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Background: Presence of micrometastases in the sentinel lymph node (SLN) is currently used to assess prognosis of melanoma patients. The immunoactivity within the SLN is known to be influenced by the primary tumor (PT), which may in turn impact the SLNs' metastatic state., Aim: We characterize the temporal dependence and underlying mechanisms of the immunological effects of the PT on the SLN., Methods: The prognostic value of SLN state as a function of PT removal time was evaluated. To put the results into a functional context, selected PTs and corresponding SLNs were analyzed for gene and protein expression patterns., Results: In a cohort of 202 patients with known distant metastasis and similar PT prognostic characteristics, SLNs removed before or within one week after the PT (IM-SLN) had a higher incidence of micrometastases than those removed at least one week after the PT (DEL-SLN). The immunoactivity in IM-SLN was found to be lower than in DEL-SLN. Specifically, in IM-SLNs, T helper 17 / regulatory T-cells were predominant, whereas in DEL-SLNs, cytotoxic γδT-cells were more frequent. The higher immune activity in DEL-SLNs was probably facilitated by CD209 + antigen-presenting cells. Indeed, in PT with high TGFβ expression CD209 + cells appear to be trapped and no increased immunoactivity was observed in DEL-SLN., Conclusions: Presence of micrometastases in DEL-SLNs have a higher negative prognostic value as in IM-SLNs since they indicate not only a melanoma's propensity to metastasize, but possibly also its capacity to escape immune responses., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. VKD received a research grant, honoraria for talks and travel support from SUN Pharma. CR is employed by Merck Serono. TG reports receiving speakers and/or advisory board honoraria from BMS, Sanofi-Genzyme, MSD, Novartis Pharma, Roche, Abbvie, Almirall, Janssen, Lilly, Pfizer, Pierre Fabre, outside the submitted work. SH has acted as a consultant and / or received travel assistance from BMS, Kyowa Kirin. RG received honoraria as speaker from BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre-Fabre, as advisory board member from BMS, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi, Pierre-Fabre, 4SC, MerckSerono, Pfizer, Immunocore, Delcath, for meeting support from SUN, Pierre-Fabre, Boehringer Ingelheim and for research projects (to institution) from Novartis, Pfizer, Johnson & Johnson, Amgen, Merck-Serono, SUN Pharma, Sanofi, Kyowa-Kirin, Admiral-Hermal. 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, Merck Sharp & Dohme, and Pierre Fabre. JCB is receiving speaker’s bureau honoraria from Amgen, Pfizer, Sanofi, and Sun Pharma, is a paid consultant/advisory board member/DSMB member for Almirall, Boehringer Ingelheim, ICON, MerckSerono, Pfizer, and Sanofi. His group receives research grants from Merck Serono, IQVIA, and Alcedis. The other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Immune checkpoint inhibition (ICI) currently is the most effective treatment to induce durable responses in metastatic melanoma. The aims of this study are the characterization of patients with early, late and non-response to ICI and analysis of survival outcomes in a real-world patient cohort., Methods: Patients who received PD-1-based immunotherapy for non-resectable stage-IV melanoma in any therapy line were selected from the prospective multicenter real-world DeCOG study ADOREG-TRIM (NCT05750511). Patients showing complete (CR) or partial (PR) response already during the first 3 months of treatment (Early Responders, EarlyR) were compared to patients showing CR/PR at a later time (Late Responders, LateR), a stable disease (SD) and to patients showing progressive disease (Non-Responders, NonR)., Results: Of 522 patients, 8.2 % were EarlyR (n = 43), 19.0 % were LateR (n = 99), 37.0 % had a SD (n = 193) and 35.8 % were NonR (n = 187). EarlyR, LateR and SD patients had comparable baseline characteristics. Multivariate logbinomial regression analyses adjusted for age and sex revealed positive tumor PD-L1 (RR=1.99, 95 %-CI=1.14-3.46, p = 0.015), and normal serum CRP (RR=1.59, 95 %-CI=0.93-2.70, p = 0.036) as independently associated with the achievement of an early response compared to NonR. The median progression-free and overall survival was 46.0 months (95 % CI 19.1; NR) and 47.8 months (95 %-CI 36.9; NR) for EarlyR, NR (95 %-CI NR; NR) for LateR, 8.1 months (7.0; 10.4) and 35.4 months (29.2; NR) for SD, and 2.0 months (95 %-CI 1.9; 2.1) and 6.1 months (95 %-CI 4.6; 8.8) for NonR patients., Conclusion: Less than 10 % of metastatic melanoma patients achieved an early response during the first 3 months of PD-1-based immunotherapy. Early responders were not superior to late responders in terms of response durability and survival., Competing Interests: Declaration of Competing Interest GCL received travel support from Sun Pharma, Pierre Fabre, research funding from Novartis. RH is employee of Helios Kliniken GmbH. PT has received honoraria from Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Pierre Fabre, CureVac, Merck Serono, Sanofi, Roche, Kyowa Kirin and Biofrontera; and travel support from Bristol-Myers Squibb and Pierre Fabre. JU received honoraria (speaker honoraria or honoraria as a consultant) and travel support from Bristol-Myers Squibb, Kyowa Kirin, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi/Regeneron, Sunpharma outside the submitted work. 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. 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. AK served as a speaker and/or consultant and/or advisory board for MSD, AbbVie, Boehringer Ingelheim, Janssen, and Sanofi. PM declares research support from Bristol Myers Squibb, Merck Sharp & Dohme and Novartis; speakers and advisory board honoraria from Bristol Myers Squibb, Beiersdorf, Merck Sharp & Dohme, Pierre Fabre, Sun Pharma, Immunocore, Sanofi and Novartis, and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Sanofi, Sun Pharma, and Pierre Fabre, outside the submitted work. RG received honoraria as speaker from BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi/Regeneron, Pierre-Fabre, as advisory board member from BMS, Novartis, Almirall Hermal, MSD, Amgen, SUN, Sanofi/Regeneron, Pierre-Fabre, 4SC, MerckSerono, Pfizer, Immunocore, Delcath, for meeting support from SUN, Pierre-Fabre, Boehringer Ingelheim and for research projects (to institution) from Amgen, Merck-Serono, SUN Pharma, Sanofi/Regeneron, Kyowa-Kirin, Almirall-Hermal. FM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD, Pierre Fabre, Sanofi and Immunocore and research funding from Novartis and Roche. MW received grants from Bristol-Myers Squibb and Merck Sharp & Dohme, consulting fees from Merck Sharp & Dohme, Immunocore and Novartis, lecture honoraria from Bristol-Myers Squibb and Merck Sharp & Dohme and Pierre-Fabre, and advisory board honoraria from Merck Sharp & Dohme. AP reports grants from Bristol Myers Squibb (BMS) and Merck Sharp & Dohme (MSD) outside the submitted work. JCB is receiving speaker’s bureau honoraria from Amgen, Pfizer, Recordati and Sanofi, and is a paid consultant/advisory board member/DSMB member for Almirall, Boehringer Ingelheim, InProTher, ICON, MerckSerono, Pfizer, 4SC, and Sanofi/Regeneron. His group received research grants from Bristol-Myers Squibb, Merck Serono, HTG, IQVIA, and Alcedis. 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. 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. DS reports partial financial support from Bristol Myers Squibb for the conduct of this study and drug supply (nivolumab and ipilimumab) support; grants (or contracts) from Amgen, Array/Pfizer, Bristol-Myers Squibb, MSD, Novartis and Roche; consulting fees from 4SC, Amgen, Array Biopharma, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Haystick, Immunocore, InFlarX, Innocent, LabCorp, Merck Serono, MSD, Nektar, NeraCare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron, Sun Pharma; honoraria from Bristol-Myers Squibb, MSD/Merck, Merck Serono, Novartis, Roche, Sanofi and Sun Pharma; support for attendings meetings or travel support from Bristol-Myers Squibb, MSD, Merck Serono, Novartis, Pierre Fabre and Sanofi; participation on drug safety monitoring or advisory boards for 4SC, Amgen, Array Biopharma, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Immunocore, InFlarX, Merck Serono, MSD, Nektar, NeraCare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron and SunPharma; leadership roles for DeCOG, German Cancer Society, Hiege-Stiftung, Deutsche Hautkrebsstiftung, NVKH e.V. and EuMelaReg. 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. All other authors declared no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: The purpose of the meta-analysis was to compare the prevalence of sarcopenia on staging computed tomography (CT) in patients with solid tumors in different world regions. Materials and Methods: MEDLINE, Embase, and SCOPUS literature databases were screened for prevalence of sarcopenia in oncologic patients up to December 2022. Two hundred eighty studies met the inclusion criteria. The methodological quality of the involved studies was checked according to the Quality Assessment of Diagnostic Studies instrument. Results: Two hundred eighty studies with 81,885 patients were included. The prevalence of sarcopenia among all patients was 35.5%. Prevalence of sarcopenia was higher in Europe (45.6%) and North America (41.2%) than in Asia (29.6%). Prevalence rates for the curative cohort were similar in all three regions, with 43.7% in Europe, 41.3% in North America, and 37.4% in Asia. In the palliative cohort, sarcopenia prevalence was higher in Europe (55.7%) and Asia (45.7%) than in North America (34.0%). In the European cohort, prostate cancer (73.9%), esophageal cancer (74.2%), pancreatic cancer (62.5%), and renal cell cancer (65.3%) showed high prevalence rates of sarcopenia. Applied cutoff values differed among regions. Conclusion: Our study shows that prevalence rates for sarcopenia of patients with solid tumors differ between regions and are different for curative and palliative settings. European studies demonstrate high prevalence rates for both settings. There is need for regional harmonization of sarcopenia definitions.

