Effectiveness and safety of nivolumab in patients with advanced melanoma: A multicenter, observational study.

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.

Effectiveness and safety of dupilumab for the treatment of atopic dermatitis in a real-life French multicenter adult cohort.

BACKGROUND: Dupilumab is the first biologic available to treat atopic dermatitis (AD). Its effectiveness and safety were demonstrated in clinical trials. OBJECTIVE: We sought to assess the effectiveness and safety of dupilumab in adults with AD in a real-life French multicenter retrospective cohort. METHODS: We included patients treated during March 2017-April 2018. Efficacy outcomes, including Scoring Atopic Dermatitis (SCORAD) and Eczema Area and Severity Index (EASI) scores, were collected at baseline and 3 months when available. Adverse events (AEs) were recorded at follow-up. RESULTS: We included 241 patients. The median ± interquartile range (IQR) follow-up time was 3.8 ± 3.7 months. A ≥75% improvement in SCORAD was achieved in 27 of 163 (16.6%) patients, and a ≥75% improvement in EASI was achieved in 40 of 82 (48.8%) patients. The median SCORAD and EASI scores at 3 months were significantly lower than those at baseline (SCORAD ± IQR, 25 ± 21 vs 56 ± 27.4, P < 10-9 and EASI ± IQR, 4.1 ± 6.8 vs 17.9 ± 15.4, P < 10-9, respectively). Conjunctivitis was reported in 84 of 241 (38.2%) patients. The proportion with eosinophilia (>500 cells/mm3) during follow-up (57%) was higher than that at baseline (33.7%) (n = 172, P < 10-6). Dupilumab was stopped in 42 cases; 27 patients stopped because of AEs. LIMITATIONS: No control group, missing data. CONCLUSION: This real-life study demonstrated a similar dupilumab effectiveness as that seen in clinical trials, but it also revealed a higher frequency of conjunctivitis and eosinophilia.

Association of occupational exposure with features of systemic sclerosis.

BACKGROUND: Occupational exposure is reported as playing a substantial causative role in systemic sclerosis (SSc). OBJECTIVE: We sought to compare the characteristics of SSc in patients with and without occupational exposure to crystalline silica/solvents. METHODS: In all, 142 patients with SSc were enrolled in this prospective study. An expert committee performed blind evaluation of occupational exposure to crystalline silica/solvents. RESULTS: Patients exposed to crystalline silica more often exhibited: diffuse cutaneous SSc (P = .02), digital ulcers (P = .05), interstitial lung disease (P = .0004), myocardial dysfunction (P = .006), and cancer (P = .06). Patients exposed to solvents more frequently developed: diffuse cutaneous SSc (P = .001), digital ulcers (P = .01), interstitial lung disease (P = .02), myocardial dysfunction (P = .04), and cancer (P = .003); in addition, these patients were more frequently anti-Scl 70 positive and anticentromere negative. Under multivariate analysis, significant factors for SSc associated with exposure to silica/solvents were: male gender (odds ratio 19.31, 95% confidence interval 15.34-69.86), cancer (odds ratio 5.97, 95% confidence interval 1.55-23.01), and digital ulcers (odds ratio 2.42, 95% confidence interval 1.05-5.56). LIMITATIONS: The cohort originated from a single geographic region. CONCLUSION: Occupational exposure to crystalline silica/solvents is correlated with more severe forms of SSc characterized by: diffuse cutaneous involvement, interstitial lung disease, general microangiopathy (digital ulcers and myocardial dysfunction), and association with cancer. Occupational exposure should be systematically checked in all patients with SSc, as exposed patients seem to develop more severe forms of SSc.

Sentinel node status and immunosuppression: recurrence factors in localized Merkel cell carcinoma.

The prognostic value of the sentinel lymph node in Merkel cell carcinoma (MCC) has been examined previously in heterogeneous retrospective studies. The current retrospective study included a homogeneous population of patients with a localized MCC, all staged with sentinel lymph node biopsy. Factors associated with 3-year progression-free survival were analysed using logistic regression. The sentinel lymph node was positive in 32% of patients. The recurrence rate was 26.9%. In first analyses (n = 108), gender (p = 0.0115) and the presence of immunosuppression (p = 0.0494) were the only significant independent factors. In further analyses (n = 80), excluding patients treated with regional radiotherapy, sentinel lymph node status was the only significant prognostic factor (p = 0.0281). Immunosuppression and positive sentinel lymph node are associated with a worse prognosis in patients with MCC. Nodal irradiation impacts on the prognostic value of the sentinel lymph node status.

First case of drug rash eosinophilia and systemic symptoms due to boceprevir.

Boceprevir and telaprevir are 2 specific inhibitors of the hepatitis C (HCV) serine protease 3. Cutaneous side effects have been reported with high frequency, essentially rash, and dry skin. We report a case of drug rash with eosinophilia and systemic symptoms (DRESS) due to boceprevir. A 56-year-old African woman with chronic hepatitis C complicated with cirrhosis and cryoglobulinemia received pegylated interferon alfa-2a (PegIFN) and ribavirin (RBV) for 4 weeks and then boceprevir was added. She was also co-infected with HIV state A2. Eight weeks after adding boceprevir she developed a generalized maculopapular exanthema with fever, facial oedema, apparition of lymph node and alteration of the general state. She presented an eosinophilia (up to 3.0 × 10(9)cells/L), no biological inflammatory syndrome. The computed tomography revealed several lymph nodes located in the abdominal and inguinal areas. The cutaneous biopsy was consistent with a drug rash reaction. The HCV treatment was stopped and the patient was treated with topical steroids. Cutaneous and systemic symptoms disappeared in few weeks. Boceprevir was considered the culprit drug. We report to our knowledge the first case of DRESS due to boceprevir.

