Hypervariabilité génotypique des mélanomes : Un défi thérapeutique

On estime à environ 5 000 le nombre annuel de nouveaux cas de mélanome en France. La proportion des formes familiales est évaluée, selon les séries, entre 5 % et 10 %. Les aspects cliniques, histologiques et biologiques de progression du mélanome sont actuellement mieux connus ; les développements technologiques récents ont, quant à eux, permis d’aborder les mécanismes moléculaires de la progression tumorale et de mettre en lumière des gènes impliqués dans cette évolution. Toutefois, des difficultés importantes persistent : il existe une grande variabilité dans l’expression de ces gènes, non seulement d’un patient à l’autre, mais aussi selon les stades de la maladie, locaux ou métastatiques ; par ailleurs, certaines des mutations retrouvées au cours du mélanome peuvent également être présentes dans des lésions bénignes (naevus). La variabilité génotypique associée au mélanome rend le ciblage thérapeutique complexe, et constitue actuellement un défi majeur en termes de traitement. Cet article, volontairement non exhaustif, insistera surtout sur les anomalies génomiques les plus étudiées, desquelles semblent naître des perspectives thérapeutiques intéressantes.Cutaneous melanoma remains a management challenge. Melanoma is the leading cause of death from skin tumors worldwide. Melanoma progression is well defined in its clinical, histopathological and biological aspects, but the molecular mechanism involved and the genetic markers associated to metastatic dissemination are only beginning to be defined. The recent development of high-throughput technologies aimed at global molecular profiling of cancer is switching on the spotlight at previously unknown candidate genes involved in melanoma. Among those genes, BRAF is one of the most supposed to be of interest and targeted therapies are ongoing in clinical trials. In familial melanoma, germline mutations in two genes, CDKN2A and CDK4, that play a pivotal role in controlling cell cycle and division. It is hope that this better understanding of the biologic features of melanoma and the mechanisms underlying tumor-induced immunosuppression will lead to efficaceous targeted therapy

Analysis of Failure Correlation in Peer-to-Peer Storage Systems

In this paper, we propose and study analytical models of self-repairing peer-to-peer storage systems subject to failures. The failures correspond to the simultaneous loss of multiple data blocks due to the definitive loss of a peer (or following a disk crash). In the system we consider that such failures happen continuously, hence the necessity of a self-repairing mechanism (data are written once for ever). We show that, whereas stochastic models of independent failures similar to those found in the literature give a correct approximation of the average behavior of real systems, they fail to capture their variations (e.g. in bandwidth needs). We propose to solve this problem using a new stochastic model based on a fluid approximation and we give a characterization of the behavior of the system according to this model (expectation and standard deviation). This new model is validated using comparisons between its theoretical behavior and computer simulations

Analysis of Failure Correlation in Peer-to-Peer Storage Systems

In this paper, we propose and study analytical models of self-repairing peer-to-peer storage systems subject to failures. The failures correspond to the simultaneous loss of multiple data blocks due to the definitive loss of a peer (or following a disk crash). In the system we consider that such failures happen continuously, hence the necessity of a self-repairing mechanism (data are written once for ever). We show that, whereas stochastic models of independent failures similar to those found in the literature give a correct approximation of the average behavior of real systems, they fail to capture their variations (e.g. in bandwidth needs). We propose to solve this problem using a new stochastic model based on a fluid approximation and we give a characterization of the behavior of the system according to this model (expectation and standard deviation). This new model is validated using comparisons between its theoretical behavior and computer simulations

Evaluation of the Knowledge of Primary Care Physicians About Important Nail Diseases Before and After a Short Online Training

Introduction: Nail diseases are often diagnosed late with a potential prognostic and functional im-pact. This could be partly due to knowledge gaps among primary care physicians (PCPs). Objectives: To evaluate the knowledge about diagnosis and management of ten common/important nailconditions in a population of French PCPs and its improvement after a 31-minute online training session. Methods: We submitted 10 pre-test and post-test clinical cases and an educative online course on the diagnosis and the management of nail diseases to 138 volunteer PCPs; 73 completed the whole training path. Results: Compared to pre-test, more PCPs in the post-test required an urgent second opinion to der-matologist for pigmented melanoma (100% versus 80.3%; P <0.05) and use of inappropriate/danger-ous systemic treatment for trauma-induced nail changes was reduced after the training program (0% versus 6.8%; P <0.05).A lack of knowledge remained after training for amelanotic melanoma with an increase of mycological/bacteriological tests (9.6% versus 0%; P <0.05). Conclusions: Management of nail diseases by our panel of PCPs was suboptimal and was improved after a short online training

Health-related quality of life in cancer immunotherapy: a systematic perspective, using causal loop diagrams.