Immune checkpoint inhibitors are standard-of-care for the treatment of advanced melanoma, but their use is limited by immune-related adverse events. Proteomic analyses and multiplex cytokine and chemokine assays from serum at baseline and at the adverse event onset indicated aberrant T cell activity with differential expression of type I and III immune signatures. This was in line with the finding of an increase in the proportion of CD4 + T cells with IL-17A expression at the adverse event onset in the peripheral blood using flow cytometry. Multiplex immunohistochemistry and spatial transcriptomics on immunotherapy-induced skin rash and colitis showed an increase in the proportion of CD4 + T cells with IL-17A expression. Anti-IL-17A was administered in two patients with mild myocarditis, colitis and skin rash with resolution of the adverse events. This study highlights the potential role of type III CD4 + T cells in adverse event development and provides proof-of-principle evidence for a clinical trial using anti-IL-17A for treating adverse events., (© 2024. The Author(s).)

Background: Melanomas lacking mutations in BRAF, NRAS and NF1 are frequently referred to as "triple wild-type" (tWT) melanomas. They constitute 5-10 % of all melanomas and remain poorly characterized regarding clinical characteristics and response to therapy. This study investigates the largest multicenter collection of tWT-melanomas to date., Methods: Targeted next-generation sequencing of the TERT promoter and 29 melanoma-associated genes were performed on 3109 melanoma tissue samples of the prospective multicenter study ADOREG/TRIM of the DeCOG revealing 292 patients suffering from tWT-melanomas. Clinical characteristics and mutational patterns were analyzed. As subgroup analysis, we analyzed 141 tWT-melanoma patients receiving either anti-CTLA4 plus anti-PD1 or anti PD1 monotherapy as first line therapy in AJCC stage IV., Results: 184 patients with cutaneous melanomas, 56 patients with mucosal melanomas, 34 patients with acral melanomas and 18 patients with melanomas of unknown origin (MUP) were included. A TERT promoter mutation could be identified in 33.2 % of all melanomas and 70.5 % of all tWT-melanomas harbored less than three mutations per sample. For the 141 patients with stage IV disease, mPFS independent of melanoma type was 6.2 months (95 % CI: 4-9) and mOS was 24.8 months (95 % CI: 14.2-53.4) after first line anti-CTLA4 plus anti-PD1 therapy. After first-line anti-PD1 monotherapy, mPFS was 4 months (95 %CI: 2.9-8.5) and mOS was 29.18 months (95 % CI: 17.5-46.2)., Conclusions: While known prognostic factors such as TERT promoter mutations and TMB were equally distributed among patients who received either anti-CTLA4 plus anti-PD1 combination therapy or anti-PD1 monotherapy as first line therapy, we did not find a prolonged mPFS or mOS in either of those. For both therapy concepts, mPFS and mOS were considerably shorter than reported for melanomas with known oncogene mutations., Competing Interests: Declaration of Competing Interest All other authors declare no conflicts of interest for the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease resulting in decreased quality of life. Histamine and specifically the H 4 receptor play a key role in the inflammatory process in AD and serve as targets for novel therapeutic approaches., Objective: In the present study we aimed to elucidate the immunopathological mechanisms with which the H 4 receptor impacts TH2 cells and contributes to AD pathophysiology., Methods: Total CD4 + T cells obtained from healthy or AD individuals and in vitro differentiated TH2 cells were cultured under different conditions and the mRNA expression or protein production of target molecules were determined using quantitative real-time PCR and ELISA., Results: H 4 receptor mRNA expression was upregulated concentration dependent upon IL-4 stimulation in in vitro differentiated TH2 cells progressively during the differentiation. Transcriptomic analysis of in vitro differentiated TH2 versus TH1 cells revealed that the H 4 receptor among other genes represents one of the highly upregulated genes in TH2 cells. Most importantly, increased amounts of IL-5 and IL-13 mRNA expression were detected in in vitro differentiated TH2 cells as well as protein secretion in the presence of histamine or of the H 4 receptor-selective-agonist when compared to the untreated control., Conclusion: We show for the first time an H 4 receptor dependent upregulation of the pro-inflammatory cytokines IL-5 and IL-13 in human TH2 cells by histamine. This suggests that the blockade of the H 4 receptor may lead to downregulation of these cytokines and amelioration of AD symptoms as reported in first clinical studies., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

This study investigated whether adjuvant treatments in stage III cutaneous melanoma (CM) influenced patterns of recurrence. Patients with primary (n = 1033) or relapsed CM (n = 350) who received adjuvant therapies with Nivolumab (N), Pembrolizumab (P), or Dabrafenib and Trametinib (D + T) were extracted from the prospective multicenter real-world skin cancer registry ADOReg. Endpoints were progression-free survival (PFS), distant metastasis-free survival (DMFS), organ-specific DMFS, and overall survival (OS). For primary cases, D + T indicated an improved PFS (1- and 2-year PFS: 90.9%; 82.7%) as compared to P (81.0%, 73.9%; p = .0208), or N (83.8%, 75.2%; p = .0539). BRAF-mutated(mut) CM demonstrated significantly lower PFS (p = .0022) and decreased DMFS (p = .0580) when treated with immune checkpoint inhibitor (ICI) instead of D + T. Besides, NRAS-mut CM tended to perform worse than wt CM upon ICI (PFS: p = .1349; DMFS: p = .0540). OS was similar between the groups. Relapsed cases showed decreased PFS, DMFS, and OS in comparison to primary (all: p < .001), without significant differences between the subgroups. Organ-specific DMFS was significantly altered for primary cases with bone (p = .0367) or brain metastases (p = .0202). In relapsed CM, the frequency of liver (D + T: 1.5%; P: 12%; N: 9%) and LN metastases (D + T: 1.5%; P: 12%; N: 10.2%) was significantly lower with adjuvant D + T than ICI. NRAS-mut CM showed increased recurrence in primary and relapsed cases. These data show that adjuvant D + T is superior to ICI in primary BRAF-mut CM., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Competing Interests: The authors declare that they have no conflict of interest.

Background: The combination of anti-PD-1 and anti-CTLA-4 has been associated with improvement in response and survival over anti-PD-1 monotherapy in unselected patients with advanced melanoma. Whether patients with liver metastases also benefit from the combination of anti-PD-1 and anti-CTLA-4 over anti-PD-1, is unclear. In this study, we sought to assess whether the combination of anti-PD-1 and anti-CTLA-4 leads to better response, progression-free survival and overall survival, compared with anti-PD-1 monotherapy for patients with liver metastases., Methods: We have conducted an international multicentre retrospective study. Patients with advanced melanoma with liver metastases treated with 1st line anti-PD1 monotherapy or with anti-CTLA-4 were included. The endpoints of this study were: objective response rate, progression-free survival and overall survival., Results: With a median follow-up from commencement of anti-PD-1 monotherapy or in combination with anti-CTLA-4 of 47 months (95% CI, 42-51), objective response rate was higher with combination therapy (47%) versus anti-PD-1 monotherapy (35%) (p = 0.0027), while progression-free survival and overall survival were not statistically different between both treatment groups. However, on multivariable analysis with multiple imputation for missing values and adjusting for predefined variables, combination of anti-PD1 and anti-CTLA-4 was associated with higher objective response (OR 2.21, 1.46 - 3.36; p < 0.001), progression-free survival (HR 0.73, 0.57 - 0.92; p = 0.009) and overall survival (HR 0.71, 0.54 - 0.94; p = 0.018) compared to anti-PD1 monotherapy., Conclusions: Findings from this study will help guide treatment selection for patients who present with liver metastases, suggesting that combination therapy should be considered for this group of patients., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: IPS had travel support by BMS and MSD, speaker fee by Pierre Fabre, Roche, BMS and MSD, and has served as consultant on advisory boards from MSD. SU had research support from BMS and Merck Serono; speakers and advisory board honoraria from BMS, MSD, Merck Serono, and Novartis; and meeting and travel support from Almirall, BMS, IGEA Clinical Biophysics, MSD, Novartis, Pierre Fabre, and Sun Pharma. FA had travel support by Novartis and MSD. AA has served on advisory boards and received travel funding from BMS, MSD, Novartis, Pierre-Fabre, Pfizer and Almirall. DBJ has served on advisory boards or as a consultant for BMS, Catalyst Biopharma, Iovance, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, Targovax, and Teiko, and has received research funding from BMS and Incyte. MSC is consultant advisor for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck and Sanofi, and received honoraria from BMS, MSD, Sanofi and Novartis. PM is consultant advisor Bristol Myers Squibb, Merck Sharpe & Dohme, Novartis, Sun Pharma, Roche, Bayersdorf, Sanofi and Regeneron. Speaker fee by Pierre Fabre, Roche, BMS, MSD, Amgen, Sun