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This article discusses the differences between checkpoint inhibitor-induced bullous pemphigoid (irBP) and spontaneous bullous pemphigoid (BP). The study compared patients with irBP to patients with BP and found that irBP patients were younger, had a shorter duration of disease, and had a better therapeutic response. However, irBP patients required permanent discontinuation of ICI therapy in 78% of cases. The article provides clinical characteristics and treatment information for both irBP and BP patients. The study also identified differentially expressed genes in irBP compared to BP and normal skin tissue, suggesting potential targets for irBP treatment. The JAK-STAT signaling pathway was found to be enriched in both irBP and BP, indicating that JAK inhibitors could be potential treatment options. The study was funded by grants and the authors declare potential conflicts of interest. [Extracted from the article]

Linked Article: Fledderus et al. Br J Dermatol 2021; 185:970–977. [ABSTRACT FROM AUTHOR]

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., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has shown remarkable outcomes in patients with systemic lupus erythematosus. The effects of CD19-targeting CAR T cells on organ manifestations in patients with systemic sclerosis have yet to be characterised. B cells have a central role in the pathogenesis of systemic sclerosis. We present a detailed analysis of the effects of CD19-targeting CAR T-cell therapy in patients with systemic sclerosis., Methods: Six patients with severe diffuse systemic sclerosis with an insufficient response to at least two treatments were consecutively recruited at the Department of Internal Medicine 3, University Hospital Erlangen (Erlangen, Germany) to receive CD19-targeting CAR T-cell treatment (1 × 10 6 CAR T cells per kg bodyweight). Events were predefined by progression of interstitial lung disease, onset of congestive heart failure, onset of renal failure, onset of arterial hypertension, or initiation of new immunosuppressive or antifibrotic therapy. Event-free time or treatment intensification after study entry was the primary outcome. Key secondary outcomes included changes in the modified Rodnan Skin Score (mRSS), imaging (a component of the assessment of lung fibrosis), laboratory assessments, patient-reported outcomes, and a modified version of the American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS), assessed at baseline, 3 months, 6 months, 9 months, and 12 months., Findings: Between April 20, 2022, and Nov 8, 2023, six patients with severe diffuse systemic sclerosis (median age 42 years [IQR 36-53]; four men and two women; all White European) were recruited and received CD19-targeted CAR T-cell therapy. The median follow-up time was 487 days (IQR 342-585). No events occurred within the observational period. Probability of improvement in the ACR-CRISS score increased to a median of 100% (IQR 100-100) at 6 months. Median mRSS decreased by 31% (IQR 29-38), corresponding to a median of 8 points (IQR 7-13) within 100 days. The extent of disease on CT scan decreased by a median of 4% (IQR 3-4) due to reduction of ground-glass opacities while the reticular pattern remained stable. Forced vital capacity improved by a median of 195 mL (IQR 18-275) at the latest observational timepoint., Interpretation: We provide the first evidence that CD19-targeting CAR T-cell therapy might intercept with the progression of fibrotic organ manifestations in patients with systemic sclerosis., Funding: Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, ELAN-Foundation Erlangen, IZKF Erlangen, and Bundesministerium für Bildung und Forschung., Competing Interests: Declaration of interests JA and ChB received a travel grant from Kyverna therapeutics. ChB received a research grant from Boehringer Ingelheim and speaker fees from Novartis. CaB received consulting fees from Almirall, Delcath, BMS, Immunocore, Pierre Fabre, MSD, Novartis, Regeneron, and Sanofi; honoraria from Almirall, Leo Pharma, BMS, Pierre Fabre, and MSD; travel support from Pierre Fabre; and participates on the data safety monitoring or advisory board of Miltenyi Biotech and InflaRx. FM received a research grant from Kite/Gilead and consulting fees from AbbVie, ArgoBio, AstraZeneca, BMS, Crispr Therapeutics, Janssen, Kite, and Novartis; honoraria from AbbVie, ArgoBio, AstraZeneca, BMS, Crispr Therapeutics, Janssen, Kite, Kyverna, Miltenyi, Novartis, and Sobi; and participates on the BMS and Biontech data safety monitoring or advisory board. TKr received grants, consulting fees, honoraria, and travel support from Novartis and Pfizer, as well as consulting fees and honoraria from Kiowa Kirin, payment for expert testimony from Novartis, and travel support from AbbVie. GS received honoraria from Cabaletta, Novartis, Janssen, and Kyverna. SoK received honoraria from BMS and