundation for immunotherapy trials with the potential to enhance treatment, tremendously benefiting patients suffering from rare, understudied cancers.

METHODS: We present an experimentally validated, data-driven computational pipeline that selects and ranks antigens in a multipronged approach. In addition to minimizing the risk of immune-related adverse events by selecting antigens based on their expression profile in tumor biopsies and healthy tissues, we incorporated a network analysis-derived antigen indispensability index based on computational modeling results, and candidate immunogenicity predictions from a machine learning ensemble model relying on peptide physicochemical characteristics.

RESULTS: In a model study of uveal melanoma, Human Leukocyte Antigen (HLA) docking simulations and experimental quantification of the peptide-major histocompatibility complex binding affinities confirmed that our approach discriminates between high-binding and low-binding affinity peptides with a performance similar to that of established methodologies. Blinded validation experiments with autologous T-cells yielded peptide stimulation-induced interferon-γ secretion and cytotoxic activity despite high interdonor variability. Dissecting the score contribution of the tested antigens revealed that peptides with the potential to induce cytotoxicity but unsuitable due to potential tissue damage or instability of expression were properly discarded by the computational pipeline.

CONCLUSIONS: In this study, we demonstrate the feasibility of the de novo computational selection of antigens with the capacity to induce an anti-tumor immune response and a predicted low risk of tissue damage. On translation to the clinic, our pipeline supports fast turn-around validation, for example, for adoptive T-cell transfer preparations, in both generalized and personalized antigen-directed immunotherapy settings.

[Recognition and management of relevant comorbidities in chronic spontaneous urticaria].

Dermatologie (Heidelb). 2024;75(4): 289-294

Wagner N, Berking C

Various mechanisms contributing to the activity of chronic spontaneous urticaria (CU) have been postulated. Associated comorbidities are increasingly leading to the discovery of further signaling pathways which may support the activity of chronic urticaria or contribute to low-grade systemic inflammation. Moreover psychoimmunological factors may also be involved. The aim of this work is to improve the clinical care of patients with CU by increasing knowledge regarding optional influencing factors due to comorbidities and to possibly influence disease activity. Chronic urticaria due to autoimmune mechanisms may dispose to other autoimmune diseases, especially autoimmune thyroiditis, which can trigger chronic disease. Association of CU with metabolic syndrome has received little attention to date. Obesity may contribute to low-grade systemic inflammation by cytokine-secreting adipose tissue and hence to mediator-release of mast cells. Furthermore, neuroimmunological pathways, especially increased release of substance P, an activating ligand of Mas-related G protein-coupled receptor X2 (MRGPX2) on mast cells, should be addressed when optimizing therapy.

Ultraviolet Filters: Dissecting Current Facts and Myths.

J Clin Med. 2024;13(10):

Breakell T, Kowalski I, Foerster Y, Kramer R, Erdmann M, Berking C, Heppt MV

Skin cancer is a global and increasingly prevalent issue, causing significant individual and economic damage. UV filters in sunscreens play a major role in mitigating the risks that solar ultraviolet ra-diation poses to the human organism. While empirically effective, multiple adverse effects of these compounds are discussed in the media and in scientific research. UV filters are blamed for the dis-ruption of endocrine processes and vitamin D synthesis, damaging effects on the environment, induction of acne and neurotoxic and carcinogenic effects. Some of these allegations are based on scientific facts while others are simply arbitrary. This is especially dangerous considering the risks of exposing unprotected skin to the sun. In summary, UV filters approved by the respective governing bodies are safe for human use and their proven skin cancer-preventing properties make them in-dispensable for sensible sun protection habits. Nonetheless, compounds like octocrylene and ben-zophenone-3 that are linked to the harming of marine ecosystems could be omitted from skin care regimens in favor of the myriad of non-toxic UV filters.

Using multiple real-world dermoscopic photographs of one lesion improves melanoma classification via deep learning.

J Am Acad Dermatol. 2024;90(5): 1028-1031

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

The Current State of Systemic Therapy of Metastatic Uveal Melanoma.

Am J Clin Dermatol. 2024;25(5): 691-700

Koch EAT, Heppt MV, Berking C

Uveal melanoma (UM) is genetically a distinct tumor compared to cutaneous melanoma (CM), and due to its low mutational burden, it is far less perceptible to the immune system. Thus, treatments that have revolutionized the treatment of CM remain widely inefficient in metastatic UM or only demonstrate effectiveness in a small subpopulation of patients. To this end, the therapeutic benefit of immune checkpoint blockade is very limited and may come at the expense of severe immune-related adverse events that could potentially affect all organ systems. Notably, tebentafusp, an entirely novel class of anti-cancer drugs, has received official authorization for the treatment of metastatic UM. It is the first agent that demonstrated a survival advantage in a randomized controlled trial of metastatic UM patients. Despite the survival benefit and approval, the restriction of tebentafusp to HLA-A*02:01-positive patients and the low objective response rate indicate the persistent need for additional therapies. Thus, liver-directed therapies are commonly used for tumor control of hepatic metastases and represent a central pillar of the daily management of liver-dominant disease. Further, promising data from targeted therapies independent of MEK-inhibitors, such as the combination of darovasertib and crizotinib, raise hope for additional options in metastatic UM in the future. This narrative review provides a timely and comprehensive overview of the current treatment landscape for metastatic UM.

Mutations in the splicing factor SF3B1 are linked to frequent emergence of HLA-DRlow/neg monocytes in lower-risk myelodysplastic neoplasms.

Leukemia. 2024;38(6): 1427-1431

Winter S, Schneider M, Oelschlaegel U, Maggioni G, Riva E, Raddi MG, Bencini S, Peruzzi B, Choy D, Antunes Dos Reis R, Güse E, Lischer C, Vera J, Timms JA, Sompairac N, Sockel K, Poloni A, Tunger A, Della Porta MG, Santini V, Schmitz M, Platzbecker U, Kordasti S

[Simultaneous presentation of two skin lesions suspected of being malignant].

Dermatologie (Heidelb). 2024;75(9): 747-750

Kaufmann MD, Erdmann M, Schliep S, Voskens C, Berking C, Bauerschmitz JP

Extracorporeal Photopheresis as a Treatment Option for Immune-Related Adverse Events: Two Case Reports and a Prospective Study.

J Immunother. 2024;47(6): 227-231

Ruf T, Rahimi F, Anz D, Tufman A, Salzer S, Zierold S, Tomsitz D, French LE, Heinzerling L

The wide use of immune checkpoint inhibitors has increased the frequency of immune-related adverse events (irAEs). While many are managed with corticosteroids or hormone substitution, up to 14.9% of irAEs are steroid-refractory or steroid-dependent and thus require second-line treatment. These should reduce irAE-related morbidity and mortality and induce a few side effects of their own while maintaining the antitumor response. There is little comparative data on second-line therapies for irAEs. Two cases of irAEs could not be sufficiently managed with corticosteroids and subsequently received treatment with extracorporeal photopheresis (ECP), including one patient with immune-related erosive oral lichen planus and one patient with immune-related colitis. In both cases, the irAE resolved with ECP in combination with immunosuppressive drugs, that is 4 weeks and 10 weeks after the start of ECP, respectively. To investigate this approach, a prospective clinical study that compares ECP and other second-line therapies for the treatment of steroid-refractory and steroid-dependent irAEs with regard to immunophenotype and therapy response has been designed. ECP could be a treatment option for steroid-refractory and steroid-dependent irAEs, given its good safety profile and lack of adverse effects on antitumor response. Comparative prospective studies are needed to generate an evidence base.

Risk of developing psoriatic arthritis in psoriasis cohorts with arthralgia: exploring the subclinical psoriatic arthritis stage.

RMD Open. 2024;10(2):

Zabotti A, Fagni F, Gossec L, Giovannini I, Sticherling M, Tullio A, Baraliakos X, De Marco G, De Vita S, Errichetti E, Quartuccio L, Silvagni E, Smolen JS, Tinazzi I, Watad A, Schett G, McGonagle DG, Simon D

OBJECTIVE: Subjects with subclinical psoriatic arthritis (PsA), defined as the presence of arthralgia in psoriasis (PsO), are at higher risk of PsA but scant real-world data exist. Our aims were to (1) estimate the probability of PsA development in subclinical PsA, (2) characterise subclinical PsA symptoms and (3) determine the clinical patterns at PsA diagnosis.

METHODS: Patients with PsO, mainly subclinical PsA, were evaluated longitudinally in two European cohorts. The key outcome was new-onset PsA. Musculoskeletal symptoms including inflammatory and non-inflammatory symptoms before PsA diagnosis were collected. Occurrence of PsA was analysed with survival analysis and cumulative incidence functions (CIFs).

RESULTS: 384 patients with PsO were included with a mean follow-up of 33.0 (±20.9) months. 311 of 384 (80.9%) had subclinical PsA with a PsA incidence rate of 7.7 per 100 patient-years. Subclinical PsA displayed a higher risk of PsA development compared with PsO (HR=11.7 (95% CI 1.57 to 86.7), p=0.016). The probability of new-onset PsA estimated by the CIF was 9.4% (95% CI 4.7% to 10.6%) at month 12 and 22.7% (95% CI 17.2% to 28.6%) at month 36. 58.9% of cases reported inflammatory symptoms in the months immediately prior to PsA diagnosis but prior non-inflammatory symptoms were evident in 83.9% prior to PsA diagnosis. Peripheral joint swelling was the predominant PsA presentation pattern (82.1%).

CONCLUSIONS: The probability of PsA development among subclinical PsA was relatively high, emphasising the importance of emergent musculoskeletal symptoms when aiming for PsA prevention. Joint swelling was the dominant feature in new-onset PsA, likely reflecting clinical confidence in recognising joint swelling.

Obesity is linked to disease severity in moderate to severe atopic dermatitis-Data from the prospective observational TREATgermany registry.

J Eur Acad Dermatol Venereol. 2024;():

Traidl S, Hollstein MM, Kroeger N, Fischer S, Heratizadeh A, Heinrich L, Kind B, Siegels D, Abraham S, Schäfer T, Augustin M, Harder I, Pinter A, Schäkel K, Wollenberg A, Ertner K, Ramaker-Brunke J, Bong A, Quist S, Gorriahn-Maiterth H, Schenck F, Sticherling M, Effendy I, Schwarz B, Handrick C, Asmussen A, Weidinger S, Schmitt J, Werfel T, TREATgermany Study Group

BACKGROUND: There are conflicting data on a potential association between obesity and atopic dermatitis (AD). The purpose of this study was to investigate the relationship between obesity and AD disease severity.

METHODS: Patients from the TREATgermany registry cohort were divided into three groups according to their body mass index (BMI). Due to low numbers, underweight patients (BMI <18.5 kg/m2) were excluded from the analysis. Physician- and patient-reported disease severity scores as well as additional phenotypic characteristics were evaluated for association with BMI. Generalized linear mixed models and multinomial logit models, respectively, were applied to investigate the association of BMI, age, sex and current systemic AD treatment with disease severity.

RESULTS: This study encompassed 1416 patients, of which 234 (16.5%) were obese (BMI ≥30 kg/m2). Obesity was associated with lower educational background and smoking. Otherwise, obese and non-obese AD patients had similar baseline characteristics. Increased BMI was associated with higher oSCORAD (adjusted β: 1.24, 95% CI: 1.05-1.46, p = 0.013) and Patient-oriented eczema measure (POEM) (adjusted β: 1.09, 95% CI: 1.01-1.17, p = 0.038). However, the absolute difference in the overall oSCORAD was small between obese and non-obese AD patients (Δ oSCORAD = 2.5). Allergic comorbidity was comparable between all three groups, with the exception of asthma which was more pronounced in obese patients (p < 0.001).

DISCUSSION: In this large and well-characterized AD patient cohort, obesity is significantly associated with physician- and patient-assessed measures of AD disease severity. However, the corresponding effect sizes were low and of questionable clinical relevance. The overall prevalence of obesity among the German AD patients was lower than in studies on other AD cohorts from different countries, which confirms previous research on the German population and suggests regional differences in the interdependence of AD and obesity prevalence.

Anatomical pattern of entheseal and synovial fibroblast activation in patients with psoriasis and its risk of developing psoriatic arthritis.

RMD Open. 2024;10(2):

Corte G, Atzinger A, Temiz SA, Noversa de Sousa R, Mutlu MY, Schoenau V, Raimondo MG, Kleyer A, Kuwert T, Ramming A, Simon D, Sticherling M, Schmidkonz C, Schett G, Fagni F

OBJECTIVES: To assess the presence and anatomical distribution of activated fibroblasts in the joints and entheses of patients with psoriasis with arthralgia and to test how fibroblast activation visualised by 68gallium-labelled fibroblast activation protein inhibitor-04 (68Ga-FAPI-04)-positron emission tomography (PET)/CT correlates with clinical tenderness, musculoskeletal ultrasound findings and progression to psoriatic arthritis (PsA).

METHODS: We conducted a prospective cohort study in patients with psoriasis and arthralgia who underwent clinical and ultrasound evaluation and whole-body PET/CT imaging with 68Ga-FAPI-04. 68Ga-FAPI-04 uptake at synovial and entheseal sites was assessed by maximal standardised uptake values (SUVmax) and PET/CT Joint Index (JI); logistic regression models were used to investigate its correlation with clinical and ultrasound findings. Survival analyses were performed on patients with at least 6 months of follow-up.

RESULTS: 36 patients with psoriasis were enrolled. 68Ga-FAPI-04 uptake was found in 318 (7.9%) joints and 369 (7.3%) entheses in 29 (80.6%) participants, with a mean SUVmax (SD) of 3.2 (1.8) for joints and 2.9 (1.6) for entheses. Large joints and the lower limbs were predominantly affected. A significant positive relationship was found between 68Ga-FAPI-04-PET/CT signal intensity and the 68 tender joint count (SUVmax: p<0.001; PET/CT-JI: p<0.001) and tender entheses count (SUVmax: p<0.001; PET/CT-JI: p=0.002). No correlations were found with ultrasound findings (SUVmax: p=0.969; PET/CT-JI: p=0.720). Patients with relevant synovio-entheseal 68Ga-FAPI-04 uptake showed a statistically significant higher risk of developing PsA (p=0.02), independent of ultrasound findings.

CONCLUSIONS: Patients with psoriasis presenting with arthralgia show localised signs of resident tissue activation in joints and entheses, which are associated with higher risk of developing PsA.

Questions from the specialist examination

Aktuelle Derm. 2024;50(06): 259-261

Sticherling M

Optimizing immune checkpoint blockade in metastatic uveal melanoma: exploring the association of overall survival and the occurrence of adverse events.

Front Immunol. 2024;15():

Koch EAT, Petzold A, Dippel E, Erdmann M, Gesierich A, Gutzmer R, Hassel JC, Haferkamp S, Kähler KC, Kreuzberg N, Leiter U, Loquai C, Meier F, Meissner M, Mohr P, Pföhler C, Rahimi F, Schell B, Terheyden P, Thoms KM, Ugurel S, Ulrich J, Utikal J, Weichenthal M, Ziller F, Berking C, Heppt MV

INTRODUCTION: Despite recent advancements in the treatment of metastatic uveal melanoma (UM), the availability of further treatment options remains limited and the prognosis continues to be poor in many cases. In addition to tebentafusp, immune checkpoint blockade (ICB, PD-1 (+/-) CTLA-4 antibodies) is commonly used for metastatic UM, in particular in HLA-A 02:01-negative patients. However, ICB comes at the cost of potentially severe immune-related adverse events (irAE). Thus, the selection of patient groups that are more likely to benefit from ICB is desirable.

METHODS: In this analysis, 194 patients with metastatic UM undergoing ICB were included. Patients were recruited from German skin cancer sites and the ADOReg registry. To investigate the association of irAE occurrence with treatment response, progression-free survival (PFS), and overall survival (OS) two cohorts were compared: patients without irAE or grade 1/2 irAE (n=137) and patients with grade 3/4 irAE (n=57).

RESULTS: In the entire population, the median OS was 16.4 months, and the median PFS was 2.8 months. Patients with grade 3/4 irAE showed more favorable survival than patients without or grade 1/2 irAE (p=0.0071). IrAE occurred in 44.7% (87/194), and severe irAE in 29.4% (57/194) of patients. Interestingly, irColitis and irHepatitis were significantly associated with longer OS (p=0.0031 and p=0.011, respectively).

CONCLUSIONS: This data may indicate an association between irAE and favorable survival outcomes in patients with metastatic UM undergoing ICB treatment and suggests that a reduced tolerance to tumor antigens could be linked to reduced tolerance to self-antigens.

Preferences of physicians for treatment-related toxicity vs. recurrence in melanoma (GERMELATOX-A): the doctors' perspective.

