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Recent incorporation of the four primary medulloblastoma subgroups into the WHO Classification of Central Nervous System Tumors necessitates globally accessible methods to discern subgroups. In this issue of Cancer Cell , Wang et al. develop a rapid and reliable machine learning workflow for pre-operative subgroup determination using routine magnetic resonance imaging. [ABSTRACT FROM AUTHOR]

Effective and less toxic therapies for medulloblastoma have proved to be highly elusive. In this issue of Cancer Cell , Yang et al. show that thyroid hormone treatment leads to the activation of neurogenic differentiation factor 1 (NeuroD1) and differentiation of medulloblastoma cells through reversing EZH2-mediated transcriptional repression of NeuroD1. [ABSTRACT FROM AUTHOR]

A recent study by Petralia et al. of 218 pediatric brain tumors across seven different entities applied an integrated approach incorporating proteomics, phosphoproteomics, whole-genome sequencing, and RNA sequencing. This elegant study unveiled new signaling pathways, the composition of tumor microenvironments, and functional effects of copy number variants and somatic mutations. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) is a major cause of infant morbidity and mortality. In these patients, magnetic resonance imaging (MRI) including diffusion-weighted imaging (DWI) is the test of choice to describe the extent of microstructural injury. Case presentation and discussion: In this case series, we describe novel acute and chronic MRI findings in four infants (6-19 months) with small, unilateral subdural hematomas in whom the etiology of head injury was suspicious for non-accidental trauma (NAT). Acute (<1-week post-injury) DWI revealed extensive areas of restricted diffusion isolated to the cerebral white matter predominantly ipsilateral to the subdural hematoma. After prolonged pediatric intensive care treatment including subdural evacuation ( n = 2) or decompressive craniectomy ( n = 1), all patients survived albeit with significant motor and cognitive deficits. Delayed structural MRI (6-9-year post-injury) demonstrated cortical and subcortical atrophy well-correlated with areas of acute restricted diffusion. Conclusion: These four cases highlight that relatively small subdural hematomas can be associated with extensive white matter injury-detectable only by early DWI-which have long-term structural and functional consequences. [ABSTRACT FROM AUTHOR]

Ependymomas are the third commonest paediatric central nervous system (CNS) tumour, accounting for 6–12% of brain tumours in children. The management of these tumours has seen considerable changes over the last two decades, leading to a significant improvement in outcomes. However, despite advances in neurosurgical, neuroimaging and postoperative adjuvant therapy, management of these tumours remain challenging, and recurrence occurs in over 50% of cases, particularly when complete resection is not achieved prior to conformal radiotherapy. To-date no chemotherapeutic regimen has proven to be of significant clinical benefit. Predicting tumour behaviour and defining robust correlates of disease outcome based on histopathology and clinical characteristics remains suboptimal. Paucity of cell lines, failure to develop ideal animal models of these tumours, have precluded better understanding of the oncogenic drivers, undermining development of targeted therapies. Over the last few years breakthrough in the understanding of the molecular biology, are now providing clues to therapeutic insights. It is clear that even with histopathological similarities, these are genetically heterogeneous tumours with diverse clinical outcomes. Rapid evolution of data based on genome-wide DNA methylation patterns, have now identified nine molecular subgroups in these tumours, across three anatomic compartments which include supratentorial (ST), posterior fossa (PF) and the spinal locations. More recently based on transcriptome profiling, two subgroups (group A and B) of PF ependymoma have been identified with distinct molecular, clinical characteristics and specific chromosomal aberrations. This review includes current management, evolving molecular biology and the shifting paradigm of treatment profile that targets molecular alterations in paediatric ependymoma. [ABSTRACT FROM AUTHOR]

Historical risk stratification criteria for medulloblastoma rely primarily on clinicopathological variables pertaining to age, presence of metastases, extent of resection, histological subtypes and in some instances individual genetic aberrations such as MYC and MYCN amplification. In 2010, an international panel of experts established consensus defining four main subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) delineated by transcriptional profiling. This has led to the current generation of biomarker-driven clinical trials assigning WNT tumors to a favorable prognosis group in addition to clinicopathological criteria including MYC and MYCN gene amplifications. However, outcome prediction of non-WNT subgroups is a challenge due to inconsistent survival reports. In 2015, a consensus conference was convened in Heidelberg with the objective to further refine the risk stratification in the context of subgroups and agree on a definition of risk groups of non-infant, childhood medulloblastoma (ages 3-17). Published and unpublished data over the past 5 years were reviewed, and a consensus was reached regarding the level of evidence for currently available biomarkers. The following risk groups were defined based on current survival rates: low risk (>90 % survival), average (standard) risk (75-90 % survival), high risk (50-75 % survival) and very high risk (<50 % survival) disease. The WNT subgroup and non-metastatic Group 4 tumors with whole chromosome 11 loss or whole chromosome 17 gain were recognized as low-risk tumors that may qualify for reduced therapy. High-risk strata were defined as patients with metastatic SHH or Group 4 tumors, or MYCN-amplified SHH medulloblastomas. Very high-risk patients are Group 3 with metastases or SHH with TP53 mutation. In addition, a number of consensus points were reached that should be standardized across future clinical trials. Although we anticipate new data will emerge from currently ongoing and recently completed clinical trials, this consensus can serve as an outline for prioritization of certain molecular subsets of tumors to define and validate risk groups as a basis for future clinical trials. [ABSTRACT FROM AUTHOR]

Gliomas represent the most common solid tumor of the nervous system, and can occur as both low and high-grade tumors. Current risk stratification and treatment approaches rely heavily on the morphological classification of gliomas whereby low-grade gliomas have an excellent prognosis, particularly pilocytic astrocytomas, while high-grade gliomas have a poor prognosis. The past decade has witnessed a dramatic increase in scholars’ knowledge of the biology of pediatric low-grade gliomas particularly through the advent of integrated genomics and next generation sequencing. Indeed, many of these biological advances are changing treatment paradigms, particularly in low-grade gliomas, where rationale targeted therapies are currently being explored in clinical trials. In this review the authors summarize the current approach to pediatric low grade gliomas and outline the biological advances over the past 10 years, which will be driving the next generation of clinical trials. [ABSTRACT FROM AUTHOR]

