Metabolic regulation and glucose sensitivity of cortical radial glial cells.

The primary stem cells of the cerebral cortex are the radial glial cells (RGCs), and disturbances in their operation lead to myriad brain disorders in all mammals from mice to humans. Here, we found in mice that maternal gestational obesity and hyperglycemia can impair the maturation of RGC fibers and delay cortical neurogenesis. To investigate potential mechanisms, we used optogenetic live-imaging approaches in embryonic cortical slices. We found that Ca2+ signaling regulates mitochondrial transport and is crucial for metabolic support in RGC fibers. Cyclic intracellular Ca2+ discharge from localized RGC fiber segments detains passing mitochondria and ensures their proper distribution and enrichment at specific sites such as endfeet. Impairment of mitochondrial function caused an acute loss of Ca2+ signaling, while hyperglycemia decreased Ca2+ activity and impaired mitochondrial transport, leading to degradation of the RGC scaffold. Our findings uncover a physiological mechanism indicating pathways by which gestational metabolic disturbances can interfere with brain development.

Primary dural lymphomas: Clinical presentation, management, and outcome.

BACKGROUND: Clinical experience is limited for primary central nervous system (CNS) lymphoma that arises from the dura mater, which is denoted with the term primary dural lymphoma (PDL). This study was aimed at determining the relative incidence, presentation, and outcomes of PDL. METHODS: The institutional databases of the Divisions of Neuro-Oncology at the Massachusetts General Hospital and the Yale School of Medicine were retrospectively searched for patients with primary CNS lymphoma. Patients with pathologically confirmed dural lymphoma and no evidence of primary cerebral or systemic involvement were identified. Clinical data, diagnostic findings, treatments, and outcomes were recorded. RESULTS: A total of 20 patients with PDL were identified, and they represented 6.3% of the individuals with primary CNS lymphomas (20 of 316). Histopathological examination of PDL revealed the following underlying subtypes: diffuse large B-cell lymphoma (10 of 20 patients), marginal zone lymphoma (6 of 20), follicular lymphoma (2 of 20), undefined B-cell non-Hodgkin lymphoma (1 of 20), and T-cell non-Hodgkin lymphoma (1 of 20). On imaging, all tumors appeared as extra-axial masses with avid contrast enhancement and mostly mimicked meningioma. The median apparent diffusion coefficient value was 667 ± 26 mm2 /s. Cerebrospinal fluid analyses and symptoms were nonspecific, and the diagnosis rested on tissue analysis. Therapeutic approaches included surgery, radiotherapy, and chemotherapy. The median overall survival was not reached after 5 years. Three patients were deceased at database closure because of tumor progression. The extent of tumor resection correlated positively with overall survival (P = .044). CONCLUSIONS: PDL is a rare variant of primary CNS lymphoma that can be radiographically mistaken for meningioma. The outcome is excellent with multimodality treatment, and aggressive surgery may convey a survival advantage in select cases.

The aged rhesus macaque manifests Braak stage III/IV Alzheimer's-like pathology.

INTRODUCTION: An animal model of late-onset Alzheimer's disease is needed to research what causes degeneration in the absence of dominant genetic insults and why the association cortex is particularly vulnerable to degeneration. METHODS: We studied the progression of tau and amyloid cortical pathology in the aging rhesus macaque using immunoelectron microscopy and biochemical assays. RESULTS: Aging macaques exhibited the same qualitative pattern and sequence of tau and amyloid cortical pathology as humans, reaching Braak stage III/IV. Pathology began in the young-adult entorhinal cortex with protein kinase A-phosphorylation of tau, progressing to fibrillation with paired helical filaments and mature tangles in oldest animals. Tau pathology in the dorsolateral prefrontal cortex paralleled but lagged behind the entorhinal cortex, not afflicting the primary visual cortex. DISCUSSION: The aging rhesus macaque provides the long-sought animal model for exploring the etiology of late-onset Alzheimer's disease and for testing preventive strategies.

Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma.

