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Background: The global incidence of skin cancer has steadily increased in recent years. Accordingly, patients require information on diagnosis and treatment options while dealing with the perceived impact of the diagnosis. In 2015, the German government enacted legislation under the Social Code (SGB V, § 27b), granting patients the right to obtain a second medical opinion., Patients and Methods: Utilizing a standardized questionnaire, our study aims to explore whether patients diagnosed with skin cancer actively pursue a second medical opinion and to evaluate any potential disruptions to their daily lives. We collected a total of 714 completed questionnaires., Results: The majority of those seeking a second opinion were diagnosed with malignant melanoma (96, 58%). Primary motivations for seeking a second opinion included seeking reassurance regarding treatment decisions and obtaining further information. Additionally, seeking a second opinion was correlated with a significantly lower internal locus of control, indicating a belief that their actions are not solely determined by their own abilities. Notably, we observed a greater impairment of daily life among younger participants and those with advanced cancer., Conclusions: Overall, our study shows that second opinions often strengthened the patient-physician interaction and provided additional reassurance, especially in patients with a weak perception of control. Moreover, we found that the impairment of quality of life and both internal and external locus of control decrease significantly in advanced tumor stages. Hence, it is imperative to identify additional interventions aimed at bolstering internal resilience and locus of control, thereby enhancing patients' capacity to cope with their cancer diagnosis., (© 2024 The Author(s). Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Purpose: AI-assisted techniques for lesion registration and segmentation have the potential to make CT-based tumor follow-up assessment faster and less reader-dependent. However, empirical evidence on the advantages of AI-assisted volumetric segmentation for lymph node and soft tissue metastases in follow-up CT scans is lacking. The aim of this study was to assess the efficiency, quality, and inter-reader variability of an AI-assisted workflow for volumetric segmentation of lymph node and soft tissue metastases in follow-up CT scans. Three hypotheses were tested: (H1) Assessment time for follow-up lesion segmentation is reduced using an AI-assisted workflow. (H2) The quality of the AI-assisted segmentation is non-inferior to the quality of fully manual segmentation. (H3) The inter-reader variability of the resulting segmentations is reduced with AI assistance., Materials and Methods: The study retrospectively analyzed 126 lymph nodes and 135 soft tissue metastases from 55 patients with stage IV melanoma. Three radiologists from two institutions performed both AI-assisted and manual segmentation, and the results were statistically analyzed and compared to a manual segmentation reference standard., Results: AI-assisted segmentation reduced user interaction time significantly by 33% (222 s vs. 336 s), achieved similar Dice scores (0.80-0.84 vs. 0.81-0.82) and decreased inter-reader variability (median Dice 0.85-1.0 vs. 0.80-0.82; ICC 0.84 vs. 0.80), compared to manual segmentation., Conclusion: The findings of this study support the use of AI-assisted registration and volumetric segmentation for lymph node and soft tissue metastases in follow-up CT scans. The AI-assisted workflow achieved significant time savings, similar segmentation quality, and reduced inter-reader variability compared to manual segmentation., (© 2024. The Author(s).)

