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Medulloblastoma is the most common malignant brain tumor in children. Overall survival rates have improved in recent years as a result of risk-stratified treatment regimens. However, medulloblastoma remains associated with substantial mortality, and survivors often experience debilitating neurological, endocrinological, and social sequelae as a result of treatment. Targeted and less toxic therapeutic strategies are therefore needed. In this issue of the JCI, Baryawno et al. report their findings that a large percentage of primary medulloblastomas and medulloblastoma cell lines are infected with human cytomegalovirus (HCMV) and suggest that targeting this virus could provide a new way to treat individuals with medulloblastoma. [ABSTRACT FROM AUTHOR]

Low grade gliomas are the most frequent brain tumors in children and encompass a spectrum of histologic entities which are currently assigned World Health Organisation grades I and II. They differ substantially from their adult counterparts in both their underlying genetic alterations and in the infrequency with which they transform to higher grade tumors. Nonetheless, children with low grade glioma are a therapeutic challenge due to the heterogeneity in their clinical behavior – in particular, those with incomplete surgical resection often suffer repeat progressions with resultant morbidity and, in some cases, mortality. The identification of up-regulation of the RAS–mitogen-activated protein kinase (RAS/MAPK) pathway as a near universal feature of these tumors has led to the development of targeted therapeutics aimed at improving responses while mitigating patient morbidity. Here, we review how molecular information can help to further define the entities which fall under the umbrella of pediatric-type low-grade glioma. In doing so we discuss the specific molecular drivers of pediatric low grade glioma and how to effectively test for them, review the newest therapeutic agents and their utility in treating this disease, and propose a risk-based stratification system that considers both clinical and molecular parameters to aid clinicians in making treatment decisions. [ABSTRACT FROM AUTHOR]

Background: The determinants of outcomes for adult survivors of pediatric low-grade glioma (PLGG) are largely unknown.Methods: This study collected population-based follow-up information for all PLGG patients diagnosed in Ontario, Canada from 1985 to 2012 (n = 1202) and determined factors affecting survival. The impact of upfront radiation treatment on overall survival (OS) was determined for a cohort of Ontario patients and an independent reference cohort from the Surveillance, Epidemiology, and End Results database.Results: At a median follow-up of 12.73 years (range, 0.02-33 years), only 93 deaths (7.7%) were recorded, and the 20-year OS rate was 90.1% ± 1.1%. Children with neurofibromatosis type 1 had excellent survival and no tumor-related deaths during adulthood. Adverse risk factors included pleomorphic xanthoastrocytoma (P < .001) and a thalamic location (P < .001). For patients with unresectable tumors surviving more than 5 years after the diagnosis, upfront radiotherapy was associated with an approximately 3-fold increased risk of overall late deaths (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.6-6.6; P = .001) and an approximately 4-fold increased risk of tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = .013). In a multivariate analysis, radiotherapy was the most significant factor associated with late all-cause deaths (HR, 3.0; 95% CI, 1.3-7.0; P = .012) and tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = 0.014). A similar association between radiotherapy and late deaths was observed in the independent reference cohort (P < .001). In contrast to early deaths, late mortality was associated not with PLGG progression but rather with tumor transformation and non-oncological causes.Conclusions: The course of PLGG is associated with excellent long-term survival, but this is hampered by increased delayed mortality in patients receiving upfront radiotherapy. These observations should be considered when treatment options are being weighed for these patients. [ABSTRACT FROM AUTHOR]

Diffuse intrinsic pontine glioma (DIPG) is the main cause of brain tumour-related death in children. In the majority of cases diagnosis is based on clinical and MRI findings, resulting in the scarcity of pre-treatment specimens available to study. Our group has developed an autopsy-based protocol to investigate the histologic and biologic spectrum of DIPG. This has also allowed us to investigate the terminal pattern of disease and gain a better understanding of what challenges we are facing in treating DIPG. Here, we review 72 DIPG cases with well documented clinical history and molecular data and describe the pathological features of this disease in relation to clinical and genetic features. Fifty-three of the samples were autopsy material (7 pre-treatment) and 19 were pre-treatment biopsy/surgical specimens. Upon histological review, 62 patients had high-grade astrocytomas (18 WHO grade III and 44 WHO grade IV patients), 8 had WHO grade II astrocytomas, and 2 had features of primitive neuroectodermal tumour (PNET). K27M-H3 mutations were exclusively found in tumours with WHO grade II-IV astrocytoma histology. K27M-H3.1 and ACVR1 mutations as well as ALT phenotype were only found in WHO grade III-IV astrocytomas, while PIK3CA mutations and PDGFRA gains/amplifications were found in WHO grade II-IV astrocytomas. Approximately 1/3 of DIPG patients had leptomeningeal spread of their tumour. Further, diffuse invasion of the brainstem, spinal cord and thalamus was common with some cases showing spread as distant as the frontal lobes. These findings suggest that focal radiation may be inadequate for some of these patients. Importantly, we show that clinically classic DIPGs represent a diverse histologic spectrum, including multiple cases which would fit WHO criteria of grade II astrocytoma which nevertheless behave clinically as high-grade astrocytomas and harbour the histone K27M-H3.3 mutation. This suggests that the current WHO astrocytoma grading scheme may not appropriately predict outcome for paediatric brainstem gliomas. [ABSTRACT FROM AUTHOR]

Congenital central nervous system (CNS) tumors are uncommon, accounting for 1% of all childhood brain tumors. They present clinically either at birth or within the first 3 months. Glioblastoma (GBM) only rarely occurs congenitally and has not been fully characterized. We examined clinicopathologic features and genetic alterations of six congenital GBMs. Tumors were seen by neuroimaging as large, complex cerebral hemispheric masses. All showed classic GBM histopathology, including diffuse infiltration, dense cellularity, GFAP-positivity, high mitotic activity, endothelial proliferation and pseudopalisading necrosis. Neurosurgical procedures and adjuvant therapies varied. Survivals ranged from 4 days to 7.5 years; two of the three long-term survivors received chemotherapy, whereas the three short-term survivors did not. Paraffin-embedded tissue sections were used for FISH analysis of EGFR, chromosomes 9p21 ( p16/CDKN2A) and 10q ( PTEN/DMBT1); sequencing of PTEN and TP53; and immunohistochemistry for EGFR and p53. We uncovered 10q deletions in two cases. No EGFR amplifications, 9p21 deletions, or mutations of TP53 or PTEN were noted; however, nuclear p53 immunoreactivity was strong in 5/6 cases. Tumors were either minimally immunoreactive (n = 3) or negative (n = 3) for EGFR. We conclude that congenital GBMs show highly variable survivals. They are genetically distinct from their adult counterparts and show a low frequency of known genetic alterations. Nonetheless, the strong nuclear expression of p53 in these and other pediatric GBMs could indicate that p53 dysregulation is important to tumorigenesis. [ABSTRACT FROM AUTHOR]