Optimizing Surgical Outcomes for Intracranial Epidermoid Tumors: A Retrospective Analysis of Clinical Predictors, Surgical Decisions, and Patient Clustering.

INTRODUCTION: Intracranial epidermoid tumors (ETs) are rare, benign lesions that present significant challenges in neurosurgical management due to their propensity to encase vital neurovascular structures. OBJECTIVE: To evaluate the impact of clinical, demographic, and tumor-specific factors on surgical decisions (gross total resection [GTR] vs. subtotal resection [STR]) and outcomes and identify patient clusters with distinct profiles and outcomes post-resection. METHODS: We retrospectively analyzed 72 epidermoid brain tumor patients treated from 1998 to 2022, employing multivariable logistic regression for GTR vs. STR predictors and Kaplan-Meier curves for progression-free survival (PFS). K-prototype clustering classified patients based on clinical data. RESULTS: The mean age of our cohort was 39.8±20.1 years. 13.9% of patients had a recurrence, with a median PFS of 108 months (IQR 57-206). Seizures significantly predicted GTR (p<0.05), whereas adherence to critical structures reduced GTR likelihood (p<0.05). Initial surgeries more often achieved GTR, correlating with longer PFS (p<0.0001) and reduced recurrence (p<0.01). History of previous ET surgery was predictive of increased recurrent tumor size (p<0.05) and reduced overall PFS (p<0.05). Clustering analysis revealed three clusters with significant differences in recurrence rates (p<0.0001), long term neurological deficits (p<0.05), PFS greater than 10 years (p<0.0001), and significant differences in median PFS between clusters 1 and 3 (p<0.0001) as well as 2 and three (p<0.01). CONCLUSION: This study emphasizes the importance of tailored surgical strategies in managing intracranial ETs, advocating for GTR to optimize long-term outcomes where possible. Future prospective studies are essential to further refine treatment approaches, enhancing survival for ET patients.

Alzheimer's disease CSF biomarkers correlate with early pathology and alterations in neuronal and glial gene expression.

INTRODUCTION: Normal pressure hydrocephalus (NPH) patients undergoing cortical shunting frequently show early AD pathology on cortical biopsy, which is predictive of progression to clinical AD. The objective of this study was to use samples from this cohort to identify CSF biomarkers for AD-related CNS pathophysiologic changes using tissue and fluids with early pathology, free of post-mortem artifact. METHODS: We analyzed Simoa, proteomic, and metabolomic CSF data from 81 patients with previously documented pathologic and transcriptomic changes. RESULTS: AD pathology on biopsy correlates with CSF ß-amyloid-40/42, neurofilament light chain (NfL), and phospho-tau-181(p-tau181)/ß-amyloid-42, while several gene expression modules correlate with NfL. Proteomic analysis highlights 7 core proteins that correlate with pathology and gene expression changes on biopsy, and metabolomic analysis of CSF identifies disease-relevant groups that correlate with biopsy data.. DISCUSSION: As additional biomarkers are added to AD diagnostic panels, our work provides insight into the CNS pathophysiology these markers are tracking.

CHD2 Regulates Neuron-glioma Interactions in Pediatric Glioma.

High-grade gliomas (HGG) are deadly diseases for both adult and pediatric patients. Recently, it has been shown that neuronal activity promotes progression of multiple subgroups of HGG. However, epigenetic mechanisms that govern this process remain elusive. Here we report that the chromatin remodeler CHD2 regulates neuron-glioma interactions in diffuse midline glioma (DMG) characterized by onco-histone H3.1K27M. Depletion of CHD2 in H3.1K27M DMG cells compromises cell viability and neuron-to-glioma synaptic connections in vitro, neuron-induced proliferation of H3.1K27M DMG cells in vitro and in vivo, activity-dependent calcium transients in vivo, and extends the survival of H3.1K27M DMG-bearing mice. Mechanistically, CHD2 coordinates with the transcription factor FOSL1 to control the expression of axon-guidance and synaptic genes in H3.1K27M DMG cells. Together, our study reveals a mechanism whereby CHD2 controls the intrinsic gene program of the H3.1K27M DMG subtype, which in turn regulates the tumor growth-promoting interactions of glioma cells with neurons.