Background: The introduction of anti-programmed cell death protein 1 (PD-1) immunotherapy has revolutionized the treatment landscape for melanoma, enhancing both response rates and survival outcomes in patients with advanced stages of the disease. Despite these remarkable advances, a noteworthy subset of patients (40%-60%) does not derive advantage from this therapeutic approach. This study aims to identify key predictive factors and create a user-friendly predictive nomogram for stage IV melanoma patients receiving first-line anti-PD-1-based immunotherapy, improving treatment decisions., Materials and Methods: In this retrospective study, we included patients with unresectable stage IV melanoma who received first-line treatment with either anti-PD-1 monotherapy or anti-PD-1 plus anti-cytotoxic T-lymphocyte associated protein 4 between 2014 and 2018. We documented clinicopathological features and blood markers upon therapy initiation. By employing the random survival forest model and backward variable selection of the Cox model, we identified variables associated with progression-free survival (PFS) after the first-line anti-PD-1-based treatment. We developed and validated a predictive nomogram for PFS utilizing the identified variables. We assessed calibration and discrimination performance metrics as part of the evaluation process., Results: The study involved 719 patients, divided into a training cohort of 405 (56%) patients and a validation cohort of 314 (44%) patients. We combined findings from the random survival forest and the Cox model to create a nomogram that incorporates the following factors: lactate dehydrogenase (LDH), S100, melanoma subtype, neutrophil-to-lymphocyte ratio (NLR), body mass index, type of immune checkpoint inhibitor, and presence of liver or brain metastasis. The resultant model had a C-index of 0.67 in the training cohort and 0.66 in the validation cohort. Performance remained in different patient subgroups. Calibration analysis revealed a favorable correlation between predicted and actual PFS rates., Conclusions: We developed and validated a predictive nomogram for long-term PFS in patients with unresectable stage IV melanoma undergoing first-line anti-PD-1-based immunotherapy., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Immune checkpoint inhibitors (ICI) induce adverse events (irAEs) that do not respond to steroids, i.e. steroid-refractory (sr) irAEs, and irAEs in which steroids cannot be tapered, i.e. steroid-dependent (sd) irAEs, in about 10% of cases. An evidence-based analysis of the effectiveness of second-line immunosuppressive agents with regard to irAE and tumor control is lacking., Methods: The international web-based Side Effect Registry Immuno-Oncology (SERIO; http://serio-registry.org) is a collaborative initiative with the Paul-Ehrlich-Institute to document rare, severe, complex or therapy-refractory immunotherapy-induced side effects. The registry was queried on August 1, 2023 for cases of irAEs which were treated with second-line therapies., Results: From a total of 1330 cases, 217 patients (16.3%) received 249 second-line therapies. A total of 19 different second-line therapies were employed, including TNF-alpha antagonists (46.5%), intravenous immunoglobulins (IVIG; 19.1%), mycophenolate mofetil (15.9%), and methotrexate (3.6%). Therapy choices were determined by the type of irAE. The time to onset of sr-/sd-irAEs after ICI initiation did not consistently differ from steroid-responsive irAEs. While 74.3% of sr-/sd-irAEs resolved and 13.1% had improved, 4.3% persisted, 3.9% resulted in permanent sequelae, and 4.3% in death with ongoing symptoms. Infliximab exhibited potential for earlier symptom improvement compared to mycophenolate mofetil or IVIG. Tumor response in patients with second-line treated sd-/sr-irAE was similar to patients with irAEs treated with steroids only., Conclusion: Several second-line therapies are effective against sr-/sd-irAEs, the second-line therapies show no clear negative impact on tumor response, and infliximab shows potential for faster improvement of symptoms. However, prospective comparative data are needed., 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Although teledermatology has been proven internationally to be an effective and safe addition to the care of patients in primary care, there are few pilot projects implementing teledermatology in routine outpatient care in Germany. The aim of this cluster randomized controlled trial was to evaluate whether referrals to dermatologists are reduced by implementing a store-and-forward teleconsultation system in general practitioner practices., Methods: Eight counties were cluster randomized to the intervention and control conditions. During the 1-year intervention period between July 2018 and June 2019, 46 general practitioner practices in the 4 intervention counties implemented a store-and-forward teledermatology system with Patient Data Management System interoperability. It allowed practice teams to initiate teleconsultations for patients with dermatologic complaints. In the four control counties, treatment as usual was performed. As primary outcome, number of referrals was calculated from routine health care data. Poisson regression was used to compare referral rates between the intervention practices and 342 control practices., Results: The primary analysis revealed no significant difference in referral rates (relative risk  = 1.02; 95% confidence interval = 0.911-1.141; p  = .74). Secondary analyses accounting for sociodemographic and practice characteristics but omitting county pairing resulted in significant differences of referral rates between intervention practices and control practices. Matched county pair, general practitioner age, patient age, and patient sex distribution in the practices were significantly related to referral rates., Conclusions: While a store-and-forward teleconsultation system was successfully implemented in the German primary health care setting, the intervention's effect was superimposed by regional factors. Such regional factors should be considered in future teledermatology research., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., Competing Interests: Declaration of Competing Interest LH received speaker and consultancy fees from BiomeDx, BMS, Kyowa Kirin, Merck, MSD, Myoncare, Novartis, Pierre-Fabre, Roche, Sanofi, SUN and Therakos. The LMU received research grants or clinical study grants from Agenus, AstraZeneca Inc., BMS, Hoffmann-La Roche AG, Huya Bioscience, Immunocore, IO Biotech, Merck, Merck Sharp & Dome GmbH, Miltenyi Biomedicine GmbH, Novartis, Pfizer, Pierre Fabre, Regeneron, Replimune, and Sanofi Aventis. AF received honoraria for presentations and travel support from: BMS, Novartis, Pierre-Fabre. AF reports on participation on Advisory Boards of MSD, BMS, Novartis, Pierre-Fabre, Immunocore and institutional research grants from BMS Stiftung Immunonkologie for other financial or non-financial interests. AH reports grants and personal fees from Amgen, grants and personal fees from BMS, grants and personal fees from MerckPfizer, grants and personal fees from MSD/Merck, grants and personal fees from Philogen, grants and personal fees from Pierre Fabre, grants and personal fees from Regeneron, grants and personal fees from Roche, grants and personal fees from Sanofi-Genzyme, grants and personal fees from Novartis Pharma, grants and personal fees from Eisai, personal fees from Immunocore, grants and personal fees from Replimune, personal fees from Seagen, personal fees from IO Biotech, personal fees from Dermagnostix, personal fees from Incyte, grants and personal fees from NeraCare, personal fees from Highlight Therapeutics, grants from Huya Biosciences, personal fees from Kyowa Kirin, personal fees from Iovance, outside the submitted work. CL received honoraria (lectures, presentations, speakers bureaus, manuscript writing or educational events) and travel support from: BMS, MSD Merck, Pierre-Fabre, Biontech, Almirall Hermal, Sun Pharma, KyowaKirin, Immunocore, Sanofi, Novartis. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, MSD, Merck Serono, MSD, Celgene, AbbVie, Sunpharma, Pierre Fabre, UCB, Nutricia Milupa, Janssen and LEO outside the submitted work. CR reports personal consulting fees from BMS, Roche, MSD, Sanofi, Pierre Fabre, Sunpharma, Pfizer, Regeneron. CR received honoraria (lectures, presentations, speakers bureaus, manuscript writing or educational events) from Pierre Fabre, Sanofi, BMS. CR reports personal fees (participation on a Data Safety Monitoring Board or Advisory Board) from Ultimovacs and Regeneron. CR reports stocks/stock options: Ribonexus. DS reports grants, personal fees, non-financial support and other from Novartis, BMS, Amgen, MSD & Array/Pfizer; personal fees and from 4SC, Agenus, Array BioPharma, Astra Zeneca, BioAlta, CureVac, Daiichi Sanyko, Erasma, Haystack, Immatics, Immunocore, InFlarX, Merck Serono, Pierre Fabre, PamGene, Philogen, Neracare NoviGenix, Ultimovacs, Sandoz/Hexal, Sanofi, Seagen, Sun Pharma, Regeneron, and Replimune. GMcA reports on grants or contracts from BMS, Genentech-Roche, Merck to his institution. DT reports consultancy, speaker fees or travel grants: BMS, Roche, Novartis, Sanofi, Recordati, Kyowa Kirin, Sun Pharma and Pierre Fabre. GMcA reports on participation on Data Safety Monitoring or Advisory Board from Pierre Fabre and Pfizer (no payments) and on National Breast Cancer Foundation Board (Australia) (no payments). 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, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron. HG reports on grants or contracts from BMS, Roche, MSD Oncology, Amgen, Novartis, Iovance Biotherapeutics to her institution. HG received consulting fees from BMS, MSD Oncology, Pierre Fabre, Sanofi/ Regeneron. HG received speakers honoraria from BMS, MSD Oncology, Pierre-Fabre, Sanofi/ Regeneron. HG received travel support from MSD, Amgen, Pfizer. JH received scientific grants from BMS, Sanofi, Sunpharma and consulting fees (for advisory boards) from GSK, MSD, Pierre Fabre, Onkowiessen, Sunpharma. JH received honoraria (talks) from Amgen, BMS, GSK, Immunocore, MSD, Novartis, Pierre Fabre, Sanofi, Sunpharma. JH received meeting/travel support from BMS, Iovance, Sunpharma. JH reports on participation on a Data Safety Monitoring Board from Nekvax. LZ declares speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Sunpharma, research support from Novartis and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sanofi, Sunpharma and Novartis; outside the submitted work. MS reports on research support from Amgen, BMS/Celgene, Gilead/Kite, Janssen, Miltenyi, Novartis, Roche, Seattle Genetics, Takeda. MS reports on participation on Advisory Boards of Astra Zeneca, Avencell, Ichnos, Incyte, Janssen, Molecular Partners. MS received honoraria (speaker’s bureau) from: Amgen, BMS/Celgene, Janssen, Gilead/Kite, Novartis, Pfizer, Takeda. PA reports on grants and contracts from BMS, Roche-Genentech, Pfizer, Sanofi. PA received consulting fees from Bristol Myers Squibb, Roche-Genentech, Merck, Sharp & Dohme, Novartis, Merck Serono, PierreFabre, Sun Pharma, Sanofi, Sandoz, Italfarmaco, Nektar, Pfizer, Lunaphore, Medicenna. Bio-Al Health, ValoTx, Replimmune, Bayer. PA received travel support from Pfizer, BIO-AI Health, Replimmune. PA reports on participation on a Data Safety Monitoring or Advisory Board from BMS, Roche-Genentech, Merck, Sharp & Dohme, Novartis, AstraZeneca, BoehringerIngelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos, Erasca. 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. RG received honoraria for advice and lectures from BristolMyers Squibb, Roche Pharma, MerckSharpDohme, Novartis, Merck-Serono, Amgen, Almirall Hermal, Pierre-Fabre, Sun Pharma, Immunocore, 4SC, Delcath, Sanofi/Regeneron. Ralf Gutzmer received travel support from SUN Pharma, Boehringer Ingelheim and PierreFabre. Ralf Gutzmer received research grants from Novartis, Sanofi/Regeneron, Merck Serono, Amgen, SUN Pharma, KyowaKirin, Admiral Hermal. RK received meeting and travel support from SunPharma, Novartis, Pierre-Fabre. SG reports on clinical trials honoraria to institution from MSD, BMS, Sanofi, Pfizer, BioNTech, EORTC, I-O Biotech, Astra Zeneca, and Regeneron. SG received consulting fees from MSD and BMS and an Online Ticket for ASCO from BMS. TE received speaker and consultancy fees from BMS, Curevac, Merck, MSD, Novartis, Pierre-Fabre, Sanofi, Almiral Hermal, and SUN. TN reports on grants or contracts from NIH, BMS, Astra Zeneca to his institution. TN received consulting fees from Genentech, BMS, Roche, Sanofi, Roivant, Race Oncology. TN participated on Data Safety Monitoring Board/ Advisory Board from Genentech. TR declared speaker’s honoraria and travel grants from Therakos and SUN. AR, CE, MK, VM have declared no conflicts of interest. BR received support from BMS, Merck and Astrazeneca. BR received honoraria (for lectures, presentations, speakers bureaus, manuscript writing or educational events) from BMS, Merck and Astrazeneca. BR reports on participation on a Data Safety Monitoring Board or Advisory Board from BMS, Merck and Astrazeneca. All remaining authors have declared no conflicts of interest., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Background: MEK inhibitors (MEKi) were shown to be clinically insufficiently effective in patients suffering from BRAF wild-type (BRAF WT) melanoma, even if the MAPK pathway was constitutively activated due to mutations in NRAS or NF-1. Thus, novel combinations are needed to increase the efficacy and duration of response to MEKi in BRAF WT melanoma. Disulfiram and its metabolite diethyldithiocarbamate are known to have antitumor effects related to cellular stress, and induction of endoplasmic reticulum (ER) stress was found to synergize with MEK inhibitors in NRAS-mutated melanoma cells. Therefore, we investigated the combination of both therapeutics to test their effects on BRAF-WT melanoma cells and compared them with monotherapy using the MEKi trametinib., Methods: The effects of combined therapy with disulfiram or its metabolite diethyldithiocarbamate and the MEKi trametinib were evaluated in a series of BRAF-WT melanoma cell lines by measuring cell viability and apoptosis induction. Cytotoxicity was additionally assessed in 3D spheroids, ex vivo melanoma slice cultures, and in vivo xenograft mouse models. The response of melanoma cells to treatment was studied at the RNA and protein levels to decipher the mode of action. Intracellular and intratumoral copper measurements were performed to investigate the role of copper ions in the antitumor cytotoxicity of disulfiram and its combination with the MEKi., Results: Diethyldithiocarbamate enhanced trametinib-induced cytotoxicity and apoptosis induction in 2D and 3D melanoma culture models. Mechanistically, copper-dependent induction of oxidative stress and ER stress led to Janus kinase (JNK)-mediated apoptosis in melanoma cells. This mechanism was also detectable in patient-derived xenograft melanoma models and resulted in a significantly improved therapeutic effect compared to monotherapy with the MEKi trametinib., Conclusions: Disulfiram and its metabolite represent an attractive pharmaceutical approach to induce ER stress in melanoma cells that potentiates the antitumor effect of MEK inhibition and may be an interesting candidate for combination therapy of BRAF WT melanoma., (© 2024. The Author(s).)