Sobi, as well as travel support from Janssen, BMS, Sobi, Novartis, and Kite/Gilead. JHWD has consultancy relationships with and is part of the speaker or advisory board of AbbVie, Active Biotech, Anamar, ARXX, AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Calliditas Therapeutics, Celgene, Galapagos, Genentech, GSK, Inventiva, Janssen, Novartis, Pfizer, Roche, and UCB; has received research funding from Anamar, Argenx, ARXX, BMS, Bayer Pharma, Boehringer Ingelheim, Cantargia, Celgene, CSL Behring, Galapagos, GSK, Inventiva, Kiniksa, Lassen, Sanofi-Aventis, RedX, and UCB; travel support from AbbVie and SOBI; and is Chief Executive Officer of 4D Science and Scientific Lead of FibroCure. AM received grants from Miltenyi Biomedicine and Kyverna, and consulting fees from BMS/Celgene, KITE/Gilead, Novartis, BioNTech, Miltenyi Biomedicine, and Century Therapeutics. AM received honoraria from BMS/Celgene, KITE/Gilead, Novartis, BioNTech, Miltenyi Biomedicine, and Century Therapeutics, and travel support from AbbVie and Janssen. RGB received grants from Kyverna and travel support from BMS and Novartis. MA received grants, honoraria, payment for expert testimony, travel support and equipment from Miltenyi Biotec; and received consulting fees, honoraria and travel support from Miltenyi Biomedicine. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Summary: Most patients with advanced melanomas have a known primary site [melanoma of known primary (MKP)]. However, 2%-9% of patients are diagnosed with melanoma metastasis of unknown primary (MUP). As MUP and MKP have similar UV-induced mutations and molecular signatures, it is proposed that the primary tumor has regressed completely in patients with MUP. As regression of the primary tumor could be indicative of enhanced recognition of melanoma antigens, we hypothesize that patients with advanced MUP have a better outcome compared with MKP.Patients with advanced MUP from 10 German university hospitals were retrospectively analyzed and matched with MKP based on the type of systemic treatment (BRAF and MEK inhibitors, PD-1 inhibitor monotherapy, combined CTLA-4 and PD-1 inhibitor therapy) therapy line (first or second line) and AJCC stage (IIIC, IV M1a-M1d). Three hundred thirty-seven patients with MUP were identified, and 152 treatments with PD-1 and CTLA-4 inhibitors, 142 treatments with PD-1 inhibitors, and 101 treatments with BRAF and MEK inhibitors were evaluated. Median time to treatment failure was significantly prolonged in patients with MUP treated with PD-1 monotherapy (17 mo, 95% CI: 9-25, P = 0.002) compared with MKP (5 mo, 95% CI: 3.4-6.6), as well as in MUP treated with combined PD-1 and CTLA-4 therapy (11 mo, 95% CI: 4.5-17.5, P < 0.0001) compared with MKP (4 mo, 95% CI: 2.9-5.1) Occurrence of immune-related adverse events and time to treatment failure for patients with BRAF and MEK inhibitors was similar in MKP and MUP. In our multicentre collective, patients with MUP have better outcomes under immunotherapy compared with MKP., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Early detection of melanoma, a potentially lethal type of skin cancer with high prevalence worldwide, improves patient prognosis. In retrospective studies, artificial intelligence (AI) has proven to be helpful for enhancing melanoma detection. However, there are few prospective studies confirming these promising results. Existing studies are limited by low sample sizes, too homogenous datasets, or lack of inclusion of rare melanoma subtypes, preventing a fair and thorough evaluation of AI and its generalizability, a crucial aspect for its application in the clinical setting., Methods: Therefore, we assessed "All Data are Ext" (ADAE), an established open-source ensemble algorithm for detecting melanomas, by comparing its diagnostic accuracy to that of dermatologists on a prospectively collected, external, heterogeneous test set comprising eight distinct hospitals, four different camera setups, rare melanoma subtypes, and special anatomical sites. We advanced the algorithm with real test-time augmentation (R-TTA, i.e., providing real photographs of lesions taken from multiple angles and averaging the predictions), and evaluated its generalization capabilities., Results: Overall, the AI shows higher balanced accuracy than dermatologists (0.798, 95% confidence interval (CI) 0.779-0.814 vs. 0.781, 95% CI 0.760-0.802; p = 4.0e-145), obtaining a higher sensitivity (0.921, 95% CI 0.900-0.942 vs. 0.734, 95% CI 0.701-0.770; p = 3.3e-165) at the cost of a lower specificity (0.673, 95% CI 0.641-0.702 vs. 0.828, 95% CI 0.804-0.852; p = 3.3e-165)., Conclusion: As the algorithm exhibits a significant performance advantage on our heterogeneous dataset exclusively comprising melanoma-suspicious lesions, AI may offer the potential to support dermatologists, particularly in diagnosing challenging cases., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

