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This study investigated the effect of various histotripsy dosages on tumor cell kill and associated bleeding in two murine brain tumor models (glioma [Gl261] and lung metastasis [LL/2-Luc2]). GL261 or LL/2-Luc2 cells were cultured and implanted into the brains of C57BL/6 mice. Histotripsy (1-cycle pulses, 5 Hz PRF, 30 MPa-P) was performed using a 1 MHz transducer for five different dosages for each cell line: 5, 20 or 200 pulses per location (PPL) at a single treatment point, or 5 or 10–20 PPL at multiple treatment points. MRI, bioluminescence imaging and histology were used to assess tumor ablation and treatment effects within 4–6 h post-treatment. All treatment groups resulted in a reduction of BLI intensity for the LL/2-Luc2 tumors, with significant signal reductions for the multi-point groups. The average pre-/post-treatment BLI flux (photons/s, ×108) for the different treatment groups were: 4.39/2.19 (5 PPL single-point), 5.49/1.80 (20 PPL single-point), 3.86/1.73 (200 PPL single-point), 2.44/1.11 (5 PPL multi-point) and 5.85/0.80 (10 PPL multi-point). MRI and H&E staining showed increased tumor damage and hemorrhagic effects with increasing histotripsy dose for both GL261 and LL/2-Luc2 tumors, but the increase in tumor damage was diminished beyond 10–20 PPL for single-point treatments and outweighed by increased hemorrhage. In general, hemorrhage was confined to be within 1 mm of the treatment boundary for all groups. Our results suggest that a lower number of histotripsy pulses at fewer focal locations can achieve substantial tumor kill while minimizing hemorrhage. [ABSTRACT FROM AUTHOR]

In this inaugural clinicopathological conference, the invited experts discussed the diagnostic approach to central nervous system infections in immunocompromised hosts. The case presented involved a pancreas‐kidney transplant recipient with multiple brain abscesses caused by Bartonella henselae. CSF metagenomic next‐generation sequencing played a significant role in the diagnosis. Bartonella henselae is a gram‐negative zoonotic pathogen that causes cat‐scratch disease, which can be transmitted to humans through cat bites or scratches. Symptoms can vary in severity, correlating with the patient's immune status. Visceral organ involvement, ocular involvement, and neurological manifestations have been reported in immunocompromised patients, but brain abscesses are rare. [ABSTRACT FROM AUTHOR]

Compressive tibial mononeuropathies are uncommon and can be caused by conditions including posterior compartment syndrome, soleal sling syndrome, and tarsal tunnel syndrome. Therefore, it is critical to consider noncompressive etiologies when a tibial mononeuropathy is suspected. This is a patient with a history of rare inherited immune dysregulation that presented to the electrodiagnostic laboratory with severe neuropathic pain in the right foot associated with plantarflexion weakness, concerning for a tibial mononeuropathy. However, the patient's clinical presentation and results on electrodiagnostic testing were not consistent with any of the above entities. Therefore, noncompressive etiologies of tibial mononeuropathies such as vasculitis had to be considered. The patient subsequently underwent sural nerve biopsy which confirmed small-vessel vasculitis as the cause of the tibial mononeuropathy. She was then started on appropriate immunosuppressive treatment which resulted in significant pain relief and was discharged home. This case highlights the importance of considering noncompressive causes of tibial nerve injury. Compressive and vasculitic tibial mononeuropathies along with their electrodiagnostic considerations are reviewed. Furthermore, this case highlights the critical role of the electromyographer and ability to maximize the impact on patient care through a solid foundation in anatomy, pathophysiology, and electrodiagnosis blended with clinical acumen. [ABSTRACT FROM AUTHOR]

A novel ATXN1-DUX4 fusion expands the spectrum of "CIC-rearranged sarcoma" of the CNS to include non-CIC alterations 5139621 19 Sugita S, Arai Y, Aoyama T, Asanuma H, Mukai W, Hama N. NUTM2A-CIC fusion small round cell sarcoma: a genetically distinct variant of CIC-rearranged sarcoma. *Previously published cases include ATXN1-NUTM1 [[17]], CIC frameshift deletion [[18]], and CIC in-frame deletion in the PFSK-1 cell line [[5]] independently profiled from two separate studies [[6], [10]] Initially described as a "Ewing-like" sarcoma [[13]], the molecular features of I CIC i -rearranged sarcomas have only recently come into focus. Collectively, these alterations led to the designation of " I CIC i -rearranged sarcoma" for both peripheral and CNS-based sarcomas harboring a I CIC i gene fusion. [Extracted from the article]

