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Pilocytic astrocytomas (PA) typically exhibit distinct clinical, radiological, histopathological, and genetic features. DNA-methylation profiling distinguishes PA according to their location (infratentorial, midline, hemispheric, or spinal). In the hemispheric location, distinguishing PA from glioneuronal tumors remains a common diagnostic challenge for neuropathologists. Furthermore, the current version of the DKFZ classifier seems to have difficulty separating them from gangliogliomas. In this study, after central radiological review, we identified a histopathologically defined set of PA (histPA, n = 11) and a cohort of DNA-methylation defined PA (mcPA, n = 11). Nine out of the 11 histPA matched the methylation class of hemispheric PA, whereas 2 cases were classified at the end of the study as dysembryoplastic neuroepithelial tumors. Similarly, the mcPA cohort contained tumors mainly classified as PA (7/11), but 4 cases were classified as glioneuronal. The analysis of the 16 tumors with an integrated diagnosis of PA revealed that they affect mainly children with a wide spectrum of radiological, histopathological (i.e. a predominantly diffuse growth pattern), and genetic characteristics (large range of mitogen-activated protein kinase alterations). Based on these results, we consider hemispheric PA to be different from their counterparts in other locations and to overlap with other glioneuronal tumors, reinforcing the necessity of interpreting all data to obtain an accurate diagnosis.

Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children1,2, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma3. Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH).ELP1was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent–offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype4and characterized by universal biallelic inactivation of ELP1owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U34) position5,6. Tumours from patients with ELP1-associated MBSHHwere characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems7–9. Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.

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Diffuse intrinsic pontine glioma (or DIPG) are pediatric high-grade gliomas associated with a dismal prognosis. They harbor specific substitution in histone H3 at position K27 that induces major epigenetic dysregulations. Most clinical trials failed so far to increase survival, and radiotherapy remains the most efficient treatment, despite only transient tumor control. We conducted the first lentiviral shRNA dropout screen in newly diagnosed DIPG to generate a cancer-lethal signature as a basis for the development of specific treatments with increased efficacy and reduced side effects compared to existing anticancer therapies. The analysis uncovered 41 DIPG essential genes among the 672 genes of human kinases tested, for which several distinct interfering RNAs impaired cell expansion of three different DIPG stem-cell cultures without deleterious effect on two control neural stem cells. Among them, PLK1, AURKB, CHEK1, EGFR, and GSK3Awere previously identified by similar approach in adult GBM indicating common dependencies of these cancer cells and pediatric gliomas. As expected, we observed an enrichment of genes involved in proliferation and cell death processes with a significant number of candidates belonging to PTEN/PI3K/AKT and EGFR pathways already under scrutiny in clinical trials in this disease. We highlighted VRK3,a gene involved especially in cell cycle regulation, DNA repair, and neuronal differentiation, as a non-oncogenic addiction in DIPG. Its repression totally blocked DIPG cell growth in the four cellular models evaluated, and induced cell death in H3.3-K27M cells specifically but not in H3.1-K27M cells, supporting VRK3 as an interesting and promising target in DIPG.

Medulloblastomas (MBs) are the most frequent childhood malignant brain tumor. Four histopathologic variants and 4 genetic subgroups have been defined in the World Health Organization (WHO) 2016 Classification and constitute major risk stratification items directly affecting the patient management. Although MB subgroups have been molecularly defined, immunohistochemical surrogates are needed. The aim of our retrospective study was to evaluate the concordance between immunohistochemistry, using 4 antibodies (YAP1, GAB1, OTX2, and β-catenin), and DNA-methylation profiling in MB subgrouping. From a series of 155 MBs, the κ coefficient of concordance was almost perfect (0.90), with only 8/152 discrepant cases (no DNA-methylation analysis was available in 3 cases). Interestingly, the discrepancies mostly concerned (7/8 cases) MBs with divergent differentiations (myogenic, melanotic, and others) with all of those classified into group 3 (n=6) and group 4 (n=1) by DNA-methylation profiling. Another discrepant case concerned a WNT-activated MB (showing only 1% of immunopositive tumor cell nuclei), highlighting the difficulties of determining an appropriate β-catenin immunostaining cutoff. The high concordance of the routine immunohistochemical panel (YAP1, GAB1, OTX2, and β-catenin) and DNA-methylation profiling confirm its utility as a reliable predictive marker of molecular subtype in MBs. We analyzed the accuracy of 10 different IHC combinations for the determination of MB subtype and found that a combination of 2 antibodies (YAP1 and OTX2) allows for the successful characterization of 144 cases of 152 cases. Finally, our series extends the molecular data of the rare morphologic variant of MBs with melanotic/myogenic differentiations.

