Clinical management of molecular alterations identified by high throughput sequencing in patients with advanced solid tumors in treatment failure: Real-world data from a French hospital

BackgroundIn the context of personalized medicine, screening patients to identify targetable molecular alterations is essential for therapeutic decisions such as inclusion in clinical trials, early access to therapies, or compassionate treatment. The objective of this study was to determine the real-world impact of routine incorporation of FoundationOne analysis in cancers with a poor prognosis and limited treatment options, or in those progressing after at least one course of standard therapy.MethodsA FoundationOneCDx panel for solid tumor or liquid biopsy samples was offered to 204 eligible patients.ResultsSamples from 150 patients were processed for genomic testing, with a data acquisition success rate of 93%. The analysis identified 2419 gene alterations, with a median of 11 alterations per tumor (range, 0–86). The most common or likely pathogenic variants were on TP53, TERT, PI3KCA, CDKN2A/B, KRAS, CCDN1, FGF19, FGF3, and SMAD4. The median tumor mutation burden was three mutations/Mb (range, 0–117) in 143 patients with available data. Of 150 patients with known or likely pathogenic actionable alterations, 13 (8.6%) received matched targeted therapy. Sixty-nine patients underwent Molecular Tumor Board, which resulted in recommendations in 60 cases. Treatment with genotype-directed therapy had no impact on overall survival (13 months vs. 14 months; p = 0.95; hazard ratio = 1.04 (95% confidence interval, 0.48–2.26)].ConclusionsThis study highlights that an organized center with a Multidisciplinary Molecular Tumor Board and an NGS screening system can obtain satisfactory results comparable with those of large centers for including patients in clinical trials

Impacts d’une exposition aux écrans sur les précurseurs de la communication chez l’enfant de 0 à 2 ans et sur les comportements parentaux

Les écrans sont omniprésents dans la vie des familles. Un nombre important d’études a déjà été publié sur les effets d’une exposition aux écrans sur le développement des enfants. Pourtant, les orthophonistes, interrogés via un questionnaire, constatent les effets des écrans sur les tout-petits. Nous avons rassemblé des recherches concernant cet impact sur les précurseurs de la communication, et les constats d’orthophonistes. Les conséquences sont nombreuses et, dans leur ensemble, négatives. Ils concernent principalement l’attention et la concentration, le développement correct du langage et de la communication, et le comportement. D’autres, moins connus, sont relevés par les orthophonistes et beaucoup corroborent des études scientifiques. Parmi eux, se trouvent des atteintes du sommeil, du raisonnement ou l’apparition, chez certains, de « traits autistiques ». Les comportements parentaux face aux écrans et l’importance des interactions parents-enfant sont moins mis en avant dans la prévention actuelle alors qu’ils impactent grandement le développement du tout-petit. Après avoir rassemblé des études à ce sujet, nous avons créé une plaquette de prévention à destination des orthophonistes et des parents, afin d’enrayer ces conduites nocives pour le nourrisson

Approches et apprentissage de la grammaire à l'école primaire : l'exemple de l'accord sujet-verbe au CE1

Suite au rapport d'Alain Bentolila en 2006, les instructions officielles de 2008 ont décidé de supprimer l'ORLF présente dans les programmes de 2002 pour revenir à une analyse grammaticale plus rigoureuse. La mise en place de ces programmes fait resurgir le débat sur les finalités de l'enseignement de la grammaire à l'école chez les grammairiens. En s'appuyant sur l'analyse de plusieurs manuels de français et d'étude de la langue en CE1 sur l'acquisition de l'accord sujet-verbe, ce mémoire vise à se questionner sur la manière d'enseigner la grammaire à l'école et tente d'y apporter des réponses

Angiomatoid fibrous histiocytoma: an atypical brain location newly described as intracranial mesenchymal tumor FET-CREB fusion-positive

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Pseudo-tumeur calcifiante du névraxe

International audienceCalcifying pseudoneoplasms of the neuraxis (CAPNON) are rare lesions of the central nervous system. To date, about 60 cases have been reported in literature. We present a case that had the peculiarity to occur in a pregnant woman. At 32 weeks of gestation, a 26-year-old woman was hospitalized to explore nocturnal epigastralgia. During the hospitalisation, the patient presented generalised seizures. As an eclampsia had been suspected, a caesarean delivery was performed. Post-operatively, the patient harboured memory disorders and neuro-imaging explorations were done. They showed an intracerebral calcified mass located in the left frontal lobe and surrounded by an oedema. A complete surgical resection was performed. Histological examination of the surgical specimen showed a calcified tissue containing a fibrillary or granular material. A dense and hyalinised eosinophilic material focally surrounded the calcifications and contained regular fusiform cells of fibroblastic type. Foci of lipomatous and osseous metaplasia were present. Immunohistochemical staining for EMA and STAT6 was negative. There was no associated meningioangiomatosis nor tumour proliferation. Forty-five months after surgery, the patient did not present any seizures and had no sequelae. CAPNON are rare lesions occurring at any age. Their location in the central nervous system is ubiquitous and they can be intra or extra axial. The treatment is surgical and the prognosis excellent. CAPNON must be recognized and distinguished from the other calcified lesions, tumoural or non-tumoural, to avoid an inadequate and potentially harmful treatment