Purpose: Implementation science endeavors to facilitate the translation of evidence-based research into clinical routine. The clinical pharmacological/pharmaceutical care program evaluated in the randomized AMBORA trial on medication safety with oral antitumor therapeutics (OAT) optimizes care delivery and provides significant benefits for patients, treatment teams, and health care systems. Thus, we aimed to investigate the implementation of this care program within the AMBORA Competence and Consultation Center (AMBORA Center)., Methods: The AMBORA Center within a University Comprehensive Cancer Center offered several services (eg, patient consultations) and was evaluated according to the RE-AIM framework. This multicenter hybrid type III trial focused on implementation outcomes (eg, patient recruitment, referring units, evaluation of services) while concurrently investigating effectiveness (eg, side effects, medication errors). Quantitative and qualitative assessments were combined., Results: The AMBORA Center conducted over 800 consultations with 420 patients in seven institutions. The primary end point of counseling 70% of patients treated with OAT was not reached. Patients were referred by 15 treatment units compared with 11 units in the AMBORA trial. On the basis of heterogeneous referral rates and characteristics across the institutions, barriers and facilitators of the implementation process were derived. Several survey results (eg, stakeholder interviews, online/paper-based questionnaires) reflected a high appreciation of services by patients and health care professionals. The severity of 60.1% (178 of 296) of detected side effects improved, and 86.3% (297 of 344) of medication errors were resolved., Conclusion: Despite not reaching the primary implementation outcome, the AMBORA Center included more treatment units and demonstrated patient benefit of the AMBORA care program by meeting all effectiveness outcomes. We outlined quantitative and qualitative implementation characteristics to enhance outreach and foster further dissemination of centers to optimize medication safety with OAT.