Pharma, Sanofi and Novartis. Research funding from Novartis, MSD and BMS. RG received honoraria for advice and lectures from Bristol Myers Squibb, Roche Pharma, MerckSharpDohme, Novartis, Merck-Serono, Amgen, Almirall Hermal, Pierre-Fabre, Sun Pharma, Immunocore, 4SC, Delcath, Sanofi/Regeneron; travel and meeting support from SUN Pharma, Boehringer Ingelheim and PierreFabre; project support (to institution) from Novartis, Sanofi/Regeneron, Merck Serono, Amgen, SUN Pharma, KyowaKirin, Almirall Hermal. AMM is a consultant advisor for BMS, MSD, Novartis, Roche, Pierre-Fabre and QBiotics.MW received honoraria from Merck Sharp & Dohme, Roche, Novartis, Bristol Myers Squibb, Sanofi; is consult advisor for Merck Sharp & Dohme, Roche, Novartis, Bristol Myers Squibb, Sun Pharma, Sanofi, Pierre Fabre; research Funding from Merck Sharp & Dohme (Inst), Millennium (Inst), Bristol Myers Squibb (Inst), Johnson & Johnson (Inst), Novartis (Inst). PL received honoraria from Novartis, Pierre Fabre, Merck, BMS, MSD, NeraCare GmbH, Amgen, Roche, Oncology Education, Nektar; is consultant advisor for Merck Sharp & Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Novartis, Nektar; Speakers’ Bureau from Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, Pierre Fabre; Research Funding from BMS, Pierre Fabre; Travel, Accommodations, Expenses from Merck Sharp & Dohme, Bristol Myers Squibb. D.S.: Reports personal fees and non-financial support from Roche/Genentech, grants, personal fees, non-financial support and other from BMS, personal fees from Merck Sharp & Dohme, personal fees and non-financial support from Merck Serono, grant, personal fees and non-financial support from Amgen, personal fees from Immunocore, personal fees from Incyte, personal fees from 4SC, personal fees from Pierre Fabre, personal fees and non-financial support from Sanofi/Regeneron, personal fees from Array BioPharma, personal fees from Pfizer, personal fees from Philogen, personal fees from Regeneron, personal fees from Nektar, personal fees from Sandoz, grants, personal fees and non-financial support from Novartis, personal fees and non-financial support from SunPharma, Neracare, Replimune, Helsinn, OncoSec and InFlaRx outside the submitted work. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Despite recent advancements in the treatment of metastatic uveal melanoma (UM), the availability of further treatment options remains limited and the prognosis continues to be poor in many cases. In addition to tebentafusp, immune checkpoint blockade (ICB, PD-1 (+/-) CTLA-4 antibodies) is commonly used for metastatic UM, in particular in HLA-A 02:01-negative patients. However, ICB comes at the cost of potentially severe immune-related adverse events (irAE). Thus, the selection of patient groups that are more likely to benefit from ICB is desirable., Methods: In this analysis, 194 patients with metastatic UM undergoing ICB were included. Patients were recruited from German skin cancer sites and the ADOReg registry. To investigate the association of irAE occurrence with treatment response, progression-free survival (PFS), and overall survival (OS) two cohorts were compared: patients without irAE or grade 1/2 irAE (n=137) and patients with grade 3/4 irAE (n=57)., Results: In the entire population, the median OS was 16.4 months, and the median PFS was 2.8 months. Patients with grade 3/4 irAE showed more favorable survival than patients without or grade 1/2 irAE (p=0.0071). IrAE occurred in 44.7% (87/194), and severe irAE in 29.4% (57/194) of patients. Interestingly, irColitis and irHepatitis were significantly associated with longer OS (p=0.0031 and p=0.011, respectively)., Conclusions: This data may indicate an association between irAE and favorable survival outcomes in patients with metastatic UM undergoing ICB treatment and suggests that a reduced tolerance to tumor antigens could be linked to reduced tolerance to self-antigens., Competing Interests: AG speaker´s honoraria from Allmirall, Amgen, Bristol-Myers Squibb, Immunocore, MSD Sharp & Dohme and Roche; intermittent advisory board relationships with Amgen, Bristol-Myers Squibb, Novartis, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, Pfizer, Roche and Sanofi Genzyme; travel and congress fee support from Bristol-Myers Squibb, MSD Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals and Roche. Clinical studies: Amgen, Array, Bristol-Myers Squibb, Delcath Systems Inc, GSK, Novartis, MSD Sharp & Dohme, Pfizer, and Roche. CB declares speaker´s and/or consultancy honoraria from Almirall, Bristol-Myers Squibb, Delcath, Immunocore, Leo Pharma, Miltenyi, MSD Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals, Regeneron, and Sanofi-Aventis outside the submitted work. CP received honoraria speaker honoraria or honoraria as a consultant and travel support from Novartis, Bristol-Myers Squibb, Roche, Merck Serono, MSD Sharp & Dohme, Celgene, AbbVie, Sun Pharma, UCB, Allergy Therapeutics, and LEO. FM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, Bristol-Myers Squibb, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, Sanofi, and Immunocore and research funding from Novartis and Roche. FZ declares speakers and advisory board honoraria and/or travel support from Bristol-Myers Squibb, MSD Sharp & Dohme, Roche, Novartis, Pierre Fabre Pharmaceuticals, and Sanofi-Aventis outside the submitted work. JCH declares research support from Bristol Myers Squibb, Sanofi, and Sunpharma, advisory board honoraria from GSK, Pierre Fabre Pharmaceuticals, Sun Pharma, speaker honoraria from Amgen, Bristol-Myers Squibb, Delcath, GSK, Immuno core, MSD Sharp & Dohme, Novartis, Sanofi and Sun Pharma and travel support from Bristol-Myers Squibb, Iovance and Sun Pharma. SH declares speakers and advisory board honoraria from Merck Sharp & Dohme, Bristol-Myers Squibb, Novartis, Sanofi, Sun Pharma, and Pierre Fabre Pharmaceuticals. JUl: Speakers and advisory board honoraria from Bristol-Myers Squibb, Kyowa-Kirin, Merck Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals and Sanofi, and travel support from Pierre Fabre Pharmaceuticals. JUt is on the advisory board or has received honoraria and travel support from Amgen, Bristol-Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre Pharmaceuticals, Roche, Sanofi outside the submitted work. KCK serves as a consultant to Philogen, Bristol-Myers Squibb, MSD Sharp & Dohme, Sanofi Aventis, and Immunocore and received travel grants and speaker fees from Philogen, Pierre Fabre Pharmaceuticals, Bristol-Myers Squibb, MSD Sharp & Dohme, Sun Pharma, Sanofi Aventis, Novartis, Medac and has received research support by Novartis. K-MT received speaker or consultant honoraria and travel support from Bristol-Myers Squibb, MSD Sharp & Dohme, Roche, Novartis, Pierre Fabre Pharmaceuticals, Sanofi Genzyme, Sun Pharma, Amgen, LEO Pharma, Galderma, Almirall, and Candela. ME declares honoraria and travel support from Bristol-Myers Squibb, Immunocore, Novartis, Pierre Fabre Pharmaceuticals, and Sanofi, outside the submitted work. MVH: Honoraria from MSD Sharp & Dohme, Bristol-Myers Squibb, Roche, Novartis, Sun Pharma, Sanofi, Almirall, Biofrontera, Galderma. PM Research support: Novartis, Bristol-Myers Squibb, MSD Sharp & Dohme. Honoraria for lectures: Roche, Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, Merck-Serono, Pierre Fabre Pharmaceuticals, Sanofi, Sun Pharma, Baiersdorf; Honoraria for advisory boards: Roche Pharma, Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, Pierre Fabre Pharmaceuticals, MSD Sharp & Dohme, Immunocore, Sun Pharma, Sanofi. PT: Bristol-Myers Squibb, Novartis, MSD Sharp & Dohme, Pierre Fabre Pharmaceuticals, CureVac, Roche, Kyowa Kirin, Biofrontera, Invited Speaker, Personal BMS, Novartis, Pierre Fabre Pharmaceuticals, Merck Serono, Sanofi, Roche, Kyowa Kirin, Advisory Board, Personal BMS, Pierre Fabre Pharmaceuticals, Other, Personal, Travel support. RG Research support: Amgen, MSD Sharp & Dohme, Sun Pharma, Sanofi/Regeneron, Almirall, Kyowa Kirin. Honoraria for lectures: Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, MSD Sharp & Dohme, Sun, Pierre Fabre Pharmaceuticals, Sanofi/Regeneron, Sun Pharma Honoraria for advisory boards: Bristol-Myers-Squibb, Novartis, MSD Sharp & Dohme, Almirall, Amgen, Pierre Fabre Pharmaceuticals, MSD Sharp & Dohme, 4SC, Immunocore, Sun Pharma, Sanofi/Regeneron, Delcath. SU declares research support from Bristol-Myers Squibb and MSD Sharp & Dohme; speakers and advisory board honoraria from Bristol-Myers Squibb, MSD Sharp & Dohme, Merck Serono, Novartis, and Roche, and travel support from Bristol-Myers Squibb, and MSD Sharp & Dohme. UL declares research support from MSD Sharp & Dohme; speakers and advisory board honoraria from MSD Sharp & Dohme, Novartis, Sanofi, and Sun Pharma, and travel support from Pierre Fabre Pharmaceuticals and Sun Pharma. BS Speakers honoria and/or travel support from Amgen, Bristol-Myers Squibb, MSD Sharp & Dohme, Jansen, Novartis, Roche, Sun Pharma, abbvie, Sanofi, Pierre Fabre Pharmaceuticals, Boehringer Ingelheim and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AT declared a past co-authorship with the author RG, JH, SH, KCK, CL, FM, MM, PT, K-MT, FZ, and MVH to the handling editor., (Copyright © 2024 Koch, Petzold, Dippel, Erdmann, Gesierich, Gutzmer, Hassel, Haferkamp, Kähler, Kreuzberg, Leiter, Loquai, Meier, Meissner, Mohr, Pföhler, Rahimi, Schell, Terheyden, Thoms, Ugurel, Ulrich, Utikal, Weichenthal, Ziller, Berking and Heppt.)

