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Metastatic melanoma is an aggressive disease that still shows high mortality despite the recent discovery of immunotherapy and targeted therapy.1,2 The criteria currently known to influence a therapeutic response are mainly LDH, CRP and the number of metastatic sites.3 Overweight (body mass index (BMI) >= 25 kg/m SP 2 sp ) or obesity (BMI >= 30 kg/m SP 2 sp ) is currently a major public health issue. We carried out a retrospective study (2012-2017) whose aim was to determine whether a BMI >= 25 kg/m SP 2 sp was an early predictive factor of response in patients with metastatic melanoma treated in first line by targeted therapy or immunotherapy. We also demonstrate that BMI is an early prognostic factor for the response to treatment (6 months) in patients in first-line therapy. Our study shows that a high BMI is significantly associated with a better early therapeutic response in patients in first line of treatment particularly with targeted therapy and is an independent predictive factor. [Extracted from the article]

Background: Biomedical data warehouses (BDWs) have become an essential tool to facilitate the reuse of health data for both research and decisional applications. Beyond technical issues, the implementation of BDWs requires strong institutional data governance and operational knowledge of the European and national legal framework for the management of research data access and use., Objective: In this paper, we describe the compound process of implementation and the contents of a regional university hospital BDW., Methods: We present the actions and challenges regarding organizational changes, technical architecture, and shared governance that took place to develop the Nantes BDW. We describe the process to access clinical contents, give details about patient data protection, and use examples to illustrate merging clinical insights., Unlabelled: More than 68 million textual documents and 543 million pieces of coded information concerning approximately 1.5 million patients admitted to CHUN between 2002 and 2022 can be queried and transformed to be made available to investigators. Since its creation in 2018, 269 projects have benefited from the Nantes BDW. Access to data is organized according to data use and regulatory requirements., Conclusions: Data use is entirely determined by the scientific question posed. It is the vector of legitimacy of data access for secondary use. Enabling access to a BDW is a game changer for research and all operational situations in need of data. Finally, data governance must prevail over technical issues in institution data strategy vis-à-vis care professionals and patients alike., (© Matilde Karakachoff, Thomas Goronflot, Sandrine Coudol, Delphine Toublant, Adrien Bazoge, Pacôme Constant Dit Beaufils, Emilie Varey, Christophe Leux, Nicolas Mauduit, Matthieu Wargny, Pierre-Antoine Gourraud. Originally published in JMIR Medical Informatics (https://medinform.jmir.org).)

Background: BRAF and MEK inhibitors have changed the landscape of treatment for advanced melanoma. Among their side effects, panniculitis has been hypothesized to be associated with better survival., Objectives: In this study, we aimed to explore the association between the occurrence of panniculitis during targeted therapy and outcome of metastatic melanoma., Materials & Methods: This was a retrospective single-centre comparative study from 2014 to 2019. An English literature review was also conducted to further our understanding of the mechanism(s) involved and identify characteristics of this association, in order to support better management., Results: Ten patients who developed panniculitis during treatment were matched to 26 controls based on potential confounders at treatment introduction. The prevalence of panniculitis was 5.3%. Median progression-free survival (PFS) for all patients was 8.5 months (range: 3.0-94.0). The median PFS for the group with panniculitis was 10.5 months (7.0-undefined) and 7.0 months (6.0-32.0) for controls (p=0.39). According to the scientific literature, panniculitis occurring during targeted therapy affects mainly young people, predominantly women, with variable delay to onset (with half reported cases occurring in the first month). In addition, panniculitis usually only affects the lower limbs or is associated with other clinical signs (fever, arthralgia), without histological specificity. Discontinuation of targeted therapy is not required as spontaneous remission is usually experienced. Symptomatic treatment may be administered but systemic corticosteroids have not been proven to be effective., Conclusion: In contrast to the belief that there is a link between panniculitis and clinical response to targeted therapy according to the literature, our results show that there is no significant association between the two.

