Recent transcriptomic approaches have demonstrated that there are at least 4 distinct subgroups in medulloblastoma (MB); however, survival studies of molecular subgroups in adult MB have been inconclusive because of small sample sizes. The aim of this study is to investigate the molecular subgroups in adult MB and identify their clinical and prognostic implications in a large, single-institution cohort. We determined gene expression profiles for 13 primary adult MBs. Bioinformatics tools were used to establish distinct molecular subgroups based on the most informative genes in the dataset. Immunohistochemistry with subgroup-specific antibodies was then used for validation within an independent cohort of 201 formalin-fixed MB tumors, in conjunction with a systematic analysis of clinical and histological characteristics. Three distinct molecular variants of adult MB were identified: the SHH, WNT, and group 4 subgroups. Validation of these subgroups in the 201-tumor cohort by immunohistochemistry identified significant differences in subgroup-specific demographics, histology, and metastatic status. The SHH subgroup accounted for the majority of the tumors (62%), followed by the group 4 subgroup (28%) and the WNT subgroup (10%). Group 4 tumors had significantly worse progression-free and overall survival compared with tumors of the other molecular subtypes. We have identified 3 subgroups of adult MB, characterized by distinct expression profiles, clinical features, pathological features, and prognosis. Clinical variables incorporated with molecular subgroup are more significantly informative for predicting adult patient outcome.

The deprivation of sensory input after hearing damage results in functional reorganization of the brain including cross-modal plasticity in the sensory cortex and changes in cognitive processing. However, it remains unclear whether partial deprivation from unilateral auditory loss (UHL) would similarly affect the neural circuitry of cognitive processes in addition to the functional organization of sensory cortex. Here, we used resting-state functional magnetic resonance imaging to investigate intrinsic activity in 34 participants with UHL from acoustic neuroma in comparison with 22 matched normal controls. In sensory regions, we found decreased regional homogeneity (ReHo) in the bilateral calcarine cortices in UHL. However, there was an increase of ReHo in the right anterior insular cortex (rAI), the key node of cognitive control network (CCN) and multimodal sensory integration, as well as in the left parahippocampal cortex (lPHC), a key node in the default mode network (DMN). Moreover, seed-based resting–state functional connectivity analysis showed an enhanced relationship between rAI and several key regions of the DMN. Meanwhile, lPHC showed more negative relationship with components in the CCN and greater positive relationship in the DMN. Such reorganizations of functional connectivity within the DMN and between the DMN and CCN were confirmed by a graph theory analysis. These results suggest that unilateral sensory input damage not only alters the activity of the sensory areas but also reshapes the regional and circuit functional organization of the cognitive control network.

SHH subgroup medulloblastoma (SHH-MB) is one of the most common malignant pediatric tumors that arises in the cerebellum. Previously, we showed that RNA m⁶A methylation participates in regulation of cerebellar development. Here we investigate whether dysregulated m⁶A methylation contributes to tumorigenesis of SHH-MB. We show that high expression of m⁶A methyltransferase METTL3 associates with worse survival in the patients with SHH-MB. A large number of hypermethylated transcripts are identified in SHH-MB tumor cells by m⁶A-seq. We find that METTL3 promotes tumor progression via activating Sonic hedgehog signaling. Mechanistically, METTL3 methylates PTCH1 and GLI2 RNAs and further regulates their RNA stability and translation. Importantly, targeting METTL3 by depleting METTL3 expression or treatment with its catalytic inhibitor STM2457 restrains tumor progression. Collectively, this study shows a critical function for METTL3 and m⁶A methylation in SHH-MB, indicative of a potential role of METTL3 as therapeutic target in SHH-MB.