PURPOSE: System science offers a unique set of tools, including causal loop diagrams (CLDs), for stakeholders to better grasp the complexity of factors surrounding quality of life. Because the health-related quality of life (HRQoL) of cancer immunotherapy patients exists within an intricate system affected by and affecting many factors across multiple dimensions, the development of a systems-level model can provide a powerful framework to aid the understanding of this complexity. We developed a CLD for HRQoL of cancer immunotherapy patients. METHODS: We first applied a literature-based approach to construct a CLD for patients following immunotherapy. We then iteratively reviewed and enhanced the CLD through interviews with subject matter experts. RESULTS: Based on the reviewed literature and subject matter expert input, we produced a CLD representing the system surrounding cancer immunotherapy patients' HRQoL. Several feedback loops are identified that span clinical experiences, oncology teams' perceptions about immunotherapy, social support structures, and further research and development in cancer immunotherapy, in addition to other components. The CLD enables visualization of thought experiments regarding how a change anywhere in the system can ultimately worsen or improve patients' HRQoL. CONCLUSION: The CLD illustrates the valuable contribution of a systems perspective to quality-of-life research. This systems-based qualitative representation gives insight on strategies to inhibit harmful effects, enhance beneficial effects, and inherent tradeoffs within the system. The CLD identifies gaps in the literature and offers a communication tool for diverse stakeholders. Our research method provides an example for studying the complexities of quality of life in other health domains

First-line, fixed-duration nivolumab plus ipilimumab followed by nivolumab in clinically diverse patient populations with unresectable stage III or IV melanoma: Checkmate 401

PURPOSE: To address the paucity of data in patients with historically poor outcomes, we conducted the single-arm phase IIIb CheckMate 401 study to evaluate the safety and efficacy of nivolumab plus ipilimumab followed by nivolumab monotherapy in clinically diverse patient populations with advanced melanoma. METHODS: Treatment-naive patients with unresectable stage III-IV melanoma received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg (240 mg following a protocol amendment) once every 2 weeks for ≤ 24 months. The primary end point was the incidence of grade 3-5 select treatment-related adverse events (TRAEs). Overall survival (OS) was a secondary end point. Outcomes were evaluated in subgroups defined by Eastern Cooperative Oncology Group performance status (ECOG PS), brain metastasis status, and melanoma subtype. RESULTS: In total, 533 patients received at least one dose of study drug. Grade 3-5 select TRAEs affecting the GI (16%), hepatic (15%), endocrine (11%), skin (7%), renal (2%), and pulmonary (1%) systems occurred in the all-treated population; similar incidence rates were observed across all subgroups. At 21.6 months\u27 median follow-up, 24-month OS rates were 63% in the all-treated population, 44% in the ECOG PS 2 subgroup (including patients with cutaneous melanoma only), 71% in the brain metastasis subgroup, 36% in the ocular/uveal melanoma subgroup, and 38% in the mucosal melanoma subgroup. CONCLUSION: Nivolumab plus ipilimumab followed by nivolumab monotherapy was tolerable in patients with advanced melanoma and poor prognostic characteristics. Efficacy was similar between the all-treated population and patients with brain metastases. Reduced efficacy was observed in patients with ECOG PS 2, ocular/uveal melanoma, and/or mucosal melanoma, highlighting the continued need for novel treatment options for these difficult-to-treat patients

First-Line, Fixed-Duration Nivolumab Plus Ipilimumab Followed by Nivolumab in Clinically Diverse Patient Populations With Unresectable Stage III or IV Melanoma: CheckMate 401

PURPOSE To address the paucity of data in patients with historically poor outcomes, we conducted the single-arm phase IIIb CheckMate 401 study to evaluate the safety and efficacy of nivolumab plus ipilimumab followed by nivolumab monotherapy in clinically diverse patient populations with advanced melanoma. METHODS Treatment-naive patients with unresectable stage III-IV melanoma received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg (240 mg following a protocol amendment) once every 2 weeks for ≤24 months. The primary end point was the incidence of grade 3-5 select treatment-related adverse events (TRAEs). Overall survival (OS) was a secondary end point. Outcomes were evaluated in subgroups defined by Eastern Cooperative Oncology Group performance status (ECOG PS), brain metastasis status, and melanoma subtype. RESULTS In total, 533 patients received at least one dose of study drug. Grade 3-5 select TRAEs affecting the GI (16%), hepatic (15%), endocrine (11%), skin (7%), renal (2%), and pulmonary (1%) systems occurred in the all-treated population; similar incidence rates were observed across all subgroups. At 21.6 months' median follow-up, 24-month OS rates were 63% in the all-treated population, 44% in the ECOG PS 2 subgroup (including patients with cutaneous melanoma only), 71% in the brain metastasis subgroup, 36% in the ocular/uveal melanoma subgroup, and 38% in the mucosal melanoma subgroup. CONCLUSION Nivolumab plus ipilimumab followed by nivolumab monotherapy was tolerable in patients with advanced melanoma and poor prognostic characteristics. Efficacy was similar between the all-treated population and patients with brain metastases. Reduced efficacy was observed in patients with ECOG PS 2, ocular/uveal melanoma, and/or mucosal melanoma, highlighting the continued need for novel treatment options for these difficult-to-treat patients

The SLOOP project: Simulations, Parallel Object-Oriented Languages, Interconnection Networks

International audienc

Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma

BACKGROUND The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma. METHODS Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated. RESULTS At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group. CONCLUSIONS As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrencefree survival than placebo, with no new toxic effects identified.