A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Contemporâneo e política

O texto aborda a crise da política e do contemporâneo como resultado de uma captura dos nomes pelo campo estatal. Quanto à política, todas as tentativas, desde 1968, de constituí-la a distância do Estado, do ponto de vista das pessoas e do interior de situações, apagaram-se atualmente. Reflete-se ainda sobre a natureza separada do Estado, e sobre o pensamento das pessoas e as formas de subjetividade. Assim, trata-se de avaliar a ruptura do pensamento, a partir da tese de que a natureza atual do Estado como Estado separado é incompatível com um pensamento das pessoas orientado para os possíveis. Busca-se, por fim, questionar o lugar da disciplina antropológica e o que ela pode enunciar sobre o contemporâneo hoje

Impact of post-brentuximab vedotin consolidation on relapsed/refractory CD30+ Hodgkin lymphomas: a large retrospective study on 240 patients enrolled in the French Named-Patient Program

International audienceBrentuximab vedotin was reported to be effective and safe against refractory/relapsed Hodgkin lymphoma in cohorts of 12 to 102 patients. Herein we report our retrospective analysis of the French experience with brentuximab vedotin used alone to treat 240 refractory/relapsed Hodgkin lymphoma patients enrolled in a named patient program between 2011 and 2013. All patients had histologically documented CD30+ Hodgkin lymphoma; 74% had refractory disease or early relapses. After a median of 3 chemotherapy lines, brentuximab vedotin was infused intravenously (1.8 mg/kg every 3 weeks). The primary endpoint was best response. Response at the end of treatment, its duration, survival data and toxicity profile were secondary endpoints. Patients received a median of 6 cycles; 68 underwent a consolidation thereafter. The best response was observed after a median of 4 cycles in 145 (60.4%) patients: 33.8% complete response/unconfirmed complete response, 26.7% partial response. Objective responses were observed decreased (39.3%) in the 28 patients \textgreater60 years. Median response duration was 8.4 months. With median follow-up at 16.1 months, median progression free-survival was 6.8 months and significantly longer for patients transplanted after brentuximab vedotin (median at 18,8 months); median overall survival was not reached. No death has been linked to brentuximab vedotin toxicity. The most common adverse events were peripheral sensory neuropathy (29.3%) and hematological toxicity. The results of this analysis support the previously reported brentuximab vedotin efficacy with manageable toxicity. Because short-term responses in most patients, high-dose therapy with stem-cell transplantation for responders should be considered rapidl