Use of Recommended Neurodiagnostic Evaluation Among Patients With Drug-Resistant Epilepsy.

Importance: Interdisciplinary practice parameters recommend that patients with drug-resistant epilepsy (DRE) undergo comprehensive neurodiagnostic evaluation, including presurgical assessment. Reporting from specialized centers suggests long delays to referral and underuse of surgery; however, longitudinal data are limited to characterize neurodiagnostic evaluation among patients with DRE in more diverse US settings and populations. Objective: To examine the rate and factors associated with neurodiagnostic studies and comprehensive evaluation among patients with DRE within 3 US cohorts. Design, Setting, and Participants: A retrospective cross-sectional study was conducted using the Observational Medical Outcomes Partnership Common Data Model including US multistate Medicaid data, commercial claims data, and Columbia University Medical Center (CUMC) electronic health record data. Patients meeting a validated computable phenotype algorithm for DRE between January 1, 2015, and April 1, 2020, were included. No eligible participants were excluded. Exposure: Demographic and clinical variables were queried. Main Outcomes and Measures: The proportion of patients receiving a composite proxy for comprehensive neurodiagnostic evaluation, including (1) magnetic resonance or other advanced brain imaging, (2) video electroencephalography, and (3) neuropsychological evaluation within 2 years of meeting the inclusion criteria. Results: A total of 33 542 patients with DRE were included in the Medicaid cohort, 22 496 in the commercial insurance cohort, and 2741 in the CUMC database. A total of 31 516 patients (53.6%) were women. The proportion of patients meeting the comprehensive evaluation main outcome in the Medicaid cohort was 4.5% (n = 1520); in the commercial insurance cohort, 8.0% (n = 1796); and in the CUMC cohort, 14.3% (n = 393). Video electroencephalography (24.9% Medicaid, 28.4% commercial, 63.2% CUMC) and magnetic resonance imaging of the brain (35.6% Medicaid, 43.4% commercial, 52.6% CUMC) were performed more regularly than neuropsychological evaluation (13.0% Medicaid, 16.6% commercial, 19.2% CUMC) or advanced imaging (3.2% Medicaid, 5.4% commercial, 13.1% CUMC). Factors independently associated with greater odds of evaluation across all 3 data sets included the number of inpatient and outpatient nonemergency epilepsy visits and focal rather than generalized epilepsy. Conclusions and Relevance: The findings of this study suggest there is a gap in the use of diagnostic studies to evaluate patients with DRE. Care setting, insurance type, frequency of nonemergency visits, and epilepsy type are all associated with evaluation. A common data model can be used to measure adherence with best practices across a variety of observational data sources.

Awake intraoperative mapping for the prevention of amusia.

The authors describe the awake surgical mapping of music skills for patients who require resection in brain areas that may support musical abilities. A 65-year-old man was diagnosed with an anterolateral right temporal nonenhancing lesion, likely a diffusely infiltrating glioma, after presenting with several episodes of altered taste and smell and one episode of loss of consciousness. The patient specializes in music and music technology and has composed scores for films. An awake surgery was planned in a semiseated position. Prerecorded melodies were designed preoperatively as a surrogate for a composition skill task. These consisted of 10- to 15-second musical clips played during bipolar electrical stimulation of the overlying cortex and were divided into three segments: listen, play, and accuracy check. During the "listen" phase, the patient listened to a musical prompt. During the "play" phase, he played a musical response on a keyboard. Stimulation at multiple temporal neocortical sites was negative for any alteration in task performance. The patient did well postoperatively with excellent clinical and radiographic results and returned to composing music without functional compromise. Musical composition tasks can be performed safely intraoperatively for patients with musical expertise. Whether stimulating more posterior nondominant temporal neocortex or