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The link between palliative care and oncology must continue to develop, taking into account advances in treatment.Immune checkpoint inhibition (ICI) for metastatic melanoma is associated with different types of response, making it difficult to assess the benefits to the patient. Some clinical trials suggest a survival advantage of ICI even in the absence of an objective radiographic response. The aim of this study is to assess the impact of continuing ICI after progression of the disease on the overall survival (OS) in a cohort of final-line metastatic melanoma patients. Clinical data from 120 patients with metastatic melanoma were collected via Melbase, a French multicentric biobank, prospectively enrolling unresectable melanoma. Two groups were defined: patients continuing final-line ICI at progression (treated) and patients stopping ICI at progression (controls). The primary end-point is the OS from progression. Propensity score weighting was used to correct for indication bias. From the 120 patients, 72 (60%) continued ICI. Median OS from progression was 4.2 months [95% confidence interval (CI) 2.6-6.27] in the treated group and median OS was 1.3 months (95% CI 0.95-1.74) in the control group (P < 0.0001). The calculated hazard ratio was 0.20 (0.13-0.33). Continued ICI was discovered to have an association with a higher rate of hospitalization at the end of life; more treatments received in the last 15 days of life and less utilization of specialist palliative care. This study discovered that patients with metastatic melanoma show a significant decrease in the instantaneous probability of mortality when they continue with finale-line ICI after progression., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The 5-year results of this trial showed that adjuvant therapy with dabrafenib plus trametinib resulted in longer relapse-free survival and distant metastasis-free survival than placebo among patients with BRAF V600-mutated stage III melanoma. Longer-term data were needed, including data regarding overall survival., Methods: We randomly assigned 870 patients with resected stage III melanoma with BRAF V600 mutations to receive 12 months of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. Here, we report the final results of this trial, including results for overall survival, melanoma-specific survival, relapse-free survival, and distant metastasis-free survival., Results: The median duration of follow-up was 8.33 years for dabrafenib plus trametinib and 6.87 years for placebo. Kaplan-Meier estimates for overall survival favored dabrafenib plus trametinib over placebo, although the benefit was not significant (hazard ratio for death, 0.80; 95% confidence interval [CI], 0.62 to 1.01; P = 0.06 by stratified log-rank test). A consistent survival benefit was seen across several prespecified subgroups, including the 792 patients with melanoma with a BRAF V600E mutation (hazard ratio for death, 0.75; 95% CI, 0.58 to 0.96). Relapse-free survival favored dabrafenib plus trametinib over placebo (hazard ratio for relapse or death, 0.52; 95% CI, 0.43 to 0.63), as did distant metastasis-free survival (hazard ratio for distant metastasis or death, 0.56; 95% CI, 0.44 to 0.71). No new safety signals were reported, a finding consistent with previous trial reports., Conclusions: After nearly 10 years of follow-up, adjuvant therapy with dabrafenib plus trametinib was associated with better relapse-free survival and distant metastasis-free survival than placebo among patients with resected stage III melanoma. The analysis of overall survival showed that the risk of death was 20% lower with combination therapy than with placebo, but the benefit was not significant. Among patients with melanoma with a BRAF V600E mutation, the results suggest that the risk of death was 25% lower with combination therapy. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: The phase III KEYNOTE-913 study was conducted to evaluate the efficacy and safety of pembrolizumab as first-line therapy in patients with advanced Merkel cell carcinoma (MCC)., Objective: The aim was to report results from the primary analysis of KEYNOTE-913., Patients and Methods: Patients with recurrent locally advanced or metastatic MCC received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 treatments (~ 2 years). The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary end points were duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 by BICR, overall survival (OS), and safety and tolerability., Results: Fifty-five patients were treated with pembrolizumab. The median time from first dose to data cutoff (February 15, 2024) was 50.3 months (range 38.7-59.4). The ORR was 49% (95% confidence interval [CI] 35-63), with 12 complete responses and 15 partial responses. The median DOR was 39.8 months (range 4.8-52.5+), and the 24-month DOR rate was 69%. The median PFS was 9.3 months (95% CI 3-26), and the 24-month PFS rate was 39%. The median OS was 24.3 months (95% CI 12.4 to not reached), and the 24-month OS rate was 51%. Any-grade treatment-related adverse events (AEs) occurred in 38 patients (69%); 13 patients (24%) experienced grade 3-5 AEs. The most common treatment-related AEs were fatigue (n = 12 [22%]), pruritus (n = 12 [22%]), and lipase increase (n = 10 [18%]). One patient died of treatment-related Guillain-Barré syndrome., Conclusions: Pembrolizumab provided durable antitumor activity and promising survival and had a manageable safety profile in patients with recurrent locally advanced or metastatic MCC, supporting its use in this population., Trial Registration: Clinicaltrials.gov, NCT03783078., (© 2024. The Author(s).)

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Currently, treatment options for patients with advanced melanoma who experience failed immunotherapy or targeted therapy are lacking. Recent studies suggest the antitumor activity of combined pembrolizumab and lenvatinib in patients with advanced melanoma progressing on immunotherapy. Herein, we report the clinical outcomes of combined lenvatinib and a programmed cell death protein-1 inhibitor (PD-1) in this population., Materials and Methods: This French multicenter real-world study was conducted between September 2020 and July 2023. The primary endpoint was the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumours (version 1.1). Secondary variables were treatment-related adverse events (TRAEs), progression-free survival (PFS), overall survival (OS), and duration of response (DOR)., Results: Of the 67 patients included (median age, 69 years; median follow-up, 5.0 months), 85% had stage IV-M1c or M1d disease. The overall ORR was 28.4% (95% CI, 18%-41%), including 3 complete (4.5%) and 16 partial (23.9%) responses. Median DOR was 3.1 (interquartile range, 1.3-4.3) months. Median PFS and OS were 3.1 (95% CI, 2.5-3.7) and 9.8 (95% CI, 5.6-13.9) months, respectively. Grades 3-5 TRAEs occurred in 16 (24%) patients; common TRAEs were fatigue (43.3%), nausea/vomiting (26.8%), diarrhea (20.9%), and hypertension (20.9%). No treatment-related deaths occurred., Conclusion: Our real-world study demonstrates an interesting response rate and acceptable safety profile in a population with poor prognostic factors. Our data support this treatment option for refractory melanoma, as it is not approved by the Food and Drug Administration or European Medicines Agency, and highlight the need for new strategies., (© The Author(s) 2024. Published by Oxford University Press.)

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Despite new treatments, the HCC rate remains important, making it necessary to develop novel therapeutic strategies. Photodynamic therapy (PDT) using a Rose-Bengal (RB) photosensitizer (RB-PDT) could be a promising approach for liver tumor treatment. However, the lack of standardization in preclinical research and the diversity of illumination parameters used make comparison difficult across studies. This work presents and characterizes a novel illumination device based on one green light-emitting diode (CELL-LED-550/3) dedicated to an in vitro RB-PDT. The device was demonstrated to deliver a low average irradiance of 0.62 mW/cm 2 over the 96 wells of a multi-well plate. Thermal characterization showed that illumination does not cause cell heating and can be performed inside an incubator, allowing a more rigorous assessment of cell viability after PDT. An in vitro cytotoxic study of the RB-PDT on an HCC cell line (HepG2) demonstrated that RB-PDT induces a significant decrease in cell viability: almost all the cells died after a light dose irradiation of 0.3 J/cm 2 using 75 µM of RB (<10% of viability). In conclusion, the RB-PDT could be a therapeutic option to treat unresectable liver lesions and subclinical disease remaining in the post-resection tumor surgical margin.

Competing Interests: Conflicts of interest CL declares consulting and advisory fees from BMS, MSD, Pierre Fabre and Sanofi. SM declares consulting and advisory fees from Novartis and Roche, and research funding from Biocartis. The other authors declare no conflicts of interest.

