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Background: In malignant melanoma, liver metastases significantly reduce survival, even despite highly effective new therapies. Given the increase in metabolic liver diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), this study investigated the impact of liver sinusoidal endothelial cell (LSEC)-specific alterations in MASLD/MASH on hepatic melanoma metastasis., Methods: Mice were fed a choline-deficient L-amino acid-defined (CDAA) diet for ten weeks to induce MASH-associated liver fibrosis, or a CDAA diet or a high fat diet (HFD) for shorter periods of time to induce early steatosis-associated alterations. Liver metastasis formation was assessed using melanoma cell lines B16F10Luc2 and Wt31. LSEC-specific GATA4 knockout mice (Gata4 LSEC-KO/BL ) developing MASH-like liver fibrosis without steatosis via a pathogenic angiocrine switch were included to compare the impact of liver fibrosis versus hepatic steatosis on hepatic melanoma metastasis. Bulk RNA-Seq of isolated LSECs from CDAA-fed and control mice was performed. Levels of adhesion molecules (VCAM1, ICAM1, E-selectin) were monitored, and ICAM1 and VCAM1 antibody therapy was employed., Results: Feeding a CDAA diet, in contrast to a HFD, led to increased metastasis before the development of liver fibrosis. Gata4 LSEC-KO/BL mice characterized by vascular changes ensuing perisinusoidal liver fibrosis without steatosis also exhibited increased metastasis. Early molecular alterations in the hepatic vascular niche, rather than fibrosis or steatosis, correlated with metastasis, as shown by LSEC dedifferentiation and upregulation of endothelial adhesion molecules. The metastatic process in CDAA-fed mice was also dependent on the respective melanoma cell lines used and on the route of their metastatic spread. ICAM1 inhibition, but not VCAM1 inhibition reduced melanoma cell retention., Conclusion: We discovered that the hepatic vascular niche acts as a delicate sensor to even short-term nutritional alterations during the development of MASLD/MASH. The dynamic adaptations to the metabolic challenges of developing MASLD/MASH caused an early shift from the normal hepatic vascular niche to a pre-metastatic vascular niche that promoted hepatic melanoma metastasis in the context of cell-autonomous and acquired melanoma cell features. Altogether, our findings provide a potential avenue for angiotargeted therapies to prevent hepatic melanoma metastasis., Competing Interests: Declarations. Ethics approval and consent to participate: All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals published by the National Academy of Sciences and the animal ethics committee of Baden Wuerttemberg (Regierungspraesidium Karlsruhe) approved all animal experiments. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Accurate melanoma diagnosis is crucial for patient outcomes and reliability of AI diagnostic tools. We assess interrater variability among eight expert pathologists reviewing histopathological images and clinical metadata of 792 melanoma-suspicious lesions prospectively collected at eight German hospitals. Moreover, we provide access to the largest panel-validated dataset featuring dermoscopic and histopathological images with metadata. Complete agreement is achieved in 53.5% of cases (424/792), and a majority vote ( ≥ five pathologists) in 90.9% (720/792). Considerable discordance is observed for non-invasive melanomas (complete agreement in only 10/73 cases). The expert panel disagrees with the local pathologists' and dermatologists' diagnoses in 14.9% and 33.5% of cases, respectively. This variability highlights the diagnostic challenges of early-stage melanomas and the need to reconsider how ground truth is established in routine care and AI research. Including at least two pathologists or virtual panels may contribute to more consistent diagnostic results., Competing Interests: Competing interests: Prof Utikal reported personal fees from