Current therapy for glioblastoma multiforme is insufficient, with nearly universal recurrence. Available drug therapies are unsuccessful because they fail to penetrate through the region of the brain containing tumor cells and they fail to kill the cells most responsible for tumor development and therapy resistance, brain cancer stem cells (BCSCs). To address these challenges, we combined two major advances in technology: (i) brain-penetrating polymeric nanoparticles that can be loaded with drugs and are optimized for intracranial convection-enhanced delivery and (ii) repurposed compounds, previously used in Food and Drug Administration-approved products, which were identified through library screening to target BCSCs. Using fluorescence imaging and positron emission tomography, we demonstrate that brain-penetrating nanoparticles can be delivered to large intracranial volumes in both rats and pigs. We identified several agents (from Food and Drug Administration-approved products) that potently inhibit proliferation and self-renewal of BCSCs. When loaded into brain-penetrating nanoparticles and administered by convection-enhanced delivery, one of these agents, dithiazanine iodide, significantly increased survival in rats bearing BCSC-derived xenografts. This unique approach to controlled delivery in the brain should have a significant impact on treatment of glioblastoma multiforme and suggests previously undescribed routes for drug and gene delivery to treat other diseases of the central nervous system.

Imaging the delivery of brain-penetrating PLGA nanoparticles in the brain using magnetic resonance.

Current therapy for glioblastoma multiforme (GBM) is largely ineffective, with nearly universal tumor recurrence. The failure of current therapy is primarily due to the lack of approaches for the efficient delivery of therapeutics to diffuse tumors in the brain. In our prior study, we developed brain-penetrating nanoparticles that are capable of penetrating brain tissue and distribute over clinically relevant volumes when administered via convection-enhanced delivery (CED). We demonstrated that these particles are capable of efficient delivery of chemotherapeutics to diffuse tumors in the brain, indicating that they may serve as a groundbreaking approach for the treatment of GBM. In the original study, nanoparticles in the brain were imaged using positron emission tomography (PET). However, clinical translation of this delivery platform can be enabled by engineering a non-invasive detection modality using magnetic resonance imaging (MRI). For this purpose, we developed chemistry to incorporate superparamagnetic iron oxide (SPIO) into the brain-penetrating nanoparticles. We demonstrated that SPIO-loaded nanoparticles, which retain the same morphology as nanoparticles without SPIO, have an excellent transverse (T(2)) relaxivity. After CED, the distribution of nanoparticles in the brain (i.e., in the vicinity of injection site) can be detected using MRI and the long-lasting signal attenuation of SPIO-loaded brain-penetrating nanoparticles lasted over a one-month timecourse. Development of these nanoparticles is significant as, in future clinical applications, co-administration of SPIO-loaded nanoparticles will allow for intraoperative monitoring of particle distribution in the brain to ensure drug-loaded nanoparticles reach tumors as well as for monitoring the therapeutic benefit with time and to evaluate tumor relapse patterns.

Single-Cell Transcriptomic Analyses of Brain Parenchyma in Patients With New-Onset Refractory Status Epilepticus (NORSE).

BACKGROUND AND OBJECTIVES: New-onset refractory status epilepticus (NORSE) occurs in previously healthy children or adults, often followed by refractory epilepsy and poor outcomes. The mechanisms that transform a normal brain into an epileptic one capable of seizing for prolonged periods despite treatment remain unclear. Nonetheless, several pieces of evidence suggest that immune dysregulation could contribute to hyperexcitability and modulate NORSE sequelae. METHODS: We used single-nucleus RNA sequencing to delineate the composition and phenotypic states of the CNS of 4 patients with NORSE, to better understand the relationship between hyperexcitability and immune disturbances. We compared them with 4 patients with chronic temporal lobe epilepsy (TLE) and 2 controls with no known neurologic disorder. RESULTS: Patients with NORSE and TLE exhibited a significantly higher proportion of excitatory neurons compared with controls, with no discernible difference in inhibitory GABAergic neurons. When examining the ratio between excitatory neurons and GABAergic neurons for each patient individually, we observed a higher ratio in patients with acute NORSE or TLE compared with controls. Furthermore, a negative correlation was found between the ratio of excitatory to GABAergic neurons and the proportion of GABAergic neurons. The ratio between excitatory neurons and GABAergic neurons correlated with the proportion of resident or infiltrating macrophages, suggesting the influence of microglial reactivity on neuronal excitability. Both patients with NORSE and TLE exhibited increased expression of genes associated with microglia activation, phagocytic activity, and NLRP3 inflammasome activation. However, patients with NORSE had decreased expression of genes related to the downregulation of the inflammatory response, potentially explaining the severity of their presentation. Microglial activation in patients with NORSE also correlated with astrocyte reactivity, possibly leading to higher degrees of demyelination. DISCUSSION: Our study sheds light on the complex cellular dynamics in NORSE, revealing the potential roles of microglia, infiltrating macrophages, and astrocytes in hyperexcitability and demyelination, offering potential avenues for future research targeting the identified pathways.