Familial adenomatous polyposis (FAP) is a cancer predisposition syndrome driven by germline loss-of-function of the APC gene and phenotypically manifests with intestinal polyposis and a variety of extra-intestinal bone and soft tissue tumors. Craniopharyngioma is not a well-described FAP-associated tumor, however, six cases have been reported in adults, all demonstrating ectopic location and adamantinomatous histology. We report the first case of craniopharyngioma associated with FAP in a pediatric patient. A seven-year-old girl who presented with headache and vomiting was found on magnetic resonance imaging to have a suprasellar mass with cystic extension to the pre-pontine space. The tumor represented an adamantinomatous craniopharyngioma (aCP) with nuclear β-catenin expression. Whole exome sequencing confirmed a CTNNB1 activating point mutation and a germline APC frameshift variant. This case represents the first FAP-associated craniopharyngioma in childhood.... expanding our understanding of the molecular underpinnings driving tumorigenesis in this unique patient. [ABSTRACT FROM AUTHOR]

Mucoepidermoid carcinomas (MEC) are the most common malignant neoplasms of salivary glands, but are uncommon in other sites. Salivary gland MEC are most frequently associated with CRTC1--MAML2 translocations. Exceedingly rare MEC of the breast demonstrate a basal-like and often triple (oestrogen and progesterone receptor, HER2)-negative immunophenotype, with a single case previously reported to show MAML2 rearrangement, although the fusion partner was not known. Comprehensive genomic studies of breast MEC are lacking. In this study, we analysed the immunophenotype and molecular landscape of two breast MEC to elucidate the pathogenesis of these rare tumours. Methods and results: Two breast MEC were subjected to capture-based next-generation DNA sequencing of 479 cancer-related genes. The presence of the CRTC1--MAML2 fusion transcript was interrogated by reverse transcriptase--polymerase chain reaction. In addition, the immunoprofiles of breast MEC were compared to salivary gland MEC. Both breast MEC harboured CRTC1--MAML2 fusions. In contrast to most triple-negative breast carcinomas of no special type, the mutational burden of MEC was very low, with one case demonstrating only an inactivating SETD2 mutation, and the other harbouring no somatic variants in genes on the panel. No copy number alterations were identified. The immunopro- files of breast and salivary gland MEC were overlapping, but not identical. Conclusions: The findings highlight MEC as a breast cancer subtype more closely related to its salivary gland counterpart than to basal-like/triple-negative breast cancers of no special type. [ABSTRACT FROM AUTHOR]

Anaplasia may be identified in a subset of tumors with a presumed pilocytic astrocytoma (PA) component or piloid features, which may be associated with aggressive behavior, but the biologic basis of this change remains unclear. Fifty‐seven resections from 36 patients (23 M, 13 F, mean age 32 years, range 3–75) were included. A clinical diagnosis of NF1 was present in 8 (22%). Alternative lengthening of telomeres (ALT) was assessed by telomere‐specific FISH and/or CISH. A combination of immunohistochemistry, DNA sequencing and FISH were used to study BRAF,ATRX,CDKN2A/p16, mutant IDH1 p.R132H and H3‐K27M proteins. ALT was present in 25 (69%) cases and ATRX loss in 20 (57%), mostly in the expected association of ALT+/ATRX‐ (20/24, 83%) or ALT‐/ATRX+ (11/11, 100%). BRAF duplication was present in 8 (of 26) (31%). H3‐K27M was present in 5 of 32 (16%) cases, all with concurrent ATRX loss and ALT. ALT was also present in 9 (of 11) cases in the benign PA precursor, 7 of which also had ATRX loss in both the precursor and the anaplastic tumor. In a single pediatric case, ALT and ATRX loss developed in the anaplastic component only, and in another adult case, ALT was present in the PA‐A component only, but ATRX was not tested. Features associated with worse prognosis included subtotal resection, adult vs. pediatric, presence of a PA precursor preceding a diagnosis of anaplasia, necrosis, presence of ALT and ATRX expression loss. ALT and ATRX loss, as well as alterations involving the MAPK pathway, are frequent in PA with anaplasia at the time of development of anaplasia or in their precursors. Additionally, a small subset of PA with anaplasia have H3‐K27M mutations. These findings further support the concept that PA with anaplasia is a neoplasm with heterogeneous genetic features and alterations typical of both PA and diffuse gliomas. [ABSTRACT FROM AUTHOR]