Background: Melanoma is one of the most fatal forms of skin cancer. Defining relevant biomarkers to predict treatment outcome based on immune checkpoint inhibitors (ICIs) is needed in order to increase overall survival of metastatic melanoma patients (MM)., Objectives: This study compared different machine learning models in terms of performance to identify biomarkers from clinical diagnosis and follow-up of MM patients, to predict treatment response to ICIs under real-life conditions., Materials & Methods: Clinical data from melanoma patients with an AJCC status of III C/D or IV, having received ICIs, were extracted from the RIC-MEL database for this pilot study. Light Gradient Boosting Machine, linear regression, Random Forest (RF), Support Vector Machine and Extreme Gradient Boosting were compared in terms of performance. The SHAP (SHapley Additive exPlanations) method was used to assess the link between the different clinical features investigated and the prediction of response to ICIs., Results: RF showed the highest scores for accuracy (0.63) and sensitivity (0.64) and high scores for precision (0.61) and specificity (0.63). AJCC stage (0.076) showed the highest SHAP mean value, thus being the most suitable feature to predict response to treatment. The number of metastatic sites per year (0.049), number of months since first treatment initiation and the Breslow index (both 0.032) were less predictive, but still showed relatively high predictive power., Conclusion: This machine learning approach confirms that a certain number of biomarkers may enable prediction of treatment success with ICIs.

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.

Background: Targeted therapy is used to treat patients with a BRAF-mutated metastatic melanoma and is continued until disease progression or severe toxicity. No robust data on the management of patients achieving a complete remission (CR) are available., Main Objective: To determine the relapse rate in the first year after targeted therapy discontinuation in patients in CR., Secondary Objectives: To determine the relapse rates throughout the follow-up and to identify prognostic factors for relapse at 1 year., Methods: A retrospective, monocentric observational study was conducted in patients with advanced melanoma included in the RIC-Mel database who discontinued targeted therapy after achieving a CR confirmed by CT scan and PET/CT scan., Results: Twenty-nine patients were included. Seventeen (58.6%) patients were treated with BRAF inhibitor (BRAFi) alone and 12 (41.4%) with a BRAFi combined with a MEK inhibitor (BRAFi + MEKi). The median treatment duration was 9.7 months. The relapse rates after discontinuation were 69% at 12 months (BRAFi: 70.6%; BRAFi + MEKi: 66.7%) and 76% at 36 months (BRAFi: 76.5%; BRAFi + MEKi: 75%). A non-significant trend towards a higher risk of relapse was found in women (p = 0.1; RR 3.36; 95% CI 0.77-17.07), in patients with an LDH level greater than the upper limits of normal (p = 0.58; RR 2.43; 95% CI 0.10-56.71), and when more than two metastatic sites were involved (p = 0.19; RR 4.6; 95% CI 0.46-46.51). After relapse, targeted therapy was resumed in 17 patients (7 with BRAFi; 10 with BRAFi + MEKi) with a response rate of 53%., Conclusions: This real-life study provided long-term data in patients who discontinued targeted therapy after CR. Most patients experienced a relapse in the first year after targeted therapy discontinuation, of whom 50% were in the first 3 months. After targeted therapy resumption, 53% of relapsing patients achieved an objective response. Patients should be followed during the first year after treatment discontinuation. In addition, patients with less than 3 metastatic sites, a baseline LDH level with normal ranges, men, and patients responding rapidly to treatment would be more likely to maintain a CR after treatment discontinuation., (© 2021 S. Karger AG, Basel.)