Histological changes associated with laser interstitial thermal therapy for radiation necrosis: illustrative cases.

BACKGROUND: Patients with lung cancer and melanoma remain the two largest groups to develop brain metastases. Immunotherapy has been approved for treatment of stage IV disease in both groups. Many of these patients are additionally treated with stereotactic radiosurgery for their brain metastases during ongoing immunotherapy. Use of immunotherapy has been reported to increase the rates of radiation necrosis (RN) after radiosurgery, causing neurological compromise due to growth of the enhancing lesion as well as worsening of associated cerebral edema. OBSERVATIONS: Laser interstitial thermal therapy (LITT) is a surgical approach that has been shown effective in the management of RN, especially given its efficacy in early reduction of perilesional edema. However, little remains known about the pathology of the post-LITT lesions and how LITT works in this condition. Here, we present two patients who needed surgical decompression after LITT for RN. Clinical, histopathological, and imaging features of both patients are presented. LESSONS: Criteria for selecting the best patients with RN for LITT therapy remains unclear. Given two similarly sized lesions and not too dissimilar clinical histories but with differing outcomes, further investigation is clearly needed to identify predictors of response to LITT in the setting of SRS and immunotherapy-induced RN.

The changing landscape in epilepsy imaging: Unmasking subtle and unique entities.

Dramatic changes have occurred recently in the field of epilepsy, including a fundamental shift in the etiology of epileptogenic substrates found at surgery. Hippocampal sclerosis is no longer the most common etiology found at epilepsy surgery and this decrease has been associated with an increase in the incidence of focal cortical dysplasia and encephaloceles. Significant advances have been made in molecular biology and genetics underlying the basis of malformations of cortical development, and our ability to detect epileptogenic abnormalities with MR imaging has markedly improved. This article begins with a discussion of these trends and reviews imaging techniques essential for detecting of subtle epilepsy findings. Representative examples of subtle imaging findings are presented, which are often overlooked but should not be missed. These include temporal lobe encephaloceles, malformations of cortical development (and especially focal cortical dysplasia), hippocampal sclerosis, hippocampal malformation (also known as HIMAL), ulegyria, autoimmune encephalitis, and Rasmussen's encephalitis. Recent findings on the pathophysiology and genetic underpinnings of several causes of localization-related epilepsy are incorporated. For instance, it has been recently found that focal cortical dysplasia IIb, tuberous sclerosis, hemimegalencephaly, and gangliogliomas are all the result of mutations of the mTOR pathway for cell growth.

Machine Learning Models for Classifying High- and Low-Grade Gliomas: A Systematic Review and Quality of Reporting Analysis.

Objectives: To systematically review, assess the reporting quality of, and discuss improvement opportunities for studies describing machine learning (ML) models for glioma grade prediction. Methods: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy (PRISMA-DTA) statement. A systematic search was performed in September 2020, and repeated in January 2021, on four databases: Embase, Medline, CENTRAL, and Web of Science Core Collection. Publications were screened in Covidence, and reporting quality was measured against the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) Statement. Descriptive statistics were calculated using GraphPad Prism 9. Results: The search identified 11,727 candidate articles with 1,135 articles undergoing full text review and 85 included in analysis. 67 (79%) articles were published between 2018-2021. The mean prediction accuracy of the best performing model in each study was 0.89 ± 0.09. The most common algorithm for conventional machine learning studies was Support Vector Machine (mean accuracy: 0.90 ± 0.07) and for deep learning studies was Convolutional Neural Network (mean accuracy: 0.91 ± 0.10). Only one study used both a large training dataset (n>200) and external validation (accuracy: 0.72) for their model. The mean adherence rate to TRIPOD was 44.5% ± 11.1%, with poor reporting adherence for model performance (0%), abstracts (0%), and titles (0%). Conclusions: The application of ML to glioma grade prediction has grown substantially, with ML model studies reporting high predictive accuracies but lacking essential metrics and characteristics for assessing model performance. Several domains, including generalizability and reproducibility, warrant further attention to enable translation into clinical practice. Systematic Review Registration: PROSPERO, identifier CRD42020209938.