COVID-19 has also been linked to hypercoagulability and elevated cerebrovascular accidents rates [[3], [6], [9]]; however, little is known regarding the impact of COVID-19-associated coagulopathy on tumor biology. Here, we discuss the case of a young adult with a thalamic high-grade glioma, COVID-19-associated coagulopathy, and histopathologic evidence of extensive vascular thrombosis within the tumor microenvironment. Post-operative head CT and MRI demonstrated successful drain placement, but exhibited marked hemorrhage in the tumor and ventricles, with displacement of the septum pellucidum (Figs. [Extracted from the article]

Myoepithelial tumours are a rare form of salivary gland neoplasm and intracranial metastases have rarely been described. The authors present the case of a 61-year-old patient with a history of primary myoepithelial carcinoma of the right foot. Metastases were found in the third ventricle, left temporal lobe and right frontal lobe. The third ventricular and left temporal lobe tumours were resected in a two-stage operation. Pathology of the third ventricular lesion was most consistent with metastasis. MRI of the spine 2 weeks after his operation revealed an intradural mass with several lesions in the lumbar thecal space suggesting further metastases. The patient succumbed to his disease 2 months after his two-stage operation and 5 years after his initial diagnosis. This appears to be the first case in the literature of multiple primary myoepithelial carcinoma metastases to the brain. Further information is needed to provide diagnostic and therapeutic recommendations. [ABSTRACT FROM AUTHOR]

Purpose: Brain tumors have become the leading cause of cancer-related mortality in young patients. Novel effective therapies on the basis of the unique biology of each tumor are urgently needed. The goal of this study was to evaluate the feasibility, utility, and clinical impact of integrative clinical sequencing and genetic counseling in children and young adults with high-risk brain tumors. Patients and Methods: Fifty-two children and young adults with brain tumors designated by the treating neuro-oncologist to be high risk (> 25% chance for treatment failure; mean age, 10.2 years; range, 0 to 39 years) were enrolled in a prospective, observational, consecutive case series, in which participants underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing and genetic counseling. Results were discussed in a multi-institutional brain tumor precision medicine teleconference. Results: Sequencing revealed a potentially actionable germline or tumor alteration in 25 (63%) of 40 tumors with adequate tissue, of which 21 (53%) resulted in an impact on treatment or change of diagnosis. Platelet-derived growth factor receptor or fibroblast growth factor receptor pathway alterations were seen in nine of 20 (45%) glial tumors. Eight (20%) sequenced tumors harbored an oncogenic fusion isolated on RNA sequencing. Seventeen of 20 patients (85%) with glial tumors were found to have a potentially actionable result, which resulted in change of therapy in 14 (70%) patients. Patients with recurrent brain tumors receiving targeted therapy had a median progression-free survival (from time on therapy) of 4 months. Conclusion: Selection of personalized agents for children and young adults with high-risk brain tumors on the basis of integrative clinical sequencing is feasible and resulted in a change in therapy in more than two thirds of children and young adults with high-risk glial tumors. [ABSTRACT FROM AUTHOR]

Pediatric brain tumors are the leading cause of childhood cancer mortality. Recurring genetic abnormalities play an essential role in the diagnosis and prognosis of pediatric brain tumors. However, clinical workup has not routinely included whole genome assessment. Here, we present high resolution whole genome array results in 11 pediatric brain tumors. Array identified clinically relevant abnormalities in all samples. Copy number aberrations with targeted therapy implication, GOPC-ROS1 fusion, CDK4 amplification, and NF1 deletion, were detected in 3 cases. In addition, array detected recurring genetic abnormalities, including KIAA1549-BRAF fusion, 19q13.42 amplification, i(17q), and monosomy 6, which assisted accurate histological diagnosis in pediatric brain tumors. In conclusion, our results show that whole genome high-resolution array detects diagnostic and treatment-relevant copy number abnormalities in pediatric brain tumors. [ABSTRACT FROM AUTHOR]