OBJECT: The aim of this study was to evaluate the clinical features of spinal schwannomas in patients with schwannomatosis and compare them with a large cohort of patients with solitary schwannomas and neurofibromatosis Type 2 (NF2). METHODS: The study was a retrospective review of 831 patients with solitary schwannomas, 65 with schwannomatosis, and 102 with NF2. The clinical, radiographic, and pathological data were extracted with specific attention to the age at onset, location of tumors, initial symptoms, family history, and treatment outcome. RESULTS: The male-to-female ratio of patients with schwannomatosis (72.3% vs 27.7%) was significantly higher than that of patients with solitary schwannomas (53.3% vs 46.7%) and NF2 (54.0% vs 46.0%), respectively (chi-square test, p = 0.012). The mean age at the first spinal schwannoma operation of patients with NF2 (24.7 ± 10.2 years) was significantly younger than that of patients with solitary schwannomas (44.8 ± 13.2 years) and schwannomatosis (44.4 ± 14.1 years; 1-way ANOVA, p < 0.001). The initial symptoms were similar among the 3 groups, with pain being the most common. The distribution of spinal tumors among the 3 groups was significantly different. The peak locations of spinal schwannomas in patients with solitary schwannomas were at C1–3 and T12–L3; in schwannomatosis, the peak location was at T12-L5. A preferred spinal location was not evident for intradural-extramedullary tumors in NF2. Only a slight prominence in the lumbar area could be observed. The patients in the 3 groups obtained similar benefits from the operation; the recovery rates in the patients with solitary schwannomas, NF2, and schwannomatosis were 50.1%, 38.0%, and 53.9%, respectively. The prognosis varied among spinal schwannomas in the patients with schwannomatosis. Up until the last date of follow-up, most patients with schwannomatosis (81.5%) had undergone a single spinal operation, but 12 patients (18.5%) had undergone multiple spinal operations. Patients with nonsegmental schwannomatosis or those with early onset disease seemed to have a poor prognosis; they were more likely to undergo multiple spinal operations. Small cauda equina nodules were common in patients with schwannomatosis (46.7%) and NF2 (86.9%); these small schwannomas appeared to have relatively static behavior. Two patients suspicious for schwannomatosis were diagnosed with NF2 with the detection of constitutional NF2 mutations; 1 had unilateral vestibular schwannoma, and the other had suspicious bilateral trigeminal schwannomas. CONCLUSIONS: The clinical features of spinal schwannomas vary among patients with solitary schwannomas, NF2, and schwannomatosis. Spinal schwannomas of patients with NF2 appear to be more aggressive than those in patients with solitary schwannomas and schwannomatosis. Spinal schwannomas of schwannomatosis predominate in the lumbar area, and most of them can be treated successfully with surgery. The prognosis varies among spinal schwannomas of schwannomatosis; some patients may need multiple operations due to newly developed schwannomas. Sometimes, it is difficult to differentiate schwannomatosis from NF2 based on clinical manifestations. It is prudent to perform close follow-up examinations in patients with undetermined schwannomatosis and their offspring.

Although extensive research on neural plasticity resulting from hearing deprivation has been conducted, the direct influence of compromised audition on the auditory cortex and the potential impact of long durations of incomplete sensory stimulation on the adult cortex are still not fully understood. In this study, using voxel-based morphometry, we evaluated gray matter (GM) volume changes that may be associated with reduced hearing ability and the duration of hearing impairment in 42 unilateral hearing loss (UHL) patients with acoustic neuromas compared to 24 normal controls. We found significant GM volume increases in the somatosensory and motor systems and GM volume decreases in the auditory (i.e., Heschl’s gyrus) and visual systems (i.e., the calcarine cortex) in UHL patients. The GM volume decreases in the primary auditory cortex (i.e., superior temporal gyrus and Heschl’s gyrus) correlated with reduced hearing ability. Meanwhile, the GM volume decreases in structures involving high-level cognitive control functions (i.e., dorsolateral prefrontal cortex and anterior cingulate cortex) correlated positively with hearing loss duration. Our findings demonstrated that the severity and duration of UHL may contribute to the dissociated morphology of auditory and high-level neural structures, providing insight into the brain’s plasticity related to chronic, persistent partial sensory loss.