Cortical injury in multiple sclerosis; the role of the immune system.

The easily identifiable, ubiquitous demyelination and neuronal damage that occurs within the cerebral white matter of patients with multiple sclerosis (MS) has been the subject of extensive study. Accordingly, MS has historically been described as a disease of the white matter. Recently, the cerebral cortex (gray matter) of patients with MS has been recognized as an additional and major site of disease pathogenesis. This acknowledgement of cortical tissue damage is due, in part, to more powerful MRI that allows detection of such injury and to focused neuropathology-based investigations. Cortical tissue damage has been associated with inflammation that is less pronounced to that which is associated with damage in the white matter. There is, however, emerging evidence that suggests cortical damage can be closely associated with robust inflammation not only in the parenchyma, but also in the neighboring meninges. This manuscript will highlight the current knowledge of inflammation associated with cortical tissue injury. Historical literature along with contemporary work that focuses on both the absence and presence of inflammation in the cerebral cortex and in the cerebral meninges will be reviewed.

Nocardia thailandica Brain Abscess in an Immunocompromised Patient.

OBJECTIVES: Successful treatment for Nocardia thailandica is not well elucidated in the literature. To the best of our knowledge, N. thailandica has not yet been described in the medical literature to cause central nervous system (CNS) infection from brain abscess. We report the case of an immunocompromised patient who underwent successful treatment to treat his brain abscess caused by N. thailandica. METHODS: After failing medical therapy, the patient underwent a craniotomy, and tissue was sent for culture. Upon identification by 16S rDNA sequencing, the organism causing infection was identified to be N. thailandica. RESULTS: Based on susceptibilities, the patient was treated with IV ceftriaxone 2 grams daily for five months. The patient demonstrated clinical and radiological improvement which persisted to 7 months after initiation of therapy. CONCLUSIONS: To the best of our knowledge, this is the first documented case of a brain abscess due to N. thailandica which was successfully treated. Due to the location of the infection, ceftriaxone was chosen because of optimal CNS penetration. Ceftriaxone monotherapy demonstrated clinical and radiographic treatment success resulting in the successful treatment of this infection.

Hemorrhage Into a Subependymal Giant Cell Astrocytoma in an Adult With Tuberous Sclerosis: Case Report.

BACKGROUND: We present an uncommon cause of intracranial hemorrhage in a young adult. Tuberous sclerosis complex is a rare genetic disorder characterized by skin changes, benign systemic or central nervous system tumors [subependymal giant cell astrocytoma (SEGA)], mental retardation, or epilepsy. Hemorrhage into SEGA is exceedingly rare. CASE PRESENTATION: We evaluated a 21-year-old college student with migraine. Biopsy of numerous popular skin lesions on his nose revealed adenoma sebaceum. Magnetic resonance imaging brain showed a subependymal nodule near the foramen of Monro suspected to be SEGA. Genetic analysis identified a tuberous sclerosis complex-1 germ line mutation. Surveillance imaging was recommended for the subependymal tumor. Fourteen months later, he presented with spontaneous hemorrhage into the tumor. Hematoma evacuation and tumor resection revealed SEGA. The college graduate was able to return to full-time work. CONCLUSIONS: We present an unusual cause of intracranial hemorrhage in a young adult. Thorough work-up and recognition of an underlying genetic predisposition can curtails diagnostic delay when life-threatening complications occur.