Background: In the phase 2 EMPOWER-CSCC-1 study (NCT02760498), cemiplimab demonstrated antitumor activity against metastatic cutaneous squamous cell carcinoma (mCSCC) and locally advanced cutaneous squamous cell carcinoma (laCSCC)., Objectives: To report final analysis of weight-based cemiplimab in mCSCC and laCSCC (groups 1 and 2), fixed-dose cemiplimab in mCSCC (group 3), and primary analysis of fixed-dose cemiplimab in mCSCC/laCSCC (group 6)., Methods: Patients received cemiplimab (3 mg/kg intravenously every 2 weeks [groups 1 and 2]) or cemiplimab (350 mg intravenously [groups 3 and 6]) every 3 weeks. The primary end point was objective response rate (ORR). Duration of response (DOR) and progression-free survival (PFS) are presented per protocol, according to post-hoc sensitivity analyses that only include the period of protocol-mandated imaging assessments., Results: At 42.5 months, ORR for groups 1-3 (n = 193) was 47.2%, estimated 12-month DOR was 88.3%, and median PFS was 26.0 months. At 8.7 months, ORR for group 6 (n = 165 patients) was 44.8%; median DOR and median PFS were not reached. Serious treatment-emergent adverse event rates (grade ≥3) were groups 1-3: 31.1% and group 6: 34.5%., Limitations: Nonrandomized study, nonsurvival primary end point., Conclusion: EMPOWER-CSCC-1 provides the largest prospective data on long-term efficacy and safety for anti-programmed cell death-1 therapy in advanced CSCC., Competing Interests: Conflicts of interest Dr Hughes reports consulting/advisory roles at AstraZeneca, Bristol-Myers Squibb, Eisai, Merck, Merck Sharp & Dohme, Pfizer, and Roche; and institutional research funding from Amgen. Dr Guminski reports personal fees and advisory board and travel support from Bristol-Myers Squibb and Sun Pharma; advisory board fees from Eisai, Merck KGaA, and Pfizer; travel support from Astellas; and clinical trial unit support from PPD Australia. Dr Bowyer reports advisory board roles for Eli Lilly Australia, Ipsen, Merck Sharp & Dohme, and Sanofi; virtual meeting sponsorship from Bristol-Myers Squibb and Merck Sharp & Dohme Australia; and travel support from Merck Sharp & Dohme and AstraZeneca. Michael Migden reports honoraria and travel expenses from Regeneron Pharmaceuticals, Inc., and Sanofi; consulting fees from Feldan Therapeutics, Replimune, Stamford Pharma, and Sun Pharma; and institutional research funding from Regeneron Pharmaceuticals, Inc., and Replimune. Dr Schmults reports steering committee membership for Castle Biosciences; steering committee membership and consultancy for Regeneron Pharmaceuticals, Inc.; consultancy for Sanofi; research funding from Castle Biosciences, Genentech, Merck, Novartis, and Regeneron Pharmaceuticals, Inc.; and serving as a chair for the National Comprehensive Cancer Network. Dr Khushalani reports grants and advisory board fees from Bristol-Myers Squibb, Merck, Novartis, and Regeneron Pharmaceuticals, Inc.; advisory board fees from AstraZeneca (data safety monitoring committee), Castle Biosciences, Incyte (data safety monitoring committee), Instil Bio, Iovance, Jounce Therapeutics, Nektar, and Replimune; grants from Celgene, GlaxoSmithKline, HUYA, Modulation Therapeutics, and Replimune; honoraria from Genzyme, National Comprehensive Cancer Network (grant funding from general research support through Pfizer), and Nektar (study steering committee); common stock ownership of Amarin, Bellicum Pharmaceuticals, and Transenetrix; study steering committee membership for Bristol-Myers Squibb, Regeneron Pharmaceuticals, Inc., and Replimune; and travel support from Regeneron Pharmaceuticals, Inc. Dr Chang reports consulting and advisory roles with Merck, and Regeneron Pharmaceuticals, Inc.; research funding from Galderma, Merck, Novartis, and Regeneron Pharmaceuticals, Inc., and consultancy for Castle Biosciences and Feldan. Dr Grob reports serving on an advisory board for Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Pfizer, Philogen, Roche, and Sanofi; and an advisory role for Bristol-Myers Squibb. Dr Lewis reports employment, stock, and other ownership interests at Regeneron Pharmaceuticals, Inc. At the time of this study, Dr Lewis was affiliated with the University of Colorado Denver Cancer Center and is now an employee of Regeneron Pharmaceuticals, Inc. Dr Day reports serving on an advisory board for Amgen, travel support from Merck; and clinical trial support (investigational medical product provision, no financial support) from AstraZeneca and Bristol-Myers Squibb. Dr Ladwa reports honoraria from AstraZeneca, Bristol-Myers Squibb, and Merck Sharp & Dohme; consulting or advisory roles for AstraZeneca, and Roche; and travel, accommodation, and expenses from Merck Sharp & Dohme. Dr Stein reports ownership of stocks/shares in Icon Group. Dr Muñoz Couselo reports serving on an advisory board for Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi; honoraria from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Roche; and clinical trial participation (principal investigator) for Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi. Dr Meier reports travel support, speaker’s fees, or advisor’s honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi; and research funding from Novartis and Roche. Dr Hauschild reports institutional grants, speaker’s honoraria, and consultancy fees from Amgen, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Pierre Fabre, Provectus, Roche, and Novartis; institutional grants and consultancy fees from Merck Serono, Philogen, and Regeneron Pharmaceuticals, Inc.; and consultancy fees from OncoSec. Dr Schadendorf reports honoraria from 4SC AG, Array BioPharma, Bristol-Myers Squibb, Immunocore, InflarxGmbH, Merck, Merck Sharp & Dohme, NeraCare GmbH, Novartis, Pierre Fabre, Pfizer, Philogen, Regeneron Pharmaceuticals, Inc., Sandoz, Sanofi, Serono, Sun Pharma, Roche/Genentech, and Ultimovacs; advisory board and consulting fees from 4SC AG, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc., Roche/Genentech, Sanofi, and Nektar; speaker fees from Bristol-Myers Squibb, Merck KGaA, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc., and Sanofi; institutional research funding from Array BioPharma/Pfizer, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche; and travel/accommodation expenses from Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc., Roche/Genentech, and Sanofi. Dr Basset-Seguin reports serving as an invited speaker, advisory board member, and consultant for Galderma, Regeneron Pharmaceuticals, Inc., Sanofi, and Sun Pharma. Dr Modi reports consulting/advisory board participation for Merck, Regeneron Pharmaceuticals, Inc., and Sanofi Genzyme; and speaker bureau participation for Regeneron Pharmaceuticals, Inc., and Sanofi Genzyme. Dr Dalac-Rat reports honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Sun Pharma. Dr Dunn reports advisory board participation for Merck and Regeneron Pharmaceuticals, Inc.; and research support from CUE-101, Regeneron Pharmaceuticals, Inc., Replimune Pharmaceuticals, and Seagen. Dr Flatz reports research funding from Hookipa Pharma; and advisory board fees from Bristol-Myers Squibb, Novartis, Philogen, and Sanofi. Dr Mortier reports personal fees and nonfinancial support from Bristol-Myers Squibb, and Merck Sharp & Dohme, Novartis, and Roche. Dr Guégan reports consulting fees from Bristol-Myers Squibb, Janssen, and Pierre Fabre; and technical support for congress attendance from Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme, and Sanofi. Dr Heinzerling reports consulting fees from Bristol-Myers Squibb, Highlight Therapeutics, Novartis, Pierre Fabre, Roche, and Sanofi; lecture fees from Astellas, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche, and Sanofi; and travel grants from Bristol-Myers Squibb, Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, and Roche. Dr Mehnert reports advisory board fees from Bristol-Myers Squibb, Eisai, Novartis, Pliant Therapeutics, Regeneron Pharmaceuticals, Inc., and Seagen; and consultancy fees from Merck. Dr Soria-Rivas reports speaker’s honoraria from Bristol-Myers Squibb, Immunocore, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche Pharma, and Sanofi Aventis; and advisory board fees from Bristol-Myers Squibb, Immunocore, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron Pharmaceuticals, Inc., and Sanofi Aventis. 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, Genesis Pharma, LEO Pharma, Novartis, and Pfizer. Dr Ulrich reports advisory board and speaker roles for Regeneron Pharmaceuticals, Inc., Roche, Sanofi, and Sun Pharma. Dr Wong reports grant funding to institution from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, F-Star Therapeutics, Genentech, Gilead, Kura Oncology, Merck Sharp & Dohme, Pfizer, Regeneron Pharmaceuticals, Inc., and TopAlliance Biosciences, and consulting fees from Blueprint Medicines Corporation, Genzyme/Sanofi, and Regeneron Pharmaceuticals, Inc. Dr Beylot-Barry reports institutional research funding from Roche and speaker honoraria from Sun Pharma. Dr Bossi reports advisory board or conference honoraria for Merck, Merck Sharp & Dohme, Sanofi-Regeneron, and Sun Pharma. Dr Bugés Sánchez reports personal fees from Amgen, Merck, Novartis, and Sanofi. Dr Chandra reports honoraria from Array BioPharma, Bristol-Myers Squibb, EMD Serono, Exicure, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., and Sanofi; consulting/advisory roles for Array BioPharma, Bristol-Myers Squibb, EMD Serono, Exicure, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., and Sanofi; and institutional research funding from Bristol-Myers Squibb, EMD Serono, Exicure, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., and Sanofi. Dr Robert reports grants, personal fees, and advisory board roles for Amgen, Biothera, Bristol-Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, and Ultimovacs. Dr Silk reports institutional research grant and funding from Biohaven Pharmaceuticals, Merck, Morphogenesis, Regeneron Pharmaceuticals, Inc., Replimune, and Shattuck Laboratories; advisory board fees from Natera, Merck and Regeneron Pharmaceuticals, Inc.; consulting fees from Leerink, and royalties from UpToDate, Inc. Ms Booth and Drs, Yoo, Seebach, Lowy, and Fury report employment, stock, and other ownership interests at Regeneron Pharmaceuticals, Inc. Dr Rischin reports institutional research grant and funding from ALX Oncology, Bristol-Myers Squibb, GlaxoSmithKline, Kura Oncology, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., Roche, and Sanofi; and uncompensated scientific committee and advisory board roles for Eisai, Bicara, GlaxoSmithKline, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., and Sanofi. Drs Ansstas, Trabelsi, and Russell have no conflicts of interest to declare., (Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Aim: Avelumab has been approved worldwide for treatment of metastatic Merkel cell carcinoma (mMCC), a rare and aggressive skin cancer. This study evaluated outcomes in patients with mMCC in France who received avelumab as second-line or later (2L+) treatment in routine clinical practice., Methods: This retrospective, noninterventional study evaluated all patients diagnosed with mMCC using two databases: CARADERM (French national database of rare dermatological cancers) and SNDS (national healthcare database), identified via probabilistic linkage. Eligible patients initiated avelumab as 2L+ treatment between August 2016 and December 2019 and were followed for 24 months. The primary endpoint was overall survival (OS) at 24 months., Results: Overall, 180 patients who received 2L+ avelumab were identified (112 from CARADERM, 68 after SNDS linkage). Median age at diagnosis was 74.0 years and 177 (98.3 %) had received chemotherapy alone as first-line treatment. Median follow-up was 13.1 months. Median OS from start of avelumab was 14.6 months (95 % CI, 9.9-21.3) in the overall population, 15.9 months (95 % CI, 8.6-28.3) in CARADERM patients, and 13.3 months (95 % CI, 6.7-19.1) in non-CARADERM patients. OS rates at 12 and 24 months were 53.8 % (95 % CI, 46.2 %-60.8 %) and 40.5 % (95 % CI, 33.2 %-47.6 %), respectively. In evaluable patients (CARADERM database), median progression-free survival was 3.6 months (95 % CI, 2.7-7.5) and the objective response rate was 55.3 % (95 % CI, 45.3-65.4), including complete response in 31.9 %., Conclusions: Real-world outcomes with 2L+ avelumab treatment for mMCC are consistent with clinical trial findings, supporting the recommendation of avelumab as a standard of care., 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.)