Amgen, Bristol Myers Squibb, GSK, Immunocore, LEO Pharma, Merck Sharp & Dohme, Novartis, Pierre Fabre, Rheacell, Roche, and Sanofi outside the submitted work. Dr Wohlfeil received honoraria from Bristol Myers Squibb, Novartis, and Sun Pharma outside the submitted work. Prof Meier reported grants from Novartis and Roche and others (travel support or/and speaker’s fees or/and advisor’s honoraria) from BMS, MSD, and Pierre Fabre outside the submitted work. Dr Hobelsberger reported clinical trial support and advisor’s honoraria from Almirall, speaker’s honoraria from Almirall, UCB, and AbbVie, and travel support from UCB, Janssen Cilag, Almirall, Novartis, Lilly, LEO Pharma, and AbbVie outside the submitted work. Prof Heinzerling reported other (clinical studies) from BMS, MSD, Pierre Fabre, Replimune, and Sanofi; personal fees from Biomedx, BMS, MSD, Sun, Pierre Fabre, Novartis, and Sanofi; and grants from Therakos outside the submitted work. Prof Haferkamp reported speaker’s fees and advisor’s honoraria from BMS, MSD, Novartis, and Pierre Fabre outside the submitted work. Dr Schlaak reported personal fees from BMS, Novartis, Immunocore, Sun Pharma, MSD, Recordati, and Sanofi Aventis outside the submitted work. Prof Berking reported personal fees from BMS, MSD, InflaRx, Novartis, Sanofi, LEO Pharma, Almirall Hermal, Pierre Fabre, Immunocore, and Delcath outside the submitted work. Dr Erdmann received travel support and speaker’s honoraria from Immunocore, Novartis, Pierre Fabre, and Sanofi outside the submitted work. Dr Sondermann reported grants from Almirall, Novartis, and Medi GmbH; and personal fees from AbbVie, Almirall, BMS, Boehringer Ingelheim, Celgene, Janssen, LEO Pharma, Lilly, Novartis, Pfizer, Sanofi Genzyme, and UCB outside the submitted work. Prof Goebeler reported grants for clinical studies from Argenx, Novartis, Janssen, and Galderma; personal fees from Almirall (consulting), Janssen (advisory board, speaker), GSK (advisory board, speaker), and Lilly (speaker) outside the submitted work. Dr Llamas-Velasco reported fees as an advisory board member, consultant, research support, participation in clinical trials, and honorary for speaking with the following pharmaceutical companies: Abbvie, Almirall, Amgen, Boehringer, BMS, Celgene, Janssen, Leo, Lilly, Kyowa kirin, Novartis and UCB, outside the submitted work. Dr. Kather declares consulting services for Owkin, France; DoMore Diagnostics, Norway; Panakeia, UK; AstraZeneca, UK; Scailyte, Switzerland; Mindpeak, Germany; and MultiplexDx, Slovakia. Furthermore, he holds shares in StratifAI GmbH, Germany, has received a research grant from GSK, and has received honoraria from AstraZeneca, Bayer, Eisai, Janssen, MSD, BMS, Roche, Pfizer, and Fresenius. Dr Gabriela Poch received travel support and speaker’s honoraria from MSD, BMS, Novartis, Sun Pharma, and Amgen outside the submitted work. Dr Brinker reported being the owner of Smart Health Heidelberg GmbH outside the submitted work. The remaining authors declare no competing interests., (© 2025. The Author(s).)

Background: Cancer immunotherapy has revolutionized melanoma treatment, but the high number of non-responders still emphasizes the need for improvement of therapy. One potential avenue for enhancing anti-tumor treatment is through the modulation of coagulation and platelet activity. Both have been found to play an important role in the tumor microenvironment, tumor growth and metastasis. Preclinical studies indicate a beneficial effect, clinical data has been inconsistent., Methods: We examined a cohort of advanced, non-resectable melanoma patients (n = 2419) derived from the German prospective multicenter skin cancer registry ADOReg, who were treated with immune checkpoint inhibitors (ICI). The patients were classified based on whether it was documented that they received platelet aggregation inhibition (PAI) (n = 137) (acetylsalicylic acid (ASA) or clopidogrel), anticoagulation (AC) (n = 185) (direct oral anticoagulation (DOAC), phenprocoumon, heparins) at the start of ICI or no antithrombotic medication (n = 2097) at any point during ICI treatment. The study endpoints were best overall response (BOR), progression-free survival (PFS) and overall survival (OS)., Results: A significantly improved PFS was observed in patients documented to receive ASA (15.1 vs 6.4 months, HR 0.67, 95 % CI: 0.5 to 0.88, p = 0.0047) as well as in patients to receive AC (15.1 vs. 6.4 months, HR 0.7, 95 % CI: 0.53 to 0.91, p = 0.01) compared to patients for whom no antithrombotic medication was documented. Multivariate analysis of OS showed significant risk reduction in patients who received DOAC (HR 0.68, 95 % CI: 0.49 to 0.92, p = 0.0170) or phenprocoumon (HR: 0.44, 95 % CI: 0.19 to 0.85, p = 0.0301)., Conclusion: Our study indicates a positive prognostic effect of anticoagulant and antiplatelet concomitant medication in melanoma patients receiving ICI. Further studies are needed to confrim the cancer-related benefit of adding anticoagulation or platelet inhibition to ICI treatment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JK has received honoraria from Bristol-Myers Squibb and Sanofi Genzyme and has received travel support from SUN Pharma and Pierre Fabre, outside the submitted work. GG has received honoraria from Bristol-Myers Squibb and has research funding from Sanofi Genzyme, outside the submitted work. IsH has received honoraria from Bristol-Myers Squibb and Sysmex, 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; outside the submitted work. UL declares research support from Merck Sharp & Dohme; speakers and advisory board honoraria from Sanofi, Regeneron, Sun Pharma, Merck Sharp & Dohme, Allmiral and Novartis; and meeting and travel support from Pierre Fabre, and Sun Pharma; outside the submitted work. CB declares honoraria as speaker and/or advisory board member from Almirall Hermal, Bristol-Myers Squibb, Delcath, Immunocore, InflaRx, Leo Pharma, MSD, Novartis, Pierre Fabre, Regeneron, and Sanofi, outside the submitted work. RG received honoraria for lectures/ advisory boards from Bristol Myers Squibb, Merck Sharp Dohme, Novartis, Merck-Serono, Amgen, Almirall Hermal, Pierre-Fabre, Sun Pharma, Immunocore, 4SC, Delcath, Sanofi/ Regeneron; Meeting support SUN Pharma, Boehringer Ingelheim, PierreFabre; Research support (to institution) Novartis, Sanofi/ Regeneron, Merck Serono, Amgen, SUN Pharma, Kyowa Kirin, Almirall Hermal. DS Honoraria: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore, Merck Serono, Array BioPharma, Pfizer, Pierre Fabre, Philogen, Regeneron, 4SC, Sanofi/Regeneron, NeraCare GmbH, Sun Pharma, InflarxGmbH, Ultimovacs, Sandoz. Consulting or Advisory Role: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi/Regeneron, Nektar. Speakers' Bureau: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi/Regeneron, Merck KGaA. Research Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Roche (Inst), MSD Oncology (Inst), Array BioPharma/Pfizer (Inst). Travel, Accommodations, Expenses: Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, Merck Sharp & Dohme, Pierre Fabre, Sanofi/Regeneron. 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. 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. IvW received honorairia as speaker from Novartis, BMS, MSD, Sanofi, Stemline, Kyowa Kirin and as consultant or advisory from BMS, MSD, Sanofi; travel, accommodations and expenses from Novartis, BMS, MSD, Sanofi, Stemline and Kyowa Kirin. FriM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, BMS, MSD, Pierre Fabre, Sanofi and Immunocore. SH declares speakers and advisory board honoraria and/or travel support from BMS, MSD, Immunocore, Novartis, Pierre-Fabre, Sanofi, Sun Pharma outside the submitted work. KD received financial support (speaker’s honoraria, advisory boards, travel expense reimbursements or grants) from Abbvie, Bristol-Myers-Squib, Novartis, and Pierre-Fabre. JU 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, Sanofi outside the submitted