Background: Cutaneous squamous cell carcinoma in situ (Bowen's disease) is a precancerous condition confined to the epidermis of the skin. Despite the critical need for effective interventions to halt its progression, there remains a notable shortage of comprehensive data comparing the efficacy of various therapeutic approaches., Objectives: This systematic review and meta-analysis endeavour to compare the different efficacies of interventions by investigating and synthesizing data from numerous trials., Methods: A pre-defined protocol was registered in PROSPERO (CRD42021242224, registration date: 16 April 2021). Systematic searches in Medline, Embase and Central, along with manual trial register searches, identified studies reporting lesion clearance rates (LCR), participant clearance rates (PCR) or recurrence rates (date of last search: 12 June 2024). Quality assessment followed guidelines from the National Heart, Lung, and Blood Institute (NHLBI). After the study arms were categorized into treatment groups and groups of study quality, the proportions were pooled using the generalized linear mixed model (GLMM) as meta-analytical method., Results: A comprehensive inclusion of 71 studies facilitated an evaluation of 3783 lesions for LCR, 1225 patients for PCR, 4073 lesions for lesion recurrence rates (LRR) and 740 patients for participant recurrence rates (PRR). Surgery demonstrated the highest LCR and PCR (0.97, 95% confidence interval (CI): 0.90-0.99) and the lowest LRR (0.04, 95% CI: 0.02-0.07)., Conclusions: This study provides a thorough overview of reported efficacy outcomes for practice-relevant interventions for Bowen's disease. Surgery outperformed other treatments for Bowen's disease. For the other intervention groups, it was not possible to show clear differences in effectiveness: LCR, PCR, LRR and PRR showed various treatment rankings, and the comparability was restricted by different numbers of studies between treatment groups and outcome measures, methodical and clinical heterogeneity. Further high-quality studies are needed to investigate practice-relevant interventions for Bowen's disease., (© 2024 The Author(s). Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: In Germany, skin cancer screening (SCS) is available free of charge every two years to all those with statutory health insurance over the age of 35. General Practitioners (GP) can carry out the screening if they have completed an 8-hour training course. GPs play a crucial role in the implementation of SCS and act as gatekeepers between initial patient contact and referral to dermatologists., Objective: To record how comprehensively GPs carry out SCS in terms of patient information and body examination, as well as to explore GPs opinions on the feasibility of SCS., Methods: A cross-sectional survey was conducted. A questionnaire was sent to GPs with permission to perform SCS in two regions of Germany (Bavaria and Saxony) between August and September 2021. Data were analyzed using descriptive analysis. Subgroup analysis was performed according to regions (federal state, location of physician´s office), professional experience (experience in years, number of monthly screenings, age) and gender. Open questions were evaluated using qualitative content analysis., Results: In the survey, 204 GPs responded. Genitalia (40.7%, 83/203), anal fold (62.3%, 127/204) and oral mucosa (66.7%, 136/204) were the least examined body regions during screening. Information on risks (false-positive findings: 18.6%, 38/203; false-negative findings: 13.2%, 27/203; overdiagnosis: 7.8%, 16/203) and benefits (48.0%, 98/202) were not always provided. GPs who performed screenings more frequently were more likely to provide information about the benefits of SCS (p<0.001; >10 vs. <5 screenings per month). Opinions were provided on uncertainties, knowledge requirements, structural and organizational requirements of SCS, SCS training and evaluation. The organization and remuneration of the SCS programme was seen as a barrier to implementation. GPs expressed uncertainties especially in unclear findings and in dermatoscopy., Conclusion: Uncertainties in the implementation of the SCS should be addressed by offering refresher courses. Good networking between GPs and dermatologists is essential to improve SCS quality., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Reinhardt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: Conflicts of interest Dr Utikal is on the advisory board or has received honoraria from Amgen, Bristol Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, and Sanofi outside the submitted work. Dr Meier has received speaker's fees or/and advisor's honoraria from Novartis, Roche, BMS, MSD, and Pierre Fabre. Dr Hobelsberger reports speaker's honoraria from Almirall, UCB, and AbbVie. Dr Gellrich has received speaker's fees or/and advisor's honoraria by Sun Pharma, Sanofi, and Merck. Dr Hauschild reports speaker's honoraria or consultancy fees from the following companies: Agenus, Amgen, BMS, Dermagnostix, Highlight Therapeutics, Immunocore, Incyte, IO Biotech, MerckPfizer, MSD, NercaCare, Novartis, Philogen, Pierre Fabre, Regeneron, Roche, Sanofi-Genzyme, Seagen, Sun Pharma, and Xenthera, outside the submitted work. Dr French is on the advisory board or has received consulting/speaker honoraria from for Galderma, Janssen, Leo Pharma, Eli Lilly, Almirall, Union Therapeutics, Regeneron, Novartis, Amgen, Abbvie, UCB, Biotest, and InflaRx. Dr Schlaak has received consultant or speaker fees or travel grants from BMS, MSD, Roche, Kyowa Kirin, Novartis, Sanofi Genzyme, Pierre Fabre, Sun Pharma, and Immunocore. Dr Erdmann declares honoraria from Bristol-Meyers Squibb, Immunocore, and Novartis outside the submitted work. Dr Haferkamp reports advisory roles for or has received honoraria from Pierre Fabre Pharmaceuticals, Novartis, Roche, BMS, Amgen, and MSD outside the submitted work. Dr Drexler has received honoraria from Pierre Fabre Pharmaceuticals and Novartis outside the submitted work. Dr Sondermann reports grants, speaker's honoraria, or consultancy fees from medi GmbH Bayreuth, Abbvie, Almirall, Amgen, Bristol-Myers Squibb, Celgene, GSK, Janssen, LEO Pharma, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi Genzyme, and UCB outside the submitted work. Dr Schilling reports advisory roles for or has received honoraria from Pierre Fabre Pharmaceuticals, Incyte, Novartis, Roche, BMS, and MSD. Dr Goebeler has received speaker's honoraria and/or has served as a consultant and/or member of advisory boards for Almirall, Argenx, Biotest, Eli Lilly, Janssen Cilag, Leo Pharma, Novartis, and UCB, outside the submitted work. Dr Kather reports consulting services for Owkin, France, Panakeia, UK, and DoMore Diagnostics, Norway and has received honoraria for lectures by MSD, Eisai, and Fresenius. Dr Brinker reports owning a company that develops mobile apps (Smart Health Heidelberg GmbH, Handschuhsheimer Landstr. 9/1, 69120 Heidelberg). Author Haggenmüller, Author Maron, Author Hekler, Dr Krieghoff-Henning, Dr Gaiser, Dr Müller, Dr Fabian, Dr Sergon, Dr Weichenthal, Dr Heinzerling, Dr Schlager, Dr Ghoreschi, Dr Hilke, Dr Pochi, Dr Korsing, Dr Berking, Dr Heppt, Dr Schadendorf, Dr Fröhling, Author Kaminski, Author Doppler, and Author Bucher have no conflicts of interest to declare.