Medulloblastoma is the most common malignant brain tumour diagnosed in children. Over the last few decades, advances in radiation and chemotherapy have significantly improved the odds of survival. Nevertheless, one third of all patients still succumb to their disease, and many long-term survivors are afflicted with neurocognitive sequelae. Large-scale multi-institutional efforts have provided insight into the transcriptional and genetic landscape of medulloblastoma. Four distinct subgroups of medulloblastoma have been identified, defined by distinct transcriptomes, genetics, demographics and outcomes. Integrated genomic profiling of each of these subgroups has revealed distinct genetic alterations, driving pathways and in some instances cells of origin. In this review, we highlight, in a subgroup-specific manner, our current knowledge of the genetic and molecular alterations in medulloblastoma and underscore the possible avenues for future therapeutic intervention. [ABSTRACT FROM AUTHOR]

Introduction: Modern understanding of the relation between the mutated cancer stem cell and its site of origin and of its interaction with the tissue environment is enhancing the importance of developmental anatomy in the diagnostic assessment of posterior fossa tumors in children. The aim of this review is to show how MR imaging can improve on the exact identification of the tumors in the brainstem and in the vicinity of the fourth ventricle in children, using both structural imaging data and a precise topographical assessment guided by the developmental anatomy. Results: The development of the hindbrain results from complex processes of brainstem segmentation, ventro-dorsal patterning, multiple germinative zones, and diverse migration pathways of the neural progenitors. Depending on their origin in the brainstem, gliomas may be infiltrative or not, as well as overwhelmingly malignant (pons), or mostly benign (cervicomedullary, medullo-pontine tegmental, gliomas of the cerebellar peduncles). In the vicinity of the fourth ventricles, the prognosis of the medulloblastomas (MB) correlates the molecular subtyping as well as the site of origin: WNT MB develop from the Wnt-expressing lower rhombic lip and have a good prognosis; SHH MB develop from the Shh-modulated cerebellar cortex with an intermediate prognosis (dependent on age); recurrences are local mostly. The poor prognosis group 3 MB is radiologically heterogeneous: some tumors present classic features but are juxtaventricular (rather than intraventricular); others have highly malignant features with a small principal tumor and an early dissemination. Group 4 MB has classic features, but characteristically usually does not enhance; dissemination is common. Although there is as yet no clear molecular subgrouping of the ependymomas, their sites of origin and their development can be clearly categorized, as most develop in an exophytic way from the ventricular surface of the medulla in clearly specific locations: the obex region with expansion in the cistern magna, or the lateral recess region with expansion in the CPA and prepontine cisterns (cerebellar ependymomas, and still more intra-brainstem ependymomas are rare). Finally, almost all cerebellar gliomas are pilocytic astrocytomas. Conclusions: A developmental and anatomic approach to the posterior fossa tumors in children (together with diffusion imaging data) provides a reliable pre-surgical identification of the tumor and of its aggressiveness. [ABSTRACT FROM AUTHOR]

Background: Ependymoma is the third most common malignant tumor of the posterior fossa and is a major cause of neurological morbidity and mortality in children. Current treatments, particularly surgery and external beam irradiation result in relatively poor outcomes with significant neurological and cognitive sequelae from treatment. Historical approaches have considered all ependymomas as similar entities based on their morphological appearance. Results: Recent advances in genomics and epigenetics have revealed, however, that ependymomas from different CNS locations represent distinct entities. Moreover, ependymoma of the posterior fossa, the most common location in children, is actually comprised of two distinct molecular variants. These two variants have marked differences in demographics, transcriptomes, structure, methylation patterns, and clinical outcomes. This allows for the development of new biology-based clinical risk stratification, which can both prioritize patients for de-escalation of therapy and identify those who will benefit from novel therapeutic strategies. Indeed, the identification of these two variants allows an opportunity for robust preclinical modeling for development of novel therapeutic strategies. Conclusions: Herein, we have summarized our current clinical approach to diagnosis and treatment of posterior fossa ependymoma, recent advances in understanding the biology of posterior fossa ependymoma and how these new insights can be translated into the clinic to form the basis of the next generation of clinical trials. [ABSTRACT FROM AUTHOR]

Telomerase reverse transcriptase ( TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes. [ABSTRACT FROM AUTHOR]

Summary: Background: Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. Methods: We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. Results: Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p<0·0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0·013) than with other subgroups, which was confirmed in cohort 2 (p=0·0075), but not cohort 3 (p=0·70). Interpretation: Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases. Funding: Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto. [ABSTRACT FROM AUTHOR]

Background Rasmussen's encephalitis (RE) is an inflammatory encephalopathy of unknown cause defined by seizures with progressive neurological disabilities. Herein, the pathogenesis of RE was investigated focusing on inflammasome activation in the brain. Methods Patients with RE at the University of Alberta, Edmonton, AB, Canada, were identified and analyzed by neuroimaging, neuropsychological, molecular, and pathological tools. Primary human microglia, astrocytes, and neurons were examined using RT-PCR, enzyme-linked immunosorbent assay (ELISA), and western blotting. Results Four patients with RE were identified at the University of Alberta. Magnetic resonance imaging (MRI) disclosed increased signal intensities in cerebral white matter adjacent to cortical lesions of RE patients, accompanied by a decline in neurocognitive processing speed (P <0.05). CD3ε, HLA-DRA, and TNFα together with several inflammasome-associated genes (IL-1β, IL-18, NLRP1, NLRP3, and CASP1) showed increased transcript levels in RE brains compared to non-RE controls (n = 6; P <0.05). Cultured human microglia displayed expression of inflammasome-associated genes and responded to inflammasome activators by releasing IL-1β, which was inhibited by the caspase inhibitor, zVAD-fmk. Major histocompatibility complex (MHC) class II, IL-1β, caspase-1, and alanine/serine/cysteine (ASC) immunoreactivity were increased in RE brain tissues, especially in white matter myeloid cells, in conjunction with mononuclear cell infiltration and gliosis. Neuroinflammation in RE brains was present in both white matter and adjacent cortex with associated induction of inflammasome components, which was correlated with neuroimaging and neuropsychological deficits. Conclusion Inflammasome activation likely contributes to the disease process underlying RE and offers a mechanistic target for future therapeutic interventions. [ABSTRACT FROM AUTHOR]