Aims: To describe the demographic characteristics of heroin and cocaine injectors with chronic injection-related trophic disorders, as well as the clinical and progressive characteristics of these disorders., Methods: A descriptive, observational, multicenter and retrospective study over the last 15 years. Patients were recruited via a call for cases and by consulting the health data warehouse of the university hospital center., Results: The population comprised 39 injection drug users, of whom 79.5% were male, with a median age of 41 years. Subjects had numerous co-addictions and 70.5% were infected with hepatitis C virus. Trophic disorders were multiple in some cases: 43.5% of patients had lymphoedema, 87% had ulcers, and 56.5% had injection-related scars. Ulcers were multiple, large, and present for a median of 3 years. They were located on the upper limbs in 32.5% of cases. Ulcers constituted a source of complications in 64.5% of cases and these were infectious in 91% of cases (local, osteoarticular or systemic). During follow-up, 8 patients died and 21.5% of patients requiring ulcer care were lost to follow-up., Conclusions: This study showed a high rate of complications, particularly infections, of ulcers in injection drug users. Localization of these ulcers to the upper limbs, although rare in the general population, is relatively frequent in this population. Follow-up is difficult and cooperation between dermatologist and addictologist is essential to improve patient care., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Olivier Cottencin has acted as a chairman or speaker of symposia organized by Janssen, Indivior, and Recordati.]., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Sonic hedgehog inhibitors (SHHis) are an effective treatment in locally advanced basal cell carcinoma (laBCC). However, the use of these drugs is limited by adverse events, and relapse at discontinuation in around one-half of patients. A few cases of patients treated concomitantly by radiotherapy (RT) and SHHis have been reported in the literature, suggesting that the combination results in an improved overall response. Maintaining complete response after stopping treatment is a concern, especially as resuming treatment in the case of relapse does not guarantee a new therapeutic response. The optimal combination and sequence of treatment to improve local control of laBCCs are not yet defined., Objectives: We hypothesized that consolidation RT after complete response to SHHis could reduce the risk of relapse at discontinuation., Methods: We present a case series of patients with laBCCs who achieved complete response after SHHi treatment and were treated with consolidation RT. Patients were evaluated by a skin cancer board. The closure RT technique and dosage were refined by a radiotherapist., Results: Eleven patients were included. SHHis were prescribed for a median 5 months (range 4-11). Consolidation RT was performed after complete response to SHHis and discontinuation. RT was delivered at a median dose of 45 Gy (range 40.5-66) in 10 fractions (range 9-33). With a median follow-up of 23 months, all patients maintained complete clinical response. This strategy was well tolerated with no grade 3 adverse events., Conclusions: SHHi treatment followed by consolidation RT after drug discontinuation seems effective and safe. Further studies are needed to develop a precise strategy for the management of laBCCs., Competing Interests: Conflicts of interest N.M. is an occasional consultant for Roche and Novartis. L.M. is an occasional consultant for Novartis, Pierre Fabre Medicament, Bristol-Myers-Squibb, Viatris medical, UCB Pharma SA, Leo Pharma, Almirall SAS, Edimark and MSD France. The other authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Mycosis fungoides (MF) has usually an indolent course. However, some patients develop a more aggressive disease and few prognostic parameters have been identified. Isolated cases of pustular MF (pMF) suggest an unfavourable prognosis., Objectives: We aim to describe the clinico-pathological characteristics and prognostic value of pMF., Methods: We retrospectively collected data of all cases of MF with histological pustules diagnosed from 2009 to 2020. The outcomes and clinico-pathological characteristics of pMF at diagnosis (pMFD) were compared to those of a cohort of non-pustular MF (NpMF)., Results: 33 pMF (including 22 pMFD) and 86 NpMF cases were included. The median age at diagnosis of pMF was 61 years [IQR=50-75]. The median follow-up of pMFD was 32 months [IQR=14-49]. Clinically, 33% of pMF had pustules. Large-cell transformation (LCT) occurred in 17 cases. pMFD were at a significantly more advanced-stage and more showed LCT at diagnosis than NpMF (50% vs 7%, p<0.001 and 23% vs 0%, p<0.001, respectively). In multivariate Cox analysis, the presence of histological pustule at diagnostic was associated with shorter OS in all patients (HR=13.90, CI95%[2.43-79]; p=0.003), and in early-stage patients (HR=11.09, CI95%[1.56-78.82]; p=0.02). In multivariate Fine and Gray model analysis, pMFD was associated with a higher cumulative incidence of LCT (SHR=13.90, CI95% [2.43-79]; p=0.003) in all patients. Median OS after the occurrence of histological pustules during follow-up of all pMF patients was 37 months, with a five-year OS of 25% (CI95% [0.06-0.5])., Conclusion: pMF often follows an aggressive course, with a high risk of LCT and shorter survival, even for early-stage patients. Histological pustules at diagnostic of MF might represent an independent poor prognostic factor, to be confirmed by further studies. Because pustules are not always clinically identified, histological pustules should be mentioned in pathology reports of MF and prompt discussion of a closer follow-up., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Significance: Multilesional basal cell carcinoma (BCC) are spread on sun exposed skin areas, including arms, face and back. The first-line treatment remains the surgical resection or Mohs surgery. Despite its high complexity, Mohs surgery is well practiced in USA and Germany and presents very good results both in esthetic and in carcinology point of view. Large lesions more than 2 cm remain challenging to remove by topical cream used in photodynamic therapy (PDT). If these larger lesions are not treated in less than 1 month, they could grow deeply in the skin, thus enhancing the risk of reoccurrence and the severity of the disease. Despite this model herein studied, that is non melanoma skin cancer is a good prognostic cancer, the therapy aims to be applied to more aggressive melanoma skin cancers., Aim: Total regression of large cutaneous lesions less than 1 month with no reoccurrence., Approach: Tumor induction on murine model bearing a 500 mm 3 subcutaneous lesion. Increasing dose of gold nanoparticles at fixed initial concentration C0 = 0.3 mg/mL, infused into the tumor then exposition of the region of interest to NIR medical laser to assess the therapy. One or two intratumoral administration(s) were compared to surgery and control, that is no treatment, laser alone or nanoparticles alone., Results: Gold nanoparticles alone or the NIR laser alone did not induce the tumor regression. The combination of laser and nanoparticles called plasmonic nanophotothermal therapy induced apoptosis. Derma and hypoderm do not show any visible gold nanoparticles and demonstrated a good cicatrization process., Conclusion: Plasmonic nanophotothermal therapy using two doses of gold nanoparticles was the only protocol that proved its efficacy on large lesions in 14 days, that is 500 mm 3 on a murine model bearing human basal cell carcinoma., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Abstract: Mycosis fungoides (MF) is the most prevalent primary cutaneous T-cell lymphoma, with an indolent or aggressive course and poor survival. The pathogenesis of MF remains unclear, and prognostic factors in the early stages are not well established. Here, we characterized the most recurrent genomic alterations using whole-exome sequencing of 67 samples from 48 patients from Lille University Hospital (France), including 18 sequential samples drawn across stages of the malignancy. Genomic data were analyzed on the Broad Institute's Terra bioinformatics platform. We found that gain7q, gain10p15.1 (IL2RA and IL15RA), del10p11.22 (ZEB1), or mutations in JUNB and TET2 are associated with high-risk disease stages. Furthermore, gain7q, gain10p15.1 (IL2RA and IL15RA), del10p11.22 (ZEB1), and del6q16.3 (TNFAIP3) are coupled with shorter survival. Del6q16.3 (TNFAIP3) was a risk factor for progression in patients at low risk. By analyzing the clonal heterogeneity and the clonal evolution of the cohort, we defined different phylogenetic pathways of the disease with acquisition of JUNB, gain10p15.1 (IL2RA and IL15RA), or del12p13.1 (CDKN1B) at progression. These results establish the genomics and clonality of MF and identify potential patients at risk of progression, independent of their clinical stage., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Sézary syndrome is an extremely rare and fatal cutaneous T-cell lymphoma (CTCL). Mogamulizumab, an anti-CCR4 monoclonal antibody, has recently been associated with increased progression-free survival in a randomized clinical trial in CTCL. We aimed to evaluate OS and prognostic factors in Sézary syndrome, including treatment with mogamulizumab, in a real-life setting., Methods: Data from patients with Sézary (ISCL/EORTC stage IV) and pre-Sézary (stage IIIB) syndrome diagnosed from 2000 to 2020 were obtained from 24 centers in Europe. Age, disease stage, plasma lactate dehydrogenases levels, blood eosinophilia at diagnosis, large-cell transformation and treatment received were analyzed in a multivariable Cox proportional hazard ratio model. This study has been registered in ClinicalTrials (SURPASSe01 study: NCT05206045)., Findings: Three hundred and thirty-nine patients were included (58% men, median age at diagnosis of 70 years, Q1-Q3, 61-79): 33 pre-Sézary (9.7% of 339), 296 Sézary syndrome (87.3%), of whom 10 (2.9%) had large-cell transformation. One hundred and ten patients received mogamulizumab. Median follow-up was 58 months (95% confidence interval [CI], 53-68). OS was 46.5% (95% CI, 40.6%-53.3%) at 5 years. Multivariable analysis showed that age ≥ 80 versus <50 (HR: 4.9, 95% CI, 2.1-11.2, p = 0.001), and large-cell transformation (HR: 2.8, 95% CI, 1.6-5.1, p = 0.001) were independent and significant factors associated with reduced OS. Mogamulizumab treatment was significantly associated with decreased mortality (HR: 0.34, 95% CI, 0.15-0.80, p = 0.013)., Interpretation: Treatment with mogamulizumab was significantly and independently associated with decreased mortality in Sézary syndrome., Funding: French Society of Dermatology, Swiss National Science Foundation (IZLIZ3&#95;200253/1) and SKINTEGRITY.CH collaborative research program., Competing Interests: AdM declares nonfinancial support from Kyowa Kirin and Recordati Rare Diseases; fees from Takeda, Almirall and Recordati Rare Diseases, and research funding, outside the scope of this study, from Kyowa Kirin, Innate Pharma, Almirall and Takeda. MB declares consultant fees from Innate Pharma, Kyowa Kirin, Takeda, BMS, Sanofi, Quantum Genomics, and research funding from Kyowa Kirin and Takeda, outside the scope of this study. SM declares consultant fees outside the scope of this study, from Pierre Fabre, Sanofi, Novartis and Biocartis, and has received research funding from BMS, Novartis and Roche. NF declares having received nonfinancial support from Kyowa Kirin. PS received a research grant from Pierre Fabre, fees unrelated to this manuscript from Bristol-Myers Squibb, MSD, Merck-Serono, Pfizer, Roche-Genentech, Pierre Fabre, and Novartis; received nonfinancial support from Bristol-Myers Squibb, MSD, Roche-Genentech, Pierre Fabre, and Novartis outside of the scope of this study. MBB declares consultant fees from Kyowa Kirin, Takeda and Recordati and research funding from Kyowa Kirin and Almirall outside the scope of this study. HMT declares consultant fees outside from the scope of this study from Innate Pharma, and has received research funding, outside the scope of this study, from Kyowa Kirin. SIHO consultant fees outside the scope of this study from Takeda and Recordati. GD declares consultant fees outside of the scope of this study from Kyowa Kirin and Recordati. EG declares consultant fees and/or grant support from Mallinckrodt, Helsinn, Takeda, Novartis and Kyowa Kirin unrelated to this work. FG declares consultant fees from Recordati and Kyowa Kirin, outside from the scope of this study. GQ declares consultant fees from Takeda, Recordati and Kyowa Kirin, outside the scope of this study. CM declares nonfinancial support from MSD, Pfizer, Novartis, Bristol-Myers Squibb, Pierre Fabre, Leo Pharma, Sanofi Aventis, Jannsen Cilag outside of the scope of this study. SB declares having received nonfinancial support from Kyowa Kirin and Recordati. MBag declares consulting fees from Kyowa Kirin, Takeda, Recordati. HB declares consultant fees from Kyowa Kirin. EH declares consultant fees outside the scope of this study from Bristol-Myers Squibb, Takeda, Sanofi, Jannsen Cilag, Blueprint Medicines, AbbVie and nonfinancial support from Kyowa Kirin, MSD, UCB Pharma, Novartis, Almirall, Pierre Fabre. The other authors declare that they have no conflict of interest., (© 2024 The Authors.)