Background: For several decades, PD-1 has been a target in malignant melanoma (MM). PD-1 inhibitors (nivolumab, pembrolizumab) and anti-CTLA-4 (CD152) (ipilimumab) have revolutionized cancer therapy. PD-1 and CTLA-4 inhibition leads to prolonged lymphocyte effects, which explains the cytotoxicity underlying immune-reaction-based adverse events (irAEs). Most irAEs occur in the first cycle of treatment at a median of 40 days. IrAEs of any grade have been observed in 68.2% of patients, with 10% of patients experiencing severe grade III/IV irAEs. Data on late-onset irAEs are lacking. Methods: Data on patients with advanced melanoma ( N = 1862) from March 2016 to March 2021 were obtained from the RicMel database, a French national multicentric biobank dedicated to the follow-up of MM patients. Patients who received anti-PD-1 therapy or a combination therapy and experienced grade III-IV irAEs were selected and analyzed at 7 months, one year and two years after treatment was initiated. Results: Superficial spreading melanoma (SSM) and previous oncological drug administration before immunotherapy are significant risk factors for late-onset irAEs over 2 years after beginning immunotherapy in the univariate and multivariate analysis. The other parameters-sex, mutational status, association of immunotherapy (PD-1i and CTLA-4i) and overall response-were not significantly associated with late-onset irAEs. In our real-life data study, the median onset time of grade III-IV irAES was 128 days after the initiation of immune checkpoint inhibitors (ICI) therapy. Conclusions: Our study, using real-life data, suggests that patients with SSM and those who have received previous oncological treatments are more likely to experience late-onset grade III-IV irAES. Further multicentric studies with wider recruitment of patients should be performed to confirm our findings, potentially leading to changes in the recommended treatment for carefully monitored at-risk patients.

This retrospective observational study aimed to determine the effectiveness, safety and patterns of the use of nivolumab in patients with advanced melanoma in real-world clinical practice in France using data from a Temporary Authorization for Use Program (ATU). Data were collected from patients with unresectable or metastatic melanoma enrolled in a French national database (Réseau pour la Recherche et l'Investigation Clinique sur le Mélanome: Ric-Mel) and treated with nivolumab during the ATU program (12 September 2014 to 31 August 2015). The primary objectives of the study were to evaluate the effect of patient characteristics on clinical response and overall survival (OS). Among 400 included patients (median age 66 years), the majority (83%) received nivolumab as second- or subsequent-line therapy. The median durations of progression-free survival and OS were 3.3 and 14.1 months, respectively, and 31.6% of patients achieved an objective response with a median duration of 20.1 months (range: 0-34.7). The safety profile of nivolumab was manageable and consistent with those of previous clinical trials, with an incidence of grade 3-5 adverse events of 13.8%. The safety and effectiveness of nivolumab in patients with advanced melanoma in real-world clinical practice in France were in line with the data reported in the Phase 3 trials CheckMate 066 and 037 of nivolumab in this patient population., (© 2021 UICC.)

The ability of early (first weeks of treatment) ctDNA kinetics to identify primary resistance to anti-PD1 immunotherapies was evaluated with a validation cohort of 49 patients treated with anti-PD1 for metastatic BRAF or NRAS-mutated melanoma, alone and pooled with the 53 patients from a previously described derivation cohort. BRAF or NRAS mutations were quantified on plasma DNA by digital PCR at baseline and after two or four weeks of treatment. ctDNA kinetics were interpreted according to pre-established biological response criteria. A biological progression (bP, i.e., a significant increase in ctDNA levels) at week two or week four was associated with a lack of benefit from anti-PD1 (4-month PFS = 0%; 1-year OS = 13%; n = 12/102). Patients without initial bP had significantly better PFS and OS (4-month PFS = 78%; 1-year OS = 73%; n = 26/102), as did patients whose ctDNA kinetics were not evaluable, due to low/undetectable baseline ctDNA (4-month PFS = 80%; 1-year OS = 81%; n = 64/102). ctDNA detection at first-line anti-PD1 initiation was an independent prognostic factor for OS and PFS in multivariate analysis. Overall, early ctDNA quantitative monitoring may allow the detection of primary resistances of metastatic melanoma to anti-PD1 immunotherapies.