Aim Neurocutaneous melanocytosis is a rare neurocutaneous syndrome defined by the presence of large and/or multiple congenital cutaneous nevi and melanocytic deposits in the central nervous system. We sought to define the spectrum of central nervous system abnormalities in children with neurocutaneous melanocytosis. Method We retrospectively reviewed cases of neurocutaneous melanocytosis referred to the pediatric neuro-oncology service at our center from 2003 to 2010. Results Of 14 patients (11 males, 3 females) identified, eight were living. Median age of survivors was 31 months (range 12mo-6y 10mo) while median age of death was 81 months (19mo-28y). Of the six patients who died, all had diffuse leptomeningeal melanocytic deposits and four had leptomeningeal melanoma. All patients had neuroimaging: six had findings suggestive of diffuse leptomeningeal melanocytosis; seven had multifocal melanocytic deposits; and one patient had normal neuroimaging but focal seizures. Spinal abnormalities were common: three patients had extensive dorsal spinal arachnoid cysts and one had a benign cervical spindle cell tumor. Seven patients had epilepsy. Three patients had profound developmental delay; the other 11 patients had no or mild delay. Interpretation Children with neurocutaneous melanocytosis exhibit a wide range of intracranial and intraspinal abnormalities and variable clinical outcomes. [ABSTRACT FROM AUTHOR]

Rapidly evolving genomic technologies have permitted progressively detailed studies of medulloblastoma biology in recent years. These data have increased our understanding of the molecular pathogenesis of medulloblastoma, identified prognostic markers, and suggested future avenues for targeted therapy. Although current randomized trials are still stratified based largely on clinical variables, the use of molecular markers is approaching routine use in the clinic. In particular, integrated genomics has uncovered that medulloblastoma comprises four distinct molecular and clinical variants: WNT, sonic hedgehog (SHH), group 3, and group 4. Children with WNT medulloblastoma have improved survival, whereas those with group 3 medulloblastoma have a dismal prognosis. Additionally, integrated genomics has shown that adult medulloblastoma is molecularly and clinically distinct from the childhood variants. Prognostic and predictive markers identified by genomics should drive changes in stratification of treatment protocols for medulloblastoma patients on clinical trials once they can be demonstrated to be reliable, reproducible, and practical. Cases with excellent prognoses (WNT cases) should be considered for therapy de-escalation, whereas those with bleak prognoses (group 3 cases) should be prioritized for experimental therapy. In this review, we will summarize the genomic data published over the past decade and attempt to interpret its prognostic significance, relevance to the clinic, and use in upcoming clinical trials. [Copyright &y& Elsevier]

Abstract: We report the case of a 29-month-old boy with spasticity and periventricular white matter changes on magnetic resonance imaging in whom a complex rearrangement consisting of a de novo duplication of 14q32.31q32.33 and deletion of 14q32.33 was identified by array-based comparative genomic hybridization. Our case replicates some of the previous features associated with chromosome 14q duplication and deletion while expanding its clinical spectrum with pyramidal tract dysfunction signs and neuroimaging features. Genomic lesions should be considered in cases of leukodystrophies, and genome-wide studies such as array-based comparative genomic hybridization could be considered in the assessment of undefined white matter disorders. [Copyright &y& Elsevier]

The past decade has witnessed a tremendous increase in our ability to identify precise genetic etiologies of developmental delay and intellectual disability. Mutations in various transcription factors were found in patients with intellectual disability. Specifically, the importance of a subgroup of transcription factors containing zinc finger motifs have been increasingly recognized in developmental delay and intellectual disability. We present a patient with intellectual disability in whom the duplication of two genes, ZNF673 and ZNF674, was identified through array-based comparative genomic hybridization. Our report reinforces the role of zinc finger transcription factors in cognitive development. Furthermore, it illustrates that not only deletions, but duplications, can cause developmental delay and intellectual disability. [ABSTRACT FROM AUTHOR]

Rett syndrome is a severe neurodegenerative disorder characterized by acquired microcephaly, communication dysfunction, psychomotor regression, seizures and stereotypical hand movements. Mutations in methyl CpG binding protein 2 (MECP2) are identified in most patients with classic Rett syndrome. Genetic studies in patients with a Rett variant have expanded the spectrum of underlying genetic etiologies. Recently, a deletion encompassing several genes in the long arm of chromosome 14 has been associated with the congenital Rett-syndrome phenotype. Using array-based comparative genomic hybridization, we identified a 3-year-old female with a Rett-like syndrome carrying a de novo single-gene deletion of FOXG1. Her presentation included intellectual disability, epilepsy and a Rett-like phenotype. The variant features included microcephaly at birth and prominent synophrys. Our results confirm that congenital Rett syndrome can be caused by copy-number variation in FOXG1 and expand the clinical phenotypic spectrum of FOXG1 defect in humans. [ABSTRACT FROM AUTHOR]

Although neonatal hypoxic-ischemic encephalopathy is a common cause of childhood developmental disability, its timing, duration, and outcomes are poorly defined. Biomarkers serve as surrogates for disease injury, evolution, and outcome, but no tissue biomarker in routine clinical use can help predict outcomes in term newborn encephalopathy. We reviewed biomarkers in human term neonatal encephalopathy, to determine if current biomarkers are strong enough for clinical use as predictors of outcomes. A comprehensive search of databases identified 110 publications that met our inclusion criteria, i.e., (1) newborns at >36 weeks; (2) neonatal encephalopathy as defined by the American College of Obstetrics and Gynecology; (3) the use of a serum, urine, or cerebrospinal fluid biomarker; and (4) reported outcomes beyond age 12 months. Of those 110 publications, 22 reported outcomes beyond age 12 months. In single reports, urine lactate (P < 0.001), first urine S100 (P < 0.0001), cord-blood interleukin-6 (P = 0.02), serum nonprotein-bound iron (P < 0.001), serum CD14 cell NFκB activation (P = 0.014), serum interleukin-8 (P = 0.03), and serum ionized calcium (P = 0.001) were potential predictors of death or abnormal outcomes. A meta-analysis identified serum interleukin-1b (P = 0.04, n = 3), serum interleukin-6 (P = 0.04, n = 2), cerebrospinal fluid neuron-specific enolase (P = 0.03, n = 3), and cerebrospinal fluid interleukin-1b (P = 0.003, n = 2) as putative predictors of abnormal outcomes in survivors, when measured before age 96 hours. Several serum, urine, and cerebrospinal fluid biomarkers of term neonatal encephalopathy may provide important information regarding long-term outcomes. None, however, were studied extensively enough to warrant routine clinical use. Validation of these markers, either alone or in combination, is required in the development of viable therapeutic interventions. [Copyright &y& Elsevier]