Clostridium difficile infection and immune checkpoint inhibitor-induced colitis in melanoma: 18 cases and a review of the literature.

Immunotherapy has become the standard of care for several types of cancer, such as melanoma. However, it can induce toxicity, including immune checkpoint inhibitor-induced colitis (CIC). CIC shares several clinical, histological, biological, and therapeutic features with inflammatory bowel disease (IBD). Clostridium difficile infection (CDI) can complicate the evolution of IBD. We aimed to characterize the association between CDI and CIC in patients treated with anti-CTLA-4 and anti-PD-1 for melanoma. Patients from nine centers treated with anti-CTLA-4 and anti-PD-1 for melanoma and presenting with CDI from 2010 to 2021 were included in this retrospective cohort. The primary endpoint was the occurrence of CIC. The secondary endpoints were findings allowing us to characterize CDI. Eighteen patients were included. Eleven were treated with anti-PD-1, four with anti-CTLA-4, and three with anti-PD-1 in combination with anti-CTLA-4. Among the 18 patients, six had isolated CDI and 12 had CIC and CDI. Among these 12 patients, eight had CIC complicated by CDI, three had concurrent CIC and CDI, and one had CDI followed by CIC. CDI was fulminant in three patients. Endoscopic and histological features did not specifically differentiate CDI from CIC. Nine of 11 patients required immunosuppressive therapy when CDI was associated with CIC. In nine cases, immunotherapy was discontinued due to digestive toxicity. CDI can be isolated or can complicate or reveal CIC. CDI in patients treated with immunotherapy shares many characteristics with CDI complicating IBD. Stool tests for Clostridium difficile should be carried out for all patients with diarrhea who are being treated with immunotherapy.

Successful use of rituximab for refractory hemophagocytic lymphohistiocytosis in a melanoma patient treated with targeted therapy.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by aberrant immune hyperactivation of T CD8 lymphocytes and macrophages driven by cytokine dysfunction. We report a 64-year-old man, with advanced BRAF-mutant melanoma treated by combined targeted therapies who had a recalcitrant and cortico-dependent Epstein-Barr virus (EBV)-induced HLH. One rituximab cycle led to a rapid and prolonged HLH remission which allowed to switch the targeted therapy for immunotherapy rituximab thus makes it possible to limit the use of corticosteroids, which limits the effectiveness of immunotherapy. The patient finally died of a cerebral tumoral progression 2 years later. Despite secondary hypogammaglobulinemia, we did not observe any severe infections during this period. This case suggests that rituximab can be a valuable option for EBV-induced HLH to avoid the T-suppressive effects of high-dose of corticosteroids in immunotherapy-treated patients.

Survival in adult patients with BRAFV600 mutation-positive advanced melanoma: a noninterventional ambispective study of patients with cobimetinib combined with vemurafenib during the French early access program: MELANIS study.

Cobimetinib combined with vemurafenib was available in France in 2015 through a 'Temporary Authorization for Use' program (TAU, preapproval access pending its marketing on 2016) for patients with v-raf murine sarcoma viral oncogene homolog B1-mutant advanced melanoma. This study aimed to provide real-world outcomes in patients previously registered in this TAU. This noninterventional, ambispective, multicentre French study, conducted in patients previously registered in TAU, aimed to estimate overall survival (OS) and progression-free survival (PFS) and to describe the tolerability of the therapeutic combination. At first cobimetinib intake (in combination with vemurafenib), 88% of the 185 evaluable patients had disease stage IV (brain metastasis: 70% of them), 31% had elevated lactate dehydrogenases, and 10% had an Eastern Cooperative Oncology Group (ECOG) index ≥2. Median OS was 16.1 months (95% CI, 12.5-20.7). Brain metastasis ( P < 0.001), ECOG index ≥2 ( P = 0.007), and hepatic impairment ( P = 0.037) were found as independent factors significantly associated with shorter survival. Median PFS was 7.3 months (95% CI, 5.2-8.4). ECOG index ≥2 ( P = 0.006) was significantly associated with shorter PFS. Between cobimetinib start and inclusion, increased CPK (3% of patients), retinal serous detachment (3%), decreased left ventricular ejection fraction (3%), increased transaminases (3%), and rash (3%) were the most reported serious adverse events. This study provides real-world outcomes in France for the vemurafenib-cobimetinib combination available in patients with BRAF-mutant-advanced melanoma. Our data tend to confirm in the real-life setting that this combination therapy is effective in such patients, with a safety profile consistent with previous interventional studies.

Panniculitis in a Woman With Opportunistic Pulmonary Coinfection by Pneumocystis jirovecii and Cryptococcus neoformans: 18F-FDG PET/CT Revealing the Infection and Assessing Treatment Response.

ABSTRACT: A 56-year-old woman, with history of psoriasis well controlled on ustekinumab, underwent 18F-FDG PET/CT to explore first onset of histologically proven skin panniculitis of unknown origin. PET/CT showed high uptake in panniculitis lesions in limbs and in a lung opacity suggestive of pneumonia. Based on PET/CT findings, a bronchoalveolar lavage revealed pulmonary coinfection by Pneumocystis jirovecii and Cryptococcus neoformans. Thus, hematogenous dissemination of infection was suspected as etiology of panniculitis. She was treated with fluconazole and trimethoprim-sulfamethoxazole, leading to total resolution of skin lesions. Posttherapeutic PET/CT showed complete metabolic response of skin and pulmonary lesions.