Background: Checkpoint inhibitors have drastically improved the therapy of patients with advanced melanoma. 18F-FDG-PET/CT parameters might act as biomarkers for response and survival and thus can identify patients that do not benefit from immunotherapy. However, little literature exists on the association of baseline 18F-FDG-PET/CT parameters with progression free survival (PFS), best overall response (BOR), and overall survival (OS)., Materials and Methods: Using a whole tumor volume segmentation approach, we investigated in a retrospective registry study (n = 50) whether pre-treatment 18F-FDG-PET/CT parameters of three subgroups (tumor burden, tumor glucose uptake and non-tumoral hematopoietic tissue metabolism), can act as biomarkers for the primary endpoints PFS and BOR as well as for the secondary endpoint OS., Results: Compared to the sole use of clinical parameters, baseline 18F-FDG-PET/CT parameters did not significantly improve a Cox proportional-hazard model for PFS (C-index/AIC: 0.70/225.17 and 0.68/223.54, respectively; p = 0.14). A binomial logistic regression analysis for BOR was not statistically significant (χ2(15) = 16.44, p = 0.35), with a low amount of explained variance (Nagelkerke's R2 = 0.38). Mean FDG uptake of the spleen contributed significantly to a Cox proportional-hazard model for OS (HR 3.55, p = 0.04)., Conclusions: The present study could not confirm the capability of the pre-treatment 18F-FDG-PET/CT parameters tumor burden, tumor glucose uptake and non-tumoral hematopoietic tissue metabolism to act as biomarkers for PFS and BOR in metastatic melanoma patients receiving first-line immunotherapy. The documented potential of 18F-FDG uptake by immune-mediating tissues such as the spleen to act as a biomarker for OS has been reproduced., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Peisen 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.)

Background: Lentigo maligna melanoma is mainly localized in the head and neck region in elderly patients. Due to its slow horizontal growth, it has a good prognosis compared to other melanoma subtypes, but specific data are rare., Objectives: The aim of this study was to investigate sentinel lymph node biopsy in lentigo maligna melanoma under local anaesthesia and to discuss the benefit., Methods: Investigation of patients with lentigo maligna melanoma and tumour thickness ≥1 mm treated at the Department of Dermatology, University Medical Centre Tuebingen, between January 2008 and October 2019., Results: In total, 204 patients (126 SLNB, 78 non-SLNB) with a median age of 75.7 years (SLNB: 73.3 years, non-SLNB: 79.7 years) could be included. Sixteen of 126 (12.7%) sentinel lymph nodes were positive. Five-year overall survival was 87.9% (88.5% SLNB; 87.4% non-SLNB) and 5-year distant metastasis-free survival was 85.8% (85.4% SLNB; 86.7% non-SLNB). There was no significant difference for distant metastasis-free survival (p = 0.861) and overall survival (p = 0.247) between patients with and without sentinel lymph node biopsy., Conclusions: Sentinel lymph node biopsy in lentigo maligna melanoma under local anaesthesia is a safe and simple method, even in very old patients. However, LMM has a very good 5-year overall survival. In high-risk patients with high tumour thickness and/or ulceration, adjuvant immunotherapy can now be offered without the need to perform this procedure., (© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

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.)

The increasing number of melanoma patients makes it necessary to develop best possible strategies for prognosis assessment in order to recommend appropriate therapy and follow-up. The prognostic significance of tumor cell pigmentation has not been fully elucidated. Hematoxylin and eosin (H&E)-stained sections of 775 melanomas diagnosed between 2012 and 2015 were independently assessed for melanin pigment abundance by two investigators, and the impact on melanoma-specific survival was calculated. Unpigmented melanomas (n = 99) had a melanoma-specific survival of 67.7%, melanomas with moderate pigmentation (n = 384) had a melanoma-specific survival of 85.9%, and strongly pigmented melanomas (n = 292) had a melanoma-specific survival of 91.4% (p < .001). In an analysis of melanoma-specific survival adjusted for pT stage and pigmentation, we found a nonsignificant impact of pigmentation abundance with a hazard ratio of 1.277 (p = .74). The study presented here provides evidence in a German cohort that patients with pigmented melanomas have a more favorable prognosis than those diagnosed with nonpigmented melanomas. Moreover, the abundance of pigmentation already seems to provide a first prognostic estimate. However, it does not appear to provide significant additional value for prognostic assessment according to the AJCC 2017 pT classification., (© 2023 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)

