H3.3K27M Mutation Controls Cell Growth and Resistance to Therapies in Pediatric Glioma Cell Lines

International audienceHigh-grade gliomas represent the most lethal class of pediatric tumors, and their resistance to both radio- and chemotherapy is associated with a poor prognosis. Recurrent mutations affecting histone genes drive the tumorigenesis of some pediatric high-grade gliomas, and H3K27M mutations are notably characteristic of a subtype of gliomas called DMG (Diffuse Midline Gliomas). This dominant negative mutation impairs H3K27 trimethylation, leading to profound epigenetic modifications of genes expression. Even though this mutation was described as a driver event in tumorigenesis, its role in tumor cell resistance to treatments has not been deciphered so far. To tackle this issue, we expressed the H3.3K27M mutated histone in three initially H3K27-unmutated pediatric glioma cell lines, Res259, SF188, and KNS42. First, we validated these new H3.3K27M-expressing models at the molecular level and showed that K27M expression is associated with pleiotropic effects on the transcriptomic signature, largely dependent on cell context. We observed that the mutation triggered an increase in cell growth in Res259 and SF188 cells, associated with higher clonogenic capacities. Interestingly, we evidenced that the mutation confers an increased resistance to ionizing radiations in Res259 and KNS42 cells. Moreover, we showed that H3.3K27M mutation impacts the sensitivity of Res259 cells to specific drugs among a library of 80 anticancerous compounds. Altogether, these data highlight that, beyond its tumorigenic role, H3.3K27M mutation is strongly involved in pediatric glioma cells’ resistance to therapies, likely through transcriptomic reprogrammin

Association between Kniest dysplasia and chondrosarcoma in a child

International audienceConstitutive COL2A1 mutations are associated with a wide variety of clinical manifestations known as type II collagenopathies. Among them is Kniest dysplasia, which is phenotypically variable and includes both skeletal (short trunk and limbs, kyphoscoliosis, prominent joints, and osteoarthritis) and craniofacial characteristics. Kniest dysplasia mutations primarily arise in the triple-helicoidal region of the alpha 1 (II) chain in COL2A1 between exons 12 and 24. Somatic COL2A1 mutations have been identified in chondrosarcoma, a rare cartilage forming neoplasm, with a hypermutability of the gene reported in 37% of cases. However, to the best of our knowledge, there is no reported increase in predisposition to chondrosarcoma in human collagenopathies, and no reported clinical association between these congenital diseases and cartilaginous tumors. In the case study presented here, we report the first description of an association between these two rare diseases involving COL2A1, in a child presenting with Kniest dysplasia and a grade I sphenoethmoidal chondrosarcoma. We also describe a new constitutive mutation in COL2A1

Congenital factor XIII deficiency: comprehensive overview of the FranceCoag cohort

International audienceThis FranceCoag network study assessed 33 patients with congenital factor XIII (FXIII) deficiency presenting FXIII levels <10 iu/dl. Diagnosis was based on abnormal bleeding in 29 patients, a positive family history in 2, recurrent miscarriages in 1 and was fortuitous in 1. Eighteen patients (62·1%) presented life‐threatening umbilical or intracranial haemorrhages (ICH). Seven of the 15 patients who experienced ICH were diagnosed but untreated, including 3 with secondary neurological sequelae. All pregnancies without prophylaxis (26/26) led to miscarriages versus 3/16 with prophylaxis. In patients exhibiting FXIII levels <10 iu/dl, prophylaxis could be discussed at diagnosis and at pregnancy. Further controlled prospective studies are needed

Bevacizumab decreases vestibular schwannomas growth rate in children and teenagers with neurofibromatosis type 2

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Persistent headaches one year after bacterial meningitis: prevalence, determinants and impact on quality of life

International audienceBackground: Little is known on headaches long-term persistence after bacterial meningitis and on their impact on patients' quality of life.Methods: In an ancillary study of the French national prospective cohort of community-acquired bacterial meningitis in adults (COMBAT) conducted between February 2013 and July 2015, we collected self-reported headaches before, at onset, and 12 months (M12) after meningitis. Determinants of persistent headache (PH) at M12, their association with M12 quality of life (SF 12), depression (Center for Epidemiologic Studies Depression Scale) and neuro-functional disability were analysed.Results: Among the 277 alive patients at M12 87/274 (31.8%), 213/271 (78.6%) and 86/277 (31.0%) reported headaches before, at the onset, and at M12, respectively. In multivariate analysis, female sex (OR: 2.75 [1.54-4.90]; p < 0.001), pre-existing headaches before meningitis (OR: 2.38 [1.32-4.30]; p < 0.01), higher neutrophilic polynuclei percentage in the CSF of the initial lumbar puncture (OR: 1.02 [1.00-1.04]; p < 0.05), and brain abscess during the initial hospitalisation (OR: 8.32 [1.97-35.16]; p < 0.01) were associated with M12 persistent headaches. Neither the responsible microorganism, nor the corticoids use were associated with M12 persistent headaches. M12 neuro-functional disability (altered Glasgow Outcome Scale; p < 0.01), M12 physical handicap (altered modified Rankin score; p < 0.001), M12 depressive symptoms (p < 0.0001), and M12 altered physical (p < 0.05) and mental (p < 0.0001) qualities of life were associated with M12 headaches.Conclusion: Persistent headaches are frequent one year after meningitis and are associated with quality of life alteration

One-Year Sequelae and Quality of Life in Adults with Meningococcal Meningitis: Lessons from the COMBAT Multicentre Prospective Study

Trial registration: ClinicalTrial.Gov identification number NCT01730690.International audienceIntroduction: COMBAT is a prospective, multicentre cohort study that enrolled consecutive adults with community-acquired bacterial meningitis (CABM) in 69 participating centres in France between February 2013 and July 2015 and followed them for 1 year.Methods: Patients aged at least 18 years old, hospitalised with CABM were followed during their hospitalisation and then contacted by phone 12 months after enrolment. Here we present the prevalence of sequelae at 12 months in a subgroup of patients with meningococcal meningitis.Results: Five of the 111 patients with meningococcal meningitis died during initial hospitalisation and two died between discharge and 12 months, leaving 104 patients alive 1 year after enrolment, 71 of whom provided 12-month follow-up data. The median age was 30.0 years and 54.1% of the patients had no identified risk factor for meningitis. More than 30% reported persistent headache, more than 40% were not satisfied with their sleep and 10% had concentration difficulties. Hearing loss was present in about 15% of the patients and more than 30% had depressive symptoms. About 13% of the patients with a previous professional activity had not resumed work. On the SF-12 Health Survey, almost 50% and 30% had physical component or mental component scores lower than the 25th percentile of the score distribution in the French general population. There was a non-significant improvement in the patients' disability scores from hospital discharge to 12 months (p = 0.16), but about 10% of the patients had residual disability.Conclusions: Although most patients in our cohort survive meningococcal meningitis, the long-term burden is substantial and therefore it is important to ensure a prolonged follow-up of survivors and to promote preventive strategies, including vaccination

Relationship between serotypes, disease characteristics and 30-day mortality in adults with invasive pneumococcal disease

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