Background: Kidney transplantation is the therapeutic of choice for patients with kidney failure. While immunosuppressive drugs can control graft rejection, their use is associated with increased infections and cancer, and they do not effectively control chronic graft rejection. Cell therapy is an attractive strategy to minimize the use of pharmacological drugs., Methods: We recently developed a protocol to generate human monocyte-derived autologous tolerogenic dendritic cells (ATDCs) from healthy volunteers. Herein, we transferred the ATDC manufacturing protocol to a Good Manufacturing Practice (GMP)-compliant facility. Furthermore, we compared the phenotype and in vitro functions of ATDCs generated from patients with end-stage renal disease to those generated from healthy volunteers., Results: We describe the critical steps for GMP-compliant production of ATDCs and define the quality criteria required to allow release of the cell products. Furthermore, we showed that ATDCs generated from healthy volunteers and patients with kidney failure display the same tolerogenic profile based on their phenotype, resistance to maturation, and ability to modulate T-cell responses., Conclusions: Together, these results allowed us to define the production process and the quality criteria for the release of ATDCs before their administration in patients receiving a kidney transplant., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Immune checkpoint inhibitors have improved the management of metastatic melanoma, however, we have witnessed an emergence of adverse cardiac events such as myocarditis., Objectives: We first aimed to assess the prevalence of adverse cardiac events in patients treated with anti-PD-1 for metastatic melanoma. Our second objective was to determine the role of troponin monitoring in the diagnosis of these events., Materials & Methods: We retrospectively analysed the prevalence of patients treated with anti-PD-1 in a real-life setting based on a cohort of 183 patients. We then performed a prospective cohort, in which clinical and biological profiles of patients were collected, along with monthly monitoring of troponin levels., Results: The prevalence of adverse cardiac events in the retrospective cohort was 2.2%, with three cases of myocarditis and one of myocardial infarction. In the prospective cohort, 14/52 patients had an abnormal baseline troponin T level. All patients had a history of cardiac or vascular complaints. Six patients showed an increase in troponin T level during follow-up, in two patients associated with clinical symptoms., Conclusion: Adverse cardiac events with immunotherapy are both frequent and life-threatening. Troponin T may be of interest to detect early adverse cardiac events before any clinical sign, however, the data supporting this remain to be confirmed.

Background: Targeted therapies such as BRAF and MEK inhibitors and immunotherapies have been made available to treat melanoma., Objectives: To provide an overview of the management of the French Stage III melanoma population after complete lymph node resection prior to new adjuvant therapies., Materials and Methods: A subgroup data analysis., Results: Data from 1,835 patients were analysed (15.58% Stage IIIA, 39.24% Stage IIIB, 43.92% Stage IIIC and 1.25% Stage IIID). Superficial spreading melanoma was the most frequent (70.98% in Stage IIIA for whom mutation analysis was performed; BRAF mutation was identified in up to 62% Stage IIIA patients). Sentinel lymph node biopsy was performed in 88.46% of Stage IIIA patients, 42.36% of Stage IIIB, 53.97% of Stage IIIC and 34.78% of Stage IIID. Up to 80% of Stage IIIA patients had no adjuvant treatment follow-up. Ulceration (p = 0.004; RR: 2.98; 95% CI: 1.4-6.3) and age at diagnosis (p = 0.0002; RR: 1.04; 95% CI: 1.02-1.06) were significant predictive factors for survival. Adjuvant interferon-α was administered in up to 13.04% of Stage IIID patients., Conclusion: Only a small number of Stage III melanoma patients were treated with interferon-α in adjuvant settings. New adjuvant therapies are currently having an effect on clinical practice in France, increasing survival and decreasing cost.

In BRAF wild type advanced melanoma, immune checkpoint blockers such as anti-PD1 (anti-programmed cell death 1) are usually continued beyond progression for a hypothetical rare further response. Chemotherapy as a second-line option is considered ineffective by many practitioners based on historical data. Continuing anti-PD1 beyond progression has a high health-economic impact and is not recommended by the FDA. This study aimed to describe the efficacy and survival of advanced melanoma patients who received second-line (or more) chemotherapy after immunotherapy failure.This was a retrospective single center study conducted in a French University Hospital during an 11-month period. All advanced melanoma patients treated with chemotherapy after immunotherapy failure were included.Eighteen patients were analyzed. Therapeutic response to chemotherapy was evaluable in 16 patients: partial response was achieved in 3/16 (19%), stable disease in 1/16 (6%) and progressive disease in 12/16 (75%). Median overall survival from chemotherapy start was 12 months. Median progression-free survival was 5.4 months. The 6-month overall survival rate was 81% and the 6-month progression-free survival rate was 40%.Although the disease control rate with chemotherapy was low (25%), survival data in our study are far superior to those previously published. This could be linked to a high proportion of patients treated with anti-PD1 just prior to chemotherapy, which may suggest a potential synergy between immunotherapy and chemotherapy.