Introduction: Glioma classification and grading has been historically based in morphologic appearance of tumor cells: astrocytomas, oligodendrogliomas, oligoastrocytomas and ependymomas. Recent molecular advances have transformed the field of neuro-oncology, as some molecular markers harbor diagnostic, prognostic and therapeutic implications. Areas covered: In this paper we will review the major molecular changes associated with gliomas and their implications in diagnosis, prognosis, and opportunities in therapeutics. Expert commentary: Based on current understanding, adult diffuse infiltrating gliomas can be molecularly divided into three to five major subgroups with different clinical outcomes. Pediatric gliomas harbor mutations for H3F3A, ATRX and DAXX but not IDH. Circumscribed low-grade gliomas tend to have BRAF alterations. Clinical behavior of ependymomas correlates more with location than WHO grading. Posterior fossa ependymomas tend to behave worse than their cerebral or spinal cord counterparts. However, with the posterior fossa ependymomas, two distinct subtypes have emerged molecularly. [ABSTRACT FROM PUBLISHER]

Clinical classification of early dementia and mild cognitive impairment (MCI) is imprecise. We reported previously that molecular imaging classification of early dementia and MCI with dual amyloid and dopamine terminal positron emission tomography differs significantly from expert clinical classification. We now report pathological diagnoses in a substantial subset of our previously imaged subjects. Among 36 subjects coming to autopsy, imaging classifications and pathological diagnosis were concordant in 33 cases (κ = 0.85). This approach enhanced specificity of Alzheimer's disease diagnosis. The strong concordance of imaging-based classifications and pathological diagnoses suggests that this imaging approach will be useful in establishing more accurate and convenient classification biomarkers for dementia research. [ABSTRACT FROM AUTHOR]

The article presents a research conducted by Minbiao Ji and his colleagues on the detection of human brain tumor infiltration with quantitative stimulated Raman scattering (SRS) microscopy. Topics discussed include detection of SRS tumor infiltration in near-perfect agreement with standard hematoxylin and eosin light microscopy; detection of tumor infiltration for improving the accuracy of brain tumor surgery; and microscopy provide data that does not requirement expert interpretation.

Objectives: Expression of strong nuclear STAT6 is thought to be a specific marker for solitary fibrous tumors (SFTs). Little is known about subtle expression patterns in other mesenchymal lesions. Methods: We performed immunohistochemical studies against the C-terminus of STAT6 in tissue microarrays and whole sections, comprising 2366 mesenchymal lesions. Results: Strong nuclear STAT6 was expressed in 285 of 2,021 tumors, including 206 of 240 SFTs, 49 of 408 well-differentiated/dedifferentiated liposarcomas, eight of 65 unclassified sarcomas, and 14 of 184 desmoid tumors, among others. Expression in SFTs was predominately limited to the nucleus. Other positive tumors typically expressed both nuclear and cytoplasmic STAT6. Complete absence of STAT6 was most common in pleomorphic liposarcoma and alveolar soft part sarcoma (60% and 72% cases negative, respectively). Conclusions: Strong nuclear STAT6 is largely specific for SFTs. Physiologic low-level cytoplasmic/nuclear expression is common in mesenchymal neoplasia and is of uncertain significance. [ABSTRACT FROM AUTHOR]

It is increasingly clear that both adult and pediatric glial tumor entities represent collections of neoplastic lesions, each with individual pathological molecular events and treatment responses. In this review, we discuss the current prognostic biomarkers validated for clin-ical use or with future clinical validity for gliomas. Accurate prognostication is crucial for managing patients as treatments may be associated with high morbidity and the benefits of high risk interventions must be judged by the treating clinicians.We also reviewbiomark-ers with predictive validity, which may become clinically relevant with the development of targeted therapies for adult and pediatric gliomas. [ABSTRACT FROM AUTHOR]

