Simple Summary Medulloblastoma is rare after puberty. Among several molecular subgroups that have been described, the sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal... Show moreSimple Summary Medulloblastoma is rare after puberty. Among several molecular subgroups that have been described, the sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal population and can be targeted with smoothened (SMO) inhibitors. However, no practice-changing prospective clinical trials have been published in adults to date. Tumors often recur, and treatment toxicity is relevant. Thus, the EORTC 1634-BTG/NOA-23 trial for post-pubertal patients with standard risk medulloblastoma will aim to increase treatment efficacy and to decrease treatment toxicity. Patients will be randomized between standard-dose vs. reduced-dosed radiotherapy, and SHH-subgroup patients will also be randomized between the SMO inhibitor sonidegib (Odomzo(TM,), Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone. In ancillary studies, we will investigate tumor tissue, blood and cerebrospinal fluid samples, magnetic resonance images, and radiotherapy plans to gain information that may improve future treatment. Patients will also be monitored long-term for late side effects of therapy, health-related quality of life, cognitive function, social and professional live outcomes, and reproduction and fertility. In summary, EORTC 1634-BTG/NOA-23 is a unique multi-national effort that will help to council patients and clinical scientists for the appropriate design of treatments and future clinical trials for post-pubertal patients with medulloblastoma. Medulloblastoma is a rare brain malignancy. Patients after puberty are rare and bear an intermediate prognosis. Standard treatment consists of maximal resection plus radio-chemotherapy. Treatment toxicity is high and produces disabling long-term side effects. The sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal and adult population and can be targeted by smoothened (SMO) inhibitors. No practice-changing prospective randomized data have been generated in adults. The EORTC 1634-BTG/NOA-23 trial will randomize patients between standard-dose vs. reduced-dosed craniospinal radiotherapy and SHH-subgroup patients between the SMO inhibitor sonidegib (Odomzo(TM), Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone to improve outcomes in view of decreased radiotherapy-related toxicity and increased efficacy. We will further investigate tumor tissue, blood, and cerebrospinal fluid as well as magnetic resonance imaging and radiotherapy plans to generate information that helps to further improve treatment outcomes. Given that treatment side effects typically occur late, long-term follow-up will monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. In summary, we will generate unprecedented data that will be translated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials. Show less
Objectives: To compare physical activity (PA), fatigue and sleep quality in adolescents and young adults (AYAs) after mild TBI (mTBI) to persons of similar age after orthopedic injury (OI) on the... Show moreObjectives: To compare physical activity (PA), fatigue and sleep quality in adolescents and young adults (AYAs) after mild TBI (mTBI) to persons of similar age after orthopedic injury (OI) on the longer term.Setting: Follow-up at least 6 months after visiting the emergency department of one of 2 general hospitals.Participants: Forty-nine patients aged 12-25 years (mean 18.4 years), diagnosed with mTBI and 54 patients aged 12-25 years (mean 15.8 years) with OI.Design: Cross-sectional electronic survey study.Main outcome measures: The Activity Questionnaire for Adults and Adolescents with results dichotomized for meeting/not meeting Dutch Health Enhancing PA recommendations (D-HEPA), the Checklist Individual Strength (range 20-140, low-high) measuring fatigue, and the Pittsburgh Sleep Quality Index (range 0-21, high-low) measuring sleep quality were administered.Results: Patients with mTBI less frequently met D-HEPA recommendations than patients with CH (49% vs. 70%; OR 2.87, 95%CI 1.07, 7.72) and reported more concentration-related fatigue problems (mean 19.1 (SD 8.0), mean 13.9 (SD 7.8), respectively; beta 3.98, 95%CI 0.39, 7.56), after adjusting for potential confounders, sex, BMI, age and time since injury. No differences were found in sleep quality.Conclusions: Identifying symptoms and limitations in activities is important after mTBI so that rehabiliation treatment can be initiated. Whether physical activity or fatigue is the best target for treatment remains to be established. (C) 2019 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. Show less