Background: Immune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with a fatality rate of 40%-46%. However, irMyocarditis can be asymptomatic. Thus, improved monitoring, detection and therapy are needed. This study aims to generate knowledge on pathogenesis and assess outcomes in cancer centers with intensified patient management., Methods: Patients with cardiac irAEs from the SERIO registry (www.serio-registry.org) were analyzed for demographics, ICI-related information (type of ICI, therapy line, combination with other drugs, onset of irAE, and tumor response), examination results, irAE treatment and outcome, as well as oncological endpoints. Cardiac biopsies of irMyocarditis cases ( n  = 12) were analyzed by Nanostring and compared to healthy heart muscle ( n  = 5) and longitudinal blood sampling was performed for immunophenotyping of irMyocarditis-patients ( n  = 4 baseline and n  = 8 during irAE) in comparison to patients without toxicity under ICI-therapy ( n  = 4 baseline and n  = 7 during ICI-therapy) using flow cytometry., Results: A total of 51 patients with 53 cardiac irAEs induced by 4 different ICIs (anti-PD1, anti-PD-L1, anti-CTLA4) were included from 12 centers in 3 countries. Altogether, 83.0% of cardiac irAEs were graded as severe or life-threatening, and 11.3% were fatal (6/53). Thus, in centers with established consequent troponin monitoring, work-up upon the rise in troponin and consequent treatment of irMyocarditis with corticosteroids and -if required-second-line therapy mortality rate is much lower than previously reported. The median time to irMyocarditis was 36 days (range 4-1,074 days) after ICI initiation, whereas other cardiotoxicities, e.g. asystolia or myocardiopathy, occurred much later. The cytokine-mediated signaling pathway was differentially regulated in myocardial biopsies as compared to healthy heart based on enrichment Gene Ontology analysis. Additionally, longitudinal peripheral blood mononuclear cell (PBMC) samples from irMyocarditis-patients indicated ICI-driven enhanced CD4+ Treg cells and reduced CD4+ T cells. Immunophenotypes, particularly effector memory T cells of irMyocarditis-patients differed from those of ICI-treated patients without side effects. LAG3 expression on T cells and PD-L1 expression on dendritic cells could serve as predictive indicators for the development of irMyocarditis., Conclusion: Interestingly, our cohort shows a very low mortality rate of irMyocarditis-patients. Our data indicate so far unknown local and systemic immunological patterns in cardiotoxicity., Competing Interests: LH received speaker and consultancy fees from BiomeDx, BMS, Immunocore, Kyowa Kirin, Merck, MSD, Myoncare, Novartis, Pieris, Pierre-Fabre, Roche, Sanofi, Stemline Therapeutics, 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. CE reports on speaker fees from BristolMyers Squibb, GSK, Immunocore, Kyowa Kirin, MSD 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. DT reports consultancy, speaker fees or travel grants: BMS, Roche, Novartis, Sanofi, Recordati, Kyowa Kirin, Sun Pharma and Pierre Fabre. LZ served as consultant and has received honoraria from BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Pierre Fabre, Sanofi, Sunpharma and Novartis, outside the submitted work. PJB reports research funding (inst) by BeiGene, BMS, MSD and Takeda; an advisory role to BeiGene, BMS, MSD, Need Inc., Stemline and Takeda; honoraria from BeiGene, BMS, Celgene, MSD, Need Inc., Stemline and Takeda and stock options from Need Inc. 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. 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. All remaining authors have declared no conflicts of interest. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Wang, Ertl, Schmitt, Hammann, Kramer, Grabmaier, Schöberl, Anz, Piseddu, Pesch, Vera, Froehlich, Weckbach, Tomsitz, Loquai, Zimmer, Mangana, Dummer, Gutzmer, Klespe, Stege, Meiss, Thoms, Terheyden, Bröckelmann, Johnson, French and Heinzerling.)

Topical tirbanibulin is a highly effective and well tolerated novel treatment option for actinic keratoses (AKs). This study aimed to characterize the mode of action of tirbanibulin in keratinocytes (NHEK) and cutaneous squamous cell carcinoma (cSCC) cell lines (A431, SCC-12) in vitro. Tirbanibulin significantly reduced proliferation in a dose-dependent manner in all investigated cell lines, inhibited migration, and induced G2/M-cell cycle arrest only in the cSCC cell lines analyzed, and induced apoptosis solely in A431, which showed the highest sensitivity to tirbanibulin. In general, we detected low basal expression of phosphorylated SRC in all cell lines analyzed, therefore, interference with SRC signaling does not appear to be the driving force regarding the observed effects of tirbanibulin. The most prominent tirbanibulin-mediated effect was on β-tubulin-polymerization, which was especially impaired in A431. Additionally, tirbanibulin induced an increase of the proinflammatory cytokines IL-1α, bFGF and VEGF in A431. In conclusion, tirbanibulin mediated anti-tumor effects predominantly in A431, while healthy keratinocytes and more dedifferentiated SCC-12 were less influenced. These effects of tirbanibulin are most likely mediated via dysregulation of β-tubulin-polymerization and may be supported by proinflammatory aspects., (© 2024. The Author(s).)

Background: Treatment with encorafenib plus binimetinib and encorafenib monotherapy is associated with improved progression-free survival (PFS) and overall survival (OS) compared with vemurafenib in patients with BRAF V600E/K-mutant metastatic melanoma. We report results from the 7-year analysis of COLUMBUS part 1 (NCT01909453) at 99.7 months (median duration between randomization and data cutoff)., Methods: 577 patients with locally advanced unresectable or metastatic BRAF V600E/K-mutant melanoma who were treatment-naive or progressed after first-line immunotherapy were randomized 1:1:1 to encorafenib 450 mg once daily (QD) plus binimetinib 45 mg twice daily (BID) (n = 192), vemurafenib 960 mg BID (n = 191), or encorafenib monotherapy 300 mg QD (n = 194). No prior BRAF/MEK inhibitor was allowed., Results: Seven-year PFS and OS rates (95 % CI) were 21.2 % (14.7-28.4 %) and 27.4 % (21.2-33.9%) in the encorafenib plus binimetinib arm and 6.4 % (2.1-14.0 %) and 18.2 % (12.8-24.3 %) in the vemurafenib arm, respectively. Median melanoma-specific survival (95 % CI) was 36.8 months (27.7-51.5 months) in the encorafenib plus binimetinib arm and 19.3 months (14.8-25.9 months) in the vemurafenib arm. Thirty-four long-term responders (complete/partial response ongoing at 7 years) were identified across arms., Conclusions: This is the longest follow-up from a phase III trial of BRAF/MEK inhibitor combination in BRAF V600E/K-mutant metastatic melanoma. Safety results were consistent with the known tolerability profile of encorafenib plus binimetinib. Results support the long-term efficacy and known safety of encorafenib plus binimetinib in this population and provide new insights on long-term responders. Interactive data visualization is available at the COLUMBUS dashboard (https://clinical-trials.dimensions.ai/columbus7/)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dirk Schadendorf. Honoraria: Roche/Genentech, Novartis, Bristol Myers Squibb, MSD, Immunocore, Merck Serono, Array BioPharma, Pfizer, Pierre Fabre, Philogen, Regeneron, 4SC, Sanofi/Regeneron, NeraCare GmbH, Sun Pharma, Inflarx GmbH, Ultimovacs, Sandoz, Amgen, Daiichi Sankyo Japan, LabCorp, Nektar, Replimune. Consulting or Advisory Role: Roche/Genentech, Novartis, Bristol Myers Squibb, MSD, Merck Serono, 4SC, Pierre Fabre, Sanofi/Regeneron, Nektar. Speakers’ Bureau: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi/Regeneron, Merck KGaA. Research Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Roche (Inst), MSD Oncology (Inst), Array BioPharma/Pfizer (Inst), Amgen (Inst). Travel, Accommodations, Expenses: Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, MSD, Pierre Fabre, Sanofi/Regeneron. Reinhard Dummer. Honoraria: Roche, Novartis, Bristol Myers Squibb, MSD, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Regeneron, Alligator Bioscience, MaxiVAX, touchIME, T3 Pharmaceuticals, Pfizer. Consulting or Advisory Role: Roche, Bristol Myers Squibb, MSD, Novartis, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Alligator Bioscience, touchIME, MaxiVAX, Regeneron, Pfizer, T3 Pharmaceuticals. Research Funding: Roche (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), MSD (Inst), Amgen (Inst). Keith T. Flaherty. Stock and Other Ownership Interests: Clovis Oncology, Loxo, X4 Pharma, Strata Oncology, PIC Therapeutics, Apricity Health, Oncoceutics, FogPharma, Tvardi Therapeutics, Checkmate Pharmaceuticals, Kinnate Biopharma, Scorpion Therapeutics, ALX Oncology, xCures, Monopteros Therapeutics, Vibliome Therapeutics, Transcode Therapeutics, Soley Therapeutics, Nextech Invest. Consulting or Advisory Role: Novartis, Lilly, Oncoceutics, Tvardi Therapeutics, Takeda, Debiopharm Group. Caroline Robert. Stock and Other Ownership Interests: Ribonexus. Consulting or Advisory Role: Bristol Myers Squibb, Roche, Novartis, Pierre Fabre, MSD, Sanofi, AstraZeneca, Pfizer. Research Funding: Novartis (Inst). Ana Arance. Consulting or Advisory Role: Bristol Myers Squibb, Roche, Novartis, Pierre