Background: Cutaneous adnexal carcinomas are a heterogeneous group of rare neoplasms. Surgical excision is the first-line treatment in localized stage. The use and effectiveness of radiotherapy have not been thoroughly evaluated in these neoplasms., Objectives: The present work analyses prognostic factors on outcomes in skin adnexal carcinomas, based on data from the CARADERM (CAncers RAres DERMatologiques) database., Methods: Data were collected retrospectively including demographic data, tumour types and therapeutic characteristics of all patients included in the CARADERM database, with at least one informative follow-up visit. Analyses were performed on three populations: patients with complete resection of the primary tumour (ADJ/primary population), patients achieving complete remission after complete resection of a recurrent tumour (ADJ/recurrent population) and patients with unresectable locally advanced or metastatic tumours (ADV/MET population). Overall and recurrence/progression-free survivals at 3-year were analysed using Cox regression models., Results: Radiotherapy did not affect overall survival (OS) in the ADJ/primary population. Adjusted recurrence-free survival (RFS) was significantly lower in the radiotherapy group in ADJ/primary group. Older patients had significantly poorer OS and RFS. Tumour size and immunosuppression were significantly associated with poorer RFS only. Radiotherapy had no effect on OS and RFS in the ADJ/recurrent population. Age was the only factor associated with a poorer OS. Radiotherapy was significantly associated with longer progression-free survival (PFS) in age-sex adjusted analysis in the ADV/MET population, without effect on OS., Conclusions: Our study shows that age, tumour size and immunosuppression are significantly associated with survival in localized adnexal carcinomas. Radiotherapy may improve PFS in the ADV/MET population but not in localized and recurrent carcinomas after complete excision., (© 2024 The Author(s). Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Nivolumab was first authorized at a weight-based dose (WBD) of 3 mg/kg every two weeks (Q2W). Since 2017, a fixed dose (FD) regimen [first 240 mg Q2W and then 480 mg per month (Q4W)] was allowed. The objective of the study was to compare a WBD regimen and an FD regimen with regard to effectiveness and safety. We conducted a single-center, retrospective, real-life study of consecutive adult patients who had received a WBD of nivolumab or an FD of 480 mg Q4W. The primary endpoint was the occurrence of grade ≥3 immune-related adverse events (irAEs). The secondary endpoints were overall survival and cost of the treatment. In all, 342 patients were included: 71 in the WBD cohort and 271 in the FD cohort. Of these patients, 201 patients (59.6%) experienced an irAE, and 24 of these events were graded as ≥3. At 12 months, there was no significant difference in irAE occurrence between the two cohorts [hazard ratio (95% confidence interval): 0.54 (0.21-1.36), P  = 0.19]. The 12-month overall survival rate was significantly lower in the WBD cohort ( P  < 0.001). Switching from a fortnightly weight dose to a fixed monthly dose halves the cost of hospitalization. Our results did not show a significant difference between WBD and FD cohort in the occurrence of severe irAEs. However overall survival appeared to be significantly higher in FD group. Some clinical trials are investigating a hybrid dosing regimen in which a WBD is capped by an FD. The present results need to be confirmed in prospective studies., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Results from the JAVELIN Merkel 200 study led to the approval of avelumab [an anti-programmed death-ligand 1 (PD-L1) antibody] for the treatment of metastatic Merkel cell carcinoma (mMCC) in multiple countries and its inclusion in the treatment guidelines as a preferred or recommended therapy in this setting. Here, we report 4-year follow-up results from the cohort of patients with mMCC who received avelumab as first-line treatment., Patients and Methods: In part B of JAVELIN Merkel 200, a single-arm, open-label, phase II study, patients with mMCC who had not received prior systemic therapy for metastatic disease received avelumab 10 mg/kg via intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. In this analysis, long-term overall survival (OS), patient disposition, and subsequent treatment were analyzed., Results: In total, 116 patients received first-line avelumab. At the data cutoff (2 February 2022), the median follow-up was 54.3 months (range 48.0-69.7 months). Seven patients (6.0%) remained on treatment and an additional 21 patients remained in follow-up (18.1%); 72 patients (62.1%) had died. The median OS was 20.3 months [95% confidence interval (CI) 12.4-42.0 months], with a 4-year OS rate of 38% (95% CI 29% to 47%). In patients with PD-L1+ or PD-L1- tumors, the 4-year OS rate was 48% (95% CI 26% to 67%) and 35% (95% CI 25% to 45%), respectively. In total, 48 patients (41.4%) received poststudy anticancer drug therapy, most commonly etoposide (20.7%), carboplatin (19.0%), and avelumab (12.1%)., Conclusions: Avelumab first-line monotherapy in patients with mMCC resulted in meaningful long-term OS, which compared favorably with historical studies of first-line chemotherapy. These results further support the role of avelumab as a standard of care for patients with mMCC., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The importance of ink rheology to the outcome of 3D printing is well recognized. However, rheological properties of printing inks containing drug nanocrystals have not been widely investigated. Therefore, the objective of this study was to establish a correlation between the composition of nanocrystal printing ink, the ink rheology, and the entire printing process. Indomethacin was used as a model poorly soluble drug to produce nanosuspensions with improved solubility properties through particle size reduction. The nanosuspensions were further developed into semisolid extrusion 3D printing inks with varying nanocrystal and poloxamer 407 concentrations. Nanocrystals were found to affect the rheological properties of the printing inks both by being less self-supporting and having higher yielding resistances. During printing, nozzle blockages occurred. Nevertheless, all inks were found to be printable. Finally, the rheological properties of the inks were successfully correlated with various printing and product properties. Overall, these experiments shed new light on the rheological properties of printing inks containing nanocrystals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Pan-negative melanomas account for 30% of melanomas. In case of immunotherapy failure, therapeutic options are limited. Oncogene fusions represent a target of interest in many solid cancers. In melanoma, the frequency of oncogene fusion is not well documented and not routinely investigated. We conducted a single-center retrospective study. The objective was to determine the frequency of oncogene fusion detected by RNA sequencing, in patients with advanced or metastatic pan-negative melanoma. In parallel, an extended molecular alteration search was performed using extended targeted next-generation sequencing. We identified 59 patients with advanced pan-negative melanoma between January 2021 and January 2023. It was a cutaneous melanoma in 71.1% of the cases, a mucous melanoma in 15.2% of the cases. We identified nine patients with a RAF fusion, including seven BRAF gene fusion and two RAF1 fusion. Of the other molecular alterations, NF1 mutation was the most frequent molecular alteration identified. Among the nine patients with RAF fusions, all the patients initially received treatment with anti-PD1 ± anti-CTLA4 immunotherapy. After immunotherapy failure, five patients benefited from second-line targeted therapy (two with BRAF and MEK inhibitors combination, three MEK inhibitors alone). The response rate was 20%. In a population of pan-negative melanoma, we detected 15.2% of RAF fusion. Fusion detection allowed the introduction of a second line of targeted therapy, in the absence of a validated therapeutic option in 55.5% of cases. This study suggests the relevance of detecting RAF fusion in a selected population., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Stereotactic radiotherapy (SBRT) potentially has a role in the management of oligometastatic melanoma. However, literature with data specific to this management is very limited. The objectives of this study were to evaluate the time to local control (LC) of extra-cranial melanoma metastases after SBRT treatment and to help establish if SBRT is a useful therapy for oligometastatic melanoma., Methods: A retrospective study was conducted with data collected from two referral centers in France between 2007 and 2020. The oligometastatic status of patients was reported based on the latest recommendations with a maximum of three lesions prior to treatment., Results: A total of 69 patients receiving SBRT for 88 oligometastatic melanoma metastases were included. The median follow-up time was 42.6 months. Most patients were treated for metachronous oligometastatic lesions. Occurrence of oligoprogression, oligorecurrence, and oligopersistence was reported in 42.0%, 39.1%, and 17.4% of cases, respectively. Treated lesions were mostly pulmonary (40.6%), followed by lymph node (34.8%) and hepatic sites (24.6%). Progression-free survival at 1, 2, and 3 years were 47.0% (35-59), 27.0% (16-39), and 25.0% (15.0-37.0), respectively. Time to LC rates at 1, 2, and 3 years were 94.2% (87.0-98.1), 90.3% (81.3-96.1), and 90.3% (81.3-96.1), respectively. Overall survival at 1, 2, and 3 years were 87% (76.0-93.0), 74.0% (76.0-93.0), and 61.0% (47.0-73.0), respectively. Only 17.4% of patients experienced acute, grade 1 or grade 2 toxicities with no reports of grade 3 or higher toxicities., Conclusion: SBRT demonstrated efficacy in managing melanoma patients with extracranial oligometastases and showed an overall low toxicity profile. Future randomized studies are needed to establish the role of SBRT in therapeutic approaches for patients with oligometastatic melanoma., Competing Interests: The 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., (Copyright © 2024 Trentesaux, Maiezza, Bogart, Le Deley, Meyer, Vanquin, Pasquier, Mortier and Mirabel.)