Embryonal tumor with abundant neuropil and true rosettes ( ETANTR) is a recently described embryonal neoplasm of the central nervous system, consisting of a well-circumscribed embryonal tumor of infancy with mixed features of ependymoblastoma (multilayer ependymoblastic rosettes and pseudorosettes) and neuroblastoma (neuroblastic rosettes) in the presence of neuropil-like islands. We present the case of a young child with a very aggressive tumor that rapidly recurred after gross total resection, chemotherapy and radiation. Prominent vascular sclerosis and circumscribed tumor led to the diagnosis of malignant astroblastoma; however, rapid recurrence and progression of this large tumor after gross total resection prompted review of the original pathology. ETANTR is histologically distinct with focal glial fibrillary acid protein ( GFAP) and synaptophysin expression in the presence of neuronal and ependymoblastic rosettes with focal neuropil islands. These architectural features, combined with unique chromosome 19q13.42 amplification, confirmed the diagnosis. In this report, we describe tumor stem cell ( TSC) marker CD133, CD15 and nestin alterations in ETANTR before and after chemotherapy. We found that TSC marker CD133 was richly expressed after chemotherapy in recurrent ETANTR, while CD15 is depleted compared with that expressed in the original tumor, suggesting that CD133+ cells likely survived initial treatment, further contributing to formation of the recurrent tumor. [ABSTRACT FROM AUTHOR]

Recent work has identified novel point mutations in isocitrate dehydrogenase 1 ( IDH1) in the majority of the World Health Organization grades II and III infiltrative gliomas and secondary grade IV glioblastomas. Gangliogliomas consist of neoplastic ganglion and glial cells and, in contrast to infiltrative gliomas, are generally indolent. Yet distinguishing between a ganglioglioma and an infiltrative glioma with admixed gray matter can be difficult, perhaps accounting for some 'gangliogliomas' that ultimately show aggressive behavior. In this multi-institutional study, 98 cases originally diagnosed as ganglioglioma were analyzed for IDH1 mutations, 86 of which had follow-up data available. Eight cases (8.2%) were positive for R132H IDH1 mutations; six had silent IDH2 mutations and two had nonsense IDH2 mutations. The presence of mutant IDH1 in gangliogliomas correlated with a greater risk of recurrence ( P = 0.0007) and malignant transformation and/or death ( P < 0.0001) compared with tumors that were IDH1 wild type. Furthermore, the age of patients with IDH1-mutant gangliogliomas was higher than those without mutations (25.5 vs. 46.1 years, P = 0.0033). IDH1/2 testing of tumors suspected of being gangliogliomas may therefore be advisable, particularly in the adult population. [ABSTRACT FROM AUTHOR]

Differentiating pseudoprogression from true tumor progression has become a significant challenge in follow-up of diffuse infiltrating gliomas, particularly high grade, which leads to a potential treatment delay for patients with early glioma recurrence. In this study, we proposed to use a multiparametric MRI data as a sequence input for the convolutional neural network with the recurrent neural network based deep learning structure to discriminate between pseudoprogression and true tumor progression. In this study, 43 biopsy-proven patient data identified as diffuse infiltrating glioma patients whose disease progressed/recurred were used. The dataset consists of five original MRI sequences; pre-contrast T1-weighted, post-contrast T1-weighted, T2-weighted, FLAIR, and ADC images as well as two engineered sequences; T1post–T1pre and T2–FLAIR. Next, we used three CNN-LSTM models with a different set of sequences as input sequences to pass through CNN-LSTM layers. We performed threefold cross-validation in the training dataset and generated the boxplot, accuracy, and ROC curve, AUC from each trained model with the test dataset to evaluate models. The mean accuracy for VGG16 models ranged from 0.44 to 0.60 and the mean AUC ranged from 0.47 to 0.59. For CNN-LSTM model, the mean accuracy ranged from 0.62 to 0.75 and the mean AUC ranged from 0.64 to 0.81. The performance of the proposed CNN-LSTM with multiparametric sequence data was found to outperform the popular convolutional CNN with a single MRI sequence. In conclusion, incorporating all available MRI sequences into a sequence input for a CNN-LSTM model improved diagnostic performance for discriminating between pseudoprogression and true tumor progression. [ABSTRACT FROM AUTHOR]