J Cancer Res Clin Oncol. 2024;150(5):

Kähler KC, Gutzmer R, Angela Y, Livingstone E, Lodde G, Meiss F, Rafei-Shamsabadi DA, Weyer-Fahlbusch SS, Nashan D, Loquai C, Hassel JC, Sachse MMM, Maul LV, Heinzerling L, Heppt MV, Colapietro C, Rusch J, Blome C

INTRODUCTION: Adjuvant treatment with immune checkpoint inhibitors, such as PD1-antibodies (ICI) ± CTLA4-antibodies (cICI) or targeted therapy with BRAF/MEK inhibitors (TT), has shown a significant improvement in disease-free survival (DFS) for high-risk melanoma patients. However, due to specific side effects, the choice of treatment is often influenced by the risk of toxicity. Therefore, the role of physicians in treatment decisions of patients is crucial. This study investigated for the first time in a multicenter setting the attitudes and preferences of dermatooncologists in Germany and Switzerland regarding adjuvant treatment with (c)ICI and TT.

METHODS: In the GERMELATOX-A study, 108 physicians (median age: 32 yrs, 67.6% female) from 11 skin cancer centers were surveyed to rate typical side effect scenarios of (c)ICI and TT treatments and then compared to patients' ratings evaluated in a previous analysis from the same centers. The scenarios described mild-to-moderate or severe toxicity and included melanoma relapse leading to death. The physicians were asked about the level of side effects they would tolerate in exchange for a reduction in melanoma relapse and an increase in survival at 5 years.

RESULTS: The preferences of physicians and patients revealed significant differences regarding adjuvant melanoma treatment with (c)ICI and TT (p < 0.05). Compared to patients, physicians tend to value a melanoma relapse less severe, according to a visual analog scale. They were also less threatened by all scenarios of side effects during adjuvant treatment with (c)ICI or TT, compared to patients. Physicians required lower risk reductions for disease-free survival (DFS) and overall survival (OS) for both ICI and TT and their drug-related side effects to accept these treatments. In case of severe side effects, physicians required similar 5-year DFS rates for ICI and TT (60-65%), while patients needed a 15% improvement of 5-year DFS for ICI compared to TT (80%/65%). For survival, physicians expected an OS improvement of + 10% for all three treatment modalities, whereas patients required a higher increase: + 18-22% for ICI and + 15% for TT.

CONCLUSION: Our study highlights the importance of understanding the patient's perspective and a potential difference to the doctor's view when making decisions about adjuvant melanoma treatment with (c)ICI and TT, especially as these treatments are increasingly being implemented in earlier stages.

Susceptibility of Melanoma Cells to Targeted Therapy Correlates with Protection by Blood Neutrophils.

Cancers (Basel). 2024;16(9):

Wendlinger S, Wohlfarth J, Siedel C, Kreft S, Kilian T, Junker S, Schmid L, Sinnberg T, Dischinger U, Heppt MV, Wistuba-Hamprecht K, Meier F, Erpenbeck L, Neubert E, Goebeler M, Gesierich A, Schrama D, Kosnopfel C, Schilling B

Elevated levels of peripheral blood and tumor tissue neutrophils are associated with poorer clinical response and therapy resistance in melanoma. The underlying mechanism and the role of neutrophils in targeted therapy is still not fully understood. Serum samples of patients with advanced melanoma were collected and neutrophil-associated serum markers were measured and correlated with response to targeted therapy. Blood neutrophils from healthy donors and patients with advanced melanoma were isolated, and their phenotypes, as well as their in vitro functions, were compared. In vitro functional tests were conducted through nonadherent cocultures with melanoma cells. Protection of melanoma cell lines by neutrophils was assessed under MAPK inhibition. Blood neutrophils from advanced melanoma patients exhibited lower CD16 expression compared to healthy donors. In vitro, both healthy-donor- and patient-derived neutrophils prevented melanoma cell apoptosis upon dual MAPK inhibition. The effect depended on cell-cell contact and melanoma cell susceptibility to treatment. Interference with protease activity of neutrophils prevented melanoma cell protection during treatment in cocultures. The negative correlation between neutrophils and melanoma outcomes seems to be linked to a protumoral function of neutrophils. In vitro, neutrophils exert a direct protective effect on melanoma cells during dual MAPK inhibition. This study further hints at a crucial role of neutrophil-related protease activity in protection.

Secukinumab in adult patients with lichen planus: Efficacy and safety results from the randomised, placebo-controlled, proof-of-concept PRELUDE study.

Br J Dermatol. 2024;():

Passeron T, Reinhardt M, Ehst B, Weiss J, Sluzevich J, Sticherling M, Reygagne P, Wohlrab J, Hertl M, Fazel N, Muscianisi E, Fan H, Hampele I, Compagno N

BACKGROUND: Patients with lichen planus (LP) refractory to available therapies often experience a high disease burden; representing a population with a clear unmet need for new treatments.

OBJECTIVES: To evaluate the efficacy and safety of secukinumab 300 mg over 32 weeks in adult patients with biopsy-proven cutaneous LP (CLP), mucosal LP (MLP) or lichen planopilaris (LPP), inadequately controlled by topical corticosteroids.

METHODS: PRELUDE was a, randomised, double-blind, placebo-controlled, Phase 2 proof-of-concept study that enrolled patients with CLP, MLP or LPP. Eligible patients were randomised to eithersecukinumab 300 mg every 4 weeks for 32 weeks (SECQ4W), or placebo for 16 weeks followed by secukinumab 300 mg every 2 weeks (SECQ2W) for 16 weeks. The primary endpoint was achievement of the newly designed Investigator's Global Assessment (IGA) score ≤2 at Week 16.

RESULTS: Overall, 111 patients were randomised (n=37 each) to CLP, MLP and LPP cohorts. As the proof-of-concept criteria were not met for any of the 3 cohorts, the primary objective was not met. A numerically higher proportion of patients achieved IGA ≤2 response at Week 16 with SECQ4W vs. placebo in the MLP (37.5% [95% credibility interval (Crl): 20.3-57.2] vs. 23.1% [95% Crl: 6.5-49.2]) and LPP cohorts (37.5% [95% Crl: 20.2-57.3] vs. 30.8% [95% Crl: 10.8-57.6]). In the LPP cohort, a sustained response for IGA ≤2 from Week 16 to Week 32 was achieved with SECQ4W (Week 16: 37.5%; Week 32: 45.8%), and a substantial improvement was observed in IGA ≤2 response in patients of this cohort switching from placebo (Week 16: 30.8%) to SECQ2W after Week 16 (Week 32: 63.6%). The safety profile was consistent with the known profile of secukinumab and showed no new or unexpected signals.

CONCLUSIONS: PRELUDE is the first randomised controlled basket trial evaluating interleukin-17A inhibition with secukinumab across 3 subtypes of LP. Secukinumab was well-tolerated and safe, showing different response rates across the 3 subtypes, with numerical IGA improvements in MLP and LPP, and no response in CLP. The study raises the question of a differential role of interleukin-17A across LP subtypes. The novel IGA score showed significant correlation with patient as well as physician reported outcome measurements.

TRIAL REGISTRATION NUMBER: NCT04300296.

Comparison of the oncolytic activity of a replication-competent and a replication-deficient herpes simplex virus 1.

Immunology. 2024;172(2): 279-294

Lindner G, Walter A, Magnus CL, Rosenhammer K, Holoborodko B, Koch V, Hirsch S, Grossmann L, Li S, Knipe DM, DeLuca N, Schuler-Thurner B, Gross S, Schwertner B, Toelge M, Rohrhofer A, Stöckl S, Bauer RJ, Knoll G, Ehrenschwender M, Haferkamp S, Schmidt B, Schuster P

In 2015, the oncolytic herpes simplex virus 1 (HSV-1) T-VEC (talimogene laherparepvec) was approved for intratumoral injection in non-resectable malignant melanoma. To determine whether viral replication is required for oncolytic activity, we compared replication-deficient HSV-1 d106S with replication-competent T-VEC. High infectious doses of HSV-1 d106S killed melanoma (n = 10), head-and-neck squamous cell carcinoma (n = 11), and chondrosarcoma cell lines (n = 2) significantly faster than T-VEC as measured by MTT metabolic activity, while low doses of T-VEC were more effective over time. HSV-1 d106S and, to a lesser extent T-VEC, triggered caspase-dependent early apoptosis as shown by pan-caspase inhibition and specific induction of caspases 3/7, 8, and 9. HSV-1 d106S induced a higher ratio of apoptosis-inducing infected cell protein (ICP) 0 to apoptosis-blocking ICP6 than T-VEC. T-VEC was oncolytic for an extended period of time as viral replication continued, which could be partially blocked by the antiviral drug aciclovir. High doses of T-VEC, but not HSV-1 d106S, increased interferon-β mRNA as part of the intrinsic immune response. When markers of immunogenic cell death were assessed, ATP was released more efficiently in the context of T-VEC than HSV-1 d106S infection, whereas HMGB1 was induced comparatively well. Overall, the early oncolytic effect on three different tumour entities was stronger with the non-replicative strain, while the replication-competent virus elicited a stronger innate immune response and more pronounced immunogenic cell death.

Consensus statement on the diagnosis and treatment of sclerosing diseases of the skin, Part 1: Localized scleroderma, systemic sclerosis and overlap syndromes.

J Eur Acad Dermatol Venereol. 2024;38(7): 1251-1280

Knobler R, Geroldinger-Simić M, Kreuter A, Hunzelmann N, Moinzadeh P, Rongioletti F, Denton CP, Mouthon L, Cutolo M, Smith V, Gabrielli A, Bagot M, Olesen AB, Foeldvari I, Jalili A, Kähäri V, Kárpáti S, Kofoed K, Olszewska M, Panelius J, Quaglino P, Seneschal J, Sticherling M, Sunderkötter C, Tanew A, Wolf P, Worm M, Skrok A, Rudnicka L, Krieg T

The term 'sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present consensus provides an update to the 2017 European Dermatology Forum Guidelines, focusing on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, updated strategies for the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 1 of this consensus provides clinicians with an overview of the diagnosis and treatment of localized scleroderma (morphea), and systemic sclerosis including overlap syndromes.

Genotype-phenotype correlation analysis in patients with generalized pustular psoriasis

Eur J Hum Genet. 2024;32 Suppl 1(): 411-412

Hayatu MD, Hueffmeir U, Uebe S, Ekici AB, Moessner R, Magnolo N, Philipp S, Prinz JC, Schaekel K, Sondermann W, Sticherling M, Gerdes S, Wilsmann-Theis D

Bullous pemphigoid induced by immune checkpoint inhibitors - an issue of relevance?

Exp Dermatol. 2024;33(3):

Sticherling M, Brueckner M, Kramer R, Erdmann M

Safety, tolerability and pharmacokinetics of TPM203, a tolerizing Topas particle mixture in pemphigus vulgaris: preliminary results from a phase 1, first in man study (EudraCT Number: 2019-001727-12)

Exp Dermatol. 2024;33(3):

Didona D, Volkmann K, Hinterseher J, Moebs C, Pollmann R, Polakova A, Pfuetzner W, Cunha T, Schauer F, Hahn M, Meier K, Magnolo N, Sticherling M, Fleischer S, Hertl M

Influence of adjuvant therapies on organ-specific recurrence of cutaneous melanoma: A multicenter study on 1383 patients of the prospective DeCOG registry ADOReg.

Int J Cancer. 2024;():

Wohlfeil SA, Kranzmann L, Weiß C, von Wasielewski I, Klespe KC, Kähler KC, Weichenthal M, Schadendorf D, Zimmer L, Mohr P, Meier F, Pfoehler C, Berking C, Heppt MV, Herbst R, Kreuter A, Gutzmer R, Ulrich J, Meiss F, Gebhardt C, Dippel E, Leiter U, Schilling B, Ugurel S, Utikal J

This study investigated whether adjuvant treatments in stage III cutaneous melanoma (CM) influenced patterns of recurrence. Patients with primary (n = 1033) or relapsed CM (n = 350) who received adjuvant therapies with Nivolumab (N), Pembrolizumab (P), or Dabrafenib and Trametinib (D + T) were extracted from the prospective multicenter real-world skin cancer registry ADOReg. Endpoints were progression-free survival (PFS), distant metastasis-free survival (DMFS), organ-specific DMFS, and overall survival (OS). For primary cases, D + T indicated an improved PFS (1- and 2-year PFS: 90.9%; 82.7%) as compared to P (81.0%, 73.9%; p = .0208), or N (83.8%, 75.2%; p = .0539). BRAF-mutated(mut) CM demonstrated significantly lower PFS (p = .0022) and decreased DMFS (p = .0580) when treated with immune checkpoint inhibitor (ICI) instead of D + T. Besides, NRAS-mut CM tended to perform worse than wt CM upon ICI (PFS: p = .1349; DMFS: p = .0540). OS was similar between the groups. Relapsed cases showed decreased PFS, DMFS, and OS in comparison to primary (all: p < .001), without significant differences between the subgroups. Organ-specific DMFS was significantly altered for primary cases with bone (p = .0367) or brain metastases (p = .0202). In relapsed CM, the frequency of liver (D + T: 1.5%; P: 12%; N: 9%) and LN metastases (D + T: 1.5%; P: 12%; N: 10.2%) was significantly lower with adjuvant D + T than ICI. NRAS-mut CM showed increased recurrence in primary and relapsed cases. These data show that adjuvant D + T is superior to ICI in primary BRAF-mut CM.

Stringent monitoring can decrease mortality of immune checkpoint inhibitor induced cardiotoxicity.

Front Cardiovasc Med. 2024;11():

Wang Y, Ertl C, Schmitt C, Hammann L, Kramer R, Grabmaier U, Schöberl F, Anz D, Piseddu I, Pesch G, Vera J, Froehlich W, Weckbach L, Tomsitz D, Loquai C, Zimmer L, Mangana J, Dummer R, Gutzmer R, Klespe KC, Stege H, Meiss F, Thoms KM, Terheyden P, Bröckelmann PJ, Johnson DB, French LE, Heinzerling L

BACKGROUND: Immune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with a fatality rate of 40%-46%. However, irMyocarditis can be asymptomatic. Thus, improved monitoring, detection and therapy are needed. This study aims to generate knowledge on pathogenesis and assess outcomes in cancer centers with intensified patient management.

METHODS: Patients with cardiac irAEs from the SERIO registry (www.serio-registry.org) were analyzed for demographics, ICI-related information (type of ICI, therapy line, combination with other drugs, onset of irAE, and tumor response), examination results, irAE treatment and outcome, as well as oncological endpoints. Cardiac biopsies of irMyocarditis cases (n = 12) were analyzed by Nanostring and compared to healthy heart muscle (n = 5) and longitudinal blood sampling was performed for immunophenotyping of irMyocarditis-patients (n = 4 baseline and n = 8 during irAE) in comparison to patients without toxicity under ICI-therapy (n = 4 baseline and n = 7 during ICI-therapy) using flow cytometry.

RESULTS: A total of 51 patients with 53 cardiac irAEs induced by 4 different ICIs (anti-PD1, anti-PD-L1, anti-CTLA4) were included from 12 centers in 3 countries. Altogether, 83.0% of cardiac irAEs were graded as severe or life-threatening, and 11.3% were fatal (6/53). Thus, in centers with established consequent troponin monitoring, work-up upon the rise in troponin and consequent treatment of irMyocarditis with corticosteroids and -if required-second-line therapy mortality rate is much lower than previously reported. The median time to irMyocarditis was 36 days (range 4-1,074 days) after ICI initiation, whereas other cardiotoxicities, e.g. asystolia or myocardiopathy, occurred much later. The cytokine-mediated signaling pathway was differentially regulated in myocardial biopsies as compared to healthy heart based on enrichment Gene Ontology analysis. Additionally, longitudinal peripheral blood mononuclear cell (PBMC) samples from irMyocarditis-patients indicated ICI-driven enhanced CD4+ Treg cells and reduced CD4+ T cells. Immunophenotypes, particularly effector memory T cells of irMyocarditis-patients differed from those of ICI-treated patients without side effects. LAG3 expression on T cells and PD-L1 expression on dendritic cells could serve as predictive indicators for the development of irMyocarditis.

CONCLUSION: Interestingly, our cohort shows a very low mortality rate of irMyocarditis-patients. Our data indicate so far unknown local and systemic immunological patterns in cardiotoxicity.

The side effect registry immuno-oncology (SERIO) - A tool for systematic analysis of immunotherapy-induced side effects.

Eur J Cancer. 2024;199():

Ertl C, Ruf T, Mentzer D, Kong M, Kramer R, Bergwelt-Baildon MV, Subklewe M, Tomsitz D, Ascierto PA, Dummer R, Gogas H, Lebbé C, Long GV, McArthur G, Neilan TG, Ribas A, Robert C, Schadendorf D, Zimmer L, Eigentler T, Grabbe S, Forschner A, Kähler KC, Milani V, Pföhler C, Hassel J, Gutzmer R, Loquai C, Routy B, Furness AJS, Blank C, Wolchok JD, French LE, Hauschild A, Heinzerling L

BACKGROUND: Immunotherapies such as immune checkpoint inhibitors (ICI) are effective in multiple tumor entities but induce a plethora of side effects. Comprehensive real-world analyses are essential to identify new signals, characterize diagnostic features, enable risk assessment, determine pathomechanisms, assess effectiveness of side effect management and compare tumor outcomes.