Introduction: Immunological checkpoint inhibitors (ICI) have led to a therapeutic revolution in the management of many cancers and indications are increasing. Neurological complications seem to have a profile quite distinct from that of toxicities related to chemotherapy, although it is possible that some manifestations remain under-reported or misdiagnosed., Objectives: (i) To evaluate the value of a self-questionnaire in screening for neurological ICI-related complications. (ii) To investigate whether, apart from the subacute complications described in the literature, neurological complications of more insidious onset might occur., Method: Patients followed in dermatology department for skin cancers treated with ICI, completed every infusion a neurological screening auto-questionnaire. Patients were selected for a neurological expertise based on the questionnaire's data., Results: In total, 149 patients completed≥1 questionnaire, with a median delay of 174 days from the start of treatment. A total of 229 questionnaires were completed between July 2019 and December 2019. 38 patients were identified for a neurological consultation. None of these patients had a neurological event attributable to ICI. During the follow-up, only one patient had a neurological event related to ICI, which was not revealed by the questionnaire., Discussion: Neurological signs in ICI-treated-skin-cancer context are more often due to tumoral progression. Neurological complications of ICI remain rare and unpredictable. The systematic neurological questionnaire has not been shown to be useful in this context. These results highlight the need to educate patients about possible subacute signs that should lead to contact the treating physicians and the need for a close cooperation between dermatologists/oncologists and neurologists., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Introduction: At first interim analysis of KEYNOTE-629, health-related quality of life (HRQoL) with pembrolizumab was stable or improved over 48 weeks in recurrent or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC). HRQoL results from the second interim analysis in R/M or locally advanced (LA) cSCC are presented., Methods: Patients received pembrolizumab 200 mg every 3 weeks for ≤ 2 years. Change in EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EQ-5D-5L scores were exploratory end points. Primary analysis was performed at week 12 to ensure adequate completion/compliance. Descriptive analyses were also conducted through weeks 48 and 75 for the LA and R/M cohorts, respectively., Results: At data cutoff (29 July 2020), mean scores in the LA cohort (n = 47) were stable from baseline to week 12 for EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) (-0.27 points [95% confidence interval (CI) -10.93 to 10.39]), physical functioning (-1.29 points [95% CI  -8.77 to 6.19]), and EQ-5D-5L visual analog scale (2.06 [95% CI -7.70 to 11.82]). HRQoL remained stable through week 48 in the LA cohort; 76.6% and 74.5% of patients had improved or stable GHS/QoL and physical functioning scores, respectively. HRQoL continued to show stability or improvement through week 75 in the R/M cohort (n = 99); 71.7% and 64.6% of patients had improved or stable GHS/QoL and physical functioning scores, respectively., Conclusions: Pembrolizumab has demonstrated antitumor activity and manageable safety. The current analysis shows pembrolizumab treatment preserved HRQoL. Collectively, these results support pembrolizumab as standard of care for LA or R/M cSCC., Trial Registration: ClinicalTrials.gov, NCT03284424-September 15, 2017., (© 2023. The Author(s).)

Background: The definition of hyperprogressive disease (HPD) is controversial in the literature and has not been widely described in melanoma. The aim of this study was to determine whether the concept of HPD applies to patients treated for advanced melanoma, using a definition with a simple, reproducible criterion, and to determine whether it is possible to identify predictive factors for HPD., Methods: This was a retrospective analysis on a prospective cohort. The data were extracted from MelBase, a French prospective, multicentre cohort of adult patients with advanced melanoma. The patients, following informed consent, were treated prospectively with anti-PD1, ipilimumab+nivolumab, BRAF/MEKi, or chemotherapy, 1st line or thereafter. HPD was defined, within 3 months following the start of the treatment, with the help of a clinical and biological criterion using Response Evaluation Criteria in Solid Tumours, Eastern Cooperative Oncology Group Performance Score, and lactate dehydrogenase., Results: The occurrence of HPD in the 4 groups was as follows (numbers of patients out of the total number): anti-PD1 98/1004 (10%), ipilumumab +nivolumab 19/327 (6%), targeted therapy 31/751 (4%), and chemotherapy 40/397 (10%). In the anti programmed cell death protein 1 (APD1) group, the relevant risk factors for HPD were: more than 3 metastatic sites (p = 0.03) and liver metastasis (p < 0.001)., Conclusion: This data, thanks to relevant clinical and biological criteria feasible in daily practice, supports the presence of a subgroup whose disease deteriorates rapidly during mono-immunotherapy. Also observed with other treatments, HPD could be the consequence of a natural and aggressive evolution of the disease, alleviated by strong-acting treatments., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Marie Fournier has no competing interests to disclose. Laurent Mortier reports personal fees and non-financial support from BMS, MSD, Pierre Fabre, Novartis; outside the submitted work. Olivier Dereure has no competing interests to disclose. Sophie Dalac has acted as a consultant and received honoraria from BMS, MSD, NOVARTIS and PFOS; outside the submitted work. Bastien Oriano has no competing interests to disclose. Stéphane Dalle reports grants from BMS, grants from MDS; outside the submitted work. Céleste Lebbé has received consulting fees from BMS, MSD, Novartis, Amgen, Roche, Merck Serono, Sanofi, Pierre Fabre, Pfizer; has received honoraria from Roche, BMS, Novartis, Amgen, MSD, Pierre-Fabre, Pfizer, Incyte; has received meeting/travel support from BMS, MSD, Novartis, Sanofi, Pierre-Fabre; has participated with a consulting role on data safety monitoring board for BMS, MSD, Novartis, Amgen, Roche, Merck Serono, Sanofi, Pierre Fabre; has financial interest with Avantis Medical Systems and InflaRx; outside the submitted work., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The tumor mutational burden (TMB) is high in melanomas owing to UV-induced oncogenesis. While a high TMB is a predictive biomarker of response to PD-1 inhibitors, it may be associated with the rise of resistant clones to targeted therapy over time. We hypothesized that survivals may depend on both the sun-exposure profile of the site of primary melanoma and the type of systemic treatment., Patients and Methods: Patients were screened from MelBase, a multicenter biobank dedicated to the prospective follow-up of stage III/IV melanoma. All patients with a known cutaneous primary melanoma who received a 1st-line systemic treatment by immunotherapy or targeted therapy were included (2013-2019). Outcomes were progression-free survival (PFS) and overall survival (OS)., Results: 973 patients received either anti PD-1(n=466), anti CTLA-4(n=143), a combination of both (n=118), or targeted therapies (n=246). Patients' characteristics at treatment initiation were: male (62%), median age of 62, AJCC stage IV (84%). Median follow-up was 15.5 months. The primary melanoma was located on chronically sun-exposed skin in 202 patients (G1: head neck), on intermittently sun-exposed skin in 699 patients (G2: trunk, arms, legs), and on sun-protected areas in 72 patients (G3: palms, soles). Median PFS was significantly higher in G1 under anti PD-1 treatment (8.7 months vs 3.3 and 3.4 months for G2 and G3, respectively) (p=0.011). PFS did not significantly differ in other groups. Similarly, median OS was significantly higher in G1 receiving 1 st line anti PD-1 treatment (45.6 months vs 31.6 and 21.4 months for G2 and G3) (p=0.04), as opposed to 1 st line targeted therapy (19.5 months vs 16.3 and 21.1 months for G1, G2 and G3 respectively)., Conclusion: Our study confirms that immunotherapy with anti PD-1 is particularly recommended for melanomas originating from chronically sun-exposed areas, but this finding needs to be confirmed by further research., Competing Interests: SD reported receiving financial support from and is a consultant for BMS, Roche, and is employed by Sanofi with stock ownership. LM reported receiving financial support from and is a consultant for BMS, Amgen, Merck, Incyte, MSD, Roche, and Novartis. OD reported receiving financial support from and is a consultant for BMS, MSD, Pierre Fabre, Recordati, Genevrier, Kiowa Kirin, Leo Pharma, and Novartis. CA reported receiving financial support from Amgen, BMS, and Roche. J-PA reported receiving financial support from BMS and MSD. SD-R reported receiving financial support from BMS, Novartis and MSD. HM reported receiving financial support from BMS, Novartis, Pierre Fabre, Leo Pharma and MSD. CD reported receiving financial support from BMS, MSD, Pierre Fabre, and Novartis. JQ reported receiving financial support from BMS, Jansen Cilag. DL reported receiving financial support from BMS, MSD, Novartis, Leo Pharma, and Merck. EM reported receiving financial support from BMS, MSD, and Novartis. PS reported receiving financial support from BMS, MSD, Novartis, Roche, and Pierre Fabre. CL reported serving as a consultant for BMS and receiving financial support from BMS, MSD, Roche, Novartis, Amgen, Merck, Pierre Fabre, Pfizer, and Incyte. LB reported receiving financial support from Novartis, Pierre Fabre, Roche, BMS, MSD. 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., (Copyright © 2023 Russo, Dalle, Dereure, Mortier, Dalac-Rat, Dutriaux, Leccia, Legoupil, Montaudié, Maubec, De Quatrebarbes, Arnault, Brocard, Saïag, Dreno, Allayous, Oriano, Lefevre, Lebbé and Boussemart.)