Circulating tumour DNA (ctDNA) can be used to identify gene alterations. The purpose of this study was to determine whether the detection of ctDNA, based on the identification of BRAF and NRAS mutations before systemic treatment initiation, was associated with the prognosis of metastatic melanoma. In total, 68 BRAF or NRAS -mutated stage IV or unresectable stage III metastatic cutaneous melanoma patients were included and tested for the presence of BRAF and NRAS mutations in circulating DNA before treatment initiation, using the Cobas BRAF/NRAS Mutation Test (Roche). The expected mutation was detected in the plasma of 34/68 patients (50% sensitivity). ctDNA detection was associated with AJCC stage, along with the number and nature of metastases. ctDNA was less frequently detected in NRAS -mutated than in BRAF -mutated melanoma (36% and 66%, respectively). At initiation of first-line treatment, ctDNA detection was associated with poor prognosis in Progression Free Survival (PFS) and Overall Survival (OS) in univariate analysis (log-rank: p = 0.002 and p < 0.0001, respectively). In multivariate analysis, ctDNA detection was an independent factor of poor prognosis in OS, after adjustment for AJCC stage, number and nature of metastases and gender (HR = 4.384; 95% CI: (1.308; 14.699); p = 0.017).

Background: Nodular melanoma (NM) is more likely to be fatal compared with other melanoma subtypes, an effect attributed to its greater Breslow thickness., Methods: Clinicopathological features of NM and superficial spreading melanoma (SSM) diagnosed in 17 centers in Europe (n = 15), the United States, and Australia between 2006 and 2015, were analyzed by multivariable logistic regression analysis, with emphasis on thin (T1 ≤ 1.0 mm) melanomas. Cox analysis assessed melanoma-specific survival. All statistical tests were two sided., Results: In all, 20 132 melanomas (NM: 5062, SSM: 15 070) were included. Compared with T1 SSM, T1 NM was less likely to have regression (odds ratio [OR] = 0.46, 95% confidence interval [CI] = 0.29 to 0.72) or nevus remnants histologically (OR = 0.60, 95% CI = 0.42 to 0.85), and more likely to have mitoses (OR = 1.97, 95% CI = 1.33 to 2.93) and regional metastasis (OR = 1.77, 95% CI = 1.02 to 3.05). T1 NM had a higher mitotic rate than T1 SSM (adjusted geometric mean = 2.2, 95% CI = 1.9 to 2.5 vs 1.6, 95% CI = 1.5 to 1.7 per mm2, P < .001). Cox multivariable analysis showed a higher risk for melanoma-specific death for NM compared with SSM for T1 (HR = 2.10, 95% CI = 1.24 to 3.56) and T2 melanomas (HR = 1.30, 95% CI = 1.01 to 1.68), and after accounting for center heterogeneity, the difference was statistically significant only for T1 (HR = 2.20, 95% CI = 1.28 to 3.78). The NM subtype did not confer increased risk within each stratum (among localized tumors or cases with regional metastasis)., Conclusions: T1 NM (compared with T1 SSM) was associated with a constellation of aggressive characteristics that may confer a worse prognosis. Our results indicate NM is a high-risk melanoma subtype that should be considered for inclusion in future prognostic classifications of melanoma., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Anti-PD1 antibodies have revolutionized the management of patients with advanced melanoma. In clinical trials, the efficacy of nivolumab is being tested in selected populations of patients., Objectives: The aim of this study was to analyse the efficacy and safety of nivolumab in patients with advanced melanoma under real-life conditions., Materials and Methods: A retrospective, observational study was conducted in patients treated with nivolumab for advanced melanoma included in the RIC-Mel network. Overall survival and progression-free survival (PFS) were assessed using the Kaplan-Meier method., Results: Eighty-seven patients were included with a median follow-up of 31 months. The median PFS was 13 months (95% CI: 7-28). Objective response rate was 33.3%. Among patients achieving a complete response, the response was maintained after treatment discontinuation in 80.7% of patients for a median duration of 21.7 months. Multivariate analysis showed that an increased lactate dehydrogenase level (p = 0.03; HR: 1.21; 95% CI: 1.02-1.45) and brain metastases (p = 0.024; HR: 2.78; 95% CI: 1.14-6.77) were correlated with a decrease in PFS. Grade 3 or 4 adverse events were found in 10.3% of patients., Conclusion: Based on our study, the efficacy and safety of nivolumab in patients with advanced melanoma are consistent with previously published data.