work. SAW received honoria from Bristol Myers Squibb, Novartis and Sun Pharma, outside the submitted work. CP served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi, Sunpharma, Pierre Fabre, AbbVie, Kyona Kirin and Amgen and received travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sunpharma and Novartis, outside the submitted work. PT served as consultant and/or received honoraria form Almirall, Bristol Myers Squibb, Biofrontera, Kyowa Kirin, L′Oréal, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sanofi, 4SC, and travel support from Bristol Myers Squibb outside the submitted work. JeU is on the advisory board or has received honoraria and travel support from Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, Pierre Fabre, Regeneron, Roche, Sanofi and SUN Pharma outside the submitted work. FraM served as consultant and/or has received honoraria from Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Sanofi Genzyme, Sun Pharma and travel support from Novartis, Sun Pharma, Pierre Fabre and Merck Sharp & Dohme, outside the submitted work. JW has received honoraria and travel support from Abbvie, Almirall, BMS, Boehringer Ingelheim, Janssen, Infectopharm Leo, Lilly, Mibe, MSD, Novartis, Pfizer and Sanofi. BS received honoraria from SUN Pharma, Allmiral, Novartis; Advisory Board for Pierre Fabre Pharma, Sanofi, Immunocore; travel support from Novartis, Pierre Fabre Pharma; Research Funding from Novartis; all outside the submitted work. FZ declares speakers and advisory board honoraria and/or travel support from BMS, MSD, Roche, Novartis, Pierre-Fabre, Sanofi, Sun Pharma outside the submitted work. AK received honoraria as speaker from InfectoPharm, Paul-Ehrlich-Gesellschaft für Chemotherapie e.V., Almirall Hermal, MSD Sharp & Dohme, Boehringer Ingelheim, Janssen-Cilag. LH declares speaker and advisory board honoraria from BMS, Immunocore, Novartis and Therakos. CL received honoraria for advisory board from BMS, MSD, Merck, Roche, Immunocore, Novartis, Pierre Fabre, Sanofi, Sun Pharma, Almirall Hermal, Kyowa Kirin, Biontech, Boehriner Ingelheim; speakers fee from BMS, MSD, Merck, Roche, Immunocore, Novartis, Pierre Fabre, Sanofi, Sun Pharma, Almirall Hermal, Kyowa Kirin, Biontech, Lilly and travel reimbursement from BMS, MSD, Merck, Roche, Immunocore, Novartis, Pierre Fabre, Sanofi, Sun Pharma, Almirall Hermal, Kyowa Kirin, Biontech, Pfizer. GS has received honoraria from Bristol-Myers Squibb and Kyowa Hakko Kirin Co. Ltd. outside the submitted work. SG declares honoraria for advisory boards, oral presentations and/ or travel expenses from Roche, Novartis, MSD, BMS, Sun Pharma, Klinge Pharma, Kyowa Kirin, Pierre Fabre, Guidepoint Global and UCB and research funds from Novartis and Pierre Fabre outside the submitted work. ND received honoraria from BMS and MSD outside the submitted work. RH and IK are employee of Helios Klinikum Erfurt GmbH. CS reports support from Kyowa Kirin, BMS, Novartis, Roche, SunPharma in context of dermatooncology as well as from Boehringer Ingelheim, Biotest AG and Janssen Cilag in other medical fields. AE is on advisory board or has received honoraria from Agenus, BioInvent, BioNTech, Boeringer Ingelheim GmbH, Brenus, CatalYm, Eurobio. IO Biotech, IQVIA, Merck&Co, MSD, Pfizer, Pierre Fabre, Sairopa BV, SkylineDX BV, Trained ImmunoTherapeutics Discovery and has Equity in IO Biotech, Sairopa BV and SkylineDX BV. MVH received honoraria from MSD, BMS, Roche, Novartis, Sun Pharma, Sanofi, Almirall, Biofrontera, Galderma, Immunocore, InfectoPharm. CG is on the advisory board or has received honoraria from Almirall, Amgen, Beiersdorf, BioNTech, Bristol-Myers Squibb, Immunocore, Janssen, MSD Sharp & Dohme, Novartis, Pierre-Fabre Pharma, Regeneron, Roche, Sanofi Genzyme, SUN Pharma and Sysmex, research funding from Bristol-Myers Squibb, Novartis, Regeneron and Sanofi, outside the submitted work. C.G. is co-founder of Dermagnostix and Dermagnostix R&D. All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)