Data regarding elderly melanoma patients treated with anti-PD-1 or anti-CTLA-4 antibodies are in favor of tolerability outcomes that are similar to those of younger counterparts. However, there are very few studies focusing on elderly patients receiving nivolumab combined with ipilimumab (NIVO + IPI). Here, we ask what are the current prescribing patterns of NIVO + IPI in the very elderly population and analyze the tolerance profile. This French multicenter retrospective study was conducted on 60 melanoma patients aged 80 years and older treated with NIVO + IPI between January 2011 and June 2022. The mean age at first NIVO + IPI administration was 83.7 years (range: 79.3-93.3 years). Fifty-five patients (92%) were in good general condition and lived at home. Two dosing regimens were used: NIVO 1 mg/kg + IPI 3 mg/kg Q3W (NIVO1 + IPI3) in 27 patients (45%) and NIVO 3 mg/kg + IPI 1 mg/kg Q3W (NIVO3 + IPI1) in 33 patients (55%). NIVO + IPI was a first-line treatment in 39 patients (65%). The global prevalence of immune-related adverse events was 63% (38/60), with 27% (16/60) being of grade 3 or higher. Grade ≥ 3 adverse events were less frequent in patients treated with NIVO3 + IPI1 compared with those treated with NIVO1 + IPI3 (12% versus 44%, p = 0.04). In conclusion, the prescribing patterns of NIVO + IPI in very elderly patients are heterogeneous in terms of the dosing regimen and line of treatment. The safety profile of NIVO + IPI is reassuring; whether or not the low-dose regimen NIVO3 + IPI1 should be preferred over NIVO1 + IPI3 in patients aged 80 years or older remains an open question.

Trichoblastic carcinoma is a rare malignant cutaneous adnexal tumor with a risk of local invasion and distant metastasis. As of today, there is no consensus for the treatment of locally advanced or metastatic trichoblastic carcinoma. "AcSé Nivolumab" is a multi-center Phase II basket clinical trial (NCT03012581) evaluating the safety and efficacy of nivolumab in several cohorts of rare, advanced cancers. Here we report the results of nivolumab in patients with trichoblastic carcinoma. Of the eleven patients enrolled in the study, five patients had been previously treated by sonic hedgehog inhibitors. The primary endpoint 12-week objective response rate was 9.1% (N = 1/11) with 1 partial response. Six patients who progressed under previous lines of treatment showed stable disease at 12 weeks, reflecting a good control of the disease with nivolumab. Furthermore, 54.5% of the patients (N = 6/11) had their disease under control at 6 months. The 1-year overall survival was 80%, and the median progression-free survival was 8.4 months (95%CI, 5.7 to NA). With 2 responders (2 complete responses), the best response rate to nivolumab at any time was 18.2% (95%CI, 2.3-51.8%). No new safety signals were identified, and adverse events observed herein were previously described and well known with nivolumab monotherapy. These results are promising, suggesting that nivolumab might be an option for patients with advanced trichoblastic carcinomas. Further studies on larger cohorts are necessary to confirm these results and define the role of nivolumab in the treatment of trichoblastic carcinomas., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Merkel cell carcinoma (MCC) is a rare type of neuroendocrine tumor. Palpebral localization represents 2.5% of MCCs. Surgery is not always possible due to the localization or comorbidities of elderly patients. We hypothesized that radiotherapy (RT) alone could be a curative treatment in patients contraindicated for oncological surgery., Methods: We performed a retrospective monocentric study of patients with localized eyelid MCC treated with curative intent using curative radiotherapy., Results: Overall, 11 patients with histologically confirmed eyelid MCC were treated with curative radiotherapy. The median age was 77 years old (range: 53-94). Curative RT was decided mainly due to difficult localization and significant co-morbidities. The median lesion dose was 57 Gy (range: 47-70). Most patients had adjuvant lymph nodes irradiation with a median dose of 50 Gy ( n = 9; 82%). The median follow-up was 62 months (6-152 months). None of the seven deaths were MCC-related. None of our patients relapsed during follow-up. Side effects related to radiotherapy were mild (no grade ≥ 2) and rare ( n = 3, 21%)., Conclusion: Our data suggest that curative radiotherapy is an effective and safe treatment for Merkel cell carcinoma of the eyelid and periocular region. Radiotherapy alone allows limiting the aesthetic and functional sequelae in elderly and comorbid patients who are contraindicated for oncological surgery.

Background: With more than 15,000 new cases /year in France and 2,000 deaths, cutaneous melanoma represents approximately 4% of incidental cancers and 1.2% of cancer related deaths. In locally advanced (stage III) or resectable metastatic (stage IV) melanomas, medical adjuvant treatment is proposed and recent advances had shown the benefit of anti-PD1/PDL1 and anti-CTLA4 immunotherapy as well as anti-BRAF and anti-MEK targeted therapy in BRAF V600 mutated tumors. However, the recurence rate at one year is approximately 30% and justify extensive research of predictive biomarkers. If in metastatic disease, the follow-up of circulating tumor DNA (ctDNA) has been demonstrated, its interest in adjuvant setting remains to be precised, especially because of a lower detection rate. Further, the definition of a molecular response could prove useful to personalized treatment., Methods: PERCIMEL is an open prospective multicentric study executed through collaboration of the Institut de Cancérologie de Lorraine (non-profit comprehensive cancer center) and 6 French university and community hospitals. A total of 165 patients with resected stage III and IV melanoma, eligible to adjuvant imunotherapy or anti-BRAF/MEK kinase inhibitors will be included. The primary endpoint is the presence of ctDNA, 2 to 3 weeks after surgery, defined as mutated ctDNA copy number calculated as the allelic fraction of a clonal mutation relative to total ctDNA. Secondary endpoints are recurrence-free survival, distant metastasis-free survival and specific survival. We will follow ctDNA along treatment, quantitatively through ctDNA mutated copy number variation, qualitatively through the presence of cfDNA and its clonal evolution. Relative and absolute variations of ctDNA during follow-up will be also analyzed. PERCIMEL study aims at provide scientific evidence that ctDNA quantitative and qualitative variations can be used to predict the recurrence of patients with melanoma treated with adjuvant immunotherapy or kinase inhibitors, thus defining the notion of molecular recurrence., (© 2023. The Author(s).)