METHODS: The international online `Side-Effect Registry Immuno-Oncology´ (SERIO; www.serio-registry.org) collects rare, complex, and severe immunotherapy-induced side effects across all tumor entities with a strong focus on ICI-induced immune-related adverse events (irAE). The relational database management system (RDMS) contains structured data on patient and tumor characteristics, type of immunotherapy, treatment of side effects, and outcome of tumor and irAE. Data are captured within 25 organ modules including new modules for immune effector cell-associated neurotoxicity syndrome (ICANS) for CAR-T-cell therapies and cytokine release syndrome (CRS) for bispecific antibodies. Information on biological samples is gathered.

RESULTS: A total of 1398 irAE cases have been documented by 58 centers from 13 countries in patients with 17 tumor types. IrAEs were induced by nine different immunotherapies including tebentafusp and CAR-T cell therapies, and resulted, among others, in neurological (7.6%), pulmonary (4.0%), and cardiac toxicities (2.9%). 50.0% of all irAEs were graded severe or life-threatening and 23.0% of patients received second-line therapy for steroid-refractory or steroid-dependent irAE. SERIO has contributed to 44 original publications on topics ranging from irMyocarditis to irEncephalitis to long-term persistent sequelae of immunotherapy.

CONCLUSIONS: A reliable evidence base is crucial for decision-making in rare, complex or therapy-refractory irAE. SERIO can help optimize side effect management and thereby reduce morbidity and mortality induced by immunotherapy.

Drug therapies for Ulcus cruris

Aktuelle Derm. 2024;():

Ronicke M, Erfurt-Berge C

Chronic wounds are a burden for many patients in Germany and around the world. Drug therapies still play a subordinate role for the more common causes such as venous leg ulcers or arterial leg ulcers, although good data is available for individual therapies. For rarer entities, such as calciphylaxis, necrobiosis lipoidica and pyoderma gangrenosum, there is often a lack of reliable studies. However, drug treatments are essential for healing in those cases. Overall, there is a lack of approved therapies for all the diseases mentioned. This article discusses possible drug therapy options for all the diseases mentioned.

Evaluating deep learning-based melanoma classification using immunohistochemistry and routine histology: A three center study.

PLoS ONE. 2024;19(1):

Wies C, Schneider L, Haggenmüller S, Bucher TC, Hobelsberger S, Heppt MV, Ferrara G, Krieghoff-Henning EI, Brinker TJ

Pathologists routinely use immunohistochemical (IHC)-stained tissue slides against MelanA in addition to hematoxylin and eosin (H&E)-stained slides to improve their accuracy in diagnosing melanomas. The use of diagnostic Deep Learning (DL)-based support systems for automated examination of tissue morphology and cellular composition has been well studied in standard H&E-stained tissue slides. In contrast, there are few studies that analyze IHC slides using DL. Therefore, we investigated the separate and joint performance of ResNets trained on MelanA and corresponding H&E-stained slides. The MelanA classifier achieved an area under receiver operating characteristics curve (AUROC) of 0.82 and 0.74 on out of distribution (OOD)-datasets, similar to the H&E-based benchmark classification of 0.81 and 0.75, respectively. A combined classifier using MelanA and H&E achieved AUROCs of 0.85 and 0.81 on the OOD datasets. DL MelanA-based assistance systems show the same performance as the benchmark H&E classification and may be improved by multi stain classification to assist pathologists in their clinical routine.

Tumor cell-intrinsic PD-1 promotes Merkel cell carcinoma growth by activating downstream mTOR-mitochondrial ROS signaling.

Sci Adv. 2024;10(3):

Martins C, Rasbach E, Heppt MV, Singh P, Kulcsar Z, Holzgruber J, Chakraborty A, Mucciarone K, Kleffel S, Brandenburg A, Hoetzenecker W, Rahbari NN, DeCaprio JA, Thakuria M, Murphy GF, Ramsey MR, Posch C, Barthel SR, Schatton T

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Inhibitors targeting the programmed cell death 1 (PD-1) immune checkpoint have improved MCC patient outcomes by boosting antitumor T cell immunity. Here, we identify PD-1 as a growth-promoting receptor intrinsic to MCC cells. In human MCC lines and clinical tumors, RT-PCR-based sequencing, immunoblotting, flow cytometry, and immunofluorescence analyses demonstrated PD-1 gene and protein expression by MCC cells. MCC-PD-1 ligation enhanced, and its inhibition or silencing suppressed, in vitro proliferation and in vivo tumor xenograft growth. Consistently, MCC-PD-1 binding to PD-L1 or PD-L2 induced, while antibody-mediated PD-1 blockade inhibited, protumorigenic mTOR signaling, mitochondrial (mt) respiration, and ROS generation. Last, pharmacologic inhibition of mTOR or mtROS reversed MCC-PD-1:PD-L1-dependent proliferation and synergized with PD-1 checkpoint blockade in suppressing tumorigenesis. Our results identify an MCC-PD-1-mTOR-mtROS axis as a tumor growth-accelerating mechanism, the blockade of which might contribute to clinical response in patients with MCC.

Diagnosis and treatment of venous leg ulcers: S2k Guideline of the German Society of Phlebology and Lymphology (DGPL) e.V.

J Dtsch Dermatol Ges. 2024;22(7): 1039-1051

Valesky EM, Hach-Wunderle V, Protz K, Zeiner KN, Erfurt-Berge C, Goedecke F, Jäger B, Kahle B, Kluess H, Knestele M, Kuntz A, Lüdemann C, Meissner M, Mühlberg K, Mühlberger D, Pannier F, Schmedt CG, Schmitz-Rixen T, Strölin A, Wilm S, Rabe E, Stücker M, Dissemond J

This S2k guideline on venous leg ulcers was created on the initiative and under the leadership of the German Society of Phlebology and Lymphology (DGPL). The guideline group also consisted of representatives from the German Society for Phlebology and Lymphology, German Dermatological Society, German Society for General Medicine, German Society for Angiology, German Society for Vascular Surgery and Vascular Medicine, German Society for Surgery, German Society for Dermatosurgery, German Society for Wound Healing and Wound Treatment, Professional Association of Phlebologists and Lymphologists and Initiative Chronische Wunden. The aim of this guideline is to combine the different approaches and levels of knowledge of the respective professional groups on the basis of consensus, so that a basic concept for the best possible treatment of patients with venous leg ulcers can be provided. A total of 70 specific recommendations were formulated and agreed upon, divided into the subject areas of diagnostics, therapy, prevention of recurrences, and everyday challenges. The guideline thus reflects the current state of scientific knowledge and is intended to be widely used as the best available document for the treatment of patients with venous leg ulcers in everyday clinical practice.

The Association between the Body Mass Index, Chronic Obstructive Pulmonary Disease and SUV of the Non-Tumorous Lung in the Pretreatment [18F]FDG-PET/CT of Patients with Lung Cancer.

Diagnostics (Basel). 2024;14(11):

Wehlte L, Walter J, Daisenberger L, Kuhnle F, Ingenerf M, Schmid-Tannwald C, Brendel M, Kauffmann-Guerrero D, Heinzerling L, Tufman A, Pfluger T, Völter F

Background: A debate persists on the prognostic value of the pre-therapeutic standardized uptake value (SUV) of non-tumorous lung tissue for the risk assessment of therapy-related pneumonitis, with most studies lacking significant correlation. However, the influence of patient comorbidities on the pre-therapeutic lung SUV has not yet been systematically evaluated. Thus, we aimed to elucidate the association between comorbidities, biological variables and lung SUVs in pre-therapeutic [18F]FDG-PET/CT. Methods: In this retrospective study, the pre-therapeutic SUV in [18F]FDG-PET/CT was measured in non-tumorous areas of both lobes of the lung. SUVMEAN, SUVMAX and SUV95 were compared to a multitude of patient characteristics and comorbidities with Spearman's correlation analysis, followed by a Bonferroni correction and multilinear regression. Results: In total, 240 patients with lung cancer were analyzed. An elevated BMI was significantly associated with increased SUVMAX (β = 0.037, p < 0.001), SUVMEAN (β = 0.017, p < 0.001) and SUV95 (β = 0.028, p < 0.001). Patients with chronic obstructive pulmonary disease (COPD) showed a significantly decreased SUVMAX (β = -0.156, p = 0.001), SUVMEAN (β = -0.107, p < 0.001) and SUV95 (β = -0.134, p < 0.001). Multiple other comorbidities did not show a significant correlation with the SUV of the non-tumorous lung. Conclusions: Failure to consider the influence of BMI and COPD on the pre-therapeutic SUV measurements may lead to an erroneous interpretation of the pre-therapeutic SUV and subsequent treatment decisions in patients with lung cancer.

Elevated aluminum excretion in patients by long-term subcutaneous immunotherapy - A cross-sectional case-control study.

Int J Hyg Environ Health. 2024;258():

Hiller J, Göen T, Drexler H, Berking C, Wagner N

BACKGROUND: Aluminum (Al) adjuvants have been used in vaccines and subcutaneous immunotherapy (SCIT) for decades. Despite indisputable neurotoxic properties of Al, there is no clear evidence of a causal relationship between their use and any neurotoxic side effects. However, recent rat studies have shown an accumulation of Al from adjuvants in tissues, especially in bones.

OBJECTIVES: Since the human toxicokinetics of Al-adjuvants are poorly understood, this study aimed to evaluate whether up-dosed or long-term SCIT with Al-coupled extracts leads to increased Al load in humans.

METHODS: This observational cross-sectional case-control study explored Al excretion in hymenoptera venom allergy patients recruited in 2020 before initiation (n = 10) and during ongoing (n = 12) SCIT with Al-based preparations. Urine samples were collected before and 24 h after the SCIT injections and analyzed for aluminum content by using atomic absorption spectrometry. The cumulative administered Al dose was extracted from patient records. Patients receiving long-term immunotherapy were treated between 2.8 and 13.6 years (mean 7.1). Other potential sources of Al exposure were surveyed.

RESULTS: Patients who had received Al-coupled immunotherapy for several years showed significantly (p < 0.001) higher Al excretion than the controls at initiation of immunotherapy (mean 18.2 μg/gC vs. 7.9 μg/gC) and predominantly (73%) were above the 95th percentile of the general populations' exposure (>15 μg/gC), however, without reaching levels of toxicological concern (>50 μg/gC). Taking both groups together excreted Al levels correlated with the cumulative administered Al dose from SCIT (linear regression: Alurine = 8.258 + 0.133*Alcum; p = 0.001).

DISCUSSION: These results suggest a relevant iatrogenic contribution of long-term SCIT to human internal Al burden and potential accumulation. Considering the medical benefits of Al-adjuvants and SCIT a differentiated risk-benefit analysis is needed. For certain scenarios of potential toxicological concern in clinical practice biomonitoring might be advisable.

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

Z Rheumatol. 2024;83(3): 200-209

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.

Identifying biomarkers and novel therapeutic targets in uveal melanoma.

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

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

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

Guselkumab demonstrates long-term efficacy and maintenance of treatment response postwithdrawal in systemic treatment-naïve patients and nonresponders to fumaric acid esters: results from parts II and III of a randomized active-comparator-controlled phase IIIb trial (POLARIS).

Br J Dermatol. 2024;191(1): 36-48

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

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

OBJECTIVES: To compare, in study part II, the sustainability of treatment responses (weeks 24-32) in GUS- and FAE-treated patients and treatment responses (weeks 32-56) in patients treated with GUS and FAE and in FAE nonresponders switching to GUS; and, in part III, to investigate the maintenance of response through week 100 in patients withdrawn from GUS at week 56.

METHODS: At week 0, systemic treatment-naïve patients were randomized 1 : 1 to GUS or FAE as per label. At week 32, patients with a Psoriasis Area and Severity Index (PASI) 75 (≥ 75% improvement in PASI score) response (r) continued assigned treatment (GUSr-GUS; FAEr-FAE), whereas nonresponders (nr) received GUS (FAEnr-GUS; GUSnr-GUS). GUS-treated patients with a week 56 PASI 90 response (≥ 90% improvement in PASI score) were withdrawn (w) and followed until loss of response or week 100.

RESULTS: At week 32, 98% (n = 54/55) of GUS- and 41% (n = 14/34) of FAE-treated patients were PASI 75 responders. At week 56, 91%, 50% and 80% of GUSr-GUS, FAEr-FAE and FAEnr-GUS patients, respectively, achieved a PASI 90 response; 72%, 29% and 45%, respectively, achieved a Dermatology Life Quality Index score of 0/1. At week 100, 44 weeks postwithdrawal, 47% (n = 17/36) and 25% (n = 3/12) of GUS-GUSw and FAE-GUSw patients, respectively, maintained a PASI score ≤ 5. Overall, the adverse event and discontinuation rates were lower for GUS than FAE.

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

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

Oncoimmunology. 2024;13(1):

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

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

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

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

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

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

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

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

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

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

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

Ren Fail. 2024;46(1):

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

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

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

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

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

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

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

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

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

Federated Learning for Decentralized Artificial Intelligence in Melanoma Diagnostics.

JAMA Dermatol. 2024;160(3): 303-311

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

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

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

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

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

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

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

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

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

Nat Commun. 2024;15(1):

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

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

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

Sci Rep. 2024;14(1):

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

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

Sun protection in outdoor workers - Development and validation of standardized questionnaires for behavior and knowledge.

J Dtsch Dermatol Ges. 2024;22(5): 665-673

Rönsch H, Rocholl M, Ludewig M, Staudt A, Langner M, Steeb T, Wilke A, John SM, Berking C, Beissert S, Bauer A

BACKGROUND AND OBJECTIVES: Outdoor workers are at increased risk of developing non-melanoma skin cancer. We aimed to address the lack of validated German-language measurement instruments for outdoor workers' sun safety behavior and knowledge by compiling and validating two questionnaires.

PARTICIPANTS AND METHODS: By expert consensus, items for the assessment of protective behavior (OccuSun) were compiled based on existing instruments. For knowledge, a translation of the Skin Cancer and Sun Knowledge (SCSK) scale was selected. After a pre-test, a validation study including 68 outdoor workers (62% female) was conducted in 2020.

RESULTS: The retest reliability was r = 0.93 (95% confidence interval: 0.86-0.96) for the protection score and rs = 0.78 (0.67-0.86) for the knowledge score. Protective behaviors were correlated with respective diary data (0.38 ≤ rs ≤ 0.74, p < 0.001) and skin pigmentation changes (-0.23 ≥ rs ≥ -0.42, 0.007 ≤ p ≤ 0.165) but not with self-reported sunburn frequency (0.21 ≥ rs ≥ -0.04).

CONCLUSIONS: Among German outdoor workers, two questionnaires for the assessment of sun protection behavior (OccuSun) and knowledge (SCSK) demonstrated good reliability. The OccuSun had generally good validity. Both instruments are fit for subsequent validation to determine their sensitivity to change.

European consensus-based interdisciplinary guideline for diagnosis, treatment and prevention of actinic keratoses, epithelial UV-induced dysplasia and field cancerization on behalf of European Association of Dermato-Oncology, European Dermatology Forum, European Academy of Dermatology and Venereology and Union of Medical Specialists (Union Européenne des Médecins Spécialistes).

J Eur Acad Dermatol Venereol. 2024;38(6): 1024-1047

Kandolf L, Peris K, Malvehy J, Mosterd K, Heppt MV, Fargnoli MC, Berking C, Arenberger P, Bylaite-Bučinskiene M, Del Marmol V, Dirschka T, Dreno B, Forsea AM, Harwood CA, Hauschild A, Heerfordt IM, Kauffman R, Kelleners Smeeths N, Lallas A, Lebbe C, Leiter U, Longo C, Mijušković Ž, Pellacani G, Puig S, Saiag P, Šitum M, Stockfleth E, Salavastru C, Stratigos A, Zalaudek I, Garbe C, European Association of Dermato-Oncology, European Dermatology Forum, European Academy of Dermatology and Venereology and Union of Medical Specialists (Union Européenne des Médecins Spécialistes)

A collaboration of multidisciplinary experts from the European Association of Dermato-Oncology, the European Dermatology Forum, the European Academy of Dermatology and Venereology, and the European Union of Medical Specialists was formed to develop European recommendations on AK diagnosis and treatment, based on current literature and expert consensus. This guideline addresses the epidemiology, diagnostics, risk stratification and treatments in immunocompetent as well as immunosuppressed patients. Actinic keratoses (AK) are potential precursors of cutaneous squamous cell carcinoma (cSCC) and display typical histopathologic and immunohistochemical features of this malignancy in an early stage. They can develop into cSSC in situ and become invasive in a low percentage of cases. AK is the most frequent neoplasia in white populations, frequently occurring within a cancerous field induced by ultraviolet radiation. Since it cannot be predicted, which lesion will progress to cSCC and when treatment is usually recommended. The diagnosis of AK and field cancerization is made by clinical examination. Dermatoscopy, confocal microscopy, optical coherence tomography or line-field confocal-OCT can help in the differential diagnosis of AK and other skin neoplasms. A biopsy is indicated in clinically and/or dermatoscopically suspicious and/or treatment-refractory lesions. The choice of treatment depends on patients' and lesion characteristics. For single non-hyperkeratotic lesions, the treatment can be started upon patient's request with destructive treatments or topical treatments. For multiple lesions, field cancerization treatment is advised with topical treatments and photodynamic therapy. Preventive measures such as sun protection, self-examination and repeated field cancerization treatments of previously affected skin areas in high-risk patients are advised.