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., Competing Interests: AG speaker´s honoraria from Allmirall, Amgen, Bristol-Myers Squibb, Immunocore, MSD Sharp & Dohme and Roche; intermittent advisory board relationships with Amgen, Bristol-Myers Squibb, Novartis, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, Pfizer, Roche and Sanofi Genzyme; travel and congress fee support from Bristol-Myers Squibb, MSD Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals and Roche. Clinical studies: Amgen, Array, Bristol-Myers Squibb, Delcath Systems Inc, GSK, Novartis, MSD Sharp & Dohme, Pfizer, and Roche. CB declares speaker´s and/or consultancy honoraria from Almirall, Bristol-Myers Squibb, Delcath, Immunocore, Leo Pharma, Miltenyi, MSD Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals, Regeneron, and Sanofi-Aventis outside the submitted work. CP received honoraria speaker honoraria or honoraria as a consultant and travel support from Novartis, Bristol-Myers Squibb, Roche, Merck Serono, MSD Sharp & Dohme, Celgene, AbbVie, Sun Pharma, UCB, Allergy Therapeutics, and LEO. FM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, Bristol-Myers Squibb, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, Sanofi, and Immunocore and research funding from Novartis and Roche. FZ declares speakers and advisory board honoraria and/or travel support from Bristol-Myers Squibb, MSD Sharp & Dohme, Roche, Novartis, Pierre Fabre Pharmaceuticals, and Sanofi-Aventis outside the submitted work. JCH declares research support from Bristol Myers Squibb, Sanofi, and Sunpharma, advisory board honoraria from GSK, Pierre Fabre Pharmaceuticals, Sun Pharma, speaker honoraria from Amgen, Bristol-Myers Squibb, Delcath, GSK, Immuno core, MSD Sharp & Dohme, Novartis, Sanofi and Sun Pharma and travel support from Bristol-Myers Squibb, Iovance and Sun Pharma. SH declares speakers and advisory board honoraria from Merck Sharp & Dohme, Bristol-Myers Squibb, Novartis, Sanofi, Sun Pharma, and Pierre Fabre Pharmaceuticals. JUl: Speakers and advisory board honoraria from Bristol-Myers Squibb, Kyowa-Kirin, Merck Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals and Sanofi, and travel support from Pierre Fabre Pharmaceuticals. JUt is on the advisory board or has received honoraria and travel support from Amgen, Bristol-Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre Pharmaceuticals, Roche, Sanofi outside the submitted work. KCK serves as a consultant to Philogen, Bristol-Myers Squibb, MSD Sharp & Dohme, Sanofi Aventis, and Immunocore and received travel grants and speaker fees from Philogen, Pierre Fabre Pharmaceuticals, Bristol-Myers Squibb, MSD Sharp & Dohme, Sun Pharma, Sanofi Aventis, Novartis, Medac and has received research support by Novartis. K-MT received speaker or consultant honoraria and travel support from Bristol-Myers Squibb, MSD Sharp & Dohme, Roche, Novartis, Pierre Fabre Pharmaceuticals, Sanofi Genzyme, Sun Pharma, Amgen, LEO Pharma, Galderma, Almirall, and Candela. ME declares honoraria and travel support from Bristol-Myers Squibb, Immunocore, Novartis, Pierre Fabre Pharmaceuticals, and Sanofi, outside the submitted work. MVH: Honoraria from MSD Sharp & Dohme, Bristol-Myers Squibb, Roche, Novartis, Sun Pharma, Sanofi, Almirall, Biofrontera, Galderma. PM Research support: Novartis, Bristol-Myers Squibb, MSD Sharp & Dohme. Honoraria for lectures: Roche, Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, Merck-Serono, Pierre Fabre Pharmaceuticals, Sanofi, Sun Pharma, Baiersdorf; Honoraria for advisory boards: Roche Pharma, Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, Pierre Fabre Pharmaceuticals, MSD Sharp & Dohme, Immunocore, Sun Pharma, Sanofi. PT: Bristol-Myers Squibb, Novartis, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, CureVac, Roche, Kyowa Kirin, Biofrontera, Invited Speaker, Personal BMS, Novartis, Pierre Fabre Pharmaceuticals, Merck Serono, Sanofi, Roche, Kyowa Kirin, Advisory Board, Personal BMS, Pierre Fabre Pharmaceuticals, Other, Personal, Travel support. RG Research support: Amgen, MSD Sharp & Dohme, Sun Pharma, Sanofi/Regeneron, Almirall, Kyowa Kirin. Honoraria for lectures: Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, MSD Sharp & Dohme, Sun, Pierre Fabre Pharmaceuticals, Sanofi/Regeneron, Sun Pharma Honoraria for advisory boards: Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, Pierre Fabre Pharmaceuticals, MSD Sharp & Dohme, 4SC, Immunocore, Sun Pharma, Sanofi/Regeneron, Delcath. SU declares research support from Bristol-Myers Squibb and MSD Sharp & Dohme; speakers and advisory board honoraria from Bristol-Myers Squibb, MSD Sharp & Dohme, Merck Serono, Novartis, and Roche, and travel support from Bristol-Myers Squibb, and MSD Sharp & Dohme. UL declares research support from MSD Sharp & Dohme; speakers and advisory board honoraria from MSD Sharp & Dohme, Novartis, Sanofi, and Sun Pharma, and travel support from Pierre Fabre Pharmaceuticals and Sun Pharma. BS Speakers honoria and/or travel support from Amgen, Bristol-Myers Squibb, MSD Sharp & Dohme, Jansen, Novartis, Roche, Sun Pharma, abbvie, Sanofi, Pierre Fabre Pharmaceuticals, Boehringer Ingelheim and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AT declared a past co-authorship with the author RG, JH, SH, KCK, CL, FM, MM, PT, K-MT, FZ, and MVH to the handling editor., (Copyright © 2024 Koch, Petzold, Dippel, Erdmann, Gesierich, Gutzmer, Hassel, Haferkamp, Kähler, Kreuzberg, Leiter, Loquai, Meier, Meissner, Mohr, Pföhler, Rahimi, Schell, Terheyden, Thoms, Ugurel, Ulrich, Utikal, Weichenthal, Ziller, Berking and Heppt.)