Decompressive hemicraniectomy has been discussed as a treatment option that increases survival in adults with malignant stroke. This approach has not been studied extensively in children. From a prospective cohort, we identified 4 children who underwent decompressive hemicraniectomy for malignant infarctions with life-threatening cerebral edema within 72 hours of their stroke. All 4 children had different causes for their stroke and experienced severe cerebral edema with increasing intracranial pressure and an impending fatal outcome. Despite massive cerebral infarction, all patients were ambulant and able to speak at the time of follow-up. Although a limited experience, decompressive hemicraniectomy is a lifesaving approach for malignant stroke in children. [ABSTRACT FROM AUTHOR]

Vanishing white matter disease is a chronically progressive leukodystrophy with periods of acute deterioration after head trauma and febrile illness. This report describes a child with genetically and clinically confirmed vanishing white matter disease exhibiting frequent episodes of right-sided hemiplegia, aphasia, and headache resolving fully within hours to days. This report describes a case of this condition presenting with episodes of hemiparesis with full discovery to baseline. Some possible mechanisms explaining this unusual presentation are provided. [Copyright &y& Elsevier]

This report describes a 15-year-old male presenting with headaches and seizures after a viral illness progressing to intractable seizures of the right hand and face. This patient presented with diffuse white matter lesions on magnetic resonance imaging which disappeared with treatment. A relapse 6 months later involving the left temporal and insular regions produced epilepsia partialis continua involving the right face and hand. The relevant literature is reviewed with an emphasis on possible etiologies, including both acute disseminated encephalomyelitis and Rasmussen’s encephalitis. [Copyright &y& Elsevier]

Acetylation and phosphorylation of the amino-terminal tails of the core histones fluctuate on a global scale in concert with other major events in chromosome metabolism. A ubiquitin ligase, the anaphase-promoting complex (APC), controls events in chromosome metabolism such as sister chromatid cohesion and may regulate H3 phosphorylation by targeting Aurora A, one of several S10-directed H3 kinases in vertebrate cells, for destruction by the proteasome. Our analysis of apc10Δ and apc11[sup ts] loss-of-function mutants reveals that the APC controls the global level of H3 S10 phosphorylation in cycling yeast cells. Surprisingly, it also regulates dephosphorylation of H3 and global deacetylation of H2B, H3, and H4 during exit from the cell cycle into G[sub 0]. Genetic, biochemical, and microarray analyses suggest that APC-dependent cell cycle control of H3 phosphorylation is exerted at the level of an Aurora H3 kinase, Ipl1p, while APC-dependent transcriptional induction of GLC7, an essential H3 phosphatase, contributes to sustained H3 dephosphorylation upon cell cycle withdrawal. Collectively, our results establish that core histone acetylation state and H3 phosphorylation are physiologically regulated by the APC and suggest a model in which global reconfiguration of H3 phosphorylation state involves APC-dependent control of both an H3 kinase and a conserved phosphatase. [ABSTRACT FROM AUTHOR]

In this issue of Cancer Cell , studies from Mazor and colleagues and Kim and colleagues use a combination of epigenetic and genetic approaches to reveal a complex evolutionary process underlying two of the biggest challenges facing neuro-oncology, specifically glioblastoma malignant progression and treatment resistance. [ABSTRACT FROM AUTHOR]

Central nervous system germ cell tumors (CNS-GCT) are malignant neoplasms that arise predominantly during adolescence and young adulthood. These tumors are typically sensitive to treatment, but resulting long-term health deficits are common. Additional clinical challenges include surgical risks associated with tumor biopsy, and need to determine treatment response for adapting radiotherapy protocols. The aim of this study was to establish the detectability of circulating-tumor DNA (ctDNA) from cerebrospinal fluid (CSF) of children with CNS-GCT as a potential biomarker. We obtained CSF from patients with CNS-GCT by lumbar puncture or intra-operatively. Cell-free DNA (cfDNA) was extracted and subjected to low-pass whole genome sequencing (LP-WGS). Copy-number alterations (CNAs) were inferred and served as a marker of measurable residual disease (MRD). Comparisons with imaging findings and tumor marker levels were made. A total of 29 CSF samples from 21 patients (16 with germinoma, 5 with non-germinomatous GCT) were sequenced. Twenty samples from 19 patients were collected at diagnosis, and 9 samples from 7 patients were collected during or after therapy. Among the diagnostic samples, CNAs were detected in samples from 17/19 patients (89%), which included 8 with marker-negative tumors. Specific clinical scenarios suggested that serial cfDNA analysis may carry utility in tracking treatment responses as well as clarifying indeterminate imaging findings. Our results provide evidence for the high-sensitivity in detecting ctDNA from CSF of CNS-GCT patients using LP-WGS, with potential utility for non-invasive diagnosis and disease monitoring in upcoming CNS-GCT studies. [ABSTRACT FROM AUTHOR]

Background: The treatment of BRAF V600E gliomas with BRAF inhibitors (BRAFis) and MEK inhibitors (MEKis) has been increasingly integrated into clinical practice for pediatric low-grade gliomas (PLGGs) and pediatric high-grade gliomas (HGGs). However, some questions remain unanswered, such as the best time to start targeted therapy, duration of treatment, and discontinuation of therapy. Given that no clinical trial has been able to address these critical questions, we developed a Canadian Consensus statement for the treatment of BRAF V600E mutated pediatric as well as adolescent and young adult (AYA) gliomas. Methods: Canadian neuro-oncologists were invited to participate in the development of this consensus. The consensus was discussed during monthly web-based national meetings, and the algorithms were revised until a consensus was achieved. Results: A total of 26 participants were involved in the development of the algorithms. Two treatment algorithms are proposed, one for the initiation of treatment and one for the discontinuation of treatment. We suggest that most patients with BRAF V600E gliomas should be treated with BRAFis ± MEKis upfront. Discontinuation of treatment can be considered in certain circumstances, and we suggest a slow wean. Conclusions: Based on expert consensus in Canada, we developed algorithms for treatment initiation of children and AYA with BRAF V600E gliomas as well as a discontinuation algorithm. [ABSTRACT FROM AUTHOR]