Molecular alterations were recently added to the World Health Organization (WHO) 2016 classification of central nervous system (CNS) tumors. We correlated the histological and radiological features of G34R mutant high-grade gliomas, a recently described hemispheric and supratentorial glioma of children and young adults.

Pediatric chordomas are rare malignant neoplasms, and few data are available for optimizing therapeutic strategies and outcome. This study aimed at evaluating how best to manage them and to identify prognostic factors. This multicentric retrospective study included 40 children diagnosed with chordomas between 1966 and 2012. Clinical, radiological, and histopathological data, treatment modalities, and outcomes were reviewed. The median age was 12 years old. Most chordomas were histologically classical forms (45.5%) and were mostly located at the skull base (72.5%). The overall survival (OS) was 66.6% and 58.6%, and progression-free survival (PFS) was 55.7% and 52% at 5 and 10 years, respectively. Total resection was correlated with a better outcome (p = 0.04 for OS and PFS, log-rank). A histopathological/immunohistochemical grading system recently crafted for adults was applied. In a multivariate analysis, it significantly correlated with outcome (PFS and OS, p = 0.004), and the loss of BAF47 immunoexpression appeared to be a significant independent prognostic factor (PFS, p = 0.033). We also identified clinical and histopathological parameters that correlated with prognosis. A new grading system combined with the quality of surgical resection could help classify patients to postpone radiotherapy in case of low risk. Targeted therapy and reirradiation at recurrence may be considered as potential therapeutic strategies.

The modified pediatric intracerebral hemorrhage score is a clinical imaging predictive outcome grading scale, built on dichotomous components routinely and rapidly assessed at bedside in the acute setting and may be used for risk stratification, early clinical care, and selection for therapeutic trials in children with nontraumatic intracerebral hemorrhage.

BACKGROUND:Multiple burr hole (MBH) surgery is a simple, safe, and effective indirect technique of revascularization in moyamoya angiopathy (MM). However, it is not yet recognized as a first-line treatment.OBJECTIVE:To assess the long-term outcome and perioperative complications in a large single-center cohort of children with MM who underwent burr hole surgery.METHODS:This study is a retrospective analysis of children who underwent surgery for MM in a national reference center for pediatric stroke between 1999 and 2015. Sixty-four children (108 hemispheres, median age 7 years) were consecutively treated. The indication for revascularization was previous stroke or transient ischemic attack (TIA) or rapidly progressive disease on brain magnetic resonance imaging (MRI) and digital subtraction angiography. Children were followed with clinical examinations, telephone interviews, and MRI with any clinical recurrence of stroke or TIA used as the primary endpoint. Surgical mortality and morbidity were documented.RESULTS:Sixty-four patients were operated (bilateral MBH n = 39, unilateral procedure n = 25). At a mean follow-up of 4.2 years and 270.6 patient years, 89.1% of patients had not suffered any recurrent stroke or TIA. A second surgery was required in 5 cases after unilateral revascularization, and in 3 cases after bilateral MBH. Mortality associated with the procedure was 0. Postoperative Matsushima angiographic grading was the only predictive factor of ischemic recurrence (P= .036).CONCLUSION:In pediatric MM, MBH compares favorably to other indirect or direct revascularization techniques in children in the prevention of stroke or TIA.

Arterial spin labeling enabled us to distinguish low-grade tumors from higher-grade tumors in posterior fossa, thalamic, and hemispheric tumors in a large cohort of patients with pediatric brain tumors.