Clinicopathologic study of glioblastoma in children with neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is characterized by low-grade tumors of the central and peripheral nervous system. There is also an increased risk of developing malignant tumors. Glioblastoma is an uncommon, malignant tumor of children that is even less frequently observed in children with NF1. PROCEDURE: We performed a retrospective review of patients with NF1 and glioblastoma to determine specific clinical and pathologic indicators of overall prognosis. RESULTS: Five patients were identified from the CHB/DFCI database for whom pathologic and imaging studies were available. All pathologic specimens demonstrated vascular proliferation and necrosis. All samples stained positively for p53. Chromogenic in situ hybridization (CISH) for epidermal growth factor receptor (EGFR) copy numbers was increased, PTEN copy numbers were normal and the promoter of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene was unmethylated in the one patient evaluated. In the same time period, there were 56 patients without NF1 diagnosed with glioblastoma who were treated at our institution. Although the small sample size precludes formal statistical analysis, the 2-year survival of patients with NF1 is 60% with median overall survival of 9.25 years compared to non-NF1 patients with a 2-year survival of 25% and median overall survival 1.08 years. CONCLUSIONS: This study provides preliminary evidence that children with NF1 may be at risk for glioblastoma, but that these patients have an increased survival compared to children without NF1. Additional molecular studies will be required to determine if the pathogenesis of these tumors differs from glioblastoma in children without NF1.

Leptomeningeal dissemination of low-grade neuroepithelial CNS tumors in adults: a 15-year experience.

BACKGROUND: Leptomeningeal dissemination (LD) in adults is an exceedingly rare complication of low-grade neuroepithelial CNS tumors (LGNs). We aimed to determine relative incidence, clinical presentation, and predictors of outcome. METHODS: We searched the quality control database of the Section of Neuro-Oncology, Yale Cancer Center, for patients with LGN (WHO grade I/II) seen between 2002 and 2017. For cases complicated by LD, we recorded demographics, clinical signs, histopathological diagnosis, and imaging findings. A comprehensive literature review was performed. RESULTS: Eleven consecutive patients with LD were identified, representing 2.3% of individuals with LGN seen at our institution between 2002 and 2017 (n = 475). Ependymoma was the predominant histological entity. Mean time interval from diagnosis of LGN to LD was 38.6 ± 10 months. Symptoms were mostly attributed to communicating hydrocephalus. Tumor deposits of LD were either nodular or linear with variable enhancement (nonenhancing lesions in 4 of 11 patients). Localized (surgery, radiosurgery, involved-field, or craniospinal radiation therapy) or systemic treatments (chemotherapy) were provided. All patients progressed radiographically. Median overall survival after LD was 102 months. Survival was prolonged when a combination of localized and systemic therapies was administered (188.5 vs 25.5 months; P = .03). Demographics and tumor spectrum reported in the literature were similar to our cohort. CONCLUSIONS: LD is a rare complication of LGNs. A high level of suspicion is required for timely diagnosis as early symptoms are nonspecific and commonly do not occur until years after initial tumor diagnosis. Repeated aggressive treatment appears to be beneficial in improving survival.

Primary, non-exophytic, optic nerve germ cell tumors.

Tumors of the optic chiasm are relatively uncommon and usually associated with phakomatoses such as neurofibromatosis. Even more rare is the presentation of a primary, non-exophytic, isolated optic chiasm germ cell tumor (GCT). These tumors have imaging characteristics nearly indistinguishable from optic chiasmatic gliomas (OCGs). Herein we describe two cases of young men who presented with similar findings of progressive, painless visual loss and hypothalamic-pituitary-adrenal axis dysfunction including diabetes insipidus. Brain imaging was non-diagnostic and suggestive of an OCG. Pathology demonstrated GCTs in each case highlighting the importance of biopsy confirmation of the diagnosis. Both patients underwent a pterional craniotomy and sub-frontal approach to the optic chiasm. The chiasm was diffusely enlarged and discolored in each case without evidence of sellar, suprasellar or perichiasmatic pathology. Pathology demonstrated a malignant mixed GCT in the first patient and a germinoma in the second. This case series highlights the importance of tissue biopsy for patients with progressive symptoms from optic chiasm tumors. Furthermore, this is the first report of a primary, non-exophytic malignant mixed GCT. As the treatment regimens differ widely between optic chiasm GCTs and chiasm gliomas, tissue diagnosis is important.

Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice.