In this issue of Cancer Cell , Pathania et al. report sporadic childhood histone K27M mutant malignant glioma mouse models that faithfully recapitulate the human tumor phenotypes. Beyond emphasizing the importance of correct timing in mouse modeling of cancer, these models will facilitate research to effectively treat this lethal childhood cancer. [ABSTRACT FROM AUTHOR]

Purpose: We investigate the impact of severe sensorineural hearing loss (SNHL) and for the first time evaluate the effect of unilateral versus bilateral SNHL on intellectual outcome in a cohort of children with embryonal brain tumors treated with and without radiation. Methods: Data were from 94 childhood survivors of posterior fossa (PF) embryonal brain tumors who were treated with either: (1) chemotherapy alone (n = 16, 7.11 [3.41] years, 11M/5F), (2) standard‐dose craniospinal irradiation (CSI) and/or large boost volumes (n = 44, 13.05 [3.26] years, 29M/15F), or (3) reduced‐dose CSI with a boost restricted to the tumor bed (n = 34, 11.07 [3.80] years, 19M/15F). We compared intellectual outcome between children who: (1) did and did not develop SNHL and (2) developed unilateral versus bilateral SNHL. A Chang grade of ≥2b that required the use of a hearing aid was considered severe SNHL. Comparisons were made overall and within each treatment group separately. Results: Patients who developed SNHL had lower full scale IQ (p = 0.007), verbal comprehension (p = 0.003), and working memory (p = 0.02) than patients without SNHL. No differences were observed between patients who had unilateral versus bilateral SNHL (all p > 0.05). Patients treated with chemotherapy alone who developed SNHL had lower mean working memory (p = 0.03) than patients who did not develop SNHL. Among patients treated with CSI, no IQ indices differed between those with and without SNHL (all p > 0.05). Conclusions: Children treated for embryonal brain tumors who develop severe SNHL have lower intellectual outcome than patients with preserved hearing: this association is especially profound in young children treated with radiation sparing approaches. We also demonstrate that intellectual outcome is similarly impaired in patients who develop unilateral versus bilateral SNHL. These findings suggest that early intervention to preserve hearing is critical. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests proton radiation therapy may offer cognitive sparing advantages over photon radiation therapy, yet dosimetry has not been compared previously. The purpose of this study was to examine dosimetric correlates of cognitive outcomes in children with medulloblastoma treated with proton versus photon radiation therapy. In this retrospective, bi-institutional study, dosimetric and cognitive data from 75 patients (39 photon and 36 proton) were analyzed. Doses to brain structures were compared between treatment modalities. Linear mixed-effects models were used to create models of global IQ and cognitive domain scores. The mean dose and dose to 40% of the brain (D40) were 2.7 and 4.1 Gy less among proton-treated patients compared with photon-treated patients (P =.03 and.007, respectively). Mean doses to the left and right hippocampi were 11.2 Gy lower among proton-treated patients (P <.001 for both). Mean doses to the left and right temporal lobes were 6.9 and 7.1 Gy lower with proton treatment, respectively (P <.001 for both). Models of cognition found statistically significant associations between higher mean brain dose and reduced verbal comprehension, increased right temporal lobe D40 with reduced perceptual reasoning, and greater left temporal mean dose with reduced working memory. Higher brain D40 was associated with reduced processing speed and global IQ scores. Proton therapy reduces doses to normal brain structures compared with photon treatment. This leads to reduced cognitive decline after radiation therapy across multiple intellectual endpoints. Proton therapy should be offered to children receiving radiation for medulloblastoma. [ABSTRACT FROM AUTHOR]

A recent study uses an integrated genomic approach to identify biologically defined subgroups of adult diffuse glioma. These results further lay the foundation for a pathological classification scheme for gliomas that incorporates both histology and molecular biomarkers, which appears far more robust than the current scheme, based solely on morphology. [ABSTRACT FROM AUTHOR]

Relapsed neuroblastoma is common, frequently lethal and poorly studied and poses a major treatment challenge. Two new studies shed light on the genomic landscape of recurrent neuroblastoma and demonstrate profound differences between the disease at diagnosis and relapse. [ABSTRACT FROM AUTHOR]

PURPOSE: Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS: We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E–mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS: Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy (P <.001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A , were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively (P =.02). CONCLUSION: Use of BRAF inhibition results in robust and durable responses in BRAF V600E–mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas. [ABSTRACT FROM AUTHOR]

Sonic Hedgehog (SHH) medulloblastomas are brain tumours that arise in the posterior fossa. Cancer-propagating cells (CPCs) provide a reservoir of cells capable of tumour regeneration and relapse post-treatment. Understanding and targeting the mechanisms by which CPCs are maintained and expanded in SHH medulloblastoma could present novel therapeutic opportunities. We identified the aryl hydrocarbon receptor (AHR) pathway as a potent tumour suppressor in a SHH medulloblastoma mouse model. Ahr-deficient tumours and CPCs grown in vitro, showed elevated activation of the TGFβ mediator, SMAD3. Pharmacological inhibition of the TGFβ/SMAD3 signalling axis was sufficient to inhibit the proliferation and promote the differentiation of Ahr-deficient CPCs. Human SHH medulloblastomas with high expression of the AHR repressor (AHRR) exhibited a significantly worse prognosis compared to AHRRlow tumours in two independent patient cohorts. Together, these findings suggest that reduced AHR pathway activity promotes SHH medulloblastoma progression, consistent with a tumour suppressive role for AHR. We propose that TGFβ/SMAD3 inhibition may represent an actionable therapeutic approach for a subset of aggressive SHH medulloblastomas characterised by reduced AHR pathway activity. [ABSTRACT FROM AUTHOR]

The article reflects on research related to role of H3K27 demethylase (JMJD3) inhibition in diffuse intrinsic pontine glioma (DIPGs) xenografts due to its antitumor activity by R. Hashizume and others. Topics discussed include identification of lysine to methionine substitution in histone proteins, delivery of GSKJ4, inhibitor of JMJD3, into the pons using high-performance liquid chromatography analysis of non?tumor-bearing mice, and continuous expression of H3K27M in Drosophila melanogaster.

