SUMMARY While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.

A B S T R A C T PurposeReports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles. Patients and MethodsWe determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas. ResultsTP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P Ͻ .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P Ͻ .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; Ϯ SE) was 41% Ϯ 9% and 81% Ϯ 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P Ͻ .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% Ϯ 9% and 97% Ϯ 3% for patients with WNT tumors with and without TP53 mutations (P ϭ .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P ϭ .012) and not WNT tumors. ConclusionSubgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients.

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon–driven, functional genomic mouse model of medulloblastoma with ‘humanized’ in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.

Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.

Dysmyelinating diseases, or leukodystrophies, encompass a wide spectrum of inherited neurodegenerative disorders affecting the integrity of myelin in the brain and peripheral nerves. Most of these disorders fall into one of three categories-lysosomal storage diseases, peroxisomal disorders, and diseases caused by mitochondrial dysfunction-and each leukodystrophy has distinctive clinical, biochemical, pathologic, and radiologic features. Magnetic resonance (MR) imaging has become the primary imaging modality in patients with leukodystrophy and plays an important role in the identification, localization, and characterization of underlying white matter abnormalities in affected patients. MR imaging has also been extensively used to monitor the natural progression of various white matter disorders and the response to therapy. Although the MR imaging features of leukodystrophy are often nonspecific, systematic analysis of the finer details of disease involvement may permit a narrower differential diagnosis, which the clinician can then further refine with knowledge of patient history, clinical testing, and metabolic analysis.

Background and Purpose-We evaluated whether basal/acetazolamide stress brain perfusion SPECT performed after revascularization surgery can predict the further clinical outcome of patients with pediatric moyamoya disease. Methods-A total of 77 (31 males, 46 females, age 6.6Ϯ3.2 years) patients with postoperative pediatric moyamoya disease who underwent basal/acetazolamide stress brain perfusion SPECT 6 to 12 months after revascularization surgery and who were followed-up Ͼ12 months after SPECT were included. Mean follow-up period after SPECT was 36Ϯ19 months. Sixty-two patients underwent bilateral ribbon encephaloduroarteriosynangiosis (EDAS), 14 bilateral EDAS, and 1 unilateral EDAS. Ordinal logistic regression analysis using 5 independent variables (infarction on preoperative MRI, age at the first operation, highest Suzuki stage on cerebral angiography, and regional cerebrovascular reserve on postoperative SPECT) against postoperative clinical outcomes was performed. Results-Fifty-one patients had preserved reserve on postoperative SPECT and their clinical outcomes were excellent (30), good (15), fair (4), and poor (2); 26 patients had decreased reserve (excellent, 1; good, 7; fair, 14; poor, 4). On ordinal logistic regression analysis, age at the first operation (Pϭ0.033) and reserve on postoperative SPECT (PϽ0.001) were statistically significant. Conclusion-Basal/acetazolamide stress brain perfusion SPECT performed at 6 to 12 months after the indirect bypass operation could predict the further clinical outcome of pediatric patients with moyamoya disease. Patients with decreased cerebrovascular reserve will have remaining neurological deficit and ischemic attacks on follow-up. (Stroke.

The relative incidences of germ cell tumors, neuronal tumors, and oligodendroglial tumors increased after the introduction of magnetic resonance imaging (MRI). In contrast, the incidence rates of medulloblastomas and ependymal tumors decreased.

Summary:The cerebellum is known to have an inhibitory effect on seizures. Nevertheless, cerebellar dysplastic lesions can be epileptogenic. A 4-month-old infant had paroxysmal facial contractions; tachypnea and nystagmoid eyeball and tremulous movements were occasionally combined. These evolved to stereotypic clinical patterns and frequencies, which increased despite administration of antiepileptic drugs (AEDs). Magnetic resonance imaging (MRI) demonstrated a mass arising from the superior cerebellar peduncle, although video-scalp EEG monitoring revealed no abnormal findings. Positron emission tomography with [ 18 F]fluorodeoxyglucose revealed focal hypermetabolism in the same area identified by MRI. A depth electrode implanted in the mass revealed focal spike-and-wave discharges. The lesion was partly removed; pathologic diagnosis was ganglioglioma. Because of incomplete seizure control and residual tumor visible on MRI, a second operation was performed. After complete excision of the tumor, the patient became seizure free without AEDs. This case confirms the presence of seizure originating from the cerebellum and emphasizes the need for the complete removal of an epileptogenic lesion.