Background: Recent advances in digital pathology have enabled accurate and standardised enumeration of tumour-infiltrating lymphocytes (TILs). Here, we aim to evaluate TILs as a percentage electronic TIL score (eTILs) and investigate its prognostic and predictive relevance in cutaneous melanoma., Methods: We included stage I to IV cutaneous melanoma patients and used hematoxylin-eosin-stained slides for TIL analysis. We assessed eTILs as a continuous and categorical variable using the published cut-off of 16.6% and applied Cox regression models to evaluate associations of eTILs with relapse-free, distant metastasis-free, and overall survival. We compared eTILs of the primaries with matched metastasis. Moreover, we assessed the predictive relevance of eTILs in therapy-naïve metastases according to the first-line therapy., Findings: We analysed 321 primary cutaneous melanomas and 191 metastatic samples. In simple Cox regression, tumour thickness (p < 0.0001), presence of ulceration (p = 0.0001) and eTILs ≤16.6% (p = 0.0012) were found to be significant unfavourable prognostic factors for RFS. In multiple Cox regression, eTILs ≤16.6% (p = 0.0161) remained significant and downgraded the current staging. Lower eTILs in the primary tissue was associated with unfavourable relapse-free (p = 0.0014) and distant metastasis-free survival (p = 0.0056). In multiple Cox regression adjusted for tumour thickness and ulceration, eTILs as continuous remained significant (p = 0.019). When comparing TILs in primary tissue and corresponding metastasis of the same patient, eTILs in metastases was lower than in primary melanomas (p < 0.0001). In therapy-naïve metastases, an eTILs >12.2% was associated with longer progression-free survival (p = 0.037) and melanoma-specific survival (p = 0.0038) in patients treated with anti-PD-1-based immunotherapy. In multiple Cox regression, lactate dehydrogenase (p < 0.0001) and eTILs ≤12.2% (p = 0.0130) were significantly associated with unfavourable melanoma-specific survival., Interpretation: Assessment of TILs is prognostic in primary melanoma samples, and the eTILs complements staging. In therapy-naïve metastases, eTILs ≤12.2% is predictive of unfavourable survival outcomes in patients receiving anti-PD-1-based therapy., Funding: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript., Competing Interests: Declaration of interests SF received personal fees from Kyowa Kirin and Takeda Pharmaceuticals, institutional grants from NeraCare, SkylineDx, and BioNTech, all outside the submitted work. TA reports institutional grants and personal fees from Novartis, institutional grants from NeraCare, Sanofi, SkylineDx, personal fees from CeCaVa, Pierre Fabre, BMS all outside the submitted work, participate on a data safety monitoring board for Unicancer. DLR reports grants and personal fees from Amgen, Astra Zeneca, Cepheid, Konica—Minolta, Lilly, NextCure personal fees from Cell Signaling Technology, Danaher, Fluidigm, GSK, Merck, Monopteros, NanoString, Odonate, Paige. AI, Regeneron, Roche, Sanofi, Ventana and Verily, royalties from Rarecyte, all outside the submitted work. CG reports grants and personal fees from NeraCare, Novartis, Roche, Sanofi, personal fees from Amgen, BMS, MSD, and Philogen, all outside the submitted work. TE reports personal fees from Novartis, BMS, Almirall Hermal, CureVac, Sanofi, MSD, Pierre Fabre and institutional grants from MSD, Sanofi, BMS, Pfizer, GenenTech, Seagan, Regeneron all outside the submitted work. IB reports having received speaker fees from Bayer, Pfizer, Takeda and AstraZeneca. MR reports grants from AB Science, Abbott, AbbVie, Alcedis, Almirall Hermal, Amgen, Anaptys Bio, Argenx, AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, CureVac, DelArrivo, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Dynavax Tech, Eli Lilly, Galderma, Genentech, GSK, Hoffmann La Roche, Hokusai, Idera Pharmaceuticals, Ilkos Therapeutic, Immatics biotechnologies, Incyte, Iovance Biotherapeutics, Janssen Cilag, Johnson & Johnson, LEO Pharma, Merck, MSD Sharp &Dohme, Novartis Pharmaceuticals, PellePharm, Pfizer, Philogen, Regeneron Pharmaceuticals, Sanofi Aventis, Schering Plough, Sun Pharma, Technische Universitat Dresden, Topaz Therapeutics, UCB, Universitatsklinik Essen, Universitatklinik Koln, Wilhelm Sander-Stiftung, 4SC. The other authors report no potential conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The need for reliable clinical biomarkers to predict which patients with melanoma will benefit from immune checkpoint blockade (ICB) remains unmet. Several different parameters have been considered in the past, including routine differential blood counts, T cell subset distribution patterns and quantification of peripheral myeloid-derived suppressor cells (MDSC), but none has yet achieved sufficient accuracy for clinical utility., Methods: Here, we investigated potential cellular biomarkers from clinical routine blood counts as well as several myeloid and T cell subsets, using flow cytometry, in two independent cohorts of a total of 141 patients with stage IV M1c melanoma before and during ICB., Results: Elevated baseline frequencies of monocytic MDSCs (M-MDSC) in the blood were confirmed to predict shorter overall survival (OS) (HR 2.086, p=0.030) and progression-free survival (HR 2.425, p=0.001) in the whole patient cohort. However, we identified a subgroup of patients with highly elevated baseline M-MDSC frequencies that fell below a defined cut-off during therapy and found that these patients had a longer OS that was similar to that of patients with low baseline M-MDSC frequencies. Importantly, patients with high M-MDSC frequencies exhibited a skewed baseline distribution of certain other immune cells but these did not influence patient survival, illustrating the paramount utility of MDSC assessment., Conclusion: We confirmed that in general, highly elevated frequencies of peripheral M-MDSC are associated with poorer outcomes of ICB in metastatic melanoma. However, one reason for an imperfect correlation between high baseline MDSCs and outcome for individual patients may be the subgroup of patients identified here, with rapidly decreasing M-MDSCs on therapy, in whom the negative effect of high M-MDSC frequencies was lost. These findings might contribute to developing more reliable predictors of late-stage melanoma response to ICB at the individual patient level. A multifactorial model seeking such markers yielded only MDSC behavior and serum lactate dehydrogenase as predictors of treatment outcome., Competing Interests: Competing interests: TA reports institutional grants from SkylineDx, institutional grants and personal fees from Novartis, institutional grants from NeraCare, personal fees from BMS, institutional grants from Sanofi, personal fees from CeCaVa, personal fees from Pierre Fabre, outside the submitted work. NW reports an advisory role for Pierre Fabre and Sanofi, consultant's honoraria from Novartis, and has received travel support from AbbVie and Amgen outside the submitted work. FM reports receiving commercial research grants from Novartis and Roche; and has received travel support and/or speaker’s fees and/or advisor’s honoraria by Novartis, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme and Pierre Fabre. PT has received travel support and/or speaker’s fees and/or advisor’s honoraria by Almirall, Biofrontera, Bristol-Myers Squibb, Curevac, Kyowa Kirin, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi and 4SC. CG reports receiving commercial research grants from Bristol-Myers Squibb, Novartis and Roche; and is a consultant/advisory board member for Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis and Roche. GP has received speaker’s honoraria from Novartis, Roche, Pfizer, GlaxoSmithKline and Astellas. TE has received travel support and/or speaker’s fees and/or advisor’s honoraria by Sanofi, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Almiral Hermal and Pierre Fabre. BW reports receiving commercial research grants from, is a consultant/advisory board member for and reports receiving travel reimbursement from Bristol-Myers Squibb and Merck Sharp & Dohme. KW-H received commercial research grants from CatalYm GmbH and travel support from Society for Immunotherapy of Cancer. No potential conflicts of interest were disclosed by the other authors., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Aim/Introduction: Despite the spectacular success of immune checkpoint inhibitor therapy (ICT) in patients with metastatic cancer, only a limited proportion of patients benefit from ICT. CD8 + cytotoxic T cells are important gatekeepers for the therapeutic response to ICT and are able to recognize MHC class I-dependent tumor antigens and destroy tumor cells. The radiolabeled minibody [ 89 Zr]Zr-Df-IAB22M2C has a high affinity for human CD8 + T cells and was successfully tested in a phase I study. Here, we aimed to gain the first clinical PET/MRI experience with the noninvasive assessment of the CD8 + T-cell distribution in cancer patients by in vivo [ 89 Zr]Zr-Df-IAB22M2C with a distinct focus of identifying potential signatures of successful ICT. Material and Methods: We investigated 8 patients with metastasized cancers undergoing ICT. Radiolabeling of Df-IAB22M2C with Zr-89 was performed according to Good Manufacturing Practice. Multiparametric PET/MRI was acquired 24 h after injection of 74.2±17.9 MBq [ 89 Zr]Zr-Df-IAB22M2C. We analyzed [ 89 Zr]Zr-Df-IAB22M2C uptake within the metastases and within primary and secondary lymphatic organs. Results: [ 89 Zr]Zr-Df-IAB22M2C injection was tolerated well without noticeable side effects. The CD8 PET/MRI data acquisitions 24 hours post-administration of [ 89 Zr]Zr-Df-IAB22M2C revealed good image quality with a relatively low background signal due to only low unspecific tissue uptake and marginal blood pool retention. Only two metastatic lesions showed markedly increased tracer uptake in our cohort of patients. Furthermore, we observed high interpatient variability in [ 89 Zr]Zr-Df-IAB22M2C uptake within the primary and secondary lymphoid organs. Four out of five ICT patients exhibited rather high [ 89 Zr]Zr-Df-IAB22M2C uptake in the bone marrow. Two of these four patients as well as two other patients yielded pronounced [ 89 Zr]Zr-Df-IAB22M2C uptake within nonmetastatic lymph nodes. Interestingly, cancer progression in ICT patients was associated with a relatively low [ 89 Zr]Zr-Df-IAB22M2C uptake in the spleen compared to the liver in 4 out of the 6 patients. Lymph nodes with enhanced [ 89 Zr]Zr-Df-IAB22M2C uptake revealed significantly reduced apparent diffusion coefficient (ADC) values in diffusion weighted MRI. Conclusion: Our first clinical experiences revealed the feasibility of [ 89 Zr]Zr-Df-IAB22M2C PET/MRI in assessing potential immune-related changes in metastases and primary and secondary lymphatic organs. According to our results, we hypothesize that alterations in [ 89 Zr]Zr-Df-IAB22M2C uptake in primary and secondary lymphoid organs might be associated with the response to ICT., Competing Interests: Competing Interests: R.K. and I.W. are employees of ImaginAB. ClF is an advisor of ImaginAB. The other authors report no conflicts of interest., (© The author(s).)

Ex-vivo confocal laser scanning microscopy provides a rapid alternative to routine histological processing using haematoxylin and eosin-stained sections. Previous studies suggest high diagnostic accuracy in basal cell carcinoma. This study investigates the diagnostic accuracy of confocal laser scanning microscopy reporting of basal cell carcinoma in a real-life setting and compares reporting by dermatopathologists inexperienced in use of confocal laser scanning microscopy with reporting by an expert in confocal laser scanning microscopy. A total of 334 confocal laser scanning microscopy scans were diagnosed by 2 dermatopathologists inexperienced in the diagnosis of confocal laser scanning microscopy as well as an experienced examiner of confocal laser scanning microscopy scans. The inexperienced examiners achieved a sensitivity of 59.5/71.1% and specificity of 94.8/89.8%. The experienced examiner achieved a sensitivity of 78.5% and specificity of 84.8%. Detection of tumour remnants in margin controls showed insufficient values among inexperienced (30.1/33.3%) and experienced (41.7%) investigators. The results of this study, of real-life setting basal cell carcinoma reporting with confocal laser scanning microscopy, found a lower diagnostic accuracy than published data regarding artificial settings. A poor accuracy in tumour margin control is clinically relevant and could restrict the use of confocal laser scanning microscopy in clinical routine. Prior knowledge of haematoxylin and eosin trained pathologists can be partially transferred to the reporting of confocal laser scanning microscopy scans; however, specific training is recommended.