Brain tumors are the leading cause of cancer-related death in children, and medulloblastoma (MB) is the most common malignant pediatric brain tumor. Advances in surgery, radiation, and chemotherapy have improved the survival of MB patients. But despite these advances, 25-30% of patients still die from the disease, and survivors suffer severe long-term side effects from the aggressive therapies they receive. Although MB is often considered a single disease, molecular profiling has revealed a significant degree of heterogeneity, and there is a growing consensus that MB consists of multiple subgroups with distinct driver mutations, cells of origin, and prognosis. Here, we review recent progress in MB research, with a focus on the genes and pathways that drive tumorigenesis, the animal models that have been developed to study tumor biology, and the advances in conventional and targeted therapy. [ABSTRACT FROM AUTHOR]

Children treated for brain tumors are at an increased risk for cognitive impairments due to the effect of radiation therapy on developing white matter (WM). Although damage to long-range WM is well documented in pediatric brain tumor survivors, the effect of radiation therapy on short-range WM remains unelucidated. We sought to clarify whether radiation treatment affects short-range WM by completing a virtual dissection of these connections and comparing their microstructural properties between brain tumor survivors and typically developing children. T1-weighted and diffusion-weighted magnetic resonance images were acquired for 26 brain tumor survivors and 26 typically developing children. Short-range WM was delineated using a novel, whole-brain approach. A random forest classifier was used to identify short-range connections with the largest differences in microstructure between patients and typically developing children. The random forest classifier identified differences in short-range WM microstructure across the brain with an accuracy of 87.5%. Nine connections showed the largest differences in short-range WM between patients and typically developing children. For these connections, fractional anisotropy and axial diffusivity were significantly lower in patients. Short-range connections in the posterior fossa were disproportionately affected, suggesting that greater radiation exposure to the posterior fossa was more injurious to short-range WM. Lower craniospinal radiation dose did not predict reduced toxicity to short-range WM. Our findings indicate that treatment for medulloblastoma resulted in changes in short-range WM in patients. Lower fractional anisotropy and axial diffusivity may reflect altered microstructural organization and coherence of these connections, especially in the posterior fossa. Short-range WM may be especially sensitive to the effect of craniospinal radiation therapy, resulting in compromise to these connections regardless of dose. [ABSTRACT FROM AUTHOR]

Background: Rasmussen's encephalitis (RE) is an inflammatory encephalopathy of unknown cause defined by seizures with progressive neurological disabilities. Herein, the pathogenesis of RE was investigated focusing on inflammasome activation in the brain.Methods: Patients with RE at the University of Alberta, Edmonton, AB, Canada, were identified and analyzed by neuroimaging, neuropsychological, molecular, and pathological tools. Primary human microglia, astrocytes, and neurons were examined using RT-PCR, enzyme-linked immunosorbent assay (ELISA), and western blotting.Results: Four patients with RE were identified at the University of Alberta. Magnetic resonance imaging (MRI) disclosed increased signal intensities in cerebral white matter adjacent to cortical lesions of RE patients, accompanied by a decline in neurocognitive processing speed (P <0.05). CD3ϵ, HLA-DRA, and TNFα together with several inflammasome-associated genes (IL-1β, IL-18, NLRP1, NLRP3, and CASP1) showed increased transcript levels in RE brains compared to non-RE controls (n = 6; P <0.05). Cultured human microglia displayed expression of inflammasome-associated genes and responded to inflammasome activators by releasing IL-1β, which was inhibited by the caspase inhibitor, zVAD-fmk. Major histocompatibility complex (MHC) class II, IL-1β, caspase-1, and alanine/serine/cysteine (ASC) immunoreactivity were increased in RE brain tissues, especially in white matter myeloid cells, in conjunction with mononuclear cell infiltration and gliosis. Neuroinflammation in RE brains was present in both white matter and adjacent cortex with associated induction of inflammasome components, which was correlated with neuroimaging and neuropsychological deficits.Conclusion: Inflammasome activation likely contributes to the disease process underlying RE and offers a mechanistic target for future therapeutic interventions. [ABSTRACT FROM AUTHOR]

Posterior fossa ependymomas (EPN_PF) in children comprise two morphologically identical, but biologically distinct tumor entities. Group-A (EPN_PFA) tumors have a poor prognosis and require intensive therapy. In contrast, group-B tumors (EPN_PFB) exhibit excellent prognosis and the current consensus opinion recommends future clinical trials to test the possibility of treatment de-escalation in these patients. Therefore, distinguishing these two tumor subtypes is critical. EPN_PFA and EPN_PFB can be distinguished based on DNA methylation signatures, but these assays are not routinely available. We have previously shown that a subset of poorly prognostic childhood EPN_PF exhibits global reduction in H3K27me3. Therefore, we set out to determine whether a simple immunohistochemical assay for H3K27me3 could be used to segregate EPN_PFA from EPN_PFB tumors. We assembled a cohort of 230 childhood ependymomas and H3K27me3 immunohistochemistry was assessed as positive or negative in a blinded manner. H3K27me3 staining results were compared with DNA methylation-based subgroup information available in 112 samples [EPN_PFA ( n = 72) and EPN_PFB tumors ( n = 40)]. H3K27me3 staining was globally reduced in EPN_PFA tumors and immunohistochemistry showed 99% sensitivity and 100% specificity in segregating EPN_PFA from EPN_PFB tumors. Moreover, H3K27me3 immunostaining was sufficient to delineate patients with worse prognosis in two independent, non-overlapping cohorts ( n = 133 and n = 97). In conclusion, immunohistochemical evaluation of H3K27me3 global reduction is an economic, easily available and readily adaptable method for defining high-risk EPN_PFA from low-risk posterior fossa EPN_PFB tumors to inform prognosis and to enable the design of future clinical trials. [ABSTRACT FROM AUTHOR]