Physical activity is the first-line treatment of cancer-related fatigue. It has shown benefits on patient's quality of life (QoL) when practiced during and after treatment. New treatments have drastically changed the prognosis of melanoma. Still, few data are available about research program of supportive care in advanced melanoma. The primary outcome was to assess the feasibility of setting up a prospective study evaluating the benefits of Adapted Physical Activity (APA) on the QoL of patients with advanced melanoma. Feasibility was defined with a combination of five criteria including completion of questionnaire, recruitment, participant retention, patient adhesion to supportive care, and absence of adverse event. Between September 2019 and March 2021, 271 melanoma patients were questioned. Around 60% of stage IV melanoma patients were interested in support care. Patient retention at 3 months was sufficient. Only one patient could not be evaluated after 3 months of enrolment because of deterioration of the general state. Adhesion to exercise and sessions was good. Supervised APA program appeared to be safe and well tolerated as no adverse events or discontinuations were reported. Setting up a prospective research program evaluating the benefits of physical activity in advanced melanoma patients seems feasible. With melanoma becoming a chronic disease, supportive care may reduce fatigue, improve QoL and help maintain a healthy lifestyle. Data supporting its benefits on this survivor population are needed., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Immunotherapy has become the standard of care for several types of cancer, such as melanoma. However, it can induce toxicity, including immune checkpoint inhibitor-induced colitis (CIC). CIC shares several clinical, histological, biological, and therapeutic features with inflammatory bowel disease (IBD). Clostridium difficile infection (CDI) can complicate the evolution of IBD. We aimed to characterize the association between CDI and CIC in patients treated with anti-CTLA-4 and anti-PD-1 for melanoma. Patients from nine centers treated with anti-CTLA-4 and anti-PD-1 for melanoma and presenting with CDI from 2010 to 2021 were included in this retrospective cohort. The primary endpoint was the occurrence of CIC. The secondary endpoints were findings allowing us to characterize CDI. Eighteen patients were included. Eleven were treated with anti-PD-1, four with anti-CTLA-4, and three with anti-PD-1 in combination with anti-CTLA-4. Among the 18 patients, six had isolated CDI and 12 had CIC and CDI. Among these 12 patients, eight had CIC complicated by CDI, three had concurrent CIC and CDI, and one had CDI followed by CIC. CDI was fulminant in three patients. Endoscopic and histological features did not specifically differentiate CDI from CIC. Nine of 11 patients required immunosuppressive therapy when CDI was associated with CIC. In nine cases, immunotherapy was discontinued due to digestive toxicity. CDI can be isolated or can complicate or reveal CIC. CDI in patients treated with immunotherapy shares many characteristics with CDI complicating IBD. Stool tests for Clostridium difficile should be carried out for all patients with diarrhea who are being treated with immunotherapy., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Currently, in the absence of BRAFV600 mutation, the management of advanced melanomas is based on immunotherapies, but only half of the patients are responders. RAF1 (also named CRAF) fusions occur in 1-2.1% of wild-type melanomas. Preclinical data suggest that the presence of RAF fusion may be sensitive to MEK inhibitors. We report the case of a patient with an advanced melanoma harboring an EFCC1-RAF1 fusion who showed a clinical benefit from and a partial response to a MEK inhibitor., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Clinical outcomes of advanced melanoma of unknown primary (MUP) in the era of novel therapies have been scarcely studied., Objective: To investigate the efficacy and safety of systemic treatments in patients with advanced MUP compared to patients with stage-matched melanoma of known cutaneous primary (cMKP)., Methods: Based on the nationwide MelBase prospective database, this study included advanced melanoma patients treated from March 2013 to June 2021 with first-line immunotherapies, targeted therapies, or chemotherapy. Co-primary outcomes were progression-free survival and overall survival. Secondary outcome was treatment-related toxicities. Multivariate and propensity score analyses were performed., Results: Of 1882 patients, 265 (14.1%) had advanced MUP. Patients with advanced MUP displayed more often unfavorable initial prognostic factors than those with cMKP. Progression-free and overall survival did not differ significantly between the groups (P = .73 and P = .93, respectively), as well as treatment-related toxicity rate and severity, regardless of treatment type., Limitations: No record of standard diagnostic criteria of MUP used in the participating centers., Conclusions: Although patients with MUP had less favorable baseline prognostic factors, they benefited from the novel therapies as much as those with cMKP. They should be managed according to similar strategies., Competing Interests: Conflicts of interest Dr Dalle received research grants by BMS and MSD, travel costs covered by BMS, spouse working for Sanofi; Dr Dereure reported a Consulting or Advisory Role with Bristol-Myers Squibb, Genevrier, Kiowa Kirin, Leo Pharma, MSD, Novartis, Pierre Fabre, and Recordati, and reports travel, accommodations, and expenses from Bristol-Myers Squibb, Novartis, Pierre Fabre, and Recordati; Dr Saiag has received outside of this study personal fees from Bristol-Myers Squibb, MSD, Merck-Serono, Pfizer, Roche-Genentech, Pierre Fabre, and Novartis; Dr Arnault consulting for NOVARTIS, Dr Lebbé reported honoraria from Amgen, Bristol-Myers Squibb, Incyte, MSD, Novartis, Pfizer, Pierre Fabre, and Roche, reports a Consulting or Advisory Role with Amgen, Bristol-Myers Squibb, Merck Serono, MSD, Novartis, Roche, and Sanofi, is on the Speakers' Bureau for Amgen, Bristol-Myers Squibb, MSD, Novartis, and Roche, received Research Funding from Bristol-Myers Squibb, and Roche, reports travel, accommodations, and expenses from Bristol-Myers Squibb and MSD, and reports other relationship with Avantis Medical Systems; and Dr Montaudié reported a Consulting or Advisory Role with Bristol-Myers Squibb, MSD, Novartis, and Pierre Fabre, received Research Funding from Leo Pharma and Novartis, and reports travel, accommodations, and expenses from Bristol-Myers Squibb, Novartis, and Pierre Fabre., (Copyright © 2022 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Basal cell carcinoma (BCC) is the most common human malignancy. In most cases, BCC has slow progression and can be definitively cured by surgery or radiotherapy. However, in rare cases, it can become locally advanced or, even more rarely, metastatic. The alternative recommended treatments are Sonic Hedgehog pathway inhibitors; however, the response is often short-lived., Methods: This was a phase 2 basket study (NCT03012581) evaluating the efficacy and safety of nivolumab in a cohort of 32 advanced BCC patients, enrolled after failure of Sonic Hedgehog inhibitors, including 29 laBCC (91%) and 3 mBCC (9%)., Results: Compared to previously published studies, our population consisted of severe patients with a poor prognosis because they had already received multiple lines of treatment: all patients received previous Sonic Hedgehog inhibitors, 53% of patients already had chemotherapy and 75% radiotherapy. At 12 weeks, we reported 3.1% of complete responses, 18.8% of partial responses, and 43.8% of stable diseases. The best response rate to nivolumab reached 12.5% of complete responses (four patients), 18.8% of partial responses (three patients), and 43.8% of stable diseases (14 patients). Adverse events (AE) were mostly grade 2 or 3, slightly different to the adverse events observed in the treatment of metastatic melanoma (higher rate of diabetes, no thyroid dysfunction)., Conclusion: Nivolumab is a relevant therapeutic option for patients with advanced relapsing/refractory BCC., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Caroline Gaudy Marquestre has declared payment for lectures/presentations/writings from BMS and MSD, and support for attending meetings from MSD, BMS and Jansen. Aurelien Marabelle has declared support for the present manuscript from Unicancer and Gustave Roussy Institute, grants or contract from BMS, MSD and Sanofi, consulting fees from Sanofi, payment for lectures/presentations/writings from BMS and MSD, support for attending meetings from BMS and MSD, participation on Advisory Board with MSD, have leadership role in the board of the French Immune-Therapy for Cancer scholar society. Marie Beylot-Barry has declared payment for lectures/presentations/writings from Sun Pharma. Nicole Basset-Seguin has declared consulting fees from Regeneron/Sanofi and Sun Pharma, payments for lectures/presentations/writings from Regeneron/Sanofi and Sun Pharma, support for attending meetings from Regeneron/Sanofi and Sun Pharma, and have participated on Advisory Board for Regeneron/Sanofi and Sun Pharma. Philippe Saiag has declared consulting fees from BMS outside the topic of this study. Philippe Jamme has declared consulting fees from BMS, support for attending meetings from Pierre Fabre, and have participated on Advisory Board with Pierre Fabre, BMS and Novartis. Celeste Lebbe has declared support for the present manuscript from Amgen, BMS, Merck Serono, MSD, Novartis, Pierre Fabre, Roche and Sanofi; she have declared consulting fees from Amgen, BMS, MSD, Novartis and Roche; payments for lectures/presentations/writings from Amgen, BMS, MSD, Novartis, Pfizer, Pierre Fabre, Roche; payment for expert testimony form Amgen, BMS, MSD, Novartis, Roche; support for attending meetings from BMS, MSD, Novartis, Pierre Fabre, Sanofi. Laurent Mortier has provided time for consulting and participation to scientific advisory boards of the following compagnies: Sun pharma, Novartis, Pierre Fabre and MSD, and have participated in congress with the same companies., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Nine drugs have been marketed for 10 years for the treatment of advanced melanoma (AM). With half of patients reaching a second line, the optimal sequence of treatments remains unclear. To inform policy-makers about their efficiency, we performed a cost-effectiveness analysis of sequential strategies in clinical practice in France, for BRAF-mutated and wild-type patients. A multistate model was developed to describe treatment sequences, associated costs, and health outcomes over 10 years. Sequences, clinical outcomes, utility scores, and economic data were extracted from the prospective Melbase cohort, collecting individual data in 1518 patients since 2013, from their AM diagnosis until their death. To adjust the differences in patients' characteristics among sequences, weighting by inverse probability was used. In the BRAF-mutated population, the MONO-targeted therapies (TT)-anti-PD1 sequence was the less expensive, whereas the anti-PD1-BI-TT sequence had an incremental cost-effectiveness ratio (ICER) of 180,441 EUR/QALY. Regarding the BRAF wild-type population, the three sequences constituted the cost-effective frontier, with ICERs ranging from 116 to 806,000 EUR/QALY. For BRAF-mutated patients, the sequence anti-PD1-BI-TT appeared to be the most efficient one in BRAF-mutated AM patients until 2018. Regarding the BRAF wild-type population until 2018, the sequence starting with IPI+NIVO appeared inefficient compared to anti-PD1, considering the extra cost for the QALY gained.