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., (© 2024 European Academy of Dermatology and Venereology.)

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.

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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. LJA received honoraria from Novartis, Sunpharma, and Bristol-Myers Squibb and travel support from Sunpharma, Takeda Pharmaceuticals, and Sanofi, outside the submitted work., FD receives/received honoraria and travel support from Merck Sharp & Dohme, Bristol Myers Squibb, Pierre Fabre and Sun Pharma., PG has received conference support from Pierre Fabre., JCH received honoraria from Amgen, BMS, GSK, Immunocore, MSD, Novartis, Onkowissen, Pierre Fabre, Sanofi, Sunpharma and travel support from BMS, Iovance and Sunpharma., ME declares honoraria and travel support from Bristol Myers Squibb, Immunocore, Novartis, Pierre Fabre and Sanofi, outside the submitted work., AF reports honoraria for presentations for BMS, MSD, Novartis, Pierre-Fabre; Travel support and congress participation support from BMS, Pierre-Fabre, Novartis; Advisory Boards from MSD, BMS, Novartis, Pierre-Fabre, Immunocore and institutional funding from BMS Stiftung Immunonkologie, outside the submitted work., DBJ has served on advisory boards or as a consultant for BMS, Catalyst Biopharma, Iovance, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, Targovax, and Teiko, and has received research funding from BMS and Incyte., GL received travel support from Sun Pharma, Pierre Fabre, research funding from Novartis, JMP served as consultant and/or has received honoraria from Bristol-Myers Squibb, Novartis, Sanofi and received travel support from Bristol-Myers Squibb, Novartis, Pierre Fabre and Therakos., FK received travel support for participation in congresses and / or (speaker) honoraria from Novartis, Almirall and Boehringer Ingelheim, outside the submitted work, AZ received travel support from Novartis, Sanofi Grenzyme, and Bristol-Myers Squibb, outside the submitted work., SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, and Novartis; and meeting and travel support from Almirall, Bristol-Myers Squibb, IGEA Clinical Biophysics, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Sun Pharma, AR reports grants from Novartis, Bristol Myers Squibb, and Adtec; personal fees from Novartis, Bristol Myers Squibb, and Merck Sharp & Dohme; and nonfinancial support from Amgen, Roche, Merck Sharp & Dohme, Novartis, Bristol Myers Squibb and Teva, outside the submitted work., CB has received honoraria for advisory and/or speaker functions from Almirall Hermal, BMS, Delcath, Immunocore, InlaRx, Leo Pharma, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron, and Sanofi, outside the submitted work., CP receives/received honoraria from AstraZeneca und Roche Pharma, outside the submitted work., AMM has served as a consultant for BMS, MSD, Novartis, Roche, Pierre-Fabre and QBiotics., GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron, RD has intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, Simcere and touchIME outside the submitted work., EL served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sanofi, Sunpharma, Takeda and travel support from Bristol-Myers Squibb, Pierre- Fabre, Sunpharma and Novartis, outside the submitted work, DS declares research support from Amgen, Bristol Myers Squibb, Merk Sharp & Dome, Novartis and Roche (all to institution); speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, PamGene, Neracare, Replimune, InFlarx, Immocore, Erasca, Philogen, BioAlta, Astra Zeneca, Daiichi-Sanyco, Formycon, Innovent Biologics, Agenus, Array Pharma, Pierre Fabre, Pfizer, Regeneron, Immatics, Curevac, Haystack Oncology, NoviGenix, Seagen, BionTech, SunPharma, UltimoVacs, and Novartis; and meeting and travel support from Pierre Fabre, LZ served as consultant and has received honoraria from BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Pierre Fabre, Sanofi, Sunpharma