Occlusive cutaneous vasculopathies as cause of chronic ulcers.

J Dtsch Dermatol Ges. 2024;22(4): 553-567

Ronicke M, Berking C, Erfurt-Berge C

The term occluding vasculopathies covers a large number of different conditions. These often manifest as skin ulcers. Occluding vasculopathies should be considered in the differential diagnosis of leg ulcers. The term "occlusive vasculopathies" encompasses pathophysiologically related entities that share structural or thrombotic obliteration of small cutaneous vessels. In this article, we will focus on livedoid vasculopathy with and without antiphospholipid syndrome and calciphylaxis with differentiation from hypertonic leg ulcer as the most relevant differential diagnoses of leg ulcer. The term also includes vascular occlusion, for example due to oxalate or cholesterol embolism, and septic vasculopathy. This often leads to acral ulceration and is therefore not a differential diagnosis with classic leg ulcers. It will not be discussed in this article. Occlusive vasculopathy may be suspected in the presence of the typical livedo racemosa or (non-inflammatory) retiform purpura as a sign of reduced cutaneous perfusion in the wound area. Inflammatory dermatoses, especially vasculitides, must be differentiated. This is achieved by histopathological evaluation of a tissue sample of sufficient size and depth taken at the appropriate time. In addition, specific laboratory parameters, particularly coagulation parameters, can support the diagnosis.

Isolated melanoma cells in sentinel lymph node in stage IIIA melanoma correlate with a favorable prognosis similar to stage IB.

Eur J Cancer. 2024;201():

Amaral T, Nanz L, Stadler R, Berking C, Ulmer A, Forschner A, Meiwes A, Wolfsperger F, Meraz-Torres F, Chatziioannou E, Martus P, Flatz L, Garbe C, Leiter U

BACKGROUND: The American Joint Committee on Cancer 8th edition (AJCC v8) defines sentinel lymph nodes (SLN) containing any tumor cells as positive SLN. Consequently, even thin melanomas with isolated tumor cells (ic) in SLN are classified as stage IIIA, making them candidates for adjuvant therapy.

OBJECTIVES AND ENDPOINTS: We aimed to evaluate survival outcomes of melanoma stage IIIA (ic) and compare them with stage IIIA with lymph node (LN) metastases > 0.1 mm. Primary endpoints were relapse-free survival (RFS) and distant metastases-free survival (DMFS). Secondary endpoint was melanoma specific survival (MSS).

RESULTS: The discovery cohort from the Department of Dermatology, University Hospital Tuebingen, included 237 patients; confirmation cohort included 143 patients from the DeCOG trial. The Tuebingen cohort included 95 patients with stage IIIA (ic) and 142 patients with stage IIIA. The DeCOG trial included 39 patients with stage IIIA (ic) and 104 patients with stage IIIA. In the Tuebingen cohort, 10-year RFS rates for stage IIIA (ic) and IIIA were 84% (95% CI 75-94) and 49% (95% CI 39-59), respectively (p < 0.001). 10-year DMFS rates for stage IIIA (ic) and IIIA were 89% (95% CI 81-97) and 56% (95% CI 45-67), respectively; (p < 0.001). In the DeCOG cohort, 10-year RFS for stage IIIA (ic) and stage IIIA were 88% (95% CI 78-99) and 35% (95% CI 7-62), respectively; (p = 0.009). 10-year DMFS for stage IIIA (ic) and IIIA was 88% (95% CI 77-99) and 60% (95% CI 39-80), respectively (p = 0.061).

CONCLUSION: Stage IIIA (ic) melanoma exhibits a prognosis similar to stage IB. Recommendation of adjuvant therapy in Stage IIIA (ic) warrants thorough discussion.

The influence of indisulam on human immune effector cells: Is a combination with immunotherapy feasible?

Exp Dermatol. 2024;33(3):

Arnet L, Emilius L, Carmo-Fonseca M, Berking C, Doerrie J, Schaft N

Checkpoint inhibitor-induced bullous pemphigoid differs from spontaneous bullous pemphigoid.

J Eur Acad Dermatol Venereol. 2024;38(8): e722-e728

Kramer N, Müller G, Zierold S, Röckel M, Fröhlich W, Schefzyk M, Kumbrink J, Hassel JC, Berking C, Ziemer M, Nashan D, French LE, Vera J, Kerl-French KE, Gutzmer R, Heinzerling L

Treatment of moderate-to-severe atopic dermatitis with baricitinib: Results from an interim analysis of the TREATgermany registry.

J Eur Acad Dermatol Venereol. 2024;():

Traidl S, Heinrich L, Siegels D, Heratizadeh A, Kind B, Haufe E, Abraham S, Schäfer T, Augustin M, Harder I, Pinter A, Schäkel K, Wollenberg A, Ertner K, Ramaker-Brunke J, Bong A, Quist S, Gorriahn-Maiterth H, Schenck F, Sticherling M, Effendy I, Schwarz B, Handrick C, Asmussen A, Weidinger S, Schmitt J, Werfel T, TREATgermany study group

Consensus statement on the diagnosis and treatment of sclerosing diseases of the skin, Part 2: Scleromyxoedema and scleroedema.

J Eur Acad Dermatol Venereol. 2024;38(7): 1281-1299

Knobler R, Geroldinger-Simić M, Kreuter A, Hunzelmann N, Moinzadeh P, Rongioletti F, Denton C, Mouthon L, Cutolo M, Smith V, Gabrielli A, Bagot M, Olesen AB, Foeldvari I, Jalili A, Kähäri VM, Kárpáti S, Kofoed K, Olszewska M, Panelius J, Quaglino P, Seneschal J, Sticherling M, Sunderkötter C, Tanew A, Wolf P, Worm M, Skrok A, Rudnicka L, Krieg T

The term 'sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present consensus provides an update to the 2017 European Dermatology Forum Guidelines, focusing on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, updated strategies for the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 2 of this consensus provides clinicians with an overview of the diagnosis and treatment of scleromyxoedema and scleroedema (of Buschke).

Guidelines for mouse and human DC generation.

Eur J Immunol. 2023;53(11):

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

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

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

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

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

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

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.

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.

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

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

Br J Dermatol. 2023;188(2):

Berking C

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

Eur J Immunol. 2023;53(12):

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

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

Guidelines for mouse and human DC functional assays.

Eur J Immunol. 2023;53(12):

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

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

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

Eur J Immunol. 2023;53(12):

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

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

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

Eur J Immunol. 2023;53(11):

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

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

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.

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.

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.

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;62(10): 3448-3458

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

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

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

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

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

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;62(9): e271-e272

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

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.

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.

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.

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.

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.

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.

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

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

Retzlaff J, Lai X, Berking C, Vera J

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

J Clin Med. 2023;12(11):

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

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

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

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

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

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

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

Front Immunol. 2023;14():

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

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

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

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

Livingstone E, Berking C

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

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

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

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

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

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

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

Hassel JC, Berking C

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

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

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

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

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

DeepNAPSI multi-reader nail psoriasis prediction using deep learning.

Sci Rep. 2023;13(1):

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

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

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

J Immunother Cancer. 2023;11(5):

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Meder C, Sticherling M

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

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

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

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

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

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

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

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

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

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

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

Siegling M, Renner R, Erfurt-Berge C

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

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

Acta Derm Venereol. 2023;103():

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

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

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

Heppt MV, Leiter U

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

Label-free discrimination of extracellular vesicles from large lipoproteins.

J Extracell Vesicles. 2023;12(8):

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Eur J Cancer. 2023;191():

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

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

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

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

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

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

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

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

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

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

Berking C, Hassel JC, Livingstone E

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

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

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

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

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

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

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

FUNDING: Bristol Myers Squibb.

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

Sci Rep. 2023;13(1):

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

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

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

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

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

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

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

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

Effect of abrocitinib in a patient with extensive necrobiosis lipoidica.

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

Arnet L, Erfurt-Berge C

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

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

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

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

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

J Clin Med. 2023;12(14):

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

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

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

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

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

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

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

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

[Individualized precision medicine].

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

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

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

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

Eur J Immunol. 2023;53(9):

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

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

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

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

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

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

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

Sci Rep. 2023;13(1):

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

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

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

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

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

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

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

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

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

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

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

Uveal melanoma

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

Hassel JC, Heppt MV

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

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

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

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

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

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

Front Immunol. 2023;14():

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

J Immunother Cancer. 2023;11(9):

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

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

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

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

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

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

Eur J Cancer. 2023;191():

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

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

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

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

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

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

Case Report: The many faces of bullous pemphigoid.

Front Immunol. 2023;14():

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

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

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

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

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

A syphilis-like picture caused by PVL-positive staphylococci

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

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

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

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

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

Blistering Autoimmune Diseases - Importance in Middle Franconia

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

Schoenfelder V, Sticherling M

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

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

Sollfrank L, Rechtien L, Sticherling M

Severe furunculoid Myiasis after a Tour of Africa

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

Rechtien L, Kaufmann M, Sticherling M

Maximal Variants of Psoriasis unguium - A Case Series

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

Rechtien L, Sollfrank L, Sticherling M

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

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

Busch D, Sticherling M

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

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

Busch D, Sticherling M

Psoriasis - Status and Care in the university Environment

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

Morcos C, Sticherling M

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Front Immunol. 2023;14():

Vu Manh TP, Dalod M, Dudziak D

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

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

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

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

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

Biomater. Adv.. 2023;154():

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Wessely A, Kammerbauer C, Berking C, Heppt MV

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Acta Derm Venereol. 2023;103():

Stockfleth E, Heppt MV, Bégeault N, Delarue A

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

Acral Fibrokeratoma in the Form of a Victory Sign

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

Lorz A, Heppt F, Krahl D

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

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

Brans R, Wagner N

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

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

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

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

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

BMC Cancer. 2023;23(1):

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Clin Transl Radiat Oncol. 2023;39():

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

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

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

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

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

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

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

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

The influence of indisulam on human immune effector cells: Is a combination with immunotherapy feasible?

J Dtsch Dermatol Ges. 2023;21 Suppl 4(): 94-95

Arnet L, Carmo-Fonseca M, Berking C, Doerrie J, Schaft N

PaM - Palliativmedizinisches Integrationsmodell beim Melanom

J Dtsch Dermatol Ges. 2023;21 Suppl 4(): 4-5

Bender-Saebelkampf S, Heckel M, Ostgathe C, Berking C, Heppt M

Efficacy and safety of tirbanibulin in actinic keratoses. Interim results of a non-interventional study

J Dtsch Dermatol Ges. 2023;21 Suppl 4(): 69-70

Heppt M, Hadshiew I, Kempf A, Melzer A, Berking C

Evaluation of immune checkpoint inhibitor avelumab combined with DC-based vaccination for the treatment of Merkel cell carcinoma

J Dtsch Dermatol Ges. 2023;21 Suppl 4(): 14-14

Sauerer T, Bremm F, Beenen A, Berking C, Schaft N, Doerrie J

Standardized computer-assisted analysis of 5-hmC immunoreactivity in dysplastic nevi and superficial spreading melanomas

J Dtsch Dermatol Ges. 2023;21 Suppl 4(): 113-114

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

Retrospective analysis of autoimmune bullous diseases in Middle Franconia.

Front Immunol. 2023;14():

Sollfrank L, Schönfelder V, Sticherling M

INTRODUCTION: Autoimmune bullous diseases (AIBDs) are a group of rare cutaneous disorders affecting cornified skin and mucous membranes. They are characterized by tense or flaccid blistering and erosions due to autoantibodies against desmosomal and hemidesmosomal structural proteins of the skin. This group of disorders can be divided into those of pemphigoid and those of pemphigus diseases. If left untreated, these autoimmune diseases can cause serious or even life-threatening complications such as loss of fluid, superinfections or impaired food intake. Due to modern standardized serological assays, the diagnosis of AIBDs can usually be confirmed in combination with their clinical appearance. Whereas for a long time corticosteroids were the major players in the treatment of these diseases, with the approval of rituximab and other immunosuppressive agents, the therapy has increasingly improved.

METHODS: In this study, we aimed to investigate epidemiologic and clinical features as well as diagnostics and therapy of bullous autoimmune diseases in Middle Franconia, a governorate within the German federal state of Bavaria. Patients diagnosed or treated because of a AIBDs between 01.04.2013 and 31.03.2019 at the dermatological department of the university hospital Erlangen were included in this retrospective study (n = 242). Patients were either diagnosed for the first time (n=176) or the diagnosis has been confirmed (n=66) at the department. The respective incidence was calculated among the 176 subjects who had been diagnosed at the center in this period. Data was taken from patient records and analyzed with Microsoft® Excel. The evaluation included the diagnoses of pemphigus vulgaris (PV), pemphigus foliaceus (PF), bullous pemphigoid (BP), mucous membrane pemphigoid (MMP), linear IgA dermatosis (LAD), epidermolysis bullosa acquisita (EBA), and dermatitis herpetiformis (DH).

RESULTS: This study shows that the incidence of each AIBDs in Middle Franconia is low and comparable (PV, PF, LAD, EBA) or lower (BP, MMP, DH) than in other studies and regions. BP is the most common newly diagnosed AIBD in Middle Franconia.

DISCUSSION: Due to the chronic and sometimes severe course of AIBDs, repeated in-house treatments are often necessary. To date, mainly topically and systemically applied corticosteroids in combination with immunomodulators are used as first-line therapy.

Logic-based modeling and drug repurposing for the prediction of novel therapeutic targets and combination regimens against E2F1-driven melanoma progression.

BMC Chem. 2023;17(1):

Singh N, Khan FM, Bala L, Vera J, Wolkenhauer O, Pützer B, Logotheti S, Gupta SK

Melanoma presents increasing prevalence and poor outcomes. Progression to aggressive stages is characterized by overexpression of the transcription factor E2F1 and activation of downstream prometastatic gene regulatory networks (GRNs). Appropriate therapeutic manipulation of the E2F1-governed GRNs holds the potential to prevent metastasis however, these networks entail complex feedback and feedforward regulatory motifs among various regulatory layers, which make it difficult to identify druggable components. To this end, computational approaches such as mathematical modeling and virtual screening are important tools to unveil the dynamics of these signaling networks and identify critical components that could be further explored as therapeutic targets. Herein, we integrated a well-established E2F1-mediated epithelial-mesenchymal transition (EMT) map with transcriptomics data from E2F1-expressing melanoma cells to reconstruct a core regulatory network underlying aggressive melanoma. Using logic-based in silico perturbation experiments of a core regulatory network, we identified that simultaneous perturbation of Protein kinase B (AKT1) and oncoprotein murine double minute 2 (MDM2) drastically reduces EMT in melanoma. Using the structures of the two protein signatures, virtual screening strategies were performed with the FDA-approved drug library. Furthermore, by combining drug repurposing and computer-aided drug design techniques, followed by molecular dynamics simulation analysis, we identified two potent drugs (Tadalafil and Finasteride) that can efficiently inhibit AKT1 and MDM2 proteins. We propose that these two drugs could be considered for the development of therapeutic strategies for the management of aggressive melanoma.

Breaking barriers: NEK2 inhibition shines in multiple myeloma treatment.

Cell Rep Med. 2023;4(10):

Lischer C, Bruns H

In their article, Cheng et al.1 reveal that NEK2 loss reshapes the tumor microenvironment, reducing tumor-associated macrophages and decreasing T cell exhaustion. They show that this ultimately favors the immune system's anti-cancer response in multiple myeloma.

Oligoclonal expansion and loss of cytotoxic functionality of CAR-T cells in a DLBCL patient after CD19.CAR-T cell therapy

Oncology Research and Treatment. 2023;46 Suppl 5(): 73-74

Mueller F, Schwingen NR, Eisenhauer N, Aigner M, Schletter M, Lutzny-Geier G, Lischer C, Guese E, Gebhard C, Rehli M, Gonzalez JV, Eckstein M, Wiesmueller M, Erber R, Bruns H, Mackensen A, Voelkl S

Oxidative DNA damage in reconstituting T cells is associated with relapse and inferior survival after allo-SCT.

