Brugada syndrome induced by BRAF and MEK inhibitors in a melanoma patient.

MEK inhibitors combined with programmed cell death-1 blockade immunotherapy for metastatic uveal melanoma: is it warranted?

In the setting of metastatic uveal melanoma (mUM), prognosis is dismal and treatment options are limited. MEK inhibition using selumetinib has led to promising results with improved progression-free survival. While immune checkpoint inhibitors such as programmed cell death-1 (PD-1) blockade therapy (anti-PD-1) has shown discrete efficacy in mUM, combining MEK inhibitors (MEKi) to anti-PD-1 might be an option as such combinations have shown synergistic efficacy in metastatic cutaneous melanoma. We report here and discuss our experience in three patients who received this combination in the absence of suitable alternative treatment. The efficacy was difficult to assess due to early severe tox…

Deux observations de granulome annulaire sous anti-PD1

Resume Introduction Le granulome annulaire fait partie des reactions granulomateuses qui peuvent etre induites par des medicaments. L’immunotherapie par anti-PD1 est utilisee dans le traitement des melanomes et d’autres cancers solides. Nous rapportons deux cas de granulome annulaire survenus chez des patientes traitees par un anti-PD1, le pembrolizumab. Observations Deux femmes traitees par pembrolizumab toutes les 3 semaines pour un melanome metastatique ont developpe un granulome annulaire sous traitement. L’immunotherapie a ete maintenue dans les deux cas. Les lesions ont continue d’evoluer par poussees et remissions chez la premiere patiente, alors qu’une disparition complete etait con…

Naturally Occurring Telomerase-Specific CD4 T-Cell Immunity in Melanoma.

CD4 T cells play a key role in anticancer immunity. In this study, we investigate the clinical relevance of circulating CD4 T helper type 1 (Th1) response against telomerase (anti-TERT Th1 response) in patients with melanoma. The spontaneous anti-TERT Th1 response was detected in 54.5% (85/156) of patients with melanoma before treatment. The prevalence of this systemic response was inversely related to Breslow thickness >1 mm and American Joint Committee on Cancer stage ≥II (P = 0.001 and 0.032, respectively). In contrast to patients treated with targeted therapies, the anti-TERT Th1 immunity was associated with an objective response after immune checkpoint inhibitors treatment. Hence, 86% …

Systematic search for neutropenia should be part of the first screening in patients with poikiloderma.

Poikiloderma occurs in a number of hereditary syndromes, the best known of which is Rothmund-Thomson syndrome (RTS). Differential diagnoses include Dyskeratosis Congenita (DC) with high genetic heterogeneity and Clericuzio-type Poikiloderma with Neutropenia (CPN) due to mutations in the C16orf57 gene. Mutations in the RECQL4 gene are only observed in two thirds of RTS patients. In this study, 10 patients referred for syndromic poikiloderma and negative for RECQL4 sequencing analysis were investigated for C16orf57 mutations. Two C16orf57 heterozygous nonsense mutations (p.W81X and p.Y89X) were identified in a 5-year-old female child presenting with generalized poikiloderma, dental dysplasia,…

Expanding the clinical spectrum of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis due to FAM111B mutations

Background Hereditary Fibrosing Poikiloderma (HFP) with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP [MIM 615704]) is a very recently described entity of syndromic inherited poikiloderma. Previously by using whole exome sequencing in five families, we identified the causative gene, FAM111B (NM_198947.3), the function of which is still unknown. Our objective in this study was to better define the specific features of POIKTMP through a larger series of patients. Methods Clinical and molecular data of two families and eight independent sporadic cases, including six new cases, were collected. Results Key features consist of: (i) early-onset poikiloderma, hypotrichosis and hypoh…

Search forReCQL4mutations in 39 patients genotyped for suspected Rothmund-Thomson/Baller-Gerold syndromes

Three overlapping conditions, namely Rothmund-Thomson (RTS), Baller-Gerold (BGS) and RAPADILINO syndromes, have been attributed to RECQL4 mutations. Differential diagnoses depend on the clinical presentation, but the numbers of known genes remain low, leading to the widespread prescription of RECQL4 sequencing. The aim of our study was therefore to determine the best clinical indicators for the presence of RECQL4 mutations in a series of 39 patients referred for RECQL4 molecular analysis and belonging to the RTS (27 cases) and BGS (12 cases) spectrum. One or two deleterious RECQL4 mutations were found in 10/27 patients referred for RTS diagnosis. Clinical and molecular reevaluation led to a…

Immunité spécifique anti-télomérase dans le mélanome

La reponse immunitaire lymphocytaire T CD4 Th1 joue un role important dans l’immunite anti tumorale et a ete etudiee dans de nombreux cancers. Nous avons evalue la reponse immunitaire T CD4 Th1 grâce a la reponse T CD4 Th1 anti-telomerase (anti-TERT) chez des patients atteints de melanome de tous stades AJCC. La reponse anti-TERT des lymphocytes de patients atteints de melanome etait evaluee par ELISpot IFN-γ et comparee aux donnees clinico-biologiques des patients. Au total, 171 patients atteints de melanome etaient inclus et 156 d’entre eux avaient une evaluation de la reponse anti-TERT disponible. Une reponse anti-TERT etait retrouvee chez 55 % des patients. La reponse anti-TERT etait mo…