Merkel cell carcinoma (MCC, ICD-O M8247/3) is a rare, malignant, primary skin tumor with epithelial and neuroendocrine differentiation. The tumor cells share many morphologic, immunohistochemical, and ultrastructural features with cutaneous Merkel cells. Nevertheless, the cell of origin of MCC is unclear. MCC appears clinically as a reddish to purple spherical tumor with a smooth, shiny surface and a soft to turgid, elastic consistency, usually showing rapid growth. Spontaneous and often complete regressions of the tumor are observed. These likely immunologically-mediated regressions explain the cases in which only lymph node or distant metastases are found at the time of initial diagnosis and why the tumor responds very well to immunomodulatory therapies even at advanced stages. Due to its aggressiveness, the usually given indication for sentinel lymph node biopsy, the indication of adjuvant therapies to be evaluated, as well as the complexity of the necessary diagnostics, clinical management should already be determined by an interdisciplinary tumor board at the time of initial diagnosis., (© 2023 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Background: High tumor mutational burden (TMB) is associated with a favorable outcome in metastatic melanoma patients treated with immune checkpoint inhibitors. However, data are limited in the adjuvant setting. As BRAF mutated patients have an alternative with targeted adjuvant therapy, it is important to identify predictive factors for relapse and recurrence-free survival (RFS) in patients receiving adjuvant anti-PD-1 antibodies., Methods: We evaluated 165 melanoma patients who started adjuvant anti-PD-1 antibody therapy at our center between March 2018 and September 2019. The initial tumor stage was assessed at the beginning of therapy according to the 8th edition of the AJCC Cancer Staging Manual. Tumor and normal tissue of the high-risk stages IIIC/D/IV were sequenced using a 700 gene NGS panel., Results: The tumor stages at the beginning of adjuvant anti-PD-1 therapy were as follows: N = 80 stage IIIA/B (48%), N = 85 stage IIIC/D/IV (52%). 72/165 patients (44%) suffered a relapse, 44/72 (61%) with only loco regional and 28/72 (39%) with distant metastases. Sequencing results were available from 83 to 85 patients with stage IIIC/D/IV. BRAF mutation status (HR 2.12, 95% CI 1.12-4.08; p = 0.022) and TMB (HR 7.11, 95% CI 2.19-23.11; p = 0.001) were significant and independent predictive factors for relapse-free survival (RFS)., Conclusion: BRAF mutation status and TMB were independent predictive factors for RFS. Patients with BRAF V600E/K mutation and TMB high had the best outcome. A classification based on BRAF mutation status and TMB is proposed to predict RFS in melanoma patients with adjuvant anti-PD-1 therapy., (© 2022. The Author(s).)

Purpose: Ipilimumab and nivolumab have each shown treatment benefit for high-risk resected melanoma. The phase III CheckMate 915 trial evaluated adjuvant nivolumab plus ipilimumab versus nivolumab alone in patients with resected stage IIIB-D or IV melanoma., Patients and Methods: In this randomized, double-blind, phase III trial, 1,833 patients received nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks (916 patients) or nivolumab 480 mg once every 4 weeks (917 patients) for ≤ 1 year. After random assignment, patients were stratified by tumor programmed death ligand 1 (PD-L1) expression and stage. Dual primary end points were recurrence-free survival (RFS) in randomly assigned patients and in the tumor PD-L1 expression-level < 1% subgroup., Results: At a minimum follow-up of approximately 23.7 months, there was no significant difference between treatment groups for RFS in the all-randomly assigned patient population (hazard ratio, 0.92; 95% CI, 0.77 to 1.09; P = .269) or in patients with PD-L1 expression < 1% (hazard ratio, 0.91; 95% CI, 0.73 to 1.14). In all patients, 24-month RFS rates were 64.6% (combination) and 63.2% (nivolumab). Treatment-related grade 3 or 4 adverse events were reported in 32.6% of patients in the combination group and 12.8% in the nivolumab group. Treatment-related deaths were reported in 0.4% of patients in the combination group and in no nivolumab-treated patients., Conclusion: Nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks did not improve RFS versus nivolumab 480 mg once every 4 weeks in patients with stage IIIB-D or stage IV melanoma. Nivolumab showed efficacy consistent with previous adjuvant studies in a population resembling current practice using American Joint Committee on Cancer eighth edition, reaffirming nivolumab as a standard of care for melanoma adjuvant treatment.

Background: Primary analysis of the phase 3 IMspire150 study showed improved investigator-assessed progression-free survival with first-line atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAF V600 mutation-positive melanoma. With a median follow-up of 18·9 months (IQR 10·4-23·8) at the primary analysis, overall survival data were immature. Here, we report the results from the second, prespecified, interim overall survival analysis., Methods: The multicentre, double-blind, placebo-controlled, randomised, phase 3 IMspire150 study was done at 108 academic and community hospitals in 20 countries. Patients aged 18 years or older with previously untreated unresectable stage IIIc or stage IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients were randomly assigned (1:1) to receive either atezolizumab (840 mg intravenously on day 1 and 15) or placebo plus vemurafenib (960 mg or 720 mg twice daily orally) and cobimetinib (60 mg once daily orally; 21 days on and 7 days off) in 28-day cycles. Atezolizumab and placebo were added to treatment regimens from cycle two onwards. Randomisation was done centrally (Durham, NC, USA) based on a permuted block randomisation scheme (block size of 4) using an interactive web-based response system and was stratified by geographical region and baseline lactate dehydrogenase concentration. Overall survival was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug according to actual treatment received. The primary endpoint was investigator-assessed progression-free survival, which was previously reported. Here, we report the second, prespecified, interim overall survival analysis, which was planned after about 270 overall survival events had occurred. The trial is ongoing, but is no longer enrolling patients, and it is registered with ClinicalTrials.gov, NCT02908672., Findings: Between Jan 13, 2017, and April 26, 2018, 514 patients (median age 54 years [IQR 43-63]; 299 [58%] men and 215 [42%] women) were enrolled in the trial and randomly assigned to the atezolizumab group (256 [50%] patients) or the control group (258 [50%] patients). At the data cutoff (Sept 8, 2021), 273 patients had died (126 in the atezolizumab group and 147 in the control group). Median follow-up was 29·1 months (IQR 10·1-45·4) for the atezolizumab group versus 22·8 months (10·6-44·1) for the control group. Median overall survival was 39·0 months (95% CI 29·9-not estimable) in the atezolizumab group versus 25·8 months (22·0-34·6) in the control group (HR 0·84 [95% CI 0·66-1·06]; p=0·14). The most common adverse events of any grade in the atezolizumab group were blood creatine phosphokinase increased (123 [53%] of 231 patients), diarrhoea (116 [50%]), and pyrexia (115 [50%]). The most common adverse events of any grade in the control group were diarrhoea (157 [56%] of 280 patients), blood creatine phosphokinase increased (135 [48%]), and rash (119 [43%]). The most common grade 3-4 adverse events were increased lipase (54 [23%] of 231 patients in the atezolizumab group vs 62 [22%] of 280 patients in the control group), increased blood creatine phosphokinase (51 [22%] vs 50 [18%]), and increased alanine aminotransferase (32 [14%] vs 26 [9%]). Serious adverse events were reported in 112 (48%) patients in the atezolizumab group and 117 (42%) patients in the control group. Grade 5 adverse events were reported in eight (3%) patients in the atezolizumab group versus six (2%) patients in the control group. Two grade 5 adverse events (hepatitis fulminant and hepatic failure) in the atezolizumab group were considered to be associated with the triplet combination, and one event in the control group (pulmonary haemorrhage) was considered to be associated with cobimetinib., Interpretation: Additional follow-up of the IMspire150 trial showed that overall survival was not significantly improved with atezolizumab, vemurafenib, and cobimetinib compared with placebo, vemurafenib, and cobimetinib in patients with BRAF V600 mutation-positive advanced melanoma. Results of the final analysis are awaited to establish whether a significant improvement in overall survival can be achieved with long-term treatment with this triplet combination versus vemurafenib plus cobimetinib., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests PAA reports grants from Bristol Myers Squibb, Roche/Genentech, Pfizer/Array, and Sanofi; consulting fees from Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre Fabre, Sun Pharma, Sanofi, Idera, Sandoz, 4SC, Italfarmaco, Nektar, Pfizer/Array, Lunaphore, Medicenna, Bio-Al Health, ValoTx, and Replimmune; travel support from Pfizer; and advisory board member for Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, AstraZeneca, Immunocore, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, and iTeos. HG reports honoraria from Bristol Myers Squibb, MSD Oncology, Pierre Fabre, and Sanofi/Regeneron; research funding from Bristol Myers Squibb, Roche, MSD Oncology, Amgen, Novartis, and Iovance Biotherapeutics; travel, accommodation, and expenses from Bristol Myers Squibb, Merck Sharp & Dohme, Amgen, and Pfizer; and a consulting or advisory role for Bristol Myers Squibb, MSD Oncology, Amgen, Pierre Fabre, and Sanofi/Regeneron. CR reports consulting fees from Roche, Novartis, Pierre Fabre, MSD, Bristol Myers Squibb, Sanofi, Pfizer, and AstraZeneca; and payment or honoraria from Roche, Novartis, Pierre Fabre, MSD, Bristol Myers Squibb, Sanofi, Pfizer, and AstraZeneca. KL reports honoraria from Array Biopharma and Iovance Biotherapeutics; a consulting or advisory role for Array Biopharma, Iovance Biotherapeutics, Merck, Nektar, Regeneron, Roche, and Sanofi; research funding from Alkermes, Amgen, Array Biopharma, Bristol Myers Squibb, Incyte, Iovance Biotherapeutics, Kartos Therapeutics, Merck, Nektar, Neon Therapeutics, OncoSec, Regeneron, Replimune, Roche/Genentech, Seagen, Senhwa Biosciences, and Ultimovacs; and travel, accommodations, or expenses from Alkermes, Merck, Neon Therapeutics, Regeneron, and Roche/Genentech. SP reports honoraria from Biocad, Roche, Bristol Myers Squibb, and Merck Sharp & Dohme; speakers bureau for Biocad, Roche, Bristol Myers Squibb, and Merck Sharp & Dohme; and research funding from Roche, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers Squibb, and Biocad. RPP reports speakers bureau for Roche and Bristol Myers Squibb and research funding from Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Bayer, and AstraZeneca. TE reports a consulting or advisory role for Bristol Myers Squibb/Medarex, Sanofi/Regeneron, Novartis, and Pierre Fabre and speakers bureau for Almirall Hermal. PR reports honoraria from Bristol Myers Squibb, MSD, Novartis, Roche, Pfizer, Pierre Fabre, Sanofi, and Merck; speaker's bureau for Pfizer, Novartis, and Pierre Fabre; consulting fee from Blueprint Medicines, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, and Philogen; research funding from Bristol Myers Squibb, Novartis, and Roche; and travel, accommodations, or expenses from Orphan Europe and Pierre Fabre. LD reports honoraria from Roche, Merck Sharp & Dohme, Bristol Myers Squibb, and Novartis and research funding from Roche, Merck Sharp & Dohme, Bristol Myers Squibb, Novartis, and Amgen. NZ reports honoraria from Roche, Novartis, Bristol Myers Squibb/Celgene, MSD Oncology, and AstraZeneca/Merck; consulting fees from Roche, MSD Oncology, Merck; and travel and accommodation expenses from MSD Oncology and Roche. JS reports a consultant or advisory role for Merck Sharp & Dohme and Bristol Myers Squibb. YY and IC report employment with Genentech and stock or other ownership with Roche/Genentech. CH and CX report employment with Roche. LK reports employment and ownership non-voting shares for Roche. GAM reports research funding to his institution from Genentech/Roche and Bristol Myers Squibb. RG reports honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, Novartis, Merck Serono, Almirall Hermal, Amgen, Sun Pharma, Pierre Fabre, Sanofi/Regeneron, and Immunocore; a consulting or advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, Novartis, Almirall Hermal, 4SC, Amgen, Pierre Fabre, Merck Serono, Sun Pharma, Sanofi, and Immunocore; research funding from Pfizer, Novartis, Johnson & Johnson, Amgen, Merck Serono, Sun Pharma, and Sanofi; and travel, accommodations, or expenses from Bristol Myers Squibb, Roche, Merck Serono, Pierre Fabre, and Sun Pharma. DS declares no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Digitally stained ex vivo confocal laser scanning microscopy (CLSM) scans are a possible alternative to formalin-fixed and paraffin-embedded (FFPE) and hematoxylin-eosin (H&E) stained slides. This study explores the diagnostic accuracy of digitally-stained CLSM scans in comparison to H&E-stained slides in various dermatologic diseases in a real-life setting., Methods: Samples of patients out of one selected dermatologic office were primarily scanned via CLSM; a diagnosis was made afterwards using FFPE- and H&E-stained slides by two experienced dermatopathologists. Primary outcomes were sensitivity and specificity of diagnosis in digitally stained CLSM scans in three separate diagnostic groups., Results: CLSM evaluation of epithelial tumors (n = 132) demonstrated a sensitivity of 64.3%/83.9% and a specificity of 84.2%/71.1%. Diagnosis of melanocytic tumors (n = 86) showed a sensitivity of 19.1%/85.1% and a specificity of 96.3%/66.7%. In the diagnosis of other tumors/cysts and inflammatory dermatoses (n = 42), a sensitivity of 96.4%/96.8% and a specificity of 57.1%/45.5% was reached., Conclusions: This study shows the possibilities and limitations of a broad use of CLSM. Because of a partly low diagnostic accuracy, such an application does not seem to be recommendable at present for every indication., Competing Interests: H.O.: no conflicts of interest. M.M.: Mavic provide a Vivascope microscope for the duration of the study. In the past, M.M. had performed studies with previous models of Vivascopes (Mavig) and HistologTMScanner (SamanTree Medical SA). G.M: no conflicts of interest. T.E.: declares speakers and advisory board honoraria from Almirall Hermal, Merck Sharp & Dome, Immunocore, Novartis, Sanofi Genzyme, Roche, Pierre Fabre and BMS. A.-K.M: no conflicts of interest. S.F: received personal fees from Kyowa Kirin and Takeda Pharamceuticals (speakers honoraria) as well as institutional grants from NeraCare, SkylineDX and BioNTech outside the submitted work.