Zika virus (ZIKV) is an emerging, mosquito-borne RNA virus. The rapid spread of ZIKV within the Americas has unveiled microcephaly 1 and Guillain-Barré syndrome2,3 as ZIKV-associated neurological complications. Recent reports have also indicated other neurological manifestations to be associated with ZIKV, including myelitis 4 , meningoencephalitis 5 and fatal encephalitis 6 . Here, we investigate the neuropathogenesis of ZIKV infection in type I interferon receptor IFNAR knockout (Ifnar1 -/- ) mice, an infection model that exhibits high viral burden within the central nervous system. We show that systemic spread of ZIKV from the site of infection to the brain requires Ifnar1 deficiency in the haematopoietic compartment. However, spread of ZIKV within the central nervous system is supported by Ifnar1-deficient non-haematopoietic cells. Within this context, ZIKV infection of astrocytes results in breakdown of the blood-brain barrier and a large influx of CD8+ effector T cells. We also find that antiviral activity of CD8+ T cells within the brain markedly limits ZIKV infection of neurons, but, as a consequence, instigates ZIKV-associated paralysis. Taken together, our study uncovers mechanisms underlying ZIKV neuropathogenesis within a susceptible mouse model and suggests blood-brain barrier breakdown and T-cell-mediated neuropathology as potential underpinnings of ZIKV-associated neurological complications in humans.

Leiomyosarcoma of the infratemporal fossa with perineurial spread along the right mandibular nerve: a case report.

Leiomyosarcomas are malignant tumors displaying strong smooth muscle differentiation. They can often develop within the GI tract and myometrium, but are particularly rare in the head and neck. Perineurial spread of head and neck cancer is observed in patients with neoplasms of the skin (squamous cell carcinoma, melanoma) or skin appendages (adenoid cystic carcinoma). We report the case of a woman who presented with diplopia and headaches. MRI showed an infratemporal mass lesion and faint enhancement tracking along the mandibular nerve into the wall of the right cavernous sinus. A nerve biopsy revealed leiomyosarcoma. We review the medical literature to provide further insight into the diagnosis and management of this tumor and its peculiar pattern of spread. A similar case was unidentifiable in the literature.

Ectopic intracranial germinoma.

Intracranial ectopic germinomas are often associated with synchronous midline disease. Germinomas involving the corpus callosum are exceedingly rare. The reported imaging appearance is not as varied as one might expect and a review of the literature reveals a few common imaging features amongst most ectopic lesions, including cyst formation. We report a 24-year-old man with panhypopituitarism. Neuroimaging revealed three enhancing lesions involving the pituitary infundibulum, the pineal region, and a parenchymal lesion involving the genu of the corpus callosum. The described ectopic mass, a parenchymal lesion, was associated with small peripheral cysts. Stereotactic biopsy and histopathological evaluation revealed this mass to be a germinoma. Following chemotherapy and radiation therapy, there was near-total resolution of the intracranial disease. Preoperative imaging plays an important role, not only in delineating the extent of disease, but also in assisting in generating an appropriate differential diagnosis. Germinomas in the corpus callosum are exceedingly rare but should be considered in the differential of any young patient with a characteristic cystic and solid intra-axial mass.

Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis.

BACKGROUND: Malignant high-grade gliomas (HGGs), including the most aggressive form, glioblastoma multiforme, show significant clinical and genomic heterogeneity. Despite recent advances, the overall survival of HGGs and their response to treatment remain poor. In order to gain further insight into disease pathophysiology by correlating genomic landscape with clinical behavior, thereby identifying distinct HGG molecular subgroups associated with improved prognosis, we performed a comprehensive genomic analysis. METHODS: We analyzed and compared 720 exome-sequenced gliomas (136 from Yale, 584 from The Cancer Genome Atlas) based on their genomic, histological, and clinical features. RESULTS: We identified a subgroup of HGGs (6 total, 4 adults and 2 children) that harbored a statistically significantly increased number of somatic mutations (mean = 9257.3 vs 76.2, P = .002). All of these "ultramutated" tumors harbored somatic mutations in the exonuclease domain of the polymerase epsilon gene (POLE), displaying a distinctive genetic profile, characterized by genomic stability and increased C-to-A transversions. Histologically, they all harbored multinucleated giant or bizarre cells, some with predominant infiltrating immune cells. One adult and both pediatric patients carried homozygous germline mutations in the mutS homolog 6 (MSH6) gene. In adults, POLE mutations were observed in patients younger than 40 years and were associated with a longer progression-free survival. CONCLUSIONS: We identified a genomically, histologically, and clinically distinct subgroup of HGGs that harbored somatic POLE mutations and carried an improved prognosis. Identification of distinctive molecular and pathological HGG phenotypes has implications not only for improved classification but also for potential targeted treatments.