For melanoma patients, surgery is a standard treatment for locoregional skin metastasis (LSM). To assess the frequency and risk factors for positive margins after excision of LSM and their impact on patient overall survival (OS) and progression-free survival (PFS). A monocentric, retrospective observational study was performed including 87 patients with LSM who had undergone surgical excision. Positive margins were found in 45% of patients after excision. After additional excision, 28% of patients still had positive margins. Interestingly, there was no difference in PFS or OS for clear margins after the first or additional excision or for margins that remained positive without additional excision. LSM size was the only identified predictive factor for positive margins. This is the first reported study investigating the frequency of, and risk factors for positive margins of cutaneous LSM, which raises the question of whether additional excision should be performed following positive margin excision.

Immunotherapies have changed the medical management of metastatic melanoma. However, the early detection of patients who do not respond to these treatments is a key issue. We evaluated the quantitative monitoring of circulating tumor DNA (ctDNA) as an early predictor of response to anti-PD1. Patients treated with anti-PD1 for metastatic mutated melanoma were selected. The somatic alteration detected on the tumor tissue was quantified on plasma DNA by digital PCR (dPCR) at treatment initiation, after 2 and 4 weeks of treatment, and then every 4 weeks until progression. The absence of biological response (defined as a significant decrease in the amount of ctDNA relative to the baseline level) after 2 weeks of treatment was associated with a lack of clinical benefit under anti-PD1. In the presence of a biological response at week 2, detection of subsequent biological progression (significant increase in the amount of ctDNA relative to its nadir) was 100% predictive of progressive disease, on average 75 days prior to radiological detection. Patients with a persistent biological response beyond week 16 did not experience any progressive disease and exhibited sustained responses. In conclusion, we show that quantitative monitoring of ctDNA, using criteria accounting for dPCR measurement imprecision, allows the early and specific detection of patients who do not respond to anti-PD1 therapy., Competing Interests: CONFLICTS OF INTEREST No potential conflicts of interest were disclosed.

Therapeutic strategies using anti-PD-1-blocking antibodies reported unparalleled effectiveness for melanoma immunotherapy, but deciphering immune responses modulated by anti-PD-1 treatment remains a crucial issue. Here, we analyzed the composition and functions of the large Melan-A-specific T-cell repertoire in the peripheral blood of 9 melanoma patients before and after 2 months of treatment with anti-PD-1. We observed amplification of Melan-A-specific Vß subfamilies undetectable before therapy (thereafter called emerging Vß subfamilies) in responding patients, with a predominant expansion in patients with a complete response. These emerging Vß subfamilies displayed a higher functional avidity for their cognate antigen than Vß subfamilies not amplified upon anti-PD-1 therapy and could be identified by a sustained coexpression of PD-1 and TIGIT receptors. Thus, in addition to the emergence of neoantigen-specific T cells previously documented upon anti-PD-1 therapy, our work describes the emergence of high-avidity Melan-A-specific clonotypes as a surrogate marker of treatment efficacy. Cancer Res; 77(24); 7083-93. ©2017 AACR ., (©2017 American Association for Cancer Research.)