Multiple independent genomic profiling efforts have recently identified clinically and molecularly distinct subgroups of ependymoma arising from all three anatomic compartments of the central nervous system (supratentorial brain, posterior fossa, and spinal cord). These advances motivated a consensus meeting to discuss: (1) the utility of current histologic grading criteria, (2) the integration of molecular-based stratification schemes in future clinical trials for patients with ependymoma and (3) current therapy in the context of molecular subgroups. Discussion at the meeting generated a series of consensus statements and recommendations from the attendees, which comment on the prognostic evaluation and treatment decisions of patients with intracranial ependymoma (WHO Grade II/III) based on the knowledge of its molecular subgroups. The major consensus among attendees was reached that treatment decisions for ependymoma (outside of clinical trials) should not be based on grading (II vs III). Supratentorial and posterior fossa ependymomas are distinct diseases, although the impact on therapy is still evolving. Molecular subgrouping should be part of all clinical trials henceforth. [ABSTRACT FROM AUTHOR]

Medulloblastoma comprises four distinct molecular variants with distinct genetics, transcriptomes, and outcomes. Subgroup affiliation has been previously shown to remain stable at the time of recurrence, which likely reflects their distinct cells of origin. However, a therapeutically relevant question that remains unanswered is subgroup stability in the metastatic compartment. We assembled a cohort of 12-paired primary-metastatic tumors collected in the MAGIC consortium, and established their molecular subgroup affiliation by performing integrative gene expression and DNA methylation analysis. Frozen tissues were collected and profiled using Affymetrix gene expression arrays and Illumina methylation arrays. Class prediction and hierarchical clustering were performed using existing published datasets. Our molecular analysis, using consensus integrative genomic data, establishes the unequivocal maintenance of molecular subgroup affiliation in metastatic medulloblastoma. We further validated these findings by interrogating a non-overlapping cohort of 19 pairs of primary-metastatic tumors from the Burdenko Neurosurgical Institute using an orthogonal technique of immunohistochemical staining. This investigation represents the largest reported primary-metastatic paired cohort profiled to date and provides a unique opportunity to evaluate subgroup-specific molecular aberrations within the metastatic compartment. Our findings further support the hypothesis that medulloblastoma subgroups arise from distinct cells of origin, which are carried forward from ontogeny to oncology. [ABSTRACT FROM AUTHOR]

Furthermore, we show that, in the context of retained histone H3 lysine 27 trimethylation (H3K27me3), I ACVR1 i -mutant PF ependymomas exhibit a DNA methylation signature distinct from other PF ependymomas. I TERT i promoter mutations combined with monosomy of chromosome 6 were recently shown to identify a group of clinically aggressive posterior fossa ependymal tumors with hybrid histologic and epigenetic features of ependymoma and subependymoma (EPN/SE) [[13]]. Here, we show that posterior fossa ependymomas harboring I ACVR1 i mutation with retained H3K27me3 have overlapping clinicopathologic features with PFB ependymomas but resolve into a unique epigenetic subgroup distinct from other currently recognized ependymoma/subependymoma DNA methylation classes. In contrast to I ACVR1 i -mutant DMG, I ACVR1 i -mutant PF ependymomas lacked histone H3 mutation and co-occurring alterations in I PIK3CA i , I PIK3R1 i , and I PPM1D i (Fig. [Extracted from the article]

Medulloblastoma (MB) is the most common primary malignant pediatric brain cancer. We recently identified novel roles for the MEK/MAPK pathway in regulating human Sonic Hedgehog (SHH) MB tumorigenesis. The MEK inhibitor, selumetinib, decreased SHH MB growth while extending survival in mouse models. However, the treated mice ultimately succumbed to disease progression. Here, we perform RNA sequencing on selumetinib-treated orthotopic xenografts to identify molecular pathways that compensate for MEK inhibition specifically in vivo. Notably, the JAK/STAT3 pathway exhibits increased activation in selumetinib-treated tumors. The combination of selumetinib and the JAK/STAT3 pathway inhibitor, pacritinib, further reduces growth in two xenograft models and also enhances survival. Multiplex spatial profiling of proteins in drug-treated xenografts reveals shifted molecular dependencies and compensatory changes following combination drug treatment. Our study warrants further investigation into MEK and JAK/STAT3 inhibition as a novel combinatory therapeutic strategy for SHH MB. RNA sequencing of MEK inhibitor (selumetinib)-treated tumors reveals an upregulation of the JAK/STAT3 pathway, with combinatorial therapeutic strategies of JAK/STAT3 inhibitors and selumetinib investigated for the SHH subgroup of medulloblastoma. [ABSTRACT FROM AUTHOR]

In a screen designed to isolate Saccharomyces cerevisiae strains defective for in vitro chromatin assembly, two temperature-sensitive (ts) mutants were obtained: rmc1 and rmc3 (remodeling of chromatin). Cloning of RMC1 and RMC3 revealed a broad role for the ubiquitin-dependent targeting cascade as the ubiquitin-protein ligases (E3s), the anaphase promoting complex (APC; RMC1 encodes APC5) and Rsp5p, respectively, were identified. Genetic studies linked the rmc1/apc5 chromatin assembly defect to APC function: rmc1/apc5 genetically interacted with apc9Δ, apc10Δ, and cdc26Δ mutants. Furthermore, phenotypes associated with the rmc1/apc5 allele were consistent with defects in chromatin metabolism and in APC function: (i) UV sensitivity, (ii) plasmid loss, (iii) accumulation of G2/M cells, and (iv,) suppression of the ts defect by growth on glucose-free media and by expression of ubiquitin. On the other hand, the multifunctional E3, Rsp5p, was shown to be required for both in vitro and in vivo chromatin assembly, as well as for the proper transcriptional and translational control of at least histone H3. The finding that the distinctly different E3 enzymes, APC and Rsp5p, both play roles in regulating chromatin assembly highlight the depth of the regulatory networks at play. The significance of these findings will be discussed. [ABSTRACT FROM AUTHOR]

Aberrant activation of telomerase in human cancer is achieved by various alterations within the TERT promoter, including cancer-specific DNA hypermethylation of the TERT hypermethylated oncological region (THOR). However, the impact of allele-specific DNA methylation within the TERT promoter on gene transcription remains incompletely understood. Using allele-specific next-generation sequencing, we screened a large cohort of normal and tumor tissues (n = 652) from 10 cancer types and identified that differential allelic methylation (DAM) of THOR is restricted to cancerous tissue and commonly observed in major cancer types. THOR-DAM was more common in adult cancers, which develop through multiple stages over time, than in childhood brain tumors. Furthermore, THOR-DAM was especially enriched in tumors harboring the activating TERT promoter mutations (TPMs). Functional studies revealed that allele-specific gene expression of TERT requires hypomethylation of the core promoter, both in TPM and TERT WT cancers. However, the expressing allele with hypomethylated core TERT promoter universally exhibits hypermethylation of THOR, while the nonexpressing alleles are either hypermethylated or hypomethylated throughout the promoter. Together, our findings suggest a dual role for allelespecific DNA methylation within the TERT promoter in the regulation of TERT expression in cancer. [ABSTRACT FROM AUTHOR]

