Etude de l'impact de l'interféron alpha 2B à hautes doses sur les caractéristiques cliniques, histologiques et immunologiques des naevus atypiques chez des malades porteurs de mélanome à fort risque de rechute

LYON1-BU Santé (693882101) / SudocPARIS-BIUM (751062103) / SudocPARIS-Académie Médecine (751065201) / SudocSudocFranceF

Utilisation de la dermoscopie (enquête parmi les centres hospitaliers français)

La dermoscopie est reconnu pour améliorer la précision du diagnostic de mélanome par plusieurs méta-analyses. Cependant, la Haute Autorité de Santé considère le niveau de preuve de la dermoscopie comme faible. Pourtant, comme le montre des études australiennes, américaines et française, la dermoscopie est utilisée par la plupart des dermatologues en pratique libérale. Objectifs: Analyser l'utilisation, les croyances, l'enseignement dispensé et la recherche sur la dermoscopie dans les services de dermatologie des hôpitaux français. Méthode: Un questionnaire interrogeant sur ces différents domaines a été envoyé à tous les chefs de service de dermatologie dans les centres hospitaliers français, universitaires ou non. Résultats: Soixante-seize des 110 questionnaires envoyés ont été retournés. La majorité des centres utilise la dermoscopie (97,5%), la proportion des non utilisateurs est associée à la hiérarchie et l'âge du praticien. L'utilisation de la dermoscopie est 4 fois plus élevé dans les centres non universitaires (p = 0,015). Les centres situés dans le sud-est de la France sont de plus grands utilisateurs comparativement aux autres centres (p = 0,004). La détection précoce du mélanome est le principal avantage rapporté, le temps d'entraînement est le principal inconvénient. Peu de centres (14,5%) ont des programmes d'enseignement sur la dermoscopie. La plupart des centres (74,7%) déclare une utilisation de la dermoscopie dans le diagnostic des maladies non tumorales. Conclusions: Il s'agit de la première étude européenne évaluant l'utilisation de la dermoscopie parmi les centres hospitaliers. Malgré une large utilisation rapportée, l'enseignement et la recherche dans ce domaine semblent insuffisants.LYON1-BU Santé (693882101) / SudocSudocFranceF

French cohort of children and adolescents with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas: CASSIOPEA study

Surgery is a treatment option for neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (PN), but complete resection is often not feasible. Real-world studies are warranted to understand disease burden, pro-gression, and need for medical treatment in patients with inoperable PN.CASSIOPEA was a retrospective study of French pediatric patients (aged ≥3 to <18 years) presenting at a national multidisciplinary team (MDT) review with NF1 and ≥1 symptomatic, inoperable PN. Medical records were reviewed from the time of MDT review and over a follow-up period of up to 2 years. Primary objectives were to describe patient characteristics and target PN-associated therapy patterns. A secondary objective was evolution of target PN-related morbidities. Patients with prior, ongoing, or MDT recommendation of mitogen-activated protein kinase kinase (MEK) inhibitor treatment were excluded.Overall, 78 target PN were identified in 76 patients. At MDT review, median age was 8.4 years, with approximately 30% of patients aged 3–6 years. Target PN were primarily internal (77.3%), and 43.2% were progressive. Target PN location was evenly distributed. 34 target PN had documented MDT recommendations; of these, a majority (76.5%) were for non-medication management, including surveillance. At least one follow-up visit was recorded for 74 target PN. Despite initially being considered inoperable, 12.3% of patients underwent surgery for target PN. At MDT review, most (98.7%) target PN were associated with ≥1 morbidity, primarily pain (61.5%) and deformity (24.4%); severe morbidities were identified in 10.3%. Of 74 target PN with follow-up data, 89.2% were associated with ≥1 morbidity, primarily pain (60.8%) and deformity (25.7%). Of 45 target PN associated with pain, pain improved in 26.7%, was stable in 44.4%, and deteriorated in 28.9%. Deformity improved in 15.8% and remained stable in 84.2% of 19 target PN associated with deformity. None deteriorated.In this real-world study in France, NF1-PN disease burden was considerable, and a considerable proportion of patients were very young. Most patients received only supportive care without medication for target PN man-agement. Target PN-related morbidities were frequent, heterogeneous, and generally did not improve during follow-up. These data highlight the importance of effective treatments that target PN progression and improve disease burden

Individual Response to Radiation of Individuals with Neurofibromatosis Type I: Role of the ATM Protein and Influence of Statins and Bisphosphonates