Recessive mutations in RTTN, encoding the protein rotatin, were originally identified as cause of polymicrogyria, a cortical malformation. With time, a wide variety of other brain malformations has... Show moreRecessive mutations in RTTN, encoding the protein rotatin, were originally identified as cause of polymicrogyria, a cortical malformation. With time, a wide variety of other brain malformations has been ascribed to RTTN mutations, including primary microcephaly. Rotatin is a centrosomal protein possibly involved in centriolar elongation and ciliogenesis. However, the function of rotatin in brain development is largely unknown and the molecular disease mechanism underlying cortical malformations has not yet been elucidated. We performed both clinical and cell biological studies, aimed at clarifying rotatin function and pathogenesis. Review of the 23 published and five unpublished clinical cases and genomic mutations, including the effect of novel deep intronic pathogenic mutations on RTTN transcripts, allowed us to extrapolate the core phenotype, consisting of intellectual disability, short stature, microcephaly, lissencephaly, periventricular heterotopia, polymicrogyria and other malformations. We show that the severity of the phenotype is related to residual function of the protein, not only the level of mRNA expression. Skin fibroblasts from eight affected individuals were studied by high resolution immunomicroscopy and flow cytometry, in parallel with in vitro expression of RTTN in HEK293T cells. We demonstrate that rotatin regulates different phases of the cell cycle and is mislocalized in affected individuals. Mutant cells showed consistent and severe mitotic failure with centrosome amplification and multipolar spindle formation, leading to aneuploidy and apoptosis, which could relate to depletion of neuronal progenitors often observed in microcephaly. We confirmed the role of rotatin in functional and structural maintenance of primary cilia and determined that the protein localized not only to the basal body, but also to the axoneme, proving the functional interconnectivity between ciliogenesis and cell cycle progression. Proteomics analysis of both native and exogenous rotatin uncovered that rotatin interacts with the neuronal (non-muscle) myosin heavy chain subunits, motors of nucleokinesis during neuronal migration, and in human induced pluripotent stem cell-derived bipolar mature neurons rotatin localizes at the centrosome in the leading edge. This illustrates the role of rotatin in neuronal migration. These different functions of rotatin explain why RTTN mutations can lead to heterogeneous cerebral malformations, both related to proliferation and migration defects. Show less
Candian, A.; Gomes Rachid, M.; MacIsaac, H.; Staroverov, V.N.; Peeters, E.; Cami, J. 2019
To determine self-reported physical activity (PA) levels and relationships with fatigue and sleep quality in adolescents and young adults after mild traumatic brain injury (mTBI).\nFollow-up 6-18... Show moreTo determine self-reported physical activity (PA) levels and relationships with fatigue and sleep quality in adolescents and young adults after mild traumatic brain injury (mTBI).\nFollow-up 6-18 months after visiting the emergency department of one of 2 general hospitals.\nForty-nine adolescents and young adults aged 12-25 years (mean 18.4 years), 22 (45%) male with mTBI.\nCross-sectional survey study.\nThe Activity Questionnaire for Adults and Adolescents (AQuAA), with results dichotomized into meeting or not meeting Dutch Health Enhancing PA recommendations (D-HEPA), the Checklist Individual Strength (CIS, 4 subscores) and the Pittsburgh Sleep Quality Index (PSQI, total score) were administered.\nTwenty-five participants (51%) did not meet the D-HEPA recommendations. After adjusting for sex, BMI and age, not meeting the recommendations was associated with a higher CIS Total Score (OR 1.04 95%CI 1.01, 1.07) but not with PSQI Total Score (OR 0.99, 95%CI 0.80, 1.21).\nIn adolescents and young adults with mTBI the level of reported PA is associated with fatigue but not with sleep quality. It remains to be established whether interventions aiming to promote PA should primarily be focused on PA or fatigue or both.\nOBJECTIVES\nSETTING\nPARTICIPANTS\nDESIGN\nMAIN OUTCOME MEASURES\nRESULTS\nCONCLUSIONS Show less
Andrews, H.; Peeters, E.; Tielens, A.G.G.M.; Okada, Y. 2018