Background: Macrophages are an important component of the innate immune system. They are abbreviated as Mφ, MΦ, or MP. The name is derived from Greek: large eaters, μακρóς (makrós) = large, φαγεῖν (phagein) = to eat, because they engulf and digest pathogens. Tumor-associated macrophages (TAMs) are associated with drug resistance in cancers, including melanoma, and targeting them may improve cancer treatment., Objectives: The purpose of this article is to examine the role of TAMs in cancer, particularly in melanoma. The relationship between TAM and treatment resistance and their potential application in the treatment of melanoma are discussed., Materials and Methods: A literature search in PubMed and Google Scholar databases for TAM and melanoma was performed. Clinical trials were searched via clinicaltrials.gov and graphical representations were created using BioRender., Results: In melanoma, macrophages are among the most abundant immune cells in the tumor microenvironment (TME). TAMs are associated with poor prognosis and resistance. They are involved in tumorigenesis and metastasis development. M2 is the predominant type of TAM and the M2 markers CD163 and CD204 are unfavorable prognostic biomarkers. Therapeutic approaches aim to decrease their recruitment, modulate their function, or reprogram them. Treatment using chimeric antigen receptor (CAR)-M cells and nanoparticles are currently being investigated. Drugs being tested for melanoma include signal transducer and activator of transcription 3 (STAT3) inhibitors, macrophage colony-stimulating factor (M-CSF) antagonists, interferons (IFN), talimogene laherparepvec (TVEC), histone deacetylase (HDAC) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, colony-stimulating factor 1 receptor (CSF-1R) antagonists, CD40 agonists, arginase 1 (ARG-1) inhibitors, and phosphoinositide 3‑kinase γ (PI3K-γ) inhibitors., Conclusions: TAMs participate in developing resistance to current melanoma therapies. Treatment directed against them may help reduce the development of resistance and improve survival., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

The global incidence of skin cancer has steadily increased in recent years, and malignant melanoma still has one of the fastest-growing incidence rates among all malignant tumors in the western world. Thus, newly diagnosed patients have an increased need for health information concerning their disease. Using a standardized questionnaire, our study aims to investigate our patients' primary sources of health-related information as well as their self-proclaimed eHealth literacy. We received 714 questionnaires. Regardless of age, the primary source of information was the treating dermato-oncologist, followed by the treating general practitioner and the Internet. However, with increasing age, the usage of the Internet decreased. Hence, younger participants were better equipped to find health-related information while using the Internet. Additionally, comprehending health-related information and gaining medical knowledge was significantly increased in better-educated participants. Overall, our study shows that with increased use of eHealth services, accessing web-based information increased, correlating with a better eHealth literacy of our patients. eHealth technologies are increasingly becoming more prevalent as a primary source of information in our modern health care system. Thus, it is crucial to educate cancer patients in eHealth literacy to make autonomous, informed decisions and gain more confidence in dealing with their disease.

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX + CD8 + T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration., Competing Interests: Declaration of interests B.I. has received honoraria from consulting with Merck, Janssen Pharmaceuticals, Astra Zeneca, and Volastra Therapeutics. M.A.D. has been a consultant to Roche/Genentech, Array, Pfizer (New York, NY, United States of America), Novartis, BMS, GSK, Sanofi-Aventis (Bridgewater, NJ, United States of America), Vaccinex, Apexigen, EISAI, and ABM Therapeutics and he has been the PI of research grants to MD Anderson by Roche/Genentech (South San Francisco, CA, United States of America), GSK, Sanofi-Aventis, Merck, Myriad, and Oncothyreon. A.R. has received honoraria from consulting with CStone, Merck, and Vedanta, is or has been a member of the scientific advisory board and holds stock in Advaxis, Appia, Apricity, Arcus, Compugen, CytomX, Highlight, ImaginAb, ImmPact, ImmuneSensor, Inspirna, Isoplexis, Kite-Gilead, Lutris, MapKure, Merus, PACT, Pluto, RAPT, Synthekine, and Tango, has received research funding from Agilent (Santa Clara, CA, United States of America) and from Bristol-Myers Squibb through Stand Up to Cancer (SU2C), and patent royalties from Arsenal Bio. T.E. has acted as a consultant for Almiral Hermal, Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre, and Sanofi. E.Z.M. is a consultant for Curio Bioscience. The other authors do not declare competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: This study investigated whether a machine-learning-based combination of radiomics and clinical parameters was superior to the use of clinical parameters alone in predicting therapy response after three months, and overall survival after six and twelve months, in stage-IV malignant melanoma patients undergoing immunotherapy with PD-1 checkpoint inhibitors and CTLA-4 checkpoint inhibitors., Methods: A random forest model using clinical parameters (demographic variables and tumor markers = baseline model) was compared to a random forest model using clinical parameters and radiomics (extended model) via repeated 5-fold cross-validation. For this purpose, the baseline computed tomographies of 262 stage-IV malignant melanoma patients treated at a tertiary referral center were identified in the Central Malignant Melanoma Registry, and all visible metastases were three-dimensionally segmented ( n = 6404)., Results: The extended model was not significantly superior compared to the baseline model for survival prediction after six and twelve months (AUC (95% CI): 0.664 (0.598, 0.729) vs. 0.620 (0.545, 0.692) and AUC (95% CI): 0.600 (0.526, 0.667) vs. 0.588 (0.481, 0.629), respectively). The extended model was not significantly superior compared to the baseline model for response prediction after three months (AUC (95% CI): 0.641 (0.581, 0.700) vs. 0.656 (0.587, 0.719))., Conclusions: The study indicated a potential, but non-significant, added value of radiomics for six-month and twelve-month survival prediction of stage-IV melanoma patients undergoing immunotherapy.