International audienceNeurofibromatosis type 1 (NF1) is a disease characterized by high occurrence of benign and malignant brain tumours and caused by mutations of the neurofibromin protein. While there is an increasing evidence that NF1 is associated with radiosensitivity and radiosusceptibility, few studies have dealt with the molecular and cellular radiation response of cells from individuals with NF1. Here, we examined the ATM-dependent signalling and repair pathways of the DNA double-strand breaks (DSB), the key-damage induced by ionizing radiation, in skin fibroblast cell lines from 43 individuals with NF1. Ten minutes after X-rays irradiation, quiescent NF1 fibroblasts showed abnormally low rate of recognized DSB reflected by a low yield of nuclear foci formed by phosphorylated H2AX histones. Irradiated NF1 fibroblasts also presented a delayed radiation-induced nucleoshuttling of the ATM kinase (RIANS), potentially due to a specific binding of ATM to the mutated neurofibromin in cytoplasm. Lastly, NF1 fibroblasts showed abnormally high MRE11 nuclease activity suggesting a high genomic instability after irradiation. A combination of bisphosphonates and statins complemented these impairments by accelerating the RIANS, increasing the yield of recognized DSB and reducing genomic instability. Data from NF1 fibroblasts exposed to radiation in radiotherapy and CT scan conditions confirmed that NF1 belongs to the group of syndromes associated with radiosensitivity and radiosusceptibility

Neurological toxicities of targeted therapies in melanoma: a multicenter national observational study of the French Group of Skin Cancers (Groupe de Cancérologie Cutanée, GCC)

International audienceNo abstract availabl

Combined Nivolumab and Ipilimumab in Octogenarian and Nonagenarian Melanoma Patients

International audienceData 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

Association of Anti–Programmed Cell Death 1 Antibody Treatment With Risk of Recurrence of Toxic Effects After Immune-Related Adverse Events of Ipilimumab in Patients With Metastatic Melanoma

International audienceImportance: Since 2011, many patients with metastatic melanoma have been treated with ipilimumab therapy and have developed severe immune-related adverse events (AEs). Because several immune therapies are now available to treat metastatic melanoma, a better knowledge of mechanisms and recurrence risks of immune-related AEs is needed before reintroduction of immunotherapies.Objectives: To evaluate the risk of a recurrence of immune toxic effects associated with anti-programmed cell death 1 antibody (anti-PD-1) therapy after discontinuation of ipilimumab monotherapy because of severe AEs.Design, settings, and participants: This cohort study conducted at 19 French melanoma referral centers included patients with metastatic melanoma who experienced severe immune-related AEs after ipilimumab therapy and then were treated with anti-PD-1 therapy between February 1, 2013, and December 31, 2016. The study cutoff was June 1, 2017. Statistical analysis was performed from June 1, 2016, to August 31, 2017.Exposures: Monotherapy with at least 1 cycle of ipilimumab that was associated with a grade 3 or 4 immune-related AE and subsequent treatment with at least 1 cycle of an anti-PD-1 (nivolumab or pembrolizumab) therapy.Main outcomes and measures: The primary outcome was the rate of immune-related AEs associated with anti-PD-1 therapy. Secondary outcomes were characteristics of ipilimumab-related and anti-PD-1 immune-related AEs and overall response rate and overall survival associated with anti-PD-1 therapy.Results: Of 56 patients with metastatic melanoma included in the study, all of whom experienced severe immune-related AEs after ipilimumab therapy (31 [55%] male; mean [SD] age, 64 [14.9] years), 20 (36%) experienced at least 1 immune-related AE associated with pembrolizumab (6 of 20 [30%]) or nivolumab (14 of 20 [70%]) therapy. A total of 12 patients (21%) experienced grade 3 or 4 immune-related AEs, and among these patients, 4 (33%) presented with the same immune-related AE as with ipilimumab therapy. Severe immune-related AEs were resolved with use of systemic corticosteroids (7 [58%]) and/or anti-tumor necrosis factor (1 [8%]), and no grade 5 toxic effects were reported. Five patients discontinued anti-PD-1 therapy because of immune-related AEs. The overall response rate was 43%, with a median overall survival of 21 months (interquartile range, 18 to ongoing).Conclusions and relevance: The findings suggest that anti-PD-1 therapy may be associated with reduced risk of toxic effects and improved survival among patients who have experienced severe toxic effects after ipilimumab therapy