Blood. 2023;141(13): 1626-1639

Karl F, Liang C, Boettcher-Loschinski R, Stoll A, Flamann CS, Richter S, Lischer C, Völkl S, Jacobs B, Böttcher M, Jitschin R, Bruns H, Fischer T, Holler E, Roesler W, Dandekar T, Mackensen A, Mougiakakos D

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only curative treatment option for a number of hematologic malignancies. Its therapeutic potential relies on the potency of donor T cells to eliminate residual malignant cells, the so-called graft-versus-leukemia (GVL) effect. Disease relapse remains the most frequent treatment failure and is associated with poor outcome. Therefore, it is inevitable to decipher mechanisms that weaken GVL. In recent years, studies of tumor biology have revealed that metabolic remodeling of the micromilieu can critically regulate immune responses. Accumulation of reactive oxygen species leads to a metabolic condition known as oxidative stress, which can severely hamper T cells. Currently, only a few studies, mainly using preclinical models, have demonstrated the occurrence of oxidative stress after allo-SCTs. Therefore, we sought to investigate oxidative stress in a well-characterized group of patients who underwent allo-SCT and its impact on reconstituting T cells. We identified high concentrations of serum 8-hydroxydeoxyguanosine (8-OHdG) as an established biomarker for oxidative stress. 8-OHdG is one of the major products of DNA oxidation, which is normally rapidly removed. After allo-SCT, T cells accumulated oxidative DNA damage. High cellular 8-OHdG content (8-OHdGhi) was associated not only with signs of enhanced T-cell activation but also premature exhaustion. The inability of 8-OHdGhi T cells to efficiently target malignant cells or produce cytotoxic granzyme B and interferon gamma was associated with a significantly increased relapse risk and a shorter overall survival. Taken together, our novel findings could give reason to focus on bolstering DNA repair in reconstituting T cells as a means to improve GVL efficacy.

Analytical and numerical characterisation of terminal velocities of Tenebrio molitor larvae in a new, asymmetrical zigzag based separation system

J. Insects Food Feed. 2023;9(11): 1515-1522

Baur A, Batmaz E, Gatternig B, Delgado A

Separation of Tenebrio molitor larvae from unwanted residues, like frass, feed or exuviae is a key process step for an industrial scale plant. One method to separate larvae from residues is using a zigzag air classifier. For designing and for an efficient operation of a zigzag air classifier, the terminal velocity is a key parameter to separate larvae from different residues with a high separation sensitivity. In this work, the terminal velocities of different larvae sizes are evaluated analytically, numerically and experimentally. For this, the sizes of 3 week to 12 week old larvae were used to calculate and simulate the terminal velocity. To validate the results, an experiment was carried out and compared with the analytical and numerical data. For this, a model for T. molitor larvae was designed to calculate the surface and volume of a larva to produce equivalent spheres with the same physical properties as a real larva. The results are showing similar curves with terminal velocities from 5 m/s for young larvae (3 weeks old) to 12 m/s for older larvae (12 weeks old). The deviations between each method are 1 m/s for smaller larvae and 1.5 m/s for bigger larvae. In further experiments and simulations, approaches with calculation methods for non-spherical particles are necessary to achieve results closer to reality due to the cylindrical shape of T. molitor larvae.

Effectiveness, safety and quality-of-life effects of guselkumab and ustekinumab in patients with psoriasis: Week 104 results from the non-interventional, prospective, German multicentre PERSIST study.

J Eur Acad Dermatol Venereol. 2023;():

Gerdes S, Hoffmann M, Asadullah K, Korge B, Mortazawi D, Krüger N, Personke Y, Tabori S, Gomez M, Wegner S, Kreimendahl F, Taut F, Sticherling M

BACKGROUND: PERSIST was a prospective, non-interventional, real-world study of guselkumab and ustekinumab in adult patients with moderate-to-severe plaque psoriasis in Germany.

OBJECTIVES: To examine effectiveness, safety and quality-of-life (QoL) outcomes to Week (W) 104 of treatment with guselkumab and ustekinumab in patients with moderate-to-severe plaque psoriasis.

METHODS: Patients (≥18 years of age) received guselkumab or ustekinumab as per routine clinical practice. Outcomes to W104 were examined separately in guselkumab and ustekinumab recipients. An ad hoc exploratory analysis of outcomes with guselkumab versus ustekinumab was also performed following propensity score matching.

RESULTS: Overall, 302 and 313 patients received guselkumab and ustekinumab, respectively. Patients in both cohorts experienced improvements in disease activity and QoL that were maintained to W104, with 64.7% and 63.6% of guselkumab- and 54.6% and 64.4% of ustekinumab-treated patients achieving a Psoriasis Area and Severity Index (PASI) 90 response and a Dermatology Life Quality Index (DLQI) 0/1 score, respectively. Propensity score matching yielded well-balanced baseline characteristics except for prior biologic use, which was higher in guselkumab versus ustekinumab recipients (51.7% vs. 32.0%). Achievement of PASI ≤1 at W104 was more common in guselkumab versus ustekinumab recipients (58.7% vs. 49.7%). The W104 PASI90 response rate was 65.6% with guselkumab and 56.0% with ustekinumab; corresponding rates for PASI100 were 44.3% and 28.5%. In guselkumab recipients, response rates were higher in biologic-naïve versus biologic-experienced patients (PASI90, 77.1% vs. 53.4%; PASI100, 55.0% vs. 33.0%). A high level of response for QoL outcomes was observed for both treatments.

CONCLUSIONS: Ustekinumab and guselkumab led to improvements in physician-assessed and patient-reported outcomes that were sustained for up to 2 years, with no new safety signals identified. Following propensity score matching, greater improvements in PASI outcomes were observed with guselkumab versus ustekinumab. Improvements with guselkumab were highest in biologic-naïve patients, highlighting the value of early treatment.

Health literacy and information needs among German skin cancer patients in comparison to people without skin cancer: A survey

JEADV Clin. Pract.. 2023;2(4): 830-838

Hoffmann J, Steeb T, Weber C, Doppler A, Schmitt J, Schadendorf D, Berking C, Meier F

BackgroundAn increasing number of patients are seeking health information on the internet. Health literacy and the quality of information are crucial to enable patients to find relevant high-quality information.ObjectivesTo investigate the relevance of quality criteria for health information and to determine the health literacy of skin cancer patients (SC) in comparison to those without skin cancer (NSC).MethodsBetween December 2021 until February 2022 we undertook an online survey on the importance of multiple criteria to investigate the relevance of quality criteria of online health information. SC and NSC were eligible for participation. The questionnaire assessed participants<acute accent> health information-seeking behavior and the evaluation of relevance of quality criteria for health information on a 5-point-LIKERT-Scale. The participants<acute accent> health literacy was measured according to the health literacy measurement scale ranging from 0-100. Comparisons between SC and NSC were investigated with t-tests.ResultsWe retrieved data from 268 participants, of whom 98 (38%) were SC. Participants assigned the highest relevance to the health information topics treatment (4.7 +/- 0.64) and effects of a disease (4.49 +/- 0.76). Participants ranked the content of information with a mean of 4.72 (+/- 0.57) to be the most relevant criterion, followed by objectivity (4.61 +/- 0.67) and completeness of the information (4.59 +/- 0.61). Participants showed the highest competence in understanding of information (62.4 +/- 22.5) and in disease prevention (58.32 +/- 22.9). They reached low values in accessing health related information (46.78 +/- 25.62) and appraising it (33.16 +/- 20.11). Subgroup analysis indicated that SC had a greater need for practical information that is helpful in dealing with a disease compared to NSC. They showed significantly lower health literacy than NSC.ConclusionsOur study documents that SC and NSC have a high need for different dimensions of quality of health information. These differences in the importance of criteria should be considered in the development of future targeted health information.</acute></acute>

THE PREVALENCE OF ALOPECIA AREATA IN GERMANY: RESULTS OF AN INSURANCE CLAIMS DATABASE ANALYSIS

Value Health. 2023;26 Suppl S(12): S240-S240

Augustin M, Maqhuzu PN, Suess S, Mauer AP, Haeckl D, Sticherling M, Pumnea T, Schwichtenberg U

DISTURBED SPATIAL WNT ACTIVATION - A POTENTIAL MEDIATOR OF DISTURBED SKIN POLARIZATION IN SYSTEMIC SCLEROSIS (SSC)

Ann Rheum Dis. 2023;82 Suppl 1(): 76-76

Fakhouri SC, Konstantinidis L, Honglin Z, Eckstein M, Dees C, Kreuter A, Sticherling M, Schett G, Joerg D, Bergmann C

CHRONIC TENOSYNOVITIS IS ASSOCIATED WITH LOSS OF GRIP STRENGTH IN PATIENTS WITH PSORIASIS AND PSORIATIC ARTHRITIS

Ann Rheum Dis. 2023;82 Suppl 1(): 47-47

Bayat S, Coppers B, Kleyer A, Godonou ET, Valor L, Simon D, Fagni F, Corte G, Schoenau V, Tascilar K, Hueber A, Sticherling M, Schett G, Liphardt AM

XCR1 expression licenses anti-viral effector functions of human conventional dendritic cells type 1

Eur J Immunol. 2023;53 Suppl 2(): 5-5

Heger L, Hatscher L, Lehmann C, Amon L, Kaszubowski T, Luehr J, Schaft N, Doerrie J, Irrgang P, Tenbusch M, Liang C, Kunz M, Socher E, Autenrieth S, Purbojo A, Sirbu H, Hartmann A, Alexiou C, Cesnjevar R, Dudziak D

Development of highly sensitive ddPCR assays to detect GNAQ, GNA11 and SF3B1 mutations in ctDNA of Uveal melanoma patients

Oncology Research and Treatment. 2023;46 Suppl 5(): 174-175

Schwandt J, Axt F, Grisanti S, Kakkassery V, Doerrie J, Schuler G, Schuler-Thurner B, Dazert E, Scherer F, von Bubnoff N

The future of affordable cancer immunotherapy.

Front Immunol. 2023;14():

Schaft N, Dörrie J, Schuler G, Schuler-Thurner B, Sallam H, Klein S, Eisenberg G, Frankenburg S, Lotem M, Khatib A

The treatment of cancer was revolutionized within the last two decades by utilizing the mechanism of the immune system against malignant tissue in so-called cancer immunotherapy. Two main developments boosted cancer immunotherapy: 1) the use of checkpoint inhibitors, which are characterized by a relatively high response rate mainly in solid tumors; however, at the cost of serious side effects, and 2) the use of chimeric antigen receptor (CAR)-T cells, which were shown to be very efficient in the treatment of hematologic malignancies, but failed to show high clinical effectiveness in solid tumors until now. In addition, active immunization against individual tumors is emerging, and the first products have reached clinical approval. These new treatment options are very cost-intensive and are not financially compensated by health insurance in many countries. Hence, strategies must be developed to make cancer immunotherapy affordable and to improve the cost-benefit ratio. In this review, we discuss the following strategies: 1) to leverage the antigenicity of "cold tumors" with affordable reagents, 2) to use microbiome-based products as markers or therapeutics, 3) to apply measures that make adoptive cell therapy (ACT) cheaper, e.g., the use of off-the-shelf products, 4) to use immunotherapies that offer cheaper platforms, such as RNA- or peptide-based vaccines and vaccines that use shared or common antigens instead of highly personal antigens, 5) to use a small set of predictive biomarkers instead of the "sequence everything" approach, and 6) to explore affordable immunohistochemistry markers that may direct individual therapies.

SOLUBLE CD83 IMPROVES WOUND HEALING IN A 3D WOUND HEALING MODEL AND PROMOTES RESOLUTION OF THE INFLAMMATORY MILIEU IN CHRONIC WOUNDS

Wound Repair Regen. 2023;31 Suppl 1(): S11-S12

Hollard C, Peckert-Maier K, Erfurt-Berge C, Steinkasserer A, Royzman D

Importance of biopsy in the diagnostic assessment of chronic wounds-position paper of the Initiative Chronische Wunden (ICW) e. V.

Dermatologie (Heidelb). 2023;():

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

Diagnostic assessment of chronic wounds is essential for the initiation of causal therapeutic treatment. For diagnostic classification of the wound genesis, it may be necessary to take a tissue sample for histological and/or microbiological processing. If there is clinical suspicion of a specific cause of the wound such as a neoplasm, an inflammatory dermatosis or a pathogen-induced wound, a tissue sample for further diagnosis is required immediately. If the ulceration does not respond sufficiently to adequate causal therapy, a tissue sample for further evaluation is recommended after 12 weeks. The choice of the correct sampling technique, further storage, transport and processing are just as decisive for a reliable result as the specific question for the diagnostic laboratory.

Steroid-Refractory Immune-Related Adverse Events Induced by Checkpoint Inhibitors.

Cancers (Basel). 2023;15(9):

Tomsitz D, Ruf T, Zierold S, French LE, Heinzerling L

The occurrence, second-line management and outcome of sr/sd-irAEs was investigated in patients with skin cancer. All skin cancer patients treated with immune checkpoint inhibitors (ICIs) between 2013 and 2021 at a tertiary care center were analyzed retrospectively. Adverse events were coded by CTCAE version 5.0. The course and frequency of irAEs were summarized using descriptive statistics. A total of 406 patients were included in the study. In 44.6% (n = 181) of patients, 229 irAEs were documented. Out of those, 146 irAEs (63.8%) were treated with systemic steroids. Sr-irAEs and sd-irAEs (n = 25) were detected in 10.9% of all irAEs, and in 6.2% of ICI-treated patients. In this cohort, infliximab (48%) and mycophenolate mofetil (28%) were most often administered as second-line immunosuppressants. The type of irAE was the most important factor associated with the choice of second-line immunosuppression. The Sd/sr-irAEs resolved in 60% of cases, had permanent sequelae in 28% of cases, and required third-line therapy in 12%. None of the irAEs were fatal. Although these side effects manifest in only 6.2% of patients under ICI therapy, they impose difficult therapy decisions, especially since there are few data to determine the optimal second-line immunosuppression.

B-cells in psoriasis?

Exp Dermatol. 2023;32(4): E88-E88

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

SYNOVIAL IMPRINTING OF SKIN-DERIVED IMMUNE CELLS INITIATES SPREADING OF INFLAMMATION FROM SKIN TO JOINT IN PSORIATIC ARTHRITIS

Ann Rheum Dis. 2023;82 Suppl 1(): 71-71

Raimondo MG, Rauber S, Mohammadian H, Vogg M, Xu C, Rigau AR, Luber M, Labinsky H, Soare A, Distler J, Fearon U, Veale D, Sticherling M, Canete JDD, Schett G, Ramming A

DOES SUBJECTIVELY PERCEIVED LOSS OF HAND FUNCTION SUFFICIENTLY REPRESENT ULTRASONOGRAPHY-DETECTED SYNOVITIS AND TENOSYNOVITIS IN PATIENTS WITH PSORIASIS AND PSORIATIC ARTHRITIS?

Ann Rheum Dis. 2023;82 Suppl 1(): 215-216

Coppers B, Bayat S, Godonou ET, Valor L, Simon D, Fagni F, Corte G, Tascilar K, Hueber A, Schonau V, Sticherling M, Schett G, Kleyer A, Liphardt AM

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

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

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

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

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

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

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

TRIAL REGISTRATION NUMBER: NCT04691232.

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.

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.

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.

Increased CD47 expression inhibits phagocytosis of alloreactive donor T cells after allo-HSCT

Oncology Research and Treatment. 2022;45 Suppl 2(SUPPL 2): 245-245

Flamann C, Matos C, Kreutz M, Shaikh H, Beilhack A, Buettner-Herold M, Lischer C, Voelkl S, Kellner C, Zeun J, Kremer A, Bitterer K, Saul D, Mougiakakos D, Mackensen A, Bruns H

Increased CD47 expression antagonizes phagocytosis of alloreactive donor T cells after allo-HSCT

Eur J Immunol. 2022;52 Suppl 1(): 410-410

Flamann C, Matos C, Kreutz M, Shaikh H, Beilhack A, Buettner-Herold M, Lischer C, Voelkl S, Zeun J, Kremer A, Bitterer K, Kellner C, Saul D, Mougiakakos D, Mackensen A, Bruns H

Single-cell Transcriptome Analysis and clonal Kinetics in a Patient after CD19.CAR-T Cell Therapy

Oncology Research and Treatment. 2022;45 Suppl 2(SUPPL 2): 125-125

Lischer C, Eisenhauer N, Aigner M, Jacobs B, Schletter M, Gebhard C, Rehli M, Bruns H, Muller F, Mackensen A, Gonzalez JV, Volkl S

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

[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.

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.

Atypical Mycobacteriosis During TNF Blockade.

Dtsch Arztebl Int. 2022;119(21):

Kaufmann MD, Erfurt-Berge C, Wörl P

[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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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

[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.

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.

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

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.

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.

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

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

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

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

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.

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

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

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

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.

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.

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.