Purpose: Mitogen-activating protein kinase inhibitors (MAPKis) are largely used in V600E/K BRAF-mutated metastatic melanomas, but data regarding effectiveness of targeted therapy in patients with rare BRAF mutations and molecular description of these infrequent mutations are scarce., Patients and Methods: A multicenter study was conducted on patients with metastatic melanoma harboring a well-identified mutation of BRAF and enrolled from March 2013 to June 2021 in the French nationwide prospective cohort MelBase. The molecular BRAF mutation pattern, response to MAPKis when applicable, and survival data were analyzed., Results: Of 856 selected patients, 51 (6%) harbored a non-V600E/K BRAF mutation involving codons V600 (24 of 51, 47%; V600G 27.4%, V600R 15.6%), K601 (6 of 51, 11.7%), and L597 (4 of 51, 7.8%). An objective response to MAPKis either BRAF inhibitor (BRAFi) alone or combined with MEK inhibitor was achieved in 56% (353 of 631) of V600E/K, 58% (11 of 19) of non-E/K V600, and 22% (2 of 9) of non-V600 BRAF-mutated patients, with a median progression-free survival of 7.7, 7.8, and 2.8 months, respectively. Overall, objective response rate was higher with BRAFi + MEK inhibitor combination than with BRAFi in monotherapy for each subset., Conclusion: Rare BRAF mutations are not anecdotal in the metastatic melanoma population. Although data interpretation must remain careful owing to the limited size of some subsets of patients, non-E/K V600 BRAF mutations seem to confer a high sensitivity to targeted therapy, whereas MAPKis seem less effective in patients with non-V600 BRAF mutations. However, this strategy may be used as an alternative option in the case of immunotherapy failure in the latter population.

Background: Despite the poor prognosis associated with melanoma brain metastases (BM), data concerning these patients and their inclusion in clinical trials remains scarce. We report here the efficacy results of a subgroup analysis in patients with BRAFV600-mutant melanoma and BM treated with BRAF and MEK inhibitors dabrafenib (D) and trametinib (T)., Patients and Methods: This phase IIIb single-arm, open-label, multicenter, French study included patients with unresectable stage IIIc or IV BRAFV600-mutant melanoma with or without BM. The present analysis focuses on patients with BM. Response rates were determined clinically and/or radiologically as per standard clinical practice. Progression-free survival (PFS) was estimated using the Kaplan Meier analysis and modelled with multivariate Cox regression model. Risk subgroups were identified using an exponential regression tree analysis. Significance was set at p &lt; 0.05., Results: Between March 2015 and November 2016, 856 patients were included and 275 (32%) patients had BM. Median PFS was 5.68 months (95% confidence interval [CI], 5.29-6.87). Significant independent factors associated with shorter PFS were ECOG ≥1, elevated serum lactate dehydrogenase (LDH), ≥3 metastatic sites, and non-naïve status. The binary-split classification and regression tree modelling identified baseline LDH and ECOG status as major prognostic factors., Conclusion: This is to date the largest, close to real-world, study in advanced BRAFV600-mutant melanoma patients with BM treated with D+T. ECOG &gt;1, ≥3 metastatic sites and elevated LDH were associated with shorter PFS, a finding previously demonstrated only in patients without BM. Further studies are warranted to determine the optimal treatment sequence in this population., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Caroline Dutriaux has served as a member of an advisory board or as an investigator for Novartis. Caroline Robert has acted as a consultant for BMS, MSD, Sanofi, Novartis, Roche and Amgen, and has served as a member of an advisory board and steering committee for Pierre Fabre. Jean-Jacques Grob has received honoraria from BMS, MSD, Merck, Pfizer, Incyte, Novartis, Roche, Amgen and Pierre Fabre, has received travel grant support from BMS, MSD and Roche, has acted as a consultant and advisor for BMS, MSD, Roche, Novartis, Amgen, Merck, Pierre Fabre, Pfizer and Incyte. Laurent Mortier has acted as a consultant and advisor for BMS, MSD, Roche, Novartis, Amgen, and Leo and has participated to clinical studies sponsored by Amgen, BMS, Roche, GSK/Novartis, Merck Serono, Leo, and MSD. He has received honoraria from Roche, BMS, MSD, Sanofi, Novartis, Amgen and Pierre Fabre. Céléste Lebbe has received honoraria from BMS, MSD, Roche, Novartis, Amgen, Merck, Pierre Fabre, Pfizer and Incyte, has acted as a consultant or has served as a member of an advisory board for BMS, and has received travel grant support from BMS and MSD. Sandrine Mansard has served as a member of an advisory board for Novartis. Eve-Marie Neidhart has received honoraria from BMS. Florent Grange has served as a member of an advisory board for Novartis. Thierry Lesimple has served as a member of an advisory board for MSD, Incyte and Pierre Fabre; He has participated to research sponsored by Roche. Christophe Bedane has served as a member of an advisory board for Novartis. Sophie Dalac-Rat has served as a member of an advisory board for Novartis, Roche, BMS and Pierre Fabre. Charlée Nardin has acted as a consultant for Novartis, BMS and MSD. Alexandra Szenik and Amine Denden are employees of Novartis. Olivier Dereure, Laurent Machet and Hervé Maillard have nothing to disclose related to this research. Philippe Saiag has received personal fees from Amgen, Bristol-Myers Squibb, MSD, Merck-Serono, Pfizer, Roche-Genentech, Pierre Fabre, Sanofi and Novartis; he has received nonfinancial support from Bristol-Myers Squibb, MSD, Roche-Genentech, and Novartis; and has received a funding grant from Roche-Genentech., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Skin phototype, latitude and sun exposure are classic risk factors for melanomas but are not relevant to acrolentiginous melanomas (ALM). ALM is not related to chronic sun exposure because the thick stratum corneum acts as a barrier to penetration of UV rays, whereas LMM occurs in skin with high photoaging due to chronic sun exposure., Objectives: This study aimed to determine if any difference exists between "solar" melanomas and "non-solar" melanomas based on a comparison between LMM and ALM., Materials & Methods: We extracted all data for ALM and LMM patients, from March 2012 to September 2020, from the RIC-Mel national database to perform a descriptive cohort analysis of 1,056 Caucasian cases., Conclusion: The profiles of solar-related and non-solar melanoma seem to be different, and prognostic factors of ALM at diagnosis are less favourable compared to LMM, suggesting that non-solar melanoma is more aggressive than solar-related melanoma and that sentinel lymph node biopsy should be performed.

Oral mucosal melanoma (OMM) is the subject of few studies, resulting in a lack of understanding. The aim of this study is to review the current literature on OMM. The term searched was "oral mucosal melanoma" between 01/01/2000 and 03/15/2021 in the PubMed Database (MEDLINE). Patients presenting with OMM and treated in our center between January 2009 and January 2020 were included in a case series. Demographics, location, risk factors, genetic mutations, treatment performed, and overall survival (OS) rates were evaluated. The PubMed database search yielded a total of 513 results, thirty-eight articles were finally included, which amounted to 2230 cases of OMM. 13 patients were included in the case series. A male-to-female ratio of 1.28:1.00 was found with a mean age at first diagnosis of 58.2 years old. Hard palate (1060 cases) and then gingiva (794 cases) were the two main locations. No risk factors could be identified. OMM were staged III or IV at diagnosis. Mutations were described as such: KIT in 14.6% of cases, BRAF in 7%, and NRAS in 5.6%. Treatment protocols varied but radical surgery was the cornerstone treatment associated with adjuvant therapies. Immunotherapy has not been evaluated for OMM. OS rates were 43.4% at 3 years, 33.1% at 5 year and 15.4% at 10 years. OMM show distinct features from cutaneous melanoma (CM): typical locations, no identified risk factors, different mutations profile, worse prognosis with advanced stage at diagnosis. Targeted therapies are still underused compared to CM., Competing Interests: Declaration of Competing Interest None, (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Objective: To quantify the risk of immune-related adverse events (irAEs) in patients with pre-existing autoimmune disease (pAID) treated by immune checkpoint inhibitors (ICIs) for stage III or IV melanoma., Methods: Case-control study performed on a French multicentric prospective cohort of patients with melanoma, matched for irAE risk factors and oncological staging. Risk of irAE was assessed by logistic regression., Results: 110 patients with pAID were included and matched with 330 controls, from March 2013 to October 2020. Over a median follow-up period of 7.2 months for cases and 6.9 months for controls, the ORs of developing all-grade and grade ≥3 irAEs among cases compared with controls were 1.91 (95% CI (1.56 to 2.27)) and 1.44 (95% CI (1.08 to 1.82)), respectively. Patients with pAID had an increased risk of multiple irAEs (OR 1.46, 95% CI (1.15 to 2.67)) and a shorter time to irAE onset. In contrast, there were no difference in irAE-related mortality nor in the rate of treatment discontinuation, and a landmark analysis revealed a better survival at 24 months among cases (p=0.02). Thirty per cent of cases experienced a pAID flare during follow-up, and baseline immunosuppression did not prevent irAE occurrence. Last, we report associations between the pAID clinical subsets and organ-specific irAEs., Conclusion: In our study, patients with pAID were at greater risk of all-grade, severe and multiple irAEs, yet had a better 24-month survival than controls. Thus, patients with pAID should be eligible for ICI therapy but benefit from a close monitoring for irAE occurrence, especially during the first months of therapy., Competing Interests: Competing interests: DL: fees from Novartis, BMS et MSD. PS: consulting fees from Roche, Novartis, BMS, Pierre FABRE, MSD. FB-P: consulting fees from BMS and Sanofi. TL: consulting fees from MSD, BMS, Pierre Fabre, Novartis. J-JG : consulting fees from MSD, Roche, Novartis, Amgen, Pierre-Fabre, Sanofi, Philogen, Merck, Pfizer. CA: grants from Amgen, BMS, Roche. LM: grants from BMS, Novartis, Roche, MSD, GSK, Pierre Fabre and consulting fees from BMS, Novartis, Roche, MSD, GSK, Pierre Fabre. CL: grants from BMS, MSD, Novartis, Sanofi, Pierre Fabre; consulting fees from BMS, MSD, Novartis, Amgen, Roche, Merck, Serono, Sanofi, Pierre Fabre and teaching fees from Roche, BMS, Novartis, Amgen, MSD., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)