About one third of patients with rhabdoid tumors (RT) harbor a heterozygous germline variant in SMARCB1. Molecular diagnosis therefore keeps a crucial place in the diagnosis of RT, and genetic counseling should be systematically recommended. However, immunohistochemistry has progressively replaced molecular tools to assess the status of SMARCB1 in tumors; the necessity of analyzing SMARCB1 status in the tumor may thus be less considered by neuropathologists and pediatric neuro-oncologists. In the present manuscript as aforementioned, we report on two patients with bifocal RT in the first month of life and in whom no germline variant was initially found in the SMARCB1 coding sequence. Careful analysis of SMARCB1 status in the tumors revealed that only one of the two inactivating hits was found in the coding sequence. By sequencing the tumor cells RNA, we were able to detect an insertion with an abnormal sequence, due to the same intronic variant of SMARCB1, which led to the exonisation of the first intron. This cryptic variant was absent in the germline DNA of both patients. Of note, we previously reported one patient with the same deep intronic variant in the germline in a soft tissue RT. To our mind, this additional report on two patients clearly demonstrates that this intronic variant is a new hotspot that should now be systematically added to the germline screening of SMARCB1. We therefore recommend searching for and cautiously interpreting germline analysis if SMARCB1 has not been extensively studied in the tumor.

Childhood intracerebral hemorrhage is mainly attributable to underlying brain arteriovenous malformations (bAVMs). Multimodal treatment options for bAVMs include microsurgery and embolization, allowing an immediate cure, and radiosurgery, entailing longer obliteration times. Follow-up data on pediatric ruptured bAVMs are scarce, making it difficult to assess the risk of subsequent intracerebral hemorrhage. Our aim was to assess the clinical and angiographic outcome and to analyze risk factors for rebleeding during and after combined treatment of pediatric bAVMs.

L’International Society for the Study of Vascular Anomalies (ISSVA) a défini quatre lésions vasculaires du système nerveux central (SNC) : malformations artério-veineuses, cavernomes, malformations veineuses et télangiectasies. À partir de la base de données du centre hospitalier Sainte-Anne, nous avons effectué une relecture histopathologique des lésions vasculaires du SNC sur une période de 21 ans.

Abstract

Children involved in high-speed vehicle collision could be particularly exposed to severe injuries when adult restraints are used. We report a case where adult 3-point restraint used without booster seat was responsible for severe thoracic injury resulting in complete shoulder and clavicle dislocation, occipito-atloidal dislocation, and complete disruption of right common carotid artery in a 7-year-old boy. Misplacement of the adult shoulder harness at the base of the neck could be directly responsible for these lethal injuries, which could probably be avoided by concomitant use of a booster seat.

Graphical Abstract

We report the cases of a 39-year-old woman with chronic lymphocytic leukemia and a 21-year-old man with chronic granulomatous disease treated for cerebral aspergillosis. The patients required radical surgery for infection progression despite adequate isavuconazole plasma concentration or neurological complication. We thus decided to measure the brain isavuconazole concentration.

Anaplastic ganglioglioma (AGG) is a rare and malignant variant of ganglioglioma. According to the World Health Organization classification version 2016, their histopathological grading criteria are still ill-defined. The aim of the present study was to assess the clinical, imaging, histopathological, and molecular characteristics and outcomes of AGGs in a large consecutive and retrospective adult and pediatric case series. Eighteen patients with AGGs (13 adults and 5 children) were identified (14 de novo and 4 secondary) from a cohort of 222 gangliogliomas (GG) (8%) treated at our institution between 2000 and 2015. AGGs represented a very aggressive disease with poor outcome (median progression-free survival, 10 months; median overall survival, 27 months). They were located in the temporal lobe only in 22% and presented with seizures (44%) or increased intracranial pressure (44%) at diagnosis. Concerning histopathological and molecular data, they shared morphological characteristics and BRAF V600E mutation (39%) with their benign counterparts but also showed hTERT promoter mutation (61%), p53 accumulation (39%), ATRX loss (17%), or p.K27M H3F3A mutation (17%). AGGs are malignant neoplasms requiring aggressive oncological treatment. In the perspective of targeted therapies, AGGs should be screened for BRAF V600E, hTERT, ATRX, and mutations of histone genes.

Les épendymomes supratentoriels pédiatriques (ESTP) sont des tumeurs rares dont le gradinghistologique est controversé. Des marqueurs moléculaires ont récemment été identifiés, notamment le réarrangement du gène RELAcodant pour une protéine du complexe NFκB [1,2]. L’objectif était de comparer les techniques de FISH, immuno-histochimie (IHC) et méthylome pour la recherche du réarrangement RELAet les intégrer aux données histologiques.

L’IRM arterial spin labelling(ASL) est une méthode de perfusion cérébrale sans injection, elle permet de mesurer le débit quantitatif cérébral. Nous allons présenter son intérêt dans la maturation cérébrale de l’enfant ainsi que dans les maladies mitochondriales et dans les tumeurs de la fosse postérieure.