Fabre, MSD, Merck, Sanofi. Speakers’ Bureau: Pierre Fabre, Novartis, MSD, Bristol Myers Squibb, Roche, Merck, Sanofi Research Funding: Pierre Fabre (Inst), Novartis (Inst), Roche (Inst), Bristol Myers Squibb (Inst), MSD (Inst), Merck (Inst), Sanofi (Inst). Travel, Accommodations, Expenses: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre. Jan Willem B. de Groot. Consulting or Advisory Role: Bristol Myers Squibb, Pierre Fabre, Servier. Claus Garbe. Honoraria: CeCaVa, MSD Oncology, NeraCare GmbH, Philogen. Consulting or Advisory Role: CeCaVa, MSD Oncology, NeraCare GmbH, Philogen. Helen J. Gogas. Consulting or Advisory Role: Bristol Myers Squibb, MSD, Pierre Fabre, Sanofi. Speakers’ Bureau: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi. Steering Committee Member: Amgen, Replimune. Research Funding: Amgen (Inst), Bayer (Inst), Bristol Myers Squibb (Inst), Iovance (Inst), Lilly (Inst), MSD (Inst), Pfizer (Inst), Pierre Fabre (Inst). Ralf Gutzmer. Honoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Merck Serono, Almirall Hermal GmbH, Amgen, Sun Pharma, Pierre Fabre, Sanofi/Regeneron, Immunocore. Consulting or Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Almirall Hermal GmbH, 4SC, Amgen, Pierre Fabre, Merck Serono, Sun Pharma, Sanofi/Regeneron, Immunocore, Delcath. Research Funding: Amgen (Inst), Merck Serono (Inst), Sun Pharma (Inst), Sanofi/Regeneron (Inst), Kyowa Kirin (Inst), Almirall Hermal GmbH (Inst). Travel, Accommodations, Expenses: Pierre Fabre, Sun Pharma, Boehringer Ingelheim. Ivana Krajsová. No disclosures or conflicts of interest to report. Gabriella Liszkay. Consulting or Advisory Role: Roche, MSD, Novartis, Bristol Myers Squibb/Pfizer, Sanofi, Pfizer. Speakers’ Bureau: Bristol Myers Squibb, MSD Oncology (Inst), Sanofi. Research Funding: Roche, Novartis (Inst), Incyte Corporation (Inst). Carmen Loquai. Consulting or Advisory Role: Bristol Myers Squibb (Inst), MSD (Inst), BioNTech (Inst), Novartis (Inst), Sanofi (Inst), Pierre Fabre (Inst), Almirall Hermal GmbH (Inst), Sun Pharma (Inst), Merck (Inst), Roche (Inst), Kyowa Kirin International (Inst). Travel, Accommodations, Expenses: Bristol Myers Squibb (Inst), MSD (Inst), BioNTech (Inst), Novartis (Inst), Sanofi (Inst), Pierre Fabre (Inst), Almirall Hermal GmbH (Inst), Sun Pharma (Inst), Merck (Inst), Roche (Inst), Kyowa Kirin International (Inst). Mario Mandalà. Honoraria: MSD Oncology, Novartis, Pierre Fabre, Sanofi/Aventis, Bristol Myers Squibb/Sanofi. Consulting or Advisory Role: Bristol Myers Squibb, MSD Oncology, Novartis, Pierre Fabre. Research Funding: Novartis (Inst). Naoya Yamazaki. Consulting or Advisory Role: Ono Pharmaceutical, Chugai Pharma, MSD. Speakers’ Bureau: Ono Pharmaceutical, Bristol Myers Squibb Japan, Novartis, MSD. Research Funding: Ono Pharmaceutical (Inst), Bristol Myers Squibb Japan (Inst), Novartis (Inst), Astellas Amgen BioPharma (Inst), Merck Serono (Inst), Takara Bio (Inst). Paola Queirolo. Consulting or Advisory Role: Pierre Fabre, Roche, Novartis, MSD, Bristol Myers Squibb, Sun Pharma, Sanofi/Regeneron, Merck Serono. Carolin Guenzel. Stock and Other Ownership Interests: Pfizer. Honoraria: Pfizer. Anna Polli. Stock and Other Ownership Interests: Pfizer. Honoraria: Pfizer. Mahgull Thakur. Employment: Formerly Pfizer. Alessandra di Pietro. Stock and Other Ownership Interests: Pfizer. Honoraria: Pfizer. Paolo A. Ascierto. Stock and Other Ownership Interests: PrimeVAX. Consulting or Advisory Role: Bristol Myers Squibb, Roche/Genentech, MSD, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Takis Biotech, Lunaphore Technologies, Seagen, ITeos Therapeutics, Medicenna, Bio-Al Health. Research Funding: Bristol Myers Squibb (Inst), Roche/Genentech (Inst), Array BioPharma (Inst), Sanofi (Inst). Travel, Accommodations, Expenses: MSD., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Hand-foot syndrome (HFS) and nail changes are frequent adverse events of anticancer therapies., Objectives: To provide a review of current evidence in HFS and nail disorders associated with medical tumor treatment., Materials and Methods: Basis is the current German S3 guideline "Supportive therapy in oncologic patients" and literature on this topic published since the guideline was finalized., Results: Two variants of HFS are distinguished: a chemotherapy-associated and a kinase-inhibitor-associated variant. In the first form, painful erythema, blisters and ulceration can occur, also in other areas with a high number of sweat glands such as axillary and inguinal regions. Thus, the secretion of toxic substances through sweat glands is a proposed pathogenetic mechanism. For the second form, which results in callus-like painful thickening of the horny layer on areas of mechanic pressure, a vascular mechanism is proposed. For prophylaxis of HFS, avoidance of mechanical stress, regular cleaning of predisposed areas, and also urea- and diclofenac-containing ointments are recommended; in case of infusions (taxanes, doxorubicine), cooling of hands and feet during infusion is recommended. In case of manifest HFS, dose reduction or prolongation of intervals of the associated treatment are recommended. Nail changes often develop under therapy with chemotherapeutic agents but also under treatment with agents such as checkpoint inhibitors or under targeted therapy. Different components of the nail unit may be involved such as the nail matrix, nail bed, nail plate, hyponychium, lunula and proximal and lateral nail folds., Conclusion: This work gives insight into the pathophysiology of HFS and nail disorders that develop under systemic oncologic treatments and gives recommendations for prophylaxis and treatment., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

We report a case of a 29-year-old woman with subtle partial erythematous, partial hyperpigmented streaks along the Blaschko's lines on the right side of the body since early childhood. Primary DNA results of the skin and blood assay diagnosed focal dermal hypoplasia in mosaic form. The postzygotic mutation in the PORCN gene was only detectable in the affected skin and not in the blood assay. This article illustrates that clinically very discrete hypopigmentation and poikiloderma along Blaschko lines should raise awareness for robust diagnostic analysis in order to recognize this variable multisystem disease and to ensure an appropriate search for extracutaneous abnormalities and human genetic counseling, ideally before pregnancy. Careful correlation of clinical, histological, and genetic features along with close multidisciplinary cooperation of specialists from the fields of human genetics, dermatology, pediatrics, orthopedics and ophthalmology is crucial for final diagnosis, assessment of the prognosis and targeted genetic counseling of affected individuals., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Introduction: Adjuvant treatment with immune checkpoint inhibitors, such as PD1-antibodies (ICI) ± CTLA4-antibodies (cICI) or targeted therapy with BRAF/MEK inhibitors (TT), has shown a significant improvement in disease-free survival (DFS) for high-risk melanoma patients. However, due to specific side effects, the choice of treatment is often influenced by the risk of toxicity. Therefore, the role of physicians in treatment decisions of patients is crucial. This study investigated for the first time in a multicenter setting the attitudes and preferences of dermatooncologists in Germany and Switzerland regarding adjuvant treatment with (c)ICI and TT., Methods: In the GERMELATOX-A study, 108 physicians (median age: 32 yrs, 67.6% female) from 11 skin cancer centers were surveyed to rate typical side effect scenarios of (c)ICI and TT treatments and then compared to patients' ratings evaluated in a previous analysis from the same centers. The scenarios described mild-to-moderate or severe toxicity and included melanoma relapse leading to death. The physicians were asked about the level of side effects they would tolerate in exchange for a reduction in melanoma relapse and an increase in survival at 5 years., Results: The preferences of physicians and patients revealed significant differences regarding adjuvant melanoma treatment with (c)ICI and TT (p < 0.05). Compared to patients, physicians tend to value a melanoma relapse less severe, according to a visual analog scale. They were also less threatened by all scenarios of side effects during adjuvant treatment with (c)ICI or TT, compared to patients. Physicians required lower risk reductions for disease-free survival (DFS) and overall survival (OS) for both ICI and TT and their drug-related side effects to accept these treatments. In case of severe side effects, physicians required similar 5-year DFS rates for ICI and TT (60-65%), while patients needed a 15% improvement of 5-year DFS for ICI compared to TT (80%/65%). For survival, physicians expected an OS improvement of + 10% for all three treatment modalities, whereas patients required a higher increase: + 18-22% for ICI and + 15% for TT., Conclusion: Our study highlights the importance of understanding the patient's perspective and a potential difference to the doctor's view when making decisions about adjuvant melanoma treatment with (c)ICI and TT, especially as these treatments are increasingly being implemented in earlier stages., (© 2024. The Author(s).)