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

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

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

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

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

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

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

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

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

Ronicke M, Sticherling M, Wagner N

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

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

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

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

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

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

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

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

Front Immunol. 2022;13():

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Interdisciplinary Approach to the Diagnosis and Treatment of Leg Ulcers

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

Erfurt-Berge C, Renner R

How does Nutrition Affect Wound Healing?

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

Renner R, Erfurt-Berge C

Interference during the complex wound healing process might lead to a delayed or absence of wound closure. One possible disruptive factor can be wrong nutrition. It is necessary to differentiate between quantitative and qualitative malnutrition. Preferential obese patients suffer from a qualitative malnutrition and sarkopenia.

Specific diseases require a specific nutritional recommendation. For example, patients with dialysis, decubitus, or leg ulcers often have a lack of proteins. In addition, other nutrient deficiencies with vitamin C, zinc, folate, vitamin D or trace elements might have a negative impact on wound healing.

Prospective studies should clarify if substitution of those nutrient deficiencies might improve wound healing. It seems to be reasonable to strive for an improvement in the consumption of vitamins, trace elements and proteins adopted to a balanced alimentation and adjusted to individual dietary habits.

Blockade of tumor cell-intrinsic PD-1 inhibits Merkel cell carcinoma growth

J Invest Dermatol. 2022;142 Suppl S(12): S258-S258

Heppt MV, Martins C, Rasbach E, Kleffel S, Mucciarone K, Brandenburg A, Thakuria M, Rahbari N, Murphy G, Ramsey MR, Barthel SR, Posch C, Schatton TF

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

J Invest Dermatol. 2022;142 Suppl S(12): S265-S265

Martins C, Silva M, Itoh Y, Rasbach E, Heppt MV, Meurer A, Brandenburg A, Barthel SR, Schatton TF

Tim-3 is a growth-suppressive immune checkpoint receptor intrinsic to melanoma cells

J Invest Dermatol. 2022;142 Suppl S(12): S261-S261

Martins C, Itoh Y, Silva M, Rasbach E, Singh P, Heppt MV, Schlapbach C, Ramsey MR, Barthel SR, Schatton TF

Cost-effectiveness of Response-Adapted De-escalation of Immunotherapy in Advanced Melanoma.

JAMA Dermatol. 2022;158(12): 1387-1393

Cartun Z, Kunz WG, Heinzerling L, Tomsitz D, Guertler A, Westphalen CB, Ricke J, Weir W, Unterrainer M, Mehrens D

IMPORTANCE: Combination immunotherapy with nivolumab and ipilimumab has markedly improved outcomes for patients with advanced melanoma. However, these therapies pose a considerable financial burden to both patients and the health care system. The ADAPT-IT trial demonstrated comparable progression-free and overall survival for patients with response-adapted ipilimumab discontinuation compared with standard of care (SOC).

OBJECTIVE: To determine the cost-effectiveness of ipilimumab discontinuation for patients with interim imaging-confirmed tumor response in the treatment of advanced melanoma.

DESIGN, SETTING, AND PARTICIPANTS: This cost-effectiveness analysis was performed using data from the ADAPT-IT (follow-up of 33 months) and CheckMate 067 (follow-up of 6.5 years) trials, as well as published literature over the ADAPT-IT trial duration of 33 months. The analysis was performed in a US setting from a US-payer perspective, and the willingness-to-pay (WTP) threshold was set at $100 000/quality-adjusted life-year (QALY). A total of 355 patients with previously untreated melanoma (unresectable stage III or IV metastatic melanoma) were included.

EXPOSURE: Response-adapted ipilimumab discontinuation compared with SOC therapy.

MAIN OUTCOMES AND MEASURES: The primary outcomes of the CheckMate trial were overall survival and progression-free survival, while that of ADAPT-IT was objective response. This informed a decision model to estimate lifetime costs and QALYs associated with both strategies. Incremental cost, effectiveness, and cost-effectiveness ratio were assessed. Sensitivity and scenario analyses were performed to account for variability in trials and input parameters.

RESULTS: Of the 355 patients included in the analysis, 41 patients were from the ADAPT-IT trial (median age, 65 years; 28 [68%] male) and 314 patients from the CheckMate 067 trial (median age, 61 years; 206 [66%] male). Response-adapted treatment was the cost-effective option in 94.0% of scenarios based on Monte Carlo simulations, with a dominant incremental cost-effectiveness ratio and an incremental net monetary benefit of $28 849 compared with SOC therapy. Cost savings were estimated at $19 891 per patient compared with SOC. In scenario analyses, current SOC was only considered as a cost-effective option under best survival assumptions and if the willingness-to-pay threshold exceeded $630 000/QALY.

CONCLUSIONS AND RELEVANCE: This economic evaluation demonstrated that response-adapted treatment de-escalation in patients with advanced melanoma may lead to considerable savings in health care costs and could represent the most cost-effective strategy across various resource settings. Future trials should aim to provide further evidence on noninferiority.

Global Circumferential and Radial Strain Among Patients With Immune Checkpoint Inhibitor Myocarditis.

JACC Cardiovasc Imaging. 2022;15(11): 1883-1896

Quinaglia T, Gongora C, Awadalla M, Hassan MZO, Zafar A, Drobni ZD, Mahmood SS, Zhang L, Coelho-Filho OR, Suero-Abreu GA, Rizvi MA, Sahni G, Mandawat A, Zatarain-Nicolás E, Mahmoudi M, Sullivan R, Ganatra S, Heinzerling LM, Thuny F, Ederhy S, Gilman HK, Sama S, Nikolaidou S, Mansilla AG, Calles A, Cabral M, Fernández-Avilés F, Gavira JJ, González NS, García de Yébenes Castro M, Barac A, Afilalo J, Zlotoff DA, Zubiri L, Reynolds KL, Devereux R, Hung J, Picard MH, Yang EH, Gupta D, Michel C, Lyon AR, Chen CL, Nohria A, Fradley MG, Thavendiranathan P, Neilan TG

BACKGROUND: Global circumferential strain (GCS) and global radial strain (GRS) are reduced with cytotoxic chemotherapy. There are limited data on the effect of immune checkpoint inhibitor (ICI) myocarditis on GCS and GRS.

OBJECTIVES: This study aimed to detail the role of GCS and GRS in ICI myocarditis.

METHODS: In this retrospective study, GCS and GRS from 75 cases of patients with ICI myocarditis and 50 ICI-treated patients without myocarditis (controls) were compared. Pre-ICI GCS and GRS were available for 12 cases and 50 controls. Measurements were performed in a core laboratory blinded to group and time. Major adverse cardiovascular events (MACEs) were defined as a composite of cardiogenic shock, cardiac arrest, complete heart block, and cardiac death.

RESULTS: Cases and controls were similar in age (66 ± 15 years vs 63 ± 12 years; P = 0.20), sex (male: 73% vs 61%; P = 0.20) and cancer type (P = 0.08). Pre-ICI GCS and GRS were also similar (GCS: 22.6% ± 3.4% vs 23.5% ± 3.8%; P = 0.14; GRS: 45.5% ± 6.2% vs 43.6% ± 8.8%; P = 0.24). Overall, 56% (n = 42) of patients with myocarditis presented with preserved left ventricular ejection fraction (LVEF). GCS and GRS were lower in myocarditis compared with on-ICI controls (GCS: 17.5% ± 4.2% vs 23.6% ± 3.0%; P < 0.001; GRS: 28.6% ± 6.7% vs 47.0% ± 7.4%; P < 0.001). Over a median follow-up of 30 days, 28 cardiovascular events occurred. A GCS (HR: 4.9 [95% CI: 1.6-15.0]; P = 0.005) and GRS (HR: 3.9 [95% CI: 1.4-10.8]; P = 0.008) below the median was associated with an increased event rate. In receiver-operating characteristic (ROC) curves, GCS (AUC: 0.80 [95% CI: 0.70-0.91]) and GRS (AUC: 0.76 [95% CI: 0.64-0.88]) showed better performance than cardiac troponin T (cTnT) (AUC: 0.70 [95% CI: 0.58-0.82]), LVEF (AUC: 0.69 [95% CI: 0.56-0.81]), and age (AUC: 0.54 [95% CI: 0.40-0.68]). Net reclassification index and integrated discrimination improvement demonstrated incremental prognostic utility of GRS over LVEF (P = 0.04) and GCS over cTnT (P = 0.002).

CONCLUSIONS: GCS and GRS are lower in ICI myocarditis, and the magnitude of reduction has prognostic significance.

Persistent immune-related adverse events after cessation of checkpoint inhibitor therapy: Prevalence and impact on patients' health-related quality of life.

Eur J Cancer. 2022;176(): 88-99

Schulz TU, Zierold S, Sachse MM, Pesch G, Tomsitz D, Schilbach K, Kähler KC, French LE, Heinzerling L

BACKGROUND: Immune checkpoint inhibitors (ICIs) may induce persistent immune-related adverse events (irAEs). We investigated persistent irAEs and implications on patients' lives compared to non-ICI-induced autoimmune diseases (AIs).

METHODS: The multicentre, cross-sectional study comprised 200 patients with cancer ≥12 weeks after ICI cessation (ICI-patients) and 2705 patients with AIs (AI-patients), recruited in German outpatient clinics and support groups. The prevalence of persistent irAEs subdivided in long-term (12 weeks to <12 months) and chronic irAEs (≥12 months) since ICI discontinuation, health-related quality of life (HRQoL) using the EuroQol 5D-5L (EQ-Index/VAS score), and burden of autoimmune symptoms and respective therapies were assessed.

RESULTS: Long-term/chronic irAEs occurred in 51.9%/35.5% of outpatient ICI-patients, including arthralgia (16.7%/16.1%), myalgia (13.0%/14.0%), hypothyroidism (11.1%/10.8%), xerostomia (7.4%/8.6%), vitiligo (13.0%/7.5%) and hypophysitis (9.3%/7.5%). ICI-patients with long-term/chronic irAEs reported clinically significantly reduced HRQoL compared to ICI-patients without long-term/chronic irAEs (EQ-Index score: 0.767/0.752 versus 0.920/0.923, p < 0.001/0.001; EQ-VAS score: 52.2/52.0 versus 63.6/74.7, p =/< 0.040/0.001). Multiple linear regression analyses confirmed clinically significant reductions in HRQoL scores by chronic irAEs (EQ-Index/VAS score: -0.163/-23.4, p < 0.001/0.001). HRQoL, burden of autoimmune symptoms and burden of respective therapies in ICI-patients with chronic irAEs were similar to AI-patients with non-exacerbated AIs. Patients with chronic irAEs felt inadequately informed about side-effects compared to patients without chronic irAEs (p < 0.001).

CONCLUSION: Persistent irAEs impose a significant burden on patients after ICI cessation. Especially in early tumour stages, risk-benefit ratios must be carefully evaluated, and patients need to be informed about potential long-term sequelae.

Dataset of a retrospective multicenter cohort study on characteristics of immune checkpoint inhibitor-induced encephalitis and comparison with HSV-1 and anti-LGI1 encephalitis.

Data Brief. 2022;45():

Müller-Jensen L, Zierold S, Versluis JM, Boehmerle W, Huehnchen P, Endres M, Mohr R, Compter A, Blank CU, Hagenacker T, Meier F, Reinhardt L, Gesierich A, Salzmann M, Hassel JC, Ugurel S, Zimmer L, Banks P, Spain L, Soon JA, Enokida T, Tahara M, Kähler KC, Seggewiss-Bernhardt R, Harvey C, Long GV, Schöberl F, von Baumgarten L, Hundsberger T, Schlaak M, French LE, Knauss S, Heinzerling LM

Over the past decade, cancer immunotherapy with immune checkpoint inhibitors (ICIs) has significantly improved the outcome of many malignancies. However, with the broad use of ICIs, neurological immune related adverse events (irAE) are increasingly recognized. ICI-induced encephalitis (ICI-iE) is a particularly severe irAE, often leading to treatment termination, long-term sequalae or death. Despite its high morbidity and mortality, data on clinical features and diagnostic criteria are limited. We aimed to define clinical, radiologic and laboratory characteristics of ICI-iE and identify factors that discriminate it from anti-leucine-rich glioma-inactivated (anti-LGI)-1 encephalitis and herpes simplex virus (HSV)-1 encephalitis - two alternative causes of encephalitis - to increase the awareness of ICI-iE and improve its diagnosis and management. To that end, we retrospectively collected 30 cases of ICI-iE that were reported to the Side Effect Registry Immuno-Oncology (SERIO) and 46 cases of anti-LGI1 encephalitis or herpes simplex virus (HSV)-1 encephalitis that presented to a large German neurological referral center (Charité Universitätsmedizin Berlin) between January 2015 and September 2021. Signs and symptoms, imaging and electroencephalogram features, laboratory findings and outcome measures were assessed using standardized case report forms as well as patients' medical records and compared between the groups. The data reported here represents the largest primary cohort of patients with ICI-iE to date and the first comparison with other types of encephalitis. As all three disorders - ICI-iE, HSV-1 encephalitis and anti-LGI1 encephalitis - are rare neurological entities, this dataset can be used as a reference in future clinical studies on ICI-induced neurotoxicity, neurological autoimmune disorders, and central nervous system infections.

Development of Lymphopenia during Therapy with Immune Checkpoint Inhibitors Is Associated with Poor Outcome in Metastatic Cutaneous Melanoma.

Cancers (Basel). 2022;14(13):

Tomsitz D, Schlaak M, Zierold S, Pesch G, Schulz TU, Müller G, Zecha C, French LE, Heinzerling L

Predictive markers for immune checkpoint inhibitor (ICI) therapy are needed. Thus, baseline blood counts have been investigated as biomarkers, showing that lymphopenia at the start of therapy with (ICI) is associated with a worse outcome in metastatic melanoma. We investigated the relationship between the occurrence of lymphopenia under ICI and disease outcome. Patients with metastatic melanoma who had undergone therapy with ICI were identified in our database. Only patients with a normal lymphocyte count at baseline were included in this retrospective study. Progression-free survival (PFS) and overall survival (OS) were compared between patients in which lymphopenia occurred during ICI therapy and those who did not develop lymphopenia. In total, 116 patients were analyzed. Lymphopenia occurred in 42.2% of patients, with a mean onset after 17 weeks (range 1-180 weeks). The occurrence of lymphopenia during immunotherapy was significantly associated with a shorter PFS and OS. Patients who developed lymphopenia (n = 49) had a mean PFS of 13.3 months (range 1-67 months) compared to 16.9 months (range 1-73 months) for patients who did not develop lymphopenia (n = 67; p = 0.025). Similarly, patients with lymphopenia had a significantly shorter OS of 28.1 months (range 2-70 months) compared with 36.8 months (range 4-106 months) in patients who did not develop lymphopenia (p = 0.01). Patients with metastatic melanoma who develop lymphopenia during ICI therapy have a worse prognosis with significantly shorter PFS and OS compared with patients who do not develop lymphopenia.

Health-related quality of life (EuroQol 5D-5L) in patients with autoimmunity in the context of immunotherapy: A large dataset comprising cancer patients after cessation of checkpoint inhibitor therapy and patients with autoimmune diseases.

Data Brief. 2022;45():

Schulz TU, Zierold S, Sachse MM, Pesch G, Tomsitz D, Schilbach K, Kähler KC, French LE, Heinzerling L

This dataset contains demographic, clinical, and health-related quality of life (HRQoL) data from 2905 patients including 200 cancer patients after immune checkpoint inhibitor (ICI) cessation and 2705 patients with a wide variety of autoimmune diseases. Within this multicenter, cross-sectional survey study data were collected questionnaire-based in cancer patients (ICI-patients) ≥ 18 years of age who had received at least one dose of ICI with ≥ 12 weeks since ICI discontinuation. Patients with autoimmune diseases (AI-patients) were ≥ 18 years, had at least one autoimmune disease and had never received ICI. ICI-patients were recruited in three skin cancer centers and via support groups. AI-patients were recruited in an outpatient clinic for internal medicine and via support groups. Specific questionnaires for ICI-patients/AI-patients were provided paper-based for patients from outpatient clinics and online for patients from support groups. Both questionnaires contained sections with demographic information, clinical data, and the standardized patient-reported outcome measure EuroQol 5D-5L (EQ-5D-5L) to assess HRQoL. Clinical data focused on autoimmunity and therapy of autoimmunity in (1) ICI-patients referring to particularly persistent immune-related adverse events (persistent irAEs) and in (2) AI-patients referring to respective autoimmune diseases. Additionally, specific items on cancer and cancer therapy were included in ICI-patients, and AI-patients were asked about the presence of acute exacerbations of autoimmune diseases. This dataset contains the raw data for ICI-patients and AI-patients, analyzed data on patient demographics, clinical characteristics and HRQoL scores among ICI-patients with/without persistent irAEs and among AI-patients. The data provide a basis for further investigations within the cohort of ICI-patients after ICI cessation and/or for AI-patients with different autoimmune diseases with regard to HRQoL, autoimmunity and therapy of autoimmunity.

Characteristics of immune checkpoint inhibitor-induced encephalitis and comparison with HSV-1 and anti-LGI1 encephalitis: A retrospective multicentre cohort study.

