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

Skin cancers are the most frequent cancers in fair-skinned populations, but we can prevent them

: Cancers of the skin are the most commonly occurring cancers in humans. In fair-skinned populations, up to 95% of keratinocyte skin cancers and 70-95% of cutaneous melanomas are caused by ultraviolet radiation and are thus theoretically preventable. Currently, however, there is no comprehensive global advice on practical steps to be taken to reduce the toll of skin cancer. To address this gap, an expert working group comprising clinicians and researchers from Africa, America, Asia, Australia, and Europe, together with learned societies (European Association of Dermato-Oncology, Euromelanoma, Euroskin, European Union of Medical Specialists, and the Melanoma World Society) reviewed the extant evidence and issued the following evidence-based recommendations for photoprotection as a strategy to prevent skin cancer. Fair skinned people, especially children, should minimise their exposure to ultraviolet radiation, and are advised to use protective measures when the UV index is forecast to reach 3 or higher. Protective measures include a combination of seeking shade, physical protection (e.g. clothing, hat, sunglasses), and applying broad-spectrum, SPF 30 + sunscreens to uncovered skin. Intentional exposure to solar ultraviolet radiation for the purpose of sunbathing and tanning is considered an unhealthy behaviour and should be avoided. Similarly, use of solaria and other artificial sources of ultraviolet radiation to encourage tanning should be strongly discouraged, through regulation if necessary. Primary prevention of skin cancer has a positive return on investment. We encourage policymakers to communicate these messages to the general public and promote their wider implementation

Pimasertib Versus Dacarbazine in Patients With UnresectableNRAS-Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover

This study investigated the efficacy and safety of pimasertib (MEK1/MEK2 inhibitor) versus dacarbazine (DTIC) in patients with untreated NRAS-mutated melanoma. Phase II, multicenter, open-label trial. Patients with unresectable, stage IIIc/IVM1 NRAS-mutated cutaneous melanoma were randomized 2:1 to pimasertib (60 mg; oral twice-daily) or DTIC (1000 mg/m2 ; intravenously) on Day 1 of each 21-day cycle. Patients progressing on DTIC could crossover to pimasertib. Primary endpoint: investigator-assessed progression-free survival (PFS); secondary endpoints: overall survival (OS), objective response rate (ORR), quality of life (QoL), and safety. Overall, 194 patients were randomized (pimasertib n = 130, DTIC n = 64), and 191 received treatment (pimasertib n = 130, DTIC n = 61). PFS was significantly improved with pimasertib versus DTIC (median 13 versus 7 weeks, respectively; hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.42–0.83; p = 0.0022). ORR was improved with pimasertib (odds ratio 2.24, 95% CI 1.00–4.98; p = 0.0453). OS was similar between treatments (median 9 versus 11 months, respectively; HR 0.89, 95% CI 0.61–1.30); 64% of patients receiving DTIC crossed over to pimasertib. Serious adverse events (AEs) were more frequent for pimasertib (57%) than DTIC (20%). The most common treatment-emergent AEs were diarrhea (82%) and blood creatine phosphokinase (CPK) increase (68%) for pimasertib, and nausea (41%) and fatigue (38%) for DTIC. Most frequent grade ≥3 AEs were CPK increase (34%) for pimasertib and neutropenia (15%) for DTIC. Mean QoL scores (baseline and last assessment) were similar between treatments. Pimasertib has activity in NRAS-mutated cutaneous melanoma and a safety profile consistent with known toxicities of MEK inhibitors. Trial registration: ClinicalTrials.gov, NCT01693068

Echographie en gynécologie bovine, ovine et caprine, réalisation d'un CD-Rom didactique

L'échographie est un outil de diagnostic à l'innocuité avérée, fiable et précoce, couramment utilisé par les vétérinaires chez les ruminants et très bien accepté par les éleveurs qui y ont vu la supériorité d'un tel moyen d'investigation. Notre travail a consisté à concevoir et à réaliser un CD-Rom de gynécologie des ruminants, à visée didactique pour les vétérinaires et les techniciens intervenant en reproduction. Les différentes situations classiquement rencontrées en gynécologie bovine (examen des ovaires, diagnostic de gestation, contrôle d'involution utérine), ovine (diagnostic de gestation et dénombrement) et caprine (diagnostic de gestation et détection de pseudogestations) sont illustrées par des images échographiques, des photographies, des schémas et des films. Ce CD-Rom est un outil dynamique qui se veut pédagogique pour les praticiens ou les étudiants vétérinaires et doit permettre à son utilisateur d'améliorer son aptitude à réaliser et interpréter des images échographiques.MAISONS-ALFORT-Ecole Vétérin (940462302) / SudocSudocFranceF

Psychiatric Disorders with Systemic Retinoids: A Systematic Review of Case Reports.