Background: The phase III IMspire150 study (NCT02908672) demonstrated significantly improved progression-free survival (PFS) with atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAF V600 -mutated advanced melanoma. We report exploratory biomarker analyses to optimize targeting of patients who are more likely to benefit from triplet combination therapy., Patients and Methods: Five hundred fourteen patients were randomized to atezolizumab (n = 256) or control (n = 258). Outcomes were evaluated in subgroups defined by key biomarkers, including programmed death-ligand 1 (PD-L1) expression, lactate dehydrogenase (LDH) level, tumor mutational burden (TMB), and interferon-γ (IFN-γ) gene signature. Exploratory recursive partitioning analysis was then used to model associations between PFS and baseline covariates, including key biomarkers., Results: PFS benefit for atezolizumab versus control was greater in patients with high TMB [≥10 mutations/Mb; hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.52-1.02; P = 0.067] versus low TMB (<10 mutations/Mb; HR 0.92; 95% CI 0.65-1.30; P = 0.64) and similar between patients with strong IFN-γ (≥median; HR 0.76; 95% CI 0.54-1.06) versus weak IFN-γ (

Background: Patients with hepatic metastatic uveal melanoma still have a poor outcome., Purpose: To evaluate overall survival (OS), progression-free survival (PFS), and response predictors in these patients treated with chemosaturation by percutaneous hepatic perfusion with melphalan (CS-PHP)., Material and Methods: Between June 2015 and March 2020, a total of 29 patients (median age 69.7 years; age range 30-81 years; 60% women; median BMI 25.7 kg/m 2 ; range 18.7-35.3kg/m 2 ; 1-6 procedures per patient) were treated with 53 CS-PHPs. All patients received cross-sectional imaging for initial and follow-up examinations. Baseline tumor load, extrahepatic tumor load, tumor response, PFS, and OS were assessed. Non-parametric statistics were used., Results: After the initial CS-PHP, a partial response was observed in 11 patients (41%), stable disease in 12 patients (44%) and progressive disease in 4 patients (15%); two patients died before the response was evaluated. After initial CS-PHP, median OS was 12.9 ± 7.4 months and median PFS was 7.1 ± 7.4 months. OS after one year was 50%. After the second CS-PHP, median PFS was 7.9 ± 5.7 months. Seven patients had a liver tumor burden >25%, associated with a significantly shorter OS (6.0 ± 2.4 vs. 14.1 ± 12.7 months; P  = 0.008). At the time of first CS-PHP, 41% (12/29) of the patients had extrahepatic metastases that did not affect OS (11.1 ± 8.4 months vs. 12.9 ± 13.6 months; P  = 0.66)., Conclusion: CS-PHP is a safe and effective treatment for the hepatic metastatic uveal melanoma, especially for patients with a hepatic tumor burden <25%.

Background: The increasing number of melanoma patients makes it necessary to establish new strategies for prognosis assessment to ensure follow-up care. Deep-learning-based image analysis of primary melanoma could be a future component of risk stratification., Objectives: To develop a risk score for overall survival based on image analysis through artificial intelligence (AI) and validate it in a test cohort., Methods: Hematoxylin and eosin (H&E) stained sections of 831 melanomas, diagnosed from 2012-2015 were photographed and used to perform deep-learning-based group classification. For this purpose, the freely available software of Google's teachable machine was used. Five hundred patient sections were used as the training cohort, and 331 sections served as the test cohort., Results: Using Google's Teachable Machine, a prognosis score for overall survival could be developed that achieved a statistically significant prognosis estimate with an AUC of 0.694 in a ROC analysis based solely on image sections of approximately 250 × 250 µm. The prognosis group "low-risk" ( n = 230) showed an overall survival rate of 93%, whereas the prognosis group "high-risk" ( n = 101) showed an overall survival rate of 77.2%., Conclusions: The study supports the possibility of using deep learning-based classification systems for risk stratification in melanoma. The AI assessment used in this study provides a significant risk estimate in melanoma, but it does not considerably improve the existing risk classification based on the TNM classification.

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.

Background: Perusal of the literature of cutaneous squamous cell carcinoma (SCC) reveals that the role of the desmoplastic subtype is indistinct. Data on local infiltration and recurrence are inconsistent dependent on surgical technique, histological method, and investigated collective., Objective: The aim of the study was to analyze local infiltration and locoregional recurrence of the desmoplastic subtype under a uniform procedure., Methods and Materials: Between 2005 and 2015, 320 SCCs were analyzed and histological sections of all tumors were examined. Data collection included locoregional recurrence, metastasis rate, and tumor-specific death. The median follow-up was 36.5 months., Results: The desmoplastic subtype required significant more re-excisions (70.0% vs 23.9%, p < .001), more interventions until tumor-free margins were achieved (maximal 6 vs 2; p < .001), showed more widespread tumor infiltration with larger excisional margins (median 9 mm, 2-51 mm vs median 4 mm, 1-10 mm; p < .001), and a 5-fold higher local recurrence rate (26.7% vs 5.0%, p < .001). The metastasis rate (16.6% vs 2.3%, p < .001) was increased., Conclusion: The desmoplastic subtype is characterized by a widespread local infiltration associated with perineural infiltration. It seems to be a marker for decreased histological detectability with a high rate of locoregional recurrence and metastasis., (Copyright © 2022 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Advanced cutaneous squamous cell carcinoma is a challenge to treat. Conventional systemic treatment options include chemotherapy and epidermal growth factor receptor-inhibitors. The aim of this study was to assess clinical outcomes with systemic treatments in advanced cutaneous squamous cell carcinoma. Patients receiving systemic treatment at the Tübingen Dermato-Oncology centre between 2007 and 2017 were identified (n = 59). Median age was 76 years (interquartile range (IQR) 71-80 years), 83.1% of patients were male, 72.9% had metastatic cutaneous squamous cell carcinoma, and 27.1% had unresectable locally advanced cutaneous squamous cell carcinoma. During median follow-up of 52 weeks (IQR 27-97 weeks), overall response rate was 14.3%, and disease control rate was 53.6%. Median progression-free survival was 15 weeks (IQR 8-42 weeks), and median overall survival was 52 weeks (IQR 27-97 weeks). Patients receiving chemoradiation vs chemotherapy alone showed better overall survival (hazard ratio 0.41, p = 0.014,) and progression-free survival (hazard ratio 0.42, p = 0.009); no differences were observed for metastatic cutaneous squamous cell carcinoma vs locally advanced cutaneous squamous cell carcinoma patients. Although chemotherapy and/or cetuximab showed limited outcomes in advanced cutaneous squamous cell carcinoma, such therapy may still be an option when anti-PD-1 treatment is contraindicated.