Introduction: Phosphoglycerate mutase deficiency (PGAM) is a rare metabolic myopathy that results in terminal block in glycogenolysis. Clinically, patients with PGAM deficiency are asymptomatic, except when they engage in brief, strenuous efforts, which may trigger myalgias, cramps, muscle necrosis, and myoglobinuria. An unusual pathologic feature of PGAM deficiency is the association with tubular aggregates. Methods: We report an African-American patient from Panama with partial deficiency of PGAM who presented with asymptomatic elevation of creatine kinase levels and tubular aggregates on muscle biopsy. Results: Muscle biopsies showed subsarcolemmal and sarcolemmal tubular aggregates in type 2 fibers. Muscle PGAM enzymatic activity was decreased and gene sequencing revealed a heterozygous mutation in codon 78 of exon 1 of the PGAM2 gene, which is located on the short arm of chromosome 7. Conclusions: PGAM deficiency has been reported in 14 patients, 9 of whom were of African-American ethnicity, and in 5 (36%) tubular aggregates were seen on muscle biopsy. Contrary to previously reported cases, our patient was initially asymptomatic. This further expands the PGAM deficiency phenotype. Muscle Nerve, 2013 [ABSTRACT FROM AUTHOR]

The article offers information on how diffuse astrocytomas can be differentiated from astrocytosis (gliosis) on biopsies, particularly small biopsies while diagnosing neuropathology. It informs that challenging differential diagnosis arises in two general situations which includes low cellularity edges of infiltrating astrocytomas verses mild astrocytosis and florid astrocytosis verses cellular astrocytomas. It informs how molecular assays are converted to immunohistochemical stain.

Background: Rapid ("warm") autopsies of patients with advanced metastatic cancer provide important insight into the natural history, pathobiology and histomorphology of disease in treatment-resistant tumors. Plasmacytoid urothelial carcinoma (PUC) is a rare variant of urothelial carcinoma characterized by neoplastic cells morphologically resembling plasma cells. PUC is typically aggressive, high-stage at presentation, and associated with poor outcomes. Recurrence is common in PUC, with the majority of recurrences occurring in the peritoneum. Case presentation: Here, we report rapid autopsy findings from a patient with recurrent PUC. The patient had persistent pain after cystoprostatectomy, although initial post-operative imaging showed no evidence of disease. Imaging obtained shortly before his death showed only subtle growth along vascular tissue planes; however, extensive disease was seen on autopsy. Plasmacytoid tumor cells formed sheets involving many serosal surfaces. Molecular interrogation confirmed a mutation in CDH1 exon 12 leading to early truncation of the CDH1 protein in the tumor cells. Conclusions: The sheet-like growth pattern of PUC makes early phases of disease spread much more difficult to capture on cross-sectional imaging. Alternative forms of surveillance may be required for detection of recurrent PUC, and providers may need to treat based on symptoms and clinical suspicion. [ABSTRACT FROM AUTHOR]

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that has a dual role in cancer, i.e., pro- or anti-tumorigenic, depending on the context. In medulloblastoma, the most frequent malignant pediatric brain tumor, several in vitro studies previously showed that AMPK suppresses tumor cell growth. The role of AMPK in this disease context remains to be tested in vivo. Here, we investigate loss of AMPKα2 in a genetically engineered mouse model of sonic hedgehog (SHH)-medulloblastoma. In contrast to previous reports, our study reveals that AMPKα2 KO impairs SHH medulloblastoma tumorigenesis. Moreover, we performed complementary molecular and genomic analyses that support the hypothesis of a pro-tumorigenic SHH/AMPK/CNBP axis in medulloblastoma. In conclusion, our observations further underline the context-dependent role of AMPK in cancer, and caution is warranted for the previously proposed hypothesis that AMPK agonists may have therapeutic benefits in medulloblastoma patients. Note: an abstract describing the project was previously submitted to the American Society for Investigative Pathology PISA 2018 conference and appears in The American Journal of Pathology (Volume 188, Issue 10, October 2018, Page 2433). [ABSTRACT FROM AUTHOR]

Summary Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten , forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53 mutant sonic hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively. [ABSTRACT FROM AUTHOR]