International audienc

Psychiatric Disorders, Acne and Systemic Retinoids: Comparison of Risks.

International audienceBACKGROUND: The link between isotretinoin, treatment of a severe form of acne, and psychiatric disorders remains controversial, as acne itself could explain the occurrence of psychiatric disorders. This study aims at assessing the disproportionality of psychiatric adverse events reported with isotretinoin in the French National PharmacoVigilance Database, compared with other systemic acne treatments and systemic retinoids. MATERIALS AND METHODS: Data were extracted from the French National PharmacoVigilance Database for systemic acne treatments, systemic retinoids and drugs used as comparators. Each report was subjected to double-blind analysis by two psychiatric experts. A disproportionality analysis was performed, calculating the number of psychiatric ADRs divided by the total number of notifications for each drug of interest. RESULTS: Concerning acne systemic treatments: all 71 reports of severe psychiatric disorders involved isotretinoin, the highest proportion of mild/moderate psychiatric adverse events was reported with isotretinoin (14.1%). Among systemic retinoids, the highest proportion of severe and mild/moderate psychiatric events occurred with isotretinoin and alitretinoin. CONCLUSION: Our study raises the hypothesis that psychiatric disorders associated with isotretinoin are related to a class effect of retinoids, as a signal emerges for alitretinoin. Complementary studies are necessary to estimate the risk and further determine at-risk populations

Anti-PD-1 for the treatment of advanced cutaneous squamous cell carcinoma in elderly patients: a French multicenter retrospective survey

International audienceBackground: Anti-PD1 agents are currently recommended as first-line treatment in advanced cutaneous squamous cell carcinoma (acSCC) by updated European guidelines. Although acSCC frequently affects elderly patients with multiple comorbidities, this subset of patients is often excluded of registration clinical trials.Purpose: To assess anti-PD-1 efficacy and safety in elderly acSCC patients in real-life conditions and describe this specific population with oncogeriatric evaluation tools.Methods: A multicenter retrospective study including acSCC patients at least 70 years old treated with PD-1 inhibitors was conducted in French referral centers. The primary endpoint was the overall response rate (ORR). Secondary endpoints included safety data, time to response (TTR), duration of response (DOR), overall survival (OS), and progression-free survival (PFS).Results: 63 patients were included. ORR was 57.1% (95% CI 44.0-69.5), median TTR and DOR were 3 and 5.5 months respectively. Median OS was not reached (95% CI 12.5 months-not reached) at data cut-off after a median follow-up of 8 months while median PFS was 8 months. (95% CI 5 months-not reached). Grade 3-5 adverse effects occurred in 47.6% of patients. 41.3% of patients experienced degradation of ECOG performance status during anti-PD-1 treatment. Nutritional state worsened in 27% of patients and 57.1% lost weight during treatment.Conclusion: In this particular subset of acSCC patients PD-1 inhibitors obtain results similar to those obtained in younger populations included in pivotal clinical trials, with acceptable safety. A specific oncogeriatric evaluation at treatment initiation and during follow-up appears important in this setting most notably to help manage toxicity

Combined Therapy with Anti-PD1 and BRAF and/or MEK Inhibitor for Advanced Melanoma: A Multicenter Cohort Study

International audienceDespite significant progress in melanoma survival, therapeutic options are still needed in case of progression under immune checkpoint inhibitors (ICI), and resistance to targeted therapies (TT) in BRAF-mutated melanomas. This study aimed to assess the safety of combined ICI and TT as a rescue line in real-life clinical practice. We conducted a study within the prospective French multicentric MelBase cohort, including patients treated with a combination of anti-PD1 (pembrolizumab/nivolumab) and BRAF inhibitor (BRAFi: dabrafenib/vemurafenib) and/or MEK inhibitors (MEKi: trametinib/cobimetinib) for BRAF mutated or wild-type advanced melanoma. Fifty-nine patients were included: 30% received the triple combination, 34% an anti-PD1 and BRAFi, and 36% an anti-PD1 and MEKi. Grade 3–4 adverse events occurred in 12% of patients. Permanent discontinuation or dose reduction of one of the treatments for toxicity was reported in 14% and 7% of patients, respectively. In the BRAF wild-type subgroup, treatment with MEKi and anti-PD1 induced a tumor control rate of 83% and median progression-free survival of 7.1 months. The combination of anti-PD1 and BRAFi and/or MEKi was a safe rescue line for advanced melanoma patients previously treated with ICI/TT. The benefit of these combinations, specifically anti-PD1 and MEKi in BRAF wild-type melanoma patients, needs to be prospectively studied

Outdoor workers and sun exposure: Results of an international survey on sun exposure behaviours and knowledge among 17 countries, the HELIOS project

International audienceNo abstract availabl