and Novartis, outside the submitted work, All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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: Al urine  = 8.258 + 0.133*Al cum ; 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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Nicola Wagner reports a relationship with ALK-Abelló, Novartis Pharma GmbH, Allergopharma GmbH & Co KG, Sanofi-Aventis Deutschland GmbH, Shire/Takeda, Blueprint, AbbVie Deutschland GmbH & Co KG and with Biocryst that includes: consulting or advisory, funding grants, and speaking and lecture fees., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Competing Interests: Conflicts of interest Jochen S. Utikal is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche and Sanofi outside the submitted work. Friedegund Meier has received travel support and/or speaker's fees and/or advisor's honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. Sarah Hobelsberger reports clinical trial support from Almirall and speaker's honoraria from Almirall, UCB and AbbVie and has received travel support from the following companies: UCB, Janssen Cilag, Almirall, Novartis, Lilly, LEO Pharma and AbbVie outside the submitted work. Sebastian Haferkamp reports advisory roles for or has received honoraria from Pierre Fabre Pharmaceuticals, Novartis, Roche, BMS, Amgen and MSD outside the submitted work. Konstantin Drexler has received honoraria from Pierre Fabre Pharmaceuticals and Novartis. Axel Hauschild reports clinical trial support, speaker's honoraria, or consultancy fees from the following companies: Agenus, Amgen, BMS, Dermagnostix, Highlight Therapeutics, Immunocore, Incyte, IO Biotech, MerckPfizer, MSD, NercaCare, Novartis, Philogen, Pierre Fabre, Regeneron, Roche, Sanofi-Genzyme, Seagen, Sun Pharma and Xenthera outside the submitted work. Lars E. French is on the advisory board or has received consulting/speaker honoraria from Galderma, Janssen, Leo Pharma, Eli Lilly, Almirall, Union Therapeutics, Regeneron, Novartis, Amgen, AbbVie, UCB, Biotest and InflaRx. Max Schlaak reports advisory roles for Bristol-Myers Squibb, Novartis, MSD, Roche, Pierre Fabre, Kyowa Kirin, Immunocore and Sanofi-Genzyme. Wiebke Sondermann reports grants, speaker's honoraria, or consultancy fees from medi GmbH Bayreuth, AbbVie, Almirall, Amgen, Bristol-Myers Squibb, Celgene, GSK, Janssen, LEO Pharma, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi Genzyme and UCB outside the submitted work. Bastian Schilling reports advisory roles for or has received honoraria from Pierre Fabre Pharmaceuticals, Incyte, Novartis, Roche, BMS and MSD, research funding from BMS, Pierre Fabre Pharmaceuticals and MSD and travel support from Novartis, Roche, BMS, Pierre Fabre Pharmaceuticals and Amgen outside the submitted work. Matthias Goebeler has received speaker's honoraria and/or has served as a consultant and/or member of advisory boards for Almirall, Argenx, Biotest, Eli Lilly, Janssen Cilag, Leo Pharma, Novartis and UCB outside the submitted work. Michael Erdmann declares honoraria and travel support from Bristol-Meyers Squibb, Immunocore and Novartis outside the submitted work. Jakob N. Kather reports consulting services for Owkin, France, Panakeia, UK and DoMore Diagnostics, Norway and has received honoraria for lectures by MSD, Eisai and Fresenius. Titus J. Brinker reports owning a company that develops mobile apps (Smart Health Heidelberg GmbH, Handschuhsheimer Landstr. 9/1, 69,120 Heidelberg). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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 r s = 0.78 (0.67-0.86) for the knowledge score. Protective behaviors were correlated with respective diary data (0.38 ≤ r s  ≤ 0.74, p < 0.001) and skin pigmentation changes (-0.23 ≥ r s ≥ -0.42, 0.007 ≤ p ≤ 0.165) but not with self-reported sunburn frequency (0.21 ≥ r s ≥ -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., (© 2024 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