Eur J Cancer. 2022;175(): 224-235

Müller-Jensen L, Zierold S, Versluis JM, Boehmerle W, Huehnchen P, Endres M, Mohr R, Compter A, Blank CU, Hagenacker T, Meier F, Reinhardt L, Gesierich A, Salzmann M, Hassel JC, Ugurel S, Zimmer L, Banks P, Spain L, Soon JA, Enokida T, Tahara M, Kähler KC, Seggewiss-Bernhardt R, Harvey C, Long GV, Schöberl F, von Baumgarten L, Hundsberger T, Schlaak M, French LE, Knauss S, Heinzerling LM

AIM: Immune checkpoint inhibitor-induced encephalitis (ICI-iE) is a rare but life-threatening toxicity of immune checkpoint inhibitor treatment. We aim to identify the characteristics of ICI-iE and describe factors that discriminate it from herpes simplex virus (HSV)-1 encephalitis and anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis, as two alternative entities of encephalitis.

METHODS: In this retrospective multicentre cohort study, we collected patients with ICI-iE reported to the Side Effect Registry Immuno-Oncology from January 2015 to September 2021 and compared their clinical features and outcome with 46 consecutive patients with HSV-1 or anti-LGI1 encephalitis who were treated at a German neurological referral centre.

RESULTS: Thirty cases of ICI-iE, 25 cases of HSV-1 encephalitis and 21 cases of anti-LGI1 encephalitis were included. Clinical presentation of ICI-iE was highly variable and resembled that of HSV-1 encephalitis, while impairment of consciousness (66% vs. 5%, p = .007), confusion (83% vs. 43%; p = .02), disorientation (83% vs. 29%; p = .007) and aphasia (43% vs. 0%; p = .007) were more common in ICI-iE than in anti-LGI1 encephalitis. Antineuronal antibodies (17/18, 94%) and MRI (18/30, 60%) were mostly negative in ICI-iE, but cerebrospinal fluid (CSF) showed pleocytosis and/or elevated protein levels in almost all patients (28/29, 97%). Three patients (10%) died of ICI-iE. Early immunosuppressive treatment was associated with better outcome (r = 0.43).

CONCLUSIONS: ICI-iE is a heterogeneous entity without specific clinical features. CSF analysis has the highest diagnostic value, as it reveals inflammatory changes in most patients and enables the exclusion of infection. Early treatment of ICI-iE is essential to prevent sequelae and death.

NanoString technology distinguishes anti-TIF-1γ⁺ from anti-Mi-2⁺ dermatomyositis patients (vol 31, e12957, 2021)

Brain Pathol. 2022;32(2):

Heinzerling L

Molecular dynamics simulations of the delta and omicron SARS-CoV-2 spike - ACE2 complexes reveal distinct changes between both variants.

Comput Struct Biotechnol J. 2022;20(): 1168-1176

Socher E, Heger L, Paulsen F, Zunke F, Arnold P

SARS-CoV-2, the virus causing the COVID-19 pandemic, changes frequently through the appearance of mutations constantly leading to new variants. However, only few variants evolve as dominating and will be considered as "Variants of Concern" (VOCs) by the world health organization (WHO). At the end of 2020 the alpha (B.1.1.7) variant appeared in the United Kingdom and dominated the pandemic situation until mid of 2021 when it was substituted by the delta variant (B.1.617.2) that first appeared in India as predominant. At the end of 2021, SARS-CoV-2 omicron (B.1.1.529) evolved as the dominating variant. Here, we use in silico modeling and molecular dynamics (MD) simulations of the receptor-binding domain of the viral spike protein and the host cell surface receptor ACE2 to analyze and compare the interaction pattern between the wild type, delta and omicron variants. We identified residue 493 in delta (glutamine) and omicron (arginine) with altered binding properties towards ACE2.

Effectiveness and safety of dabrafenib and trametinib in patients with BRAFV600 mutated metastatic melanoma in the real-world setting: Final results of the non-interventional COMBI-r study

Ann Oncol. 2022;33 Suppl 7(7): S927-S927

Berking C, Livingstone E, Weichenthal M, Leiter-Stoppke U, Remy J, Eigentler T, Mohr P, Kiecker F, Loquai C, Debus D, Gutzmer R

Effectiveness and Safety of Dabrafenib and Trametinib in Patients with BRAFV600 Mutated Metastatic Melanoma in the Real-World Setting - Final Results of the Non-Interventional COMBI-r Study

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

Berking C, Livingstone E, Weichenthal M, Leiter-Stoeppke U, Remy J, Eigentler T, Mohr P, Kiecker F, Loquai C, Debus D, Gutzmer R

First interims analysis of a two cohort registry study for patients with advanced cutaneous squamous cell carcinoma (CSCC) treated with cemiplimab or other approaches

J Dtsch Dermatol Ges. 2022;20 Suppl 3(): 44-44

Gutzmer R, Geusau A, Heppt M, Leiter-Stoeppke U, GunTinas-Lichius O, Duecker P, Utikal JS, Loquai C, Grabbe S, Terheyden P, Ziller F, Tschechne B, Gschnell M, Mohr P, Heinzerling M, Grimmelmann J, Dippel MO, Hassel J, Kaatz M, Simon J, Zahn MO, Ulrich J, Gambichler T, Welzel J, Ramelyte E, Weichenthal M

ASSESSING SIMILARITY OF STUDIES FOR NETWORK META-ANALYSIS: THE USE OF FEASIBILITY ASSESSMENT AND SENSITIVITY ANALYSES TO ESTIMATE THE EFFICACY OF TIRBANIBULIN, A NEW DRUG FOR ACTINIC KERATOSIS

Value Health. 2022;25 Suppl S(12): S367-S368

Heppt M, Dykukha I, Chapman-Rounds M, Graziadio S, Edwards M

CHALLENGES OF NETWORK META-ANALYSIS FOR SAFETY OUTCOMES: THE ANALYSIS OF TIRBANIBULIN AGAINST COMMON TREATMENTS IN EUROPE FOR ACTINIC KERATOSIS

Value Health. 2022;25 Suppl S(12): S351-S351

Heppt M, Dykukha I, Chapman-Rounds M, Graziadio S, Edwards M

Glaucoma-TrEl: A web-based interactive database to build evidence-based hypotheses on the role of trace elements in glaucoma.

BMC Res Notes. 2022;15(1):

Choudhari JK, Eberhardt M, Chatterjee T, Hohberger B, Vera J

OBJECTIVE: Glaucoma is a chronic neurological disease that is associated with high intraocular pressure (IOP), causes gradual damage to retinal ganglion cells, and often culminates in vision loss. Recent research suggests that glaucoma is a complex multifactorial disease in which multiple interlinked genes and pathways play a role during onset and development. Also, differential availability of trace elements seems to play a role in glaucoma pathophysiology, although their mechanism of action is unknown. The aim of this work is to disseminate a web-based repository on interactions between trace elements and protein-coding genes linked to glaucoma pathophysiology.

RESULTS: In this study, we present Glaucoma-TrEl, a web database containing information about interactions between trace elements and protein-coding genes that are linked to glaucoma. In the database, we include interactions between 437 unique genes and eight trace elements. Our analysis found a large number of interactions between trace elements and protein-coding genes mutated or linked to the pathophysiology of glaucoma. We associated genes interacting with multiple trace elements to pathways known to play a role in glaucoma. The web-based platform provides an easy-to-use and interactive tool, which serves as an information hub facilitating future research work on trace elements in glaucoma.

Select hyperactivating NLRP3 ligands enhance the TH1-and TH17-inducing potential of human type 2 conventional dendritic cells

Eur J Immunol. 2022;52 Suppl 1(): 178-179

Heger L, Hatscher L, Lehmann CHK, Purbojo A, Onderka C, Liang C, Hartmann A, Cesnjevar R, Bruns H, Gross O, Nimmerjahn F, Ivanovic-Burmazovic I, Kunz M, Dudziak D

A cross-tissue protein profiling atlas reveals distinct cDC2 subpopulations within the murine conventional dendritic cell network

Eur J Immunol. 2022;52 Suppl 1(): 38-38

Amon L, Lehmann CHK, Seichter A, Heger L, Dudziak D

Eine uberma ss ige Phagozytose von Myelomzellen induziert Pyroptose in Myelom-assoziierten Makrophagen und beeintrachtigt die Wirksamkeit therapeutischer Antikorper.

Oncology Research and Treatment. 2022;45 Suppl 2(SUPPL 2): 281-281

Flamann C, Biedermann A, Mougiakakos D, Bitterer K, Karg K, Bittenbring J, Buttner-Herold M, Liebisch G, Leffler M, Lischer C, Eberhardt M, Vera-Gonzales J, Zeiser R, A. A, H. H

BISPECIFIC ANTIBODIES ENABLE SYNTHETIC AGONISTIC RECEPTOR T CELL THERAPY IN MELANOMA

J Immunother Cancer. 2022;10 Suppl 1(): A4-A5

Benmebarek M, Maerkl F, Keyl J, Cadilha B, Geiger M, Karches C, Obeck H, Schwerdtfeger M, Briukhovetska D, Jobst J, Mueller P, Seifert M, Grunmeier R, Thomas M, Marr C, Levesque M, Heppt M, Endres S, Klein C, Kobold S

Adrenaline autoinjector is under-prescribed in typical cold urticaria patients living in tropical climate countries.

Qatar Med J. 2022;2022(2):

Bizjak M, Košnik M, Dinevski D, Francis Thomsen S, Fomina D, Borzova E, Kulthanan K, Meshkova R, Aarestrup F, Melina Ahsan D, Al-Ahmad M, Altrichter S, Bauer A, Brockstädt M, Costa C, Demir S, Fachini Criado R, Felipe Ensina L, Gelincik A, Giménez-Arnau AM, Gonçalo M, Gotua M, Grønlund Holm J, Inomata N, Kasperska-Zajac A, Khoshkhui M, Klyucharova A, Kocatürk E, Lu R, Makris M, Maltseva N, Pasali M, Paulino M, Pesqué D, Peter J, Dario Ramón G, Ritchie C, Oliveira Rodrigues Valle S, Rudenko M, Sikora A, Wagner N, Xepapadaki P, Xue X, Zhao Z, Terhorst-Molawi D, Maurer M

Background: The diagnosis of typical cold urticaria (ColdU) relies on whealing in response to local cold stimulation testing (CST). It can also manifest with cold-induced anaphylaxis (ColdA). Till date, it is largely unclear how often patients with ColdU receive adrenaline treatment and are provided with an adrenaline autoinjector (AAI). Methods: An international, cross-sectional study, COLD-CE (i.e., comprehensive evaluation of ColdU and other cold-induced reactions), was carried out at 32 UCAREs. Detailed histories were taken and CST with an ice cube and/or TempTest® performed. ColdA was defined as an acute cold-induced (i.e., by cold water, air, or surfaces) involvement of the skin and/or visible mucosal tissue and at least one of the symptoms (cardiovascular manifestations, difficulty breathing, or gastrointestinal symptoms). Results: Of the 551 ColdU patients, 75% (n = 412) had a positive CST. Of them, concomitant chronic spontaneous urticaria was diagnosed in 10%. Of 372 patients with stand-alone ColdU, 69% were women and 91% adults. Their median age was 36 (IQR 26 - 48) years. Patients were also categorized into residents of countries with a tropical (n = 33), temperate (n = 264), or cold (n = 75) climate (Table 1: R13C1, R17C1, R21C1). AAI was more often prescribed to residents of temperate than tropical countries (30% vs. 12%, p = .038; Table 1: R31C1), although the frequency of ColdA did not significantly differ between these countries (44% vs. 42%, p = 1.000; R29C2). Residents of tropical countries had a higher frequency of ColdA induced by cold air than residents of temperate (36% vs. 12%, p = .001; R29C4) or cold (36% vs. 12%, p = .007; R25C4) countries. Cardiovascular manifestations induced by cold air were diagnosed in 33% (n = 11) of residents of tropical countries, but only 18% (n = 2) and 36% (n = 4) of them had received adrenaline and AAI, respectively (R13 - 15C7). Furthermore, hypotension and/or loss of consciousness induced by cold air occurred in 18% (n = 6) of patients, but only 17% (n = 1) received adrenaline (R13 - 14C10). ColdA was induced by complete cold water immersion in 9% (n = 3) of patients, and none of them received adrenaline treatment nor AAI (R13 - 15C3). Conclusion: Our findings suggest that ColdA is undertreated and call for changes in ColdU management.

Detection and Analysis of Critical Dynamic Properties of Oligodendrocyte Differentiation

Mathematics. 2022;10(16):

Nikolov SG, Wolkenhauer O, Nenov M, Vera J

In this paper, we derive a four-dimensional ordinary differential equation (ODE) model representing the main interactions between Sox9, Sox10, Olig2 and several miRNAs, which drive the process of (olygodendrocyte) differentiation. We utilize the Lyapunov-Andronov theory to analyze its dynamical properties. Our results indicated that the strength of external signaling (morphogenic gradients shh and bmp), and the transcription rate of mOlig2 explain the existence of stable and unstable (sustained oscillations) behavior in the system. Possible biological implications are discussed.

The Role of MicroRNAs in Cancer Biology and Therapy from a Systems Biology Perspective.

Adv Exp Med Biol. 2022;1385(): 1-22

Lai X, Schmitz U, Vera J

Since the discovery of microRNAs (miRNAs) in Caenorhabditis elegans, our understanding of their cellular function has progressed continuously. Today, we have a good understanding of miRNA-mediated gene regulation, miRNA-mediated cross talk between genes including competing endogenous RNAs, and miRNA-mediated signaling transduction both in normal human physiology and in diseases.Besides, these noncoding RNAs have shown their value for clinical applications, especially in an oncological context. They can be used as reliable biomarkers for cancer diagnosis and prognosis and attract increasing attention as potential therapeutic targets. Many achievements made in the miRNA field are based on joint efforts from computational and molecular biologists. Systems biology approaches, which integrate computational and experimental methods, have played a fundamental role in uncovering the cellular functions of miRNAs.In this chapter, we review and discuss the role of miRNAs in oncology from a system biology perspective. We first describe biological facts about miRNA genetics and function. Next, we discuss the role of miRNAs in cancer progression and review the application of miRNAs in cancer diagnostics and therapy. Finally, we elaborate on the role that miRNAs play in cancer gene regulatory networks. Taken together, we emphasize the importance of systems biology approaches in our continued efforts to study miRNA cancer regulation.

Impact of off-label use regulations on patient care in dermatology - a prospective study of cost-coverage applications filed by tertiary dermatology clinics throughout Germany.

J Eur Acad Dermatol Venereol. 2022;36(11): 2241-2249

Werner RN, Pennitz A, Eisert L, Schmidle P, Zink A, Abraham S, Schäkel K, Wolff I, Goebeler M, Plange J, Sollfrank L, Zielbauer S, Koll P, Amschler K, Müller V, Nast A

BACKGROUND: In dermatology, a medical speciality with a relatively high number of rare diseases, physicians often have to resort to off-label treatment options. To avoid claims, physicians in Germany can file a cost-coverage request (off-label application, OL-A).

OBJECTIVES: Our aim was to investigate the extent to which the current regulations affect patient care.

MATERIAL AND METHODS: Prospective cohort study among tertiary dermatology clinics throughout Germany, consecutively including OL-As (05/2019-09/2020) and assessing the follow-up correspondence. We modelled regressions to assess factors associated with cost-coverage decisions and the time needed by health insurers to process the OL-As.

RESULTS: Thirteen clinics provided data on 121 OL-As, two of which applied for on-label treatments. Of the remaining 119 OL-As, 70 (58.8%) were immediately approved and 44 (37.0%) rejected. Including cases with one or more appeals, 87 of 119 OL-As (73.1%) were finally approved and 26 (21.9%) rejected. There was an association of the final approval rate with (1) the class of medication/treatment, with approval rates being significantly lower for JAK inhibitors than for biologics (OR 0.16, 95%-CI: 0.03-0.82); (2) German state, with approval rates being lower in eastern than in western states (OR 0.30, 95%-CI 0.12-0.76); and (3) cost of the intervention (no linear trend). However, none of these predictors was significant in our multiple logistic regression models. The median health insurer's processing time (first response) was 29 days (IQR 22-38). Our analyses showed no evidence of an association with the predictors we assessed. In cases approved, the median time from the decision to file an OL-A to the actual initiation of the treatment was 65.5 days (IQR 51-92).

CONCLUSIONS: Our study points to substantial delays and inequalities in the provision of timely health care for dermatological patients with rare diseases, often involving treatments for which there is no adequate approved therapy.

Residual homing of α4β7-expressing β1+PI16+ regulatory T cells with potent suppressive activity correlates with exposure-efficacy of vedolizumab.