Background Radiation necrosis is a frequent complication occurring after the treatment of pediatric brain tumors; however, treatment options remain a challenge. Bevacizumab is an anti-VEGF monoclonal antibody that has been shown in small adult cohorts to confer a benefit, specifically a reduction in steroid usage, but its use in children has not been well described. Methods We describe our experience with bevacizumab use for symptomatic radiation necrosis at 5 institutions including patients treated after both initial irradiation and reirradiation. Results We identified 26 patients treated with bevacizumab for symptomatic radiation necrosis, with a wide range of underlying diagnoses. The average age at diagnosis of radiation necrosis was 10.7 years, with a median time between the last dose of radiation and the presentation of radiation necrosis of 3.8 months (range, 0.6-110 months). Overall, we observed that 13 of 26 patients (50%) had an objective clinical improvement, with only 1 patient suffering from significant hypertension. Radiological improvement, defined as reduced T2/fluid-attenuated inversion recovery signal and mass effect, was observed in 50% of patients; however, this did not completely overlap with clinical response. Both early and late radiation necrosis responded equally well to bevacizumab therapy. Overall, bevacizumab was very well tolerated, permitting a reduction of corticosteroid dose and/or duration in the majority of patients. Conclusions Bevacizumab appears to be effective and well-tolerated in children as treatment for symptomatic radiation necrosis and warrants more robust study in the context of controlled clinical trials. [ABSTRACT FROM AUTHOR]

Medulloblastoma (MB) is the most common primary malignant brain tumor of childhood and a significant contributor to pediatric morbidity and death. While metastatic dissemination is the predominant cause of morbidity and mortality for patients with this disease, most research efforts and clinical trials to date have focused on the primary tumor; this is due mostly to the paucity of metastatic tumor samples and lack of robust mouse models of MB dissemination. Most current insights into the molecular drivers of metastasis have been derived from comparative molecular studies of metastatic and non‐metastatic primary tumors. However, small studies on matched primary and metastatic tissues and recently developed mouse models of dissemination have begun to uncover the molecular biology of MB metastasis more directly. With respect to anatomical routes of dissemination, a hematogenous route for MB metastasis has recently been demonstrated, opening new avenues of investigation. The tumor micro‐environment of the primary and metastatic niches has also been increasingly scrutinized in recent years, and further investigation of these tumor compartments is likely to result in a better understanding of the molecular mediators of MB colonization and growth in metastatic compartments. [ABSTRACT FROM AUTHOR]

Background: Understanding the global impact of medulloblastoma on health related quality of life (HRQL) is critical to characterizing the broad impact of this disease and realizing the benefits of modern treatments. We evaluated HRQL in an international cohort of pediatric medulloblastoma patients. Methods: Seventy‐six patients were selected from 10 sites across North America, Europe, and Asia, who participated in the Medulloblastoma Advanced Genomics International Consortium (MAGIC). The Health Utilities Index (HUI) was administered to patients and/or parents at each site. Responses were used to determine overall HRQL and attributes (ie specific subdomains). The impact of various demographic and medical variables on HRQL was considered—including molecular subgroup. Results: The majority of patients reported having moderate or severe overall burden of morbidity for both the HUI2 and HUI3 (HUI2 = 60%; HUI3 = 72.1%) when proxy‐assessed. Self‐care in the HUI2 was rated as higher (ie better outcome) for patients from Western versus Eastern sites, P =.02. Patients with nonmetastatic status had higher values (ie better outcomes) for the HUI3 hearing, HUI3 pain, and HUI2 pain, all P <.05. Patients treated with a gross total resection also had better outcomes for the HUI3 hearing (P =.04). However, those who underwent a gross total resection reported having worse outcomes on the HUI3 vision (P =.02). No differences in HRQL were evident as a function of subgroup. Conclusions: By examining an international sample of survivors, we characterized the worldwide impact of medulloblastoma. This is a critical first step in developing global standards for evaluating long‐term outcomes. [ABSTRACT FROM AUTHOR]

In 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, and Group 4), each associated with distinct genomic features and clinical behavior. Independently, multiple recent reports have defined further intra-subgroup heterogeneity in the form of biologically and clinically relevant subtypes. However, owing to differences in patient cohorts and analytical methods, estimates of subtype number and definition have been inconsistent, especially within Group 3 and Group 4. Herein, we aimed to reconcile the definition of Group 3/Group 4 MB subtypes through the analysis of a series of 1501 medulloblastomas with DNA-methylation profiling data, including 852 with matched transcriptome data. Using multiple complementary bioinformatic approaches, we compared the concordance of subtype calls between published cohorts and analytical methods, including assessments of class-definition confidence and reproducibility. While the lowest complexity solutions continued to support the original consensus subgroups of Group 3 and Group 4, our analysis most strongly supported a definition comprising eight robust Group 3/Group 4 subtypes (types I–VIII). Subtype II was consistently identified across all component studies, while all others were supported by multiple class-definition methods. Regardless of analytical technique, increasing cohort size did not further increase the number of identified Group 3/Group 4 subtypes. Summarizing the molecular and clinico-pathological features of these eight subtypes indicated enrichment of specific driver gene alterations and cytogenetic events amongst subtypes, and identified highly disparate survival outcomes, further supporting their biological and clinical relevance. Collectively, this study provides continued support for consensus Groups 3 and 4 while enabling robust derivation of, and categorical accounting for, the extensive intertumoral heterogeneity within Groups 3 and 4, revealed by recent high-resolution subclassification approaches. Furthermore, these findings provide a basis for application of emerging methods (e.g., proteomics/single-cell approaches) which may additionally inform medulloblastoma subclassification. Outputs from this study will help shape definition of the next generation of medulloblastoma clinical protocols and facilitate the application of enhanced molecularly guided risk stratification to improve outcomes and quality of life for patients and their families. [ABSTRACT FROM AUTHOR]