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Objective: Immune checkpoint inhibitors (ICIs) for cancer therapy frequently induce immune-related adverse effects (IRAEs). Therefore, most patients with preexisting autoimmune diseases have been excluded from clinical trials of ICIs. This study was undertaken to evaluate the safety and efficacy of ICIs in patients with preexisting autoimmune disease and cancer., Methods: A retrospective cohort study was conducted from January 2017 to January 2018 via 3 French national networks of experts in oncology and autoimmunity. Adults with preexisting autoimmune disease who were receiving ICIs were assessed for the occurrence of flare of preexisting autoimmune disease, other IRAEs, and cancer response., Results: The study included 112 patients who were followed up for a median of 8 months. The most frequent preexisting autoimmune diseases were psoriasis (n = 31), rheumatoid arthritis (n = 20), and inflammatory bowel disease (n = 14). Twenty-four patients (22%) were receiving immunosuppressive therapy at ICI initiation. Autoimmune disease flare and/or other IRAE(s) occurred in 79 patients (71%), including flare of preexisting autoimmune disease in 53 patients (47%) and/or other IRAE(s) in 47 patients (42%), with a need for immunosuppressive therapy in 48 patients (43%) and permanent discontinuation of ICI in 24 patients (21%). The median progression-free survival was shorter in patients receiving immunosuppressive therapy at ICI initiation (3.8 months versus 12 months; P = 0.006), confirmed by multivariable analysis. The median progression-free survival was shorter in patients who experienced a flare of preexisting autoimmune disease or other IRAE, with a trend toward better survival in the subgroup without immunosuppressant use or ICI discontinuation., Conclusion: Our findings indicate that flares or IRAEs occur frequently but are mostly manageable without ICI discontinuation in patients with a preexisting autoimmune disease. Immunosuppressive therapy at baseline is associated with poorer outcomes., (© 2019, American College of Rheumatology.)

Targeted therapy combination (TTC: antiRAF+antiMEK) is known to improve metastatic melanoma survival. Few severe skin toxicities (grade ≥3) are described with first-line TTC (17% for vemurafenib+cobimetinib and none for dabrafenib+trametinib) in a phase III trial. Among our 42 patients treated by TTC between January 2014 and March 2017, 4.8% (2/42) of those treated in the first line presented severe skin rash versus 19% (8/42) of patients treated in the second line after previous immunotherapy. In particular, we observed one case of Stevens-Johnson syndrome and four cases of severe drug reaction with eosinophilia and systemic symptoms syndrome under TTC in patients who had received immunotherapy previously. Thus, previous immunotherapy appears to play an important role in the skin rash onset and severity induced by TTC.

Background: Uncontrolled use of tanning beds is a major public health problem. The role of UV in skin carcinogenesis has in fact been clearly demonstrated., Aims: The main purpose of the study was to assess the motivations and beliefs of the population concerning the use of indoor tanning. The secondary objectives were to compare the knowledge of users and non-users and to screen for addiction criteria among users., Patients and Methods: This was a transversal descriptive study conducted between April and June 2013 in Lille town center. The motivations of the participants were determined using a multiple-choice questionnaire. A Likert scale was used to assess beliefs and an m-CAGE questionnaire was used to screen for addiction., Results: Of the 200 respondents, 30% (n=60) had used tanning beds in a non-medical setting. The median age of first use was 23 years (15-59). 11.7% of respondents had started before the authorised age of 18 years. "To prepare the skin for exposure to the sun" was the main reason given (68.3%) for use of tanning beds. The population was aware that use of such apparatus favours onset of skin cancer and ageing of the skin. Users were more convinced than non-users that UV cabins "prepare the skin for exposure to the sun" (75% vs. 49.6%, P=0.0009) and that they "favour skin cancer" (56.9% against 36.2%, P=0.0444). Addictive behaviour was detected in 3.3% (2/60) of users., Conclusion: Users are aware of the carcinogenic risk of UV cabins but expose themselves to such risk, as they believe it prepares their skin for sun exposure., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Vemurafenib/PLX4032, a selective inhibitor of mutant BRAFV600E, constitutes a paradigm shift in melanoma therapy. Unfortunately, acquired resistance, which unavoidably occurs, represents one major limitation to clinical responses. Recent studies have highlighted that vemurafenib activated oxidative metabolism in BRAFV600E melanomas expressing PGC1α. However, the oxidative state of melanoma resistant to BRAF inhibitors is unknown. We established representative in vitro and in vivo models of human melanoma resistant to vemurafenib including primary specimens derived from melanoma patients. Firstly, our study reveals that vemurafenib increased mitochondrial respiration and ROS production in BRAFV600E melanoma cell lines regardless the expression of PGC1α. Secondly, melanoma cells that have acquired resistance to vemurafenib displayed intrinsically high rates of mitochondrial respiration associated with elevated mitochondrial oxidative stress irrespective of the presence of vemurafenib. Thirdly, the elevated ROS level rendered vemurafenib-resistant melanoma cells prone to cell death induced by pro-oxidants including the clinical trial drug, elesclomol. Based on these observations, we propose that the mitochondrial oxidative signature of resistant melanoma constitutes a novel opportunity to overcome resistance to BRAF inhibition.

Recently, the BRAF V600 inhibitor, vemurafenib, has revolutionized the therapeutic management of metastatic melanoma. However, adverse effects and the onset of resistance are frequently observed, limiting the efficacy of this treatment. Patient-derived tumor xenografts (PDTX) engrafted in immunocompromised mice have been proposed as valuable preclinical models that can predict clinical response to treatments. Here, we established a PDTX model of BRAF V600E melanoma useful for testing the efficacy of vemurafenib. First, we validated the stability of the model that was similar to the original tumor with respect to histology, immunohistochemistry, mutational status, and fluorine-18 fluorodeoxyglucose ([(18)F]FDG)-PET/computed tomography (CT). Next, the sensitivity of the xenografts to vemurafenib was determined by tumor growth inhibition and decreased in standardized uptake value on [(18)F]FDG-PET/CT. Finally, this result, using personalized PDTX, allowed successful rechallenge with vemurafenib in a patient who was administered a lower dose of vemurafenib because of the onset of adverse events. Overall, we found that PDTX provides 'real-time' results in an animal that phenocopies the biology and expected vemurafenib responses of the tumor in a patient with BRAF V600E melanoma. Thus, this 'coclinical' trial using PDTX can help guide vemurafenib treatment for metastatic melanoma.