Background: Based on its viral-associated or UV-associated carcinogenesis, Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer. Thus, clinically evident MCC occurs either in immuno-compromised patients or based on tumor-intrinsic immune escape mechanisms. This notion may explain that although advanced MCC can be effectively restrained by treatment with PD-1/PD-L1 immune checkpoint inhibitors (ICIs), a considerable percentage of patients does not benefit from ICI therapy. Biomarkers predicting ICI treatment response are currently not available., Methods: The present multicenter retrospective study investigated clinical and molecular characteristics in 114 patients with unresectable MCC at baseline before treatment with ICI for their association with therapy response (best overall response, BOR). In a subset of 21 patients, pretreatment tumor tissue was analyzed for activation, differentiation and spatial distribution of tumor infiltrating lymphocytes (TIL)., Results: Of the 114 patients, n=74 (65%) achieved disease control (BOR=complete response/partial response/stable disease) on ICI. A Bayesian cumulative ordinal regression model revealed absence of immunosuppression and a limited number of tumor-involved organ systems was highly associated with a favorable therapy response. Unimpaired overall performance status, high age, normal serum lactate dehydrogenase and normal serum C reactive protein were moderately associated with disease control. While neither tumor Merkel cell polyomavirus nor tumor PD-L1 status showed a correlation with therapy response, treatment with anti-PD-1 antibodies was associated with a higher probability of disease control than treatment with anti-PD-L1 antibodies. Multiplexed immunohistochemistry demonstrated the predominance of CD8 + effector and central memory T cells (T CM ) in close proximity to tumor cells in patients with a favorable therapy response., Conclusions: Our findings indicate the absence of immunosuppression, a limited number of tumor-affected organs, and a predominance of CD8 + T CM among TIL, as baseline parameters associated with a favorable response to PD-1/PD-L1 ICI therapy of advanced MCC. These factors should be considered when making treatment decisions in MCC patients., Competing Interests: Competing interests: 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, Novartis and Roche, and travel support from Bristol Myers Squibb, and Merck Sharp & Dohme. LZ served as consultant and/or has received honoraria from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, and Sanofi; Research funding to institution: Novartis; travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, and Novartis, outside the submitted work. PT declares invited speaker's honoraria from Bristol-Myers Squibb, Novartis, MSD, Pierre-Fabre, CureVac, Roche, Kyowa Kirin, Biofrontera, advisory board honoraria from Bristol-Myers Squibb, Novartis, Pierre-Fabre, Merck Serono, Sanofi, Roche, Kyowa Kirin, and travel support from Bristol-Myers Squibb, and Pierre-Fabre. UL declares advisory board honoraria from MSD, Roche, Sanofi, Novartis, Sun Pharma, Almirall Hermal. TE declares consulting fees from BMS, Novartis, Roche, Pierre Fabre, Sanofi; board membership and payment for lectures in speakers bureau from Pierre Fabre, MSD, Roche, BMS, Novartis and Sanofi. CL reports advisory board honoraria from MSD, BMS, Roche, Pierre Fabre, Novartis, Sun Pharma, Sanofi, Kyowa Kirin, Almiral Hermal, Biontech, Merc; speakers fee from MSD, BMS, Roche, Pierre Fabre, Novartis, Sun Pharma, Sanofi, Merck; travel reimbusment from MSD, BMS, Roche, Pierre Fabre, Novartis, Sun Pharma, Sanofi, Kyowa Kirin, Almiral Hermal, Biontech and Merck. JCH declares research support from Bristol Myers Squibb; advisory board honoraria from Pierre Fabre, Sanofi, Sun Pharma and Merck Sharp & Dome; speakers honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, Sanofi and Almirall and travel support from Pierre Fabre. TG reports receiving speakers and/or advisory board honoraria from BMS, Sanofi-Grenzyme, MSD, Novartis Pharma, Roche, Abbvie, Almirall, Janssen Lilly, Pfizer, Pierre Fabre; speakers and/or advisory board honoraria from BMS, Sanofi-Grenzyme, MSD, Novartis, Pharma, Roche, Abbvie, Almirall, Janssen Lillly, Pfizer, Pierre Fabre. SH declares advisory boards honoraria from Pierre Fabre, MSD, BMS, Novartis, Sanofi. PM reports board membership and payment for lectures in speakers bureau from Pierre Fabre, GSK, MSD, Merck Germany, Roche, BMS, Novartis, Sanofi. P. Mohr reports research support (to institution): Bristol-MyersSquibb, Novartis, MSD. Honoraria for lectures (personally): Pierre Fabre, GSK, MSD, Merck Germany, Roche, BMS, Novartis, Sanofi, Amgen, SUN-Pharma, Roche Pharma, Bristol-MyersSquibb, Novartis, MSD, Almirall-Hermal, Amgen, Merck-Serono, Bayer, Pierre-Fabre, Sanofi. Honoraria for advisory boards: Pierre Fabre, GSK, MSD, Merck Germany, Roche, BMS, Novartis, Sanofi, Beiersdorf, Almiral-Hermal, AmgenBayersdorf, Roche Pharma, Bristol-MyersSquibb, Novartis, MSD, Almirall-Hermal, Amgen, Pierre-Fabre, Merck-Serono, SUN-Pharma, SUN, Merck-Serono, Sanofi. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from Novartis, BMS, Roche, Merck Serono, MSD, Celgene, AbbVie, AMGEN, SUNPHARMA, Allergy Therapeutics and LEO. LMH served as consultant and/or has received honoraria from Amgen, BMS, Curevac, MSD, Novartis, Pierre-Fabre, Roche, Sanofi and Sun Pharma, outside the submitted work. Research funding to institution: Novartis. R. Gutzmer reports research support from Pfizer, Johnson & Johnson, Novartis, Amgen, MerckSerono, SUN Pharma; honoraria for lectures from Roche Pharma, Bristol-MyersSquibb, Novartis, MSD, Almirall-Hermal, Amgen, Merck-Serono, SUN, Pierre-Fabre, Sanofi, SUN Pharma, Bayer; honoraria for advice from Roche Pharma, Bristol-MyersSquibb, Novartis, MSD, Almirall-Hermal, Amgen, Pierre-Fabre, Merck-Serono, 4SC, Incyte, SUN Pharma, Sanofi, Pfizer. JSU is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi outside the submitted work. H-US is an employee of Targos Molecular Pathology Inc. and reports research support from Novartis Oncology and received honoraria from MSD, BMS, Roche Pharma, Novartis Oncology, AstraZeneca, Eisai, Takeda, Molecular Health, outside of the submitted work. DS reports personal fees from Amgen, GSK, BMS, Novartis, Roche, Merck, Astra Zeneca, Merck-Serono, Pfizer, Incyte, Array Pierre Fabre, Sanofi Genzyme, Regeneron, 4Sc, InFlaRx, Neracare, Ultimovacs, SunPharma, Philogen, Immunocore, Sandoz-Hexal outside the submitted work. JCB is receiving speaker's bureau honoraria from Amgen, Pfizer, MerckSerono, Recordati and Sanofi; is a paid consultant/advisory board member/DSMB member for Almirall, Boehringer Ingelheim, InProTher, ICON, MerckSerono, Pfizer, 4SC, and Sanofi/Regeneron. His group receives research grants from Bristol-Myers Squibb, Merck Serono, HTG, IQVIA, and Alcedis., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To assess the additive value of dual-energy CT (DECT) over single-energy CT (SECT) to radiomics-based response prediction in patients with metastatic melanoma preceding immunotherapy., Material and Methods: A total of 140 consecutive patients with melanoma (58 female, 63±16 years) for whom baseline DECT tumor load assessment revealed stage IV and who were subsequently treated with immunotherapy were included. Best response was determined using the clinical reports (81 responders: 27 complete response, 45 partial response, 9 stable disease). Individual lesion response was classified manually analogous to RECIST 1.1 through 1291 follow-up examinations on a total of 776 lesions (6.7±7.2 per patient). The patients were sorted chronologically into a study and a validation cohort (each n=70). The baseline DECT was examined using specialized tumor segmentation prototype software, and radiomic features were analyzed for response predictors. Significant features were selected using univariate statistics with Bonferroni correction and multiple logistic regression. The area under the receiver operating characteristic curve of the best subset was computed (AUROC). For each combination (SECT/DECT and patient response/lesion response), an individual random forest classifier with 10-fold internal cross-validation was trained on the study cohort and tested on the validation cohort to confirm the predictive performance., Results: We performed manual RECIST 1.1 response analysis on a total of 6533 lesions. Multivariate statistics selected significant features for patient response in SECT (min. brightness, R²=0.112, padj. ≤0.001) and DECT (textural coarseness, R²=0.121, padj. ≤0.001), as well as lesion response in SECT (mean absolute voxel intensity deviation, R²=0.115, padj. ≤0.001) and DECT (iodine uptake metrics, R²≥0.12, padj. ≤0.001). Applying the machine learning models to the validation cohort confirmed the additive predictive power of DECT (patient response AUROC SECT=0.5, DECT=0.75; lesion response AUROC SECT=0.61, DECT=0.85; p<0.001)., Conclusion: The new method of DECT-specific radiomic analysis provides a significant additive value over SECT radiomics approaches for response prediction in patients with metastatic melanoma preceding immunotherapy, especially on a lesion-based level. As mixed tumor response is not uncommon in metastatic melanoma, this lends a powerful tool for clinical decision-making and may potentially be an essential step toward individualized medicine., Competing Interests: Competing interests: All authors declare no conflict of interest for this study. SF and AFC are employees of Siemens Healthcare and had no control over the data., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)