Gut. 2022;71(8): 1551-1566

Becker E, Dedden M, Gall C, Wiendl M, Ekici AB, Schulz-Kuhnt A, Schweda A, Voskens C, Hegazy A, Vitali F, Atreya R, Müller TM, Atreya I, Neurath MF, Zundler S

OBJECTIVE: The anti-α4β7 integrin antibody vedolizumab is administered at a fixed dose for the treatment of IBDs. This leads to a wide range of serum concentrations in patients and previous studies had suggested that highest exposure levels are associated with suboptimal clinical response. We aimed to determine the mechanisms underlying these non-linear exposure-efficacy characteristics of vedolizumab.

DESIGN: We characterised over 500 samples from more than 300 subjects. We studied the binding of vedolizumab to T cells and investigated the functional consequences for dynamic adhesion, transmigration, gut homing and free binding sites in vivo. Employing single-cell RNA sequencing, we characterised α4β7 integrin-expressing T cell populations 'resistant' to vedolizumab and validated our findings in vitro and in samples from vedolizumab-treated patients with IBD. We also correlated our findings with a post-hoc analysis of the Gemini II and III studies.

RESULTS: Regulatory T (TReg) cells exhibited a right-shifted vedolizumab binding profile compared with effector T (TEff) cells. Consistently, in a certain concentration range, the residual adhesion, transmigration, homing of and availability of functional α4β7 on TReg cells in vivo was higher than that of/on TEff cells. We identified a vedolizumab-'resistant' α4β7-expressing β1+PI16+ TReg cell subset with pronounced regulatory properties as the substrate for this effect. Our observations correlated with exposure-efficacy data from Gemini II and III trials.

CONCLUSION: Completely blocking TEff cell trafficking with vedolizumab, while simultaneously permitting residual homing of powerful TReg cells in an optimal 'therapeutic window' based on target exposure levels might be a strategy to optimise treatment outcomes in patients with IBD.

Limited Dose-Dependent Effects of Vedolizumab on Various Leukocyte Subsets.

Clin Transl Gastroenterol. 2022;13(6):

Becker E, Schweda A, Ullrich KA, Voskens C, Atreya R, Müller TM, Atreya I, Neurath MF, Zundler S

OBJECTIVES: The anti-α4β7 integrin antibody vedolizumab (VDZ) is successfully used for the treatment of inflammatory bowel diseases. However, only a subgroup of patients respond to therapy. VDZ is administered at a fixed dose, leading to a wide range of serum concentrations in patients. Previous work from our group showed a dose-dependent preferential binding of VDZ to effector compared with regulatory CD4 + T cells. Therefore, we aimed to determine the dose-dependent binding profile of VDZ to other leukocyte subsets.

METHODS: We characterized α4β7 integrin expression on CD8 + T cells, CD19 + B cells, CD14 + monocytes, natural killer cells, and eosinophils from patients with inflammatory bowel disease and healthy controls. We studied the binding of VDZ to these cells at different concentrations and investigated the functional consequences for dynamic adhesion and transmigration in vitro .

RESULTS: The expression of α4β7 differed between the analyzed leukocyte subsets and was significantly higher on eosinophils from inflammatory bowel disease patients compared with controls. Almost all α4β7-expressing cells from these subsets were bound by VDZ at a concentration of 10 μg/mL. Dynamic cell adhesion was significantly impaired in all subsets, but there were no dose-dependent differences in the inhibition of adhesion.

DISCUSSION: Our data suggest that α4β7-expressing CD8 + T cells, CD19 + B cells, CD14 + monocytes, natural killer cells, and eosinophils are a target of VDZ. However, there do not seem to be concentration-dependent differences, regarding the effects on these cells in the clinically relevant range. Thus, the reported exposure-efficacy characteristic of VDZ can probably mainly be attributed to CD4 + T-cell subsets.

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

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.

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.

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.

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.

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

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

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.

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.

SCLE manifestation after mRNA COVID-19 vaccination.

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

Rechtien L, Erfurt-Berge C, Sticherling M

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

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

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.

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.

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.

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.

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.

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.

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.

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

Dermatologie (Heidelb). 2022;73(7): 550-555

Dissemond J, Protz K, Erfurt-Berge C, Kröger K, Kottner J

Today, patients with chronic wounds are treated in many different fields of medicine. Despite this great interdisciplinary and interprofessional importance, there is still a lack of uniformly accepted definitions and classifications. Therefore, a group of experts from the professional society Initiative Chronische Wunden (ICW) e. V. translated and adapted the classification of chronic wounds into healable, maintenance and nonhealable wounds on the basis of the internationally published literature into German. This classification results in the aim of curative, limited respectively non-curative or palliative wound care, which are very important for everyday clinical practice. It thus becomes clear that complete wound closure is not always the central intention of wound treatment. For many patients with chronic wounds, other aspects such as the best possible quality of life and the promotion of health-related self-management as well as the avoidance of complications are important for treatment concepts. These therapy intentions should be differentiated and individually discussed with patients in order to facilitate shared decision making.

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

Dermatologie (Heidelb). 2022;73(5): 369-375

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

The nomenclature used today in wound treatment varies widely across different disciplines and professions. Therefore, it is a mission of the professional association Initiative Chronische Wunde (ICW) e. V. to exactly and comprehensibly describe terms that were previously unclear. Therefore, the experts of the ICW defined in a consensus procedure debridement of chronic wounds as the removal of adherent, dead tissue, scabs or foreign bodies from wounds. There are various therapy options for this, which can be differentiated into autolytic, biosurgical, mechanical, osmotic, proteolytic/enzymatic and technical debridement. In the case of surgical debridement, a distinction is also made between sharp debridements that can usually be performed on an outpatient basis, such as minor surgical procedures, and surgical debridements with adequate anaesthesia in an operating theatre. Wound irrigation is defined by the ICW as the removal of non-adherent components on wounds with sterile solutions. Debridement and/or wound irrigation are often the first step in phase-appropriate modern wound treatment. Several methods are suitable for use in a combined or successive therapy. When deciding which therapeutic option to use, a number of individually different factors should be taken into account, depending on the patients to be treated but also on the therapists. The final individual decision for a method should be made together with the patient in each case and then adequately documented.

"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

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.

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.

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.

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

Dermatologie (Heidelb). 2022;73(7): 575-579

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

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

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.

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.

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.

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

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

Ophthalmologie. 2022;119(3): 223-233

Baldermann C, UV-Schutz-Bündnis , Berking C, Ulrich C, Breitbart E, Bunde H, Volkmer B, Janßen W, Baldermann C, Weiskopf D, Grimm F, Keller B, Kakkassery V, von Kiedrowski R, Stavermann T, Schlette S, Kessel TM, Berneburg M, Höger P, Fartasch M, Strehl C, Engelmayr E, Mons U, Schadendorf D, Helbig U, Heindl LM, Laschewski G, Stockfleth E, Greinert R, Hübner J, Katalinic A, Mohr P, Pieper B, Brose M, Panter W, Schlager H, Schäfermeyer D

Despite the serious health consequences of UV radiation, protection against UV radiation is even now still not a matter of course. The population has a largely realistic view of UV radiation-related health risks but this does not seem to instigate a change in personal risk assessments and towards an adequate UV protection behavior. This is not least due to the partly contradictory statements and recommendations regarding the positive and negative health effects, also from the scientific community. A harmonization as well as a collation of the statements and activities of individual players in UV protection related to the prevention of UV-related diseases gives the key messages the necessary strength to make UV protection a matter of course in society. To this end, the UV Protection Alliance was initiated by the Federal Office for Radiation Protection (BfS). This article reports on the UV Protection Alliance, presents the partners in the Alliance, the goals of the UV Protection Alliance, previous results of work by the Alliance and actions and interventions of the Alliance partners. The public impact of the UV Protection Alliance is explained and an outlook is given on future tasks of the Alliance.

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

Ophthalmologie. 2022;119(3): 248-249

Baldermann C, UV-Schutz-Bündnis , Berking C, Ulrich C, Breitbart E, Bunde H, Volkmer B, Janßen W, Baldermann C, Weiskopf D, Grimm F, Keller B, Kakkassery V, von Kiedrowski R, Stavermann T, Schlette S, Kessel TM, Berneburg M, Höger P, Fartasch M, Strehl C, Engelmayr E, Mons U, Schadendorf D, Helbig U, Heindl LM, Laschewski G, Stockfleth E, Greinert R, Hübner J, Katalinic A, Mohr P, Pieper B, Brose M, Panter W, Schlager H, Schäfermeyer D

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

Efficacy of Therapies for Actinic Keratosis-Reply.

JAMA Dermatol. 2022;158(6): 703-704

Heppt MV, Steeb T, Berking C

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

"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.

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.

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.

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

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.

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.

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.

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

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

[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.

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

[Talking about vaccinations-also relevant for dermatology?]

Hautarzt. 2021;72(2):

Sticherling M

[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

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.

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.

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

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

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.

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.

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.

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

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.

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.

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

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.

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

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.

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.

[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.

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.

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

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Increasing Participation Rates in Germany's Skin Cancer Screening Program (HELIOS): Protocol for a Mixed Methods Study.

JMIR Res Protoc. 2021;10(12):

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

BACKGROUND: In 2008, a nationwide skin cancer screening (SCS) program was implemented in Germany. However, participation rates remain low.

OBJECTIVE: The overall objective of the HELIOS study is to identify subgroup-specific invitation and communication strategies to increase informed SCS participation in Germany.

METHODS: Focus group discussions will be performed in Erlangen, Germany, to explore potential invitation and communication strategies as well as possible barriers and motivating factors to participate in SCS. Male and female patients of different age groups who have already been diagnosed with skin cancer, as well as participants without a prior diagnosis of skin cancer, will be invited. Based on these results, an online questionnaire will be developed to identify subgroup-specific invitation strategies. A random sample of 2500 persons from the general population aged >35 years from the Munich area will be contacted to complete the questionnaire. Besides descriptive analysis, multinomial logistic regression will be performed. Additionally, a cluster analysis will be conducted to discover patterns or similarities among the participants.

RESULTS: Recruitment for the focus group studies started in February 2021 and is ongoing. As of August 2021, we have enrolled 39 participants. We expect to end enrollment in the qualitative study in September 2021 and to finish the analysis in December 2021. The second part of the study will then start in January 2022.

CONCLUSIONS: The results of this project will enable us to derive improved and more efficient invitation and communication strategies for SCS. These may be implemented in the future to facilitate increased SCS uptake and early skin cancer detection.

INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31860.

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.

Safety and tolerability of a single infusion of autologous ex vivo expanded regulatory T cells in adults with ulcerative colitis (ER-TREG 01): protocol of a phase 1, open-label, fast-track dose-escalation clinical trial.

BMJ Open. 2021;11(12):

Voskens CJ, Stoica D, Roessner S, Vitali F, Zundler S, Rosenberg M, Wiesinger M, Wunder J, Siegmund B, Schuler-Thurner B, Schuler G, Berking C, Atreya R, Neurath MF

INTRODUCTION: Accumulating evidence suggests that the adoptive transfer of ex vivo expanded regulatory T cells (Treg) may overcome colitogenic immune responses in patients with inflammatory bowel diseases. The objective of the ER-TREG 01 trial is to assess safety and tolerability of a single infusion of autologous ex vivo expanded Treg in adults with ulcerative colitis.

METHODS AND ANALYSIS: The study is designed as a single-arm, fast-track dose-escalation trial. The study will include 10 patients with ulcerative colitis. The study intervention consists of (1) a baseline visit; (2) a second visit that includes a leukapheresis to generate the investigational medicinal product, (3) a third visit to infuse the investigational medicinal product and (4) five subsequent follow-up visits within the next 26 weeks to assess safety and tolerability. Patients will intravenously receive a single dose of 0.5×106, 1×106, 2×106, 5×106 or 10×106 autologous Treg/kg body weight. The primary objective is to define the maximum tolerable dose of a single infusion of autologous ex vivo expanded Treg. Secondary objectives include the evaluation of safety of one single infusion of autologous ex vivo expanded Treg, efficacy assessment and accompanying immunomonitoring to measure Treg function in the peripheral blood and intestinal mucosa.

ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of the Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany (number 417_19 Az). In addition, the study was approved by the Paul-Ehrlich Institute, Federal Institute for Vaccines and Biomedicines, Langen, Germany (number 3652/01). The study is funded by the German Research Foundation (DFG, KFO 257 project 08 and SFB/TransRegio 241 project C04). The trial will be conducted in compliance with this study protocol, the Declaration of Helsinki, Good Clinical Practice and Good Manufacturing Practice. The results will be published in peer-reviewed scientific journals and disseminated in scientific conferences and media.

TRIAL REGISTRATION NUMBER: NCT04691232.

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.

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.

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.

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.

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.

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.

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

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

PATIENTS WITH IMMUNE MEDIATED INFLAMMATORY DISEASES ARE OVERREPRESENTED IN LOW-FREQUENCY VIRAL SYMPTOM CLUSTERS

Ann Rheum Dis. 2021;80 Suppl 1(): 996-997

Tascilar K, Simon D, Kroenke G, Kleyer A, Ramming A, Atreya R, Tenbusch M, Ueberla K, Berking C, Sticherling M, Neurath MF, Schett G

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

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

B-cells in psoriasis?

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

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

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

THE GERMAN AD REGISTRY TREATGERMANY: RESULTS FROM AN INTERIM DATA ANALYSIS ON BASELINE CHARACTERISTICS, COMORBIDITIES AND TREATMENT HISTORY

Acta Derm Venereol. 2021;101 Suppl 221(): 24-25

Heratizadeh A, Haufe E, Stoelzl D, Abraham S, Heinrich L, Kleinheinz A, Wollenberg A, Weisshaar E, Augustin M, Wiemers F, Zink A, von Kiedrowski R, Hilgers M, Worm M, Pawlak M, Sticherling M, Fell I, Handrick C, Schaekel K, Staubach-Renz P, Asmussen A, Schwarz B, Bell M, Effendy I, Bieber T, Homey B, Gerlach B, Tchitcherina E, Stahl M, Schwichtenberg U, Rossbacher J, Buck P, Mempel M, Beissert S, Biedermann T, Weidinger S, Schmitt J, Werfel T, TREATgermany Study grp

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

Multiple thoracic Erosions after Vacation in Tunisia

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

Meder C, Sticherling M

Association of Fabry Disease and Psoriasis - therapeutically significant?

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

Sollfrank L, Sticherling M

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

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

Spectrum of peristomal Dermatoses

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

Dietmaier L, Summa S, Erfurt-Berge C

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

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.

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

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.

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

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

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

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

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.

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.

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

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

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

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

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

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

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

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

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.

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.

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

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

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.

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.

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

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.

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.

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.

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

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

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

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.

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

DIVERSITY OF CD4(+) BLOOD T-CELL CLONALITY PREDICTS LONGER SURVIVAL WITH CTLA4 OR PD-1 CHECKPOINT INHIBITION IN ADVANCED MELANOMA

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

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

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.

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

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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.

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

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.

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.

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.

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.

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.

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.

[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.

[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

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.

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.

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.

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.

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.

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.

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

TYPE 3 INNATE LYMPHOID CELLS ARE KEY DRIVERS OF PSORIATIC ARTHRITIS

Ann Rheum Dis. 2020;79 Suppl 1(): 1119-1120

Raimondo MG, Rauber S, Luber M, Rigau AR, Weber S, Anchang CG, Agarwal R, Soare A, Sticherling M, Rech J, Kleyer A, Distler J, Schett G, Ramming A

STRUCTURAL ENTHESEAL LESIONS IN PSORIASIS PATIENTS ARE ASSOCIATED WITH AN INCREASED RISK OF PROGRESSION TO PSORIATIC ARTHRITIS - A PROSPECTIVE COHORT STUDY

Ann Rheum Dis. 2020;79 Suppl 1(): 33-34

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

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

A PHASE I DOSE ESCALATION AND EXPANSION STUDY OF INTRATUMORALLY ADMINISTERED CV8102 AS A SINGLE-AGENT OR IN COMBINATION WITH ANTI-PD-1 ANTIBODIES IN PATIENTS WITH ADVANCED SOLID TUMORS

J Immunother Cancer. 2020;8 Suppl 3(): A478-A479

Eigentler T, Heinzerling L, Krauss J, Weishaupt C, Mohr P, Ochsenreither S, Terheyden P, Martin-Liberal J, Oliva M, Lebbe C, Fluck M, Brossart P, Trigo Perez JMT, Bauernfeind FG, Kays SK, Seibel T, Schoenborn-Kellenberger O, Stosnach C, Daehling A, Schmitt-Bormann B, Gnad-Vogt U

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

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

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.

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.

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.

[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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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.

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

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.

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.

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

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.

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

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.

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

[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.

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.

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.

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.

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.

[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.

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

[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.

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.

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

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

Environment

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

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

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

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

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

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.

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.

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

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

[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.

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.

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.

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.

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

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.

[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.

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.

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.

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.

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.

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.

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

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

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

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.

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.

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.

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.

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.

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

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

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.

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).

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 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.

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.