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., (© 2024 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by Wiley‐VCH GmbH on behalf of Deutsche Dermatologische Gesellschaft.)

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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

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., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

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.

Background: Although highly efficacious, immune checkpoint inhibitors induce a multitude of immune-related adverse events including lichenoid skin reactions (irLP) that are often therapy-resistant., Objectives: To compare the clinical, histological, and transcriptional features of irLP with spontaneous lichen planus (LP)., Methods: Clinical and histological presentations of irLP and LP, as well as the gene expression profiles of irLP and LP lesional and healthy skin were assessed., Results: irLP differed considerably from LP with regard to the distribution pattern of skin lesions with irLP appearing mostly in an exanthematous form, whereas lesions were more localized in the LP group. Histologically, dermal lymphocyte infiltration was significantly lower in irLP compared with LP, whereas lymphocyte exocytosis and apoptotic keratinocytes were significantly higher in irLP. Gene expression analysis revealed irLP to have a more inflammatory profile with elevated IFNG levels and a possible role of phagosome signaling compared with LP., Limitations: The study is descriptive and necessitates further investigation with larger cohorts and broader analyses., Conclusion: irLP differs from spontaneous LP on the clinical, histopathological, and gene expression level. The inflammatory gene signature in irLP suggests that topical JAK inhibitors could be an effective treatment, targeting local skin inflammation without systemic immunosuppression., Competing Interests: None disclosed., (© 2024 by the American Academy of Dermatology, Inc. Published by Elsevier Inc.)

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., (© 2023 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

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., (© 2023 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by Wiley-VCH GmbH on behalf of Deutsche Dermatologische Gesellschaft.)

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., (© 2023. The Author(s).)

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., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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., (© 2023. The Author(s).)

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/mm 2 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.

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.