A mouse model of sensory neuropathy induced by a long course of monomethyl-auristatin E treatment

International audienceAntibody-drug conjugates (ADCs) are anticancer drugs consisting of a monoclonal antibody, targeting selective tumor antigens, to which has been frequently associated a highly potent cytotoxic agent, the monomethyl auristatin E (MMAE) using a chemical linker. MMAE is a tubulin polymerization inhibitor derived from dolastin-10. These MMAE-ADCs are responsible for peripheral nerve toxicities. Our objective was to develop and characterize a mouse model of MMAE-induced peripheral neuropathy induced by free MMAE injections. MMAE was injected in Swiss mice at 50 μg/kg i.p. every other day for 7 weeks. Assessments of motor and sensory nerve functions were performed once a week on MMAE and Vehicle-treated mice. Sciatic nerve and paw skin were removed at the end of experiment for subsequent immunofluorescence and morphological analysis. MMAE did not affect motor coordination, muscular strength and heat nociception, but significantly induced tactile allodynia in MMAE-treated mice compared with Vehicle-treated mice from day 35 to day 49. MMAE significantly reduced myelinated and unmyelinated axon densities in sciatic nerves and led to a loss of intraepidermal nerve fiber in paw skin. In summary, long course of low dose of MMAE induced a peripheral sensory neuropathy associated with nerve degeneration, without general state alteration. This model may represent a ready accessible tool to screen neuroprotective strategies in the context of peripheral neuropathies induced by MMAE-ADCs

Simultaneous Combined Myositis, Inflammatory Polyneuropathy, and Overlap Myasthenic Syndrome

Immune-mediated neuromuscular disorders include pathologies of the peripheral nervous system, neuromuscular junction, and muscles. If overlap syndromes (or the association of almost two autoimmune disorders) are recognized, the simultaneous occurrence of several autoimmune neuromuscular disorders is rare. We describe two patients presenting the simultaneous occurrence of inflammatory neuropathy, myositis, and myasthenia gravis (with positive acetylcholine receptor antibodies). For each patient, we carried out a pathological analysis (nerve and muscle) and an electrophysiological study (and follow-up). To our knowledge, this is the first description of such a triple immune-mediated neuromuscular syndrome. We compared our observations with a few other cases of simultaneous diagnosis of two inflammatory neuromuscular disorders

Isolated cerebral Rosai–Dorfman disease presenting as a sole mass protruding into the fourth ventricle: A case report

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Neuroprotective effect of angiotensin II type 2 receptor stimulation in vincristine-induced mechanical allodynia

International audiencePeripheral neuropathy is the major dose-limiting side effect of many currently used chemotherapies, such as vincristine (VCR). We recently demonstrated that candesartan, an angiotensin II type 1 receptor antagonist, was neuroprotective against resiniferatoxin-induced sensory neuropathy, and that this effect is mediated by stimulation of the angiotensin II type 2 receptor (AT2R). Thus, we evaluated the effect of preventive treatment with candesartan and a specific AT2R agonist, C21, on a mouse model of VCR-induced neuropathy. Vincristine was administered daily for 7 days to male Swiss mice. Treatment with candesartan and C21 was started on day 1, before VCR treatment, and continued until day 7. We evaluated the development of VCR-induced neuropathy and the effect of treatment by functional tests, immunohistochemical analyses of intraepidermal nerve fibers and dorsal root ganglia neurons, and ultrastructural analysis of the sciatic nerve. Mice treated with VCR showed high mechanical allodynia but no modifications of motor performance or mechanical/thermal nociception. Treatment with candesartan and C21 completely restored normal tactile sensitivity of VCR-treated mice. Both drugs prevented VCR-induced nonpeptidergic intraepidermal nerve fiber loss. Only C21 displayed neuroprotective effects against VCR-induced loss and enlargement of myelinated nerve fibers in the sciatic nerve. Our finding that candesartan and C21 are protective against VCR-induced neuropathic pain through AT2R stimulation favors evaluation of its therapeutic potential in patients receiving chemotherapy