Background: Recent evidence suggests additional immunomodulatory properties of RANKL inhibition possibly boosting the clinical efficacy of immune checkpoint inhibitors (ICI)., Methods: We conducted a prospective, multicentre clinical trial in unresectable stage IV melanoma patients with bone metastases who received denosumab in parallel with dual ICI (BONEMET) and performed comprehensive immune monitoring at baseline and 4, 12, and 24 weeks after initiation of therapy. Secondary endpoints included tolerability and efficacy. For comparison, biospecimens from melanoma patients treated with dual ICI without denosumab were analyzed accordingly and served as retrospective reference cohort., Results: In both the BONEMET (n = 16) and the reference cohort (n = 18) serum levels of 17 cytokines, including IFNγ were significantly increased after 4 weeks of treatment. Patients who received ICI and denosumab showed a significantly higher increase in serum CXCL-13 and a significant decrease in VEGFc compared with the reference cohort. While no changes in T cell composition were observed at 4 weeks, patients in the BONEMET cohort showed a significant decrease in the peripheral naïve T-cell population and an increase in CD8 + effector cells after 12 weeks. Treatment-related adverse events occurred with comparable frequency (93.8% in the BONEMET cohort versus 83.3% in the reference cohort). 7/16 patients in the BONEMET cohort and 8/18 patients in the reference cohort achieved disease control., Conclusion: Denosumab in combination with dual ICI modulates cytokine expression and T-cell composition in peripheral blood. The upregulation of CXCL-13, a key factor for initiating tertiary lymphoid structures, strengthens the hypothesis that denosumab indeed boost immunological effects., Competing Interests: Declaration of Competing Interest The other authors declare no conflict of interest., (Copyright © 2024 The Authors. 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: Pain is common in patients with cancer. The World Health Organisation recommends paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) for mild pain and combined with other agents for moderate/severe pain. This study estimated associations of NSAIDs with recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and the incidence of immune-related adverse events (irAEs) in high-risk patients with resected melanoma in the EORTC 1325/KEYNOTE-054 phase III clinical trial., Patients and Methods: Patients with AJCC7 stage IIIA, IIIB or IIIC resected melanoma were randomized to receive 200 mg of adjuvant pembrolizumab (N = 514) or placebo (N = 505) 3-weekly for one year or until recurrence. As previously reported, pembrolizumab prolonged RFS and DMFS. NSAID use was defined as administration between 7 days pre-randomization and starting treatment. Multivariable Cox and Fine and Gray models were used to estimate hazard ratios (HRs) for associations of NSAIDs with RFS, DMFS and irAEs., Results: Of 1019 patients randomized, 59 and 44 patients in the pembrolizumab and placebo arms, respectively, used NSAIDs. NSAIDs were not associated with RFS (HR 0.91, 95% CI 0.58-1.43) or DMFS in the pembrolizumab (HR 1.03, 95% CI 0.65-1.66) or placebo arms (for RFS, HR 0.76, 95% CI 0.48-1.20; for DMFS, HR 0.80, 95% CI 0.49-1.31). NSAIDs were associated with the incidence of irAEs in the placebo arm (HR 3.06, 95% CI 1.45-6.45) but not in the pembrolizumab arm (HR 0.94, 95% CI 0.58-1.53)., Conclusion: NSAIDs were not associated with efficacy outcomes nor the risk of irAEs in patients with resected high-risk stage III melanoma receiving adjuvant pembrolizumab., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Oliver John Kennedy. None declared. Nina Glassee. Grants or contracts from any entity: MSD. Michal Kicinski. Grants or contracts from any entity: Bristol Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Pierre Fabre. Christian Blank. Grants or contracts from any entity: BMS, Novartis, NanoString, 4SC. Consulting fees - consultant advisor for: BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre- Payments were made to my institution, Third Rock Venture - Payments were made to me. Stock or stock options: Immagene BV and Signature Oncology - Co-founder. Georgina V Long. Consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, BMS, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, MSD Australia, MSD, Novartis, OncoSec Australia, PHMR Ltd, Pierre Fabre, Provectus Australia, Qbiotics, Regeneron. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS - Personal 1 h lecture of my own slides, Pierre Fabre, Personal 1 h lecture of my own slides. Victoria Atkinson. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, MSD, Novartis, Pierre Fabre- Speakers bureaus fees. Support for attending meetings and/or travel: BMS, Travel support. Participation on a Data Safety Monitoring Board or Advisory Board: BMS, MSD, Nektar, Novartis, Pierre Fabre, Q Biotics, Roche, Limbic - Advisory boards. Stéphane Dalle. Grants or contracts from any entity: BMS, MSD - My Institution. Support for attending meetings and/or travel: BMS, Pierre Fabre, MSD. Other financial or non-financial interests: Sanofi Pasteur - My wife is an employee of Sanofi Pasteur. Andrew M. Haydon. Payment or honoraria for lectures, presentations, speakers bureaus: BMS, MSD, Novartis. Participation to Advisory Board: BMS, Novartis, Pierre Fabre, MSD. Andrey Meshcheryakov. Grants or contracts from any entity: Sanofi, AstraZeneca, MSD - My institution, me. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, Bayer AG, BIOCAD, BMS, Eli Lilly, Merck, SERVIER, Takeda Pharmaceuticals, Eisai, AstraZeneca, Sanofi-Aventis - Honoraria for lectures, presentations, speakers bureaus. Support for attending meetings and/or travel: BIOCAD, SERVIER, MSD, Sanofi-Aventis, Merck - Attending meetings and/or travel. Participation on a Data Safety Monitoring Board or Advisory Board: Amgen, Bayer AG, BIOCAD, BMS, Eli Lilly, Merck, Servier, Takeda Pharmaceuticals, Eisai, AstraZeneca, Sanofi-Aventis - Advisory Board. Adnan Khattak. None declared. Matteo S. Carlino. Participation on Advisory Board for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche. Consulting fees: BMS, MSD, Novartis. Shahneen Sandhu. Grants or contracts from any entity: Advanced Accelerators Applications (a Novartis company), Amgen, MSD, Senwha, Genentech, AstraZeneca - Funding to the institution. Participation on an Advisory Board: AstraZeneca, BMS, MSD, Advanced Accelerators Applications (a Novartis company). - Funding to the institution. James Larkin. Grants or contracts from any entity: Achilles, BMS, MSD, Nektar, Novartis, Pfizer, Roche, Immunocore, Aveo, Pharmacyclics. Institutional research support: BMS, MSD, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, Aveo. Consulting fees from iOnctura, Apple Tree, Merck, BMS, Eisai, Debipharm, Incyte. Honorariums from Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, BMS. Speaker fee from Pierre Fabre, BMS, Ipsen, Roche, EUSA Pharma, Novartis, Aptitude, AstraZeneca, GSK, Eisai, Calithera, Ultimovacs, Seagen, Merck, eCancer, Inselgruppe, Pfizer, Goldman Sachs, MSD. Susana Puig. Grants or contracts from any entity: Almirall, ISDIN, La Roche Posay - To My Institution. Consulting fees: ISDIN, Almirall, La Roche Posay, MSD, Sanofi, Sun Pharma, Pfizer, Roche, Regeneron. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: ISDIN, La Roche Posay, Leo Pharma, Pfizer, Roche, Regeneron, BMS, Sun Pharma. Support for attending meetings and/or travel: Almirall. Participation on a Data Safety Monitoring Board or Advisory Board: Roche, Sanofi, Sun Pharma, Almirall, ISDIN, Pfizer, Novartis. Paolo A. Ascierto. Grants or contracts from any entity: BMS, Roche-Genentech, Pfizer/Array, Sanofi. Consulting fees: BMS, Roche-Genentech, MSD, Novartis, Merck Serono, Pierre-Fabre, Sun Pharma, Sanofi, Idera, Sandoz, 4SC, Italfarmaco, Nektar, Pfizer/Array, Lunaphore, Medicenna, Bio-Al Health, ValoTx, Replimmune, Bayer. Support for attending meetings and/or travel: Pfizer, Bio-Al Health, Replimmune. Participation on a Data Safety Monitoring Board or Advisory Board: BMS, Roche-Genentech, MSD, Novartis, AstraZeneca, Immunocore, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos. Piotr Rutkowski. Consulting fees: Amgen, Blueprint Medicine, BMS, Merck, MSD, Novartis, Philogen, Pierre Fabre, Sanofi - Advisory Role - Personal fees. Payment or honoraria for lectures: BMS, Merck, MSD, Novartis, Pierre Fabre, Sanofi Pasteur. Dirk Schadendorf. Grants or contracts from any entity: Amgen, Array BioPharma, Novartis. Consulting fees: 4SC, Angenus, Astra Zeneca, BMS, Daiichi Sankyo, EMD Serano, Roche, Genentech, InFlarX, Merck, Nektar, Novartis, Pfizer, Philogen, Pierre Fabre, Regeneron, Sandoz, Sanofi, UltimoVacs. Participation on a Data Safety Monitoring Board: Immunocore. Honoraria for lectures: Amgen, Novartis. Support for attending meetings and/or travel: Amgen, Novartis. Marye Boers-Sonderen. None declared. Anna Maria di Giacomo. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, MSD, Pierre Fabre, Sanofi. Support for attending meetings and/or travel: BMS, Pierre Fabre. Participation on a Data Safety Monitoring Board or Advisory Board: BMS, MSD, Nektar, Pierre Fabre, Sanofi, GSK, Novartis. Alfonsus J.M. van den Eertwegh. Grants or contracts from any entity: Roche, Sanofi, Bristol Myers Squibb, Idera. Consulting fees: BMS. Support for attending meetings and/or travel: MSD Oncology, Roche, Pfizer, Sanofi, Pierre Fabre. Participation on a Data Safety Monitoring Board or Advisory Board: BMS, MSD Oncology, Amgen, Roche, Novartis, Sanofi, Pfizer, Ipsen, Merck, Pierre Fabre. Jean-Jacques Grob. Payment for participation to an advisory board: Amgen, BMS, Hoffmann-La Roche. Consulting fees: MSD, Novartis, Philogen, Pierre Fabre, Sanofi Pasteur. Ralf Gutzmer. Grants or contracts from any entity: Pfizer, Novartis, Johnson & Johnson, Amgen, Merck Serono, Sun Pharma Industries, Sanofi. Consulting fees: BMS, MSD, Roche, Genentech, Novartis, Merck Serono, Almirall, Amgen, Sun Pharma Industries, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, Bayer AG, Immunocore. Support for attending meetings and/or travel: Bristol Myers Squibb, Roche, Merck Serono, Pierre Fabre, Sun Pharma Industries. Rahima Jamal. Grants or contracts from any entity: MSD, BMS, Iovance Biotherapeutics. Consulting fees: BMS. Alexander C.J. van Akkooi. Grants or contracts from any entity: Amgen, Merck, Pfizer. Participation on a Data Safety Monitoring Board or Advisory Board: Amgen, BMS, Novartis, MSD, Merck, Pfizer, Pierre Fabre, Provectus, Sanofi, Sirius Medical, 4SC. Sara Gandini. None declared. Emanuel Buhrer. None declared. Stefan Suciu. Grants or contracts from any entity: MSD. Caroline Robert. Consulting fees: AstraZeneca, BMS, MSD, Merck, Roche, Novartis, Pfizer, Pierre Fabre, Sanofi. Co-founder: Ribonexus. Alexander Eggermont. Consulting fees: Agenus, BioInvent, BMS, Brenus, CatalYm, Ellipses, Galecto, IO Biotech, IQVIA, ISA Pharmaceuticals, Merck, MSD, Pierre Fabre, Sairopa, Sellas, SkylineDX, TigeTx, Trained Immunity TX. Participation on a Data Safety Monitoring Board: BioNTech, GSK, and Pfizer. Lectures: BMS, MSD. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: European Academy Cancer Sciences, German Cancer Aid. Stock or stock options: IO Biotech, SkylineDx and SaiRoPA. Mario Mandala. Participation to Advisory Board: BMS, MSD, Novartis, Pierre Fabre Pharmaceuticals. Paul Lorigan. Grants or contracts from any entity: BMS, Pierre Fabre. Consulting fees: Amgen, BMS, MSD, Nektar, Novartis, Pierre Fabre. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, BMS, Merck, MSD, Nektar, NeraCare GmbH, Novartis, Oncology Education, Pierre Fabre, Roche. Support for attending meetings and/or travel: BMS, MSD. Sara Valpione. Receipient of an Institutional Amgen Research Grant., (Copyright © 2024. Published by Elsevier Ltd.)

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.)

Purpose: The interaction of gut microbiome and immune system is being studied with increasing interest. Disturbing factors, such as antibiotics may impact the immune system via gut and interfere with tumor response to immune checkpoint blockade (ICB)., Methods: In this multicenter retrospective cohort study exclusively treatment-naïve patients with cutaneous or mucosal melanoma treated with first-line anti-PD-1 based ICB for advanced, non-resectable disease between 06/2013 and 09/2018 were included. Progression-free (PFS), and overall survival (OS) according to antibiotic exposure (within 60 days prior to ICB and after the start of ICB vs. no antibiotic exposure) were analyzed. To account for immortal time bias, data from patients with antibiotics during ICB were analyzed separately in the time periods before and after start of antibiotics., Results: Among 578 patients with first-line anti-PD1 based ICB, 7% of patients received antibiotics within 60 days prior to ICB and 19% after starting ICB. Antibiotic exposure prior to ICB was associated with worse PFS (adjusted HR 1.75 [95% CI 1.22-2.52]) and OS (adjusted HR 1.64 [95% CI 1.04-2.58]) by multivariate analysis adjusting for potential confounders. The use of antibiotics after the start of ICB had no effect on either PFS (adjusted HR 1.19; 95% CI 0.89-1.60) or OS (adjusted HR 1.08; 95% CI 0.75-1.57)., Conclusions: Antibiotic exposure within 60 days prior to ICB seems to be associated with worse PFS and OS in melanoma patients receiving first-line anti-PD1 based therapy, whereas antibiotics after the start of ICB do not appear to affect PFS or OS., Competing Interests: Declaration of Competing Interest E.C. received travel support from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, UCB and Almirall outside the submitted work. B.S. Honoraria from MSD, BMS, SUN Pharma, Allmiral, Novartis; Advisory Board for MSD, BMS, Pierre Fabre Pharma, Sanofi; travel support from BMS, Novartis, Pierre Fabre Pharma; Research Funding from Novartis; all outside the submitted work. M.S. received speaker honoraria from Novartis and advisory board honoraria from Sanofi Genzyme. R.G. declares research support from Novartis, Amgen, Sanofi, Merck-Serono, Admiral, SUN Pharma and Kyowa-Kirin; honoraria for lectures from Roche Pharma, Bristol-Myers Scuibb, Novartis, MSD. Almirall, Amgen, Merck-Serono, SUN Pharma, Pierre-Fabre, and Sanofi; advisory honoraria from Roche Pharma, Bristol-Myers Squibb, Novartis, MSD, Admiral, Amgen, Pierre-Fabre, Merck-Serono, 4SC, Sun Pharma, Merck-Serono, Sanofi, Delcath and Immunocore. C.L. receives personal fees and travel reimbursement from MSD, BMS, Merck, Sanofi, Almirall Hermal, Kyowa Kirin, Biontech, Pierre Fabre, Novartis and Sun Pharma outside the submitted work. K.K. has served as consultant or/and has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. A.Z.M. received travel support from Novartis, Genzyme, and Bristol-Myers Squibb, outside the submitted work. J.M.P. served as consultant and/or has received honoraria from Bristol-Myers Squibb, Novartis, Sanofi and received travel support from Bristol-Myers Squibb, Novartis, Pierre Fabre and Therakos. E.G. received travel support from Pierre-Fabre, outside the submitted work. A.M. received travel support from Novartis, outside the submitted work. A.R. received grants, personal fees, and non-financial support from Novartis; grants and non-financial support from Bristol-Myers Squibb; personal fees and non-financial support from Roche; personal fees from Merck Sharp & Dohme; and non-financial support from Amgen, outside the submitted work. S.U. 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. D.S. received grants and other support from Bristol-Myers Squibb, personal fees from Bristol-Myers Squibb during the conduct of the study; personal fees from Amgen; personal fees from Boehringer Ingelheim; personal fees from InFlarX; personal fees and other support from Roche; grants, personal fees and other support from Novartis; personal fees from Incyte; personal fees and other support from Regeneron; personal fees from 4SC; personal fees from Sanofi; personal fees from Neracare; personal fees from Pierre-Fabre; personal fees and other support from Merck-EMD; personal fees from Pfizer; personal fees and other support from Philiogen; personal fees from Array, personal fees and other support from MSD Sharp & Dohme, outside the submitted work. E.L. 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.A.S. L.Z. served as consultant and/or has received honoraria from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre-Fabre, and Sanofi; and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre-Fabre, and Novartis, outside the submitted work. All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Conflicts of interest Dr Stratigos reports advisory board or steering committee roles for Janssen, Regeneron Pharmaceuticals, Inc, Roche, and Sanofi; and research support from AbbVie, Bristol Myers Squibb, LEO Pharma, Pfizer, Genesis Pharma, and Novartis. Dr Sekulic reports advisory roles for Regeneron Pharmaceuticals, Inc and Roche. Dr Peris reports advisory board roles for AbbVie, LEO Pharma, Janssen, Almirall, Eli Lilly, Galderma, Novartis, Pierre Fabre, Sun Pharma, and Sanofi, outside the submitted work. Dr Bechter reports advisory board roles for Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, and Ultimovacs. Dr Prey reports no conflict of interest. Dr Lewis reports grants and personal fees from Regeneron Pharmaceuticals, Inc, and is now an employee of Regeneron Pharmaceuticals, Inc. Dr Basset-Seguin is a consultant and investigator for Regeneron Pharmaceuticals, Inc, Sanofi, and Sun Pharma. Dr Chang reports advisory roles for Castle, Feldan, Merck, and Regeneron Pharmaceuticals, Inc; and research funding from Regeneron Pharmaceuticals, Inc, Merck, Novartis, and Galderma. Dr Dalle reports research grants and travel fees from Bristol Myers Squibb and Merck Sharp & Dohme; and reports that their spouse is an employee of Sanofi with stock options. Dr Fernández Orland declares no conflict of interest. Dr Licitra reports institutional grants and personal fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Debiopharm International SA, Eisai, Novartis, and Roche; institutional grants from Celgene International, Exelixis, Hoffmann-La Roche, IRX Therapeutics, Medpace, Merck Serono, and Pfizer; and personal fees from Sobi, Ipsen, Incyte Biosciences Italy SRL, Doxa Pharma, Amgen, Nanobiotics SA, GSK, AccMed, Medical Science Foundation G. Lorenzini, Associazione Sinapsi, Think 2 IT, Aiom Servizi, Prime Oncology, WMA Congress Education, Fasi, DueCi Promotion SRL, MI&T, Net Congress & Education, PRMA Consulting, Kura Oncology, Health & Life SRL, and Immuno-Oncology Hub. Dr Robert reports grants, personal fees, and advisory board roles for Bristol Myers Squibb, Pierre Fabre, Novartis, Amgen, Merck, Roche, Merck Sharp & Dohme, Sanofi, Biothera, and Ultimovacs. Dr Ulrich reports advisory board and speaker roles for Roche, Sanofi, Regeneron Pharmaceuticals, and Sun Pharma. Dr Hauschild reports institutional funding and personal fees from Amgen, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme, Merck & Co, Philogen, Pierre Fabre, Provectus, Regeneron Pharmaceuticals, Inc, Roche, Sanofi Genzyme, and Novartis; and consultancy fees from OncoSec, Almirall Hermal, and Sun Pharma. Dr Migden reports advisory roles for and travel fees from Regeneron Pharmaceuticals, Inc, and Sun Pharmaceuticals; an advisory role for Rakuten Medical; and research funding from Regeneron Pharmaceuticals, Inc, and PellePharm. Dr Dummer reports intermittent, project-focused consultant and advisory roles for Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron Pharmaceuticals, Inc, Alligator, MaxiVAX SA, and touchIME outside the submitted work. Drs Yoo, Inocencio, Chen, Seebach, Lowy, and Fury are employees and shareholders of Regeneron Pharmaceuticals, Inc. Mr Okoye is also an employee and shareholder of Regeneron Pharmaceuticals, Inc. Dr Bassukas reports non-financial support from Leo Pharma and Novartis, and institutional grants from Leo Pharma. Dr Loquai reports personal fees from Roche, Sun Pharma, Bristol Myers Squibb, Merck Sharp & Dohme, Merck, Novartis, Pierre Fabre, Kyowa Kirin, Almirall Hermal, and BioNTech. Dr De Giorgi reports no conflict of interest. Dr Eroglu reports advisory board fees from Regeneron Pharmaceuticals, Inc, Novartis, Pfizer, Genentech, Eisai, OncoSec, and Natera; and research grants from Novartis, Pfizer, and Boehringer Ingelheim. Dr Gutzmer reports documentation fees to their institution from Regeneron Pharmaceuticals, Inc; personal fees and non-financial support from Amgen, Bristol Myers Squibb, Roche Pharma, Merck Serono, Pierre Fabre, Sanofi, and Regeneron Pharmaceuticals, Inc; grants, personal fees, and non-financial support from Novartis; grants and personal fees from Pfizer; grants from Johnson & Johnson; and personal fees from Merck Sharp & Dohme, Almirall Hermal, Sun Pharma, 4SC, and Immunocore. Dr Ulrich reports grants and personal fees from Sanofi, Bristol Myers Squibb, Novartis, and Merck Sharp & Dohme; and personal fees from Roche, medac, and Sun Pharma. Dr Puig reports personal fees and non-financial support from Sanofi, Regeneron Pharmaceuticals, Inc, and Pfizer; grants from Avene; non-financial support from MAVIG, FotoFinder, 3Gen, AbbVie, Eli Lilly, and Merck Sharp & Dohme; grants, personal fees, and non-financial support from ISDIN, La Roche-Posay, and Roche; grants and personal fees from Sun Pharma, Leo Pharma, and Almirall; and personal fees from Ojer Pharma and Pierre Fabre. Dr LaFontaine reports employment at Sanofi and holds shares or stock in the company.

Background: The impact of immunosuppressive therapy (IST) on immune-checkpoint inhibition (ICI) is unclear., Methods: Patients with unresectable advanced melanoma (MM) treated with ICI in the years 2011-2020 were identified from the prospective multicenter German skin cancer registry ADOREG. Patients with IST within 60 days before, or within 30 days after start of ICI were compared to patients without IST. End points were disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) determined by Kaplan-Meier method. Prognostic factors were evaluated in a Cox regression model., Results: Of 814 patients treated with ICI, 73 (9%) received concomitant IST, mainly steroids. Patients with brain metastases (BM) received IST more frequently (n = 34/130 patients; 26%), than patients without BM (39/684 patients; 6%). In patients without BM, IST initiated before, but not IST initiated after start of ICI was significantly associated with worse PFS (univariate hazard ratio (HR) 2.59, 95% confidence interval (95%-CI) 1.07-6.28, p = 0.035; multivariate HR 3.48, 95%-CI 1.26-9.6, p = 0.016). There was no association between IST and OS or DCR. In patients with BM, IST initiated before, but not after start of ICI was significantly associated with worse OS (univariate HR 2.06, 95%-CI 1.07-3.95, p = 0.031; multivariate HR 5.91, 95%-CI 1.74-20.14, p = 0.004). There was no association between IST and PFS or DCR., Conclusion: Patients receiving IST 60 days before start of ICI showed a tendency to an impaired therapy outcome. IST initiated within 30 days after start of ICI, mainly due to early side effects, did not affect the efficacy of ICI therapy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Corinna Kochanek: None. Catharina Gilde: None. Lisa Zimmer: served as consultant and/or has received honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from Merck Sharp & Dohme, Bristol Myers Squibb, Pierre Fabre, Sunpharma, Sanofi and Novartis; outside the submitted work. Selma Ugurel: 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. Friedegund Meier: has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Sanofi and Immunocore and research funding from Novartis and Roche; outside the submitted work. Jochen Utikal: is on the advisory board or has received honoraria and travel support from Amgen, Bristol-Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, Sanofi; outside the submitted work. Claudia Pföhler: received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Celgene, AbbVie, Sunpharma, Pierre Fabre, UCB, Nutricia Milupa, Janssen and LEO; outside the submitted work. Rudolf Herbst: is an employee of Helios Kliniken Erfurt GmbH. Sebastian Haferkamp: declares research support from Bristol Myers Squibb speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre and Novartis; outside the submitted work. Julia Welzel: has received honoraria and travel support from Almirall, Bristol Myers Squibb, Novartis, Pierre Fabre and Merck Sharp & Dohme; outside the submitted work. Pia Dücker: declares research support from Bristol Myers Squibb, Merck and Novartis. Speakers and advisory board honoraria from Bristol Myers Squibb, Roche, Sanofi-Aventis, AbbVie, Merck Sharp and Dohme and Pierre Fabre; outside the submitted work. Ulrike Leiter: reports research support from Merck Sharp and Dohme, consulting fees and honoraria from Sun Pharma, Sanofi (personal and institutional), Merck Sharp and Dohme (personal and institutional), Novartis, Roche, Almirall Hermal, support for attending meeting from Sun Pharma and participation on a Data Safety Monitoring Board or Advisory Board from Sun Pharma, Sanofi, Merck Sharp and Dohme, Novartis, Roche, Almirall Hermal; outside the submitted work. Michael Weichenthal: None. Imke von Wasielewski: Honoraria: Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Sanofi, Stemline, Kyowa Kirin. Consultant or Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme, Sanofi; Travel, Accommodations. Expenses: Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Sanofi, Stemline, Kyowa Kirin; outside the submitted work. Yenny Angela: None. Ralf Gutzmer: declares research support from Novartis, Amgen, Sanofi, Merck-Serono, Admiral, SUN Pharma and Kyowa-Kirin; honoraria for lectures from Roche Pharma, Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme. Almirall, Amgen, Merck-Serono, SUN Pharma, Pierre-Fabre, and Sanofi; advisory honoraria from Roche Pharma, Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Almirall, Amgen, Pierre-Fabre, Merck-Serono, 4SC, Sun Pharma, Merck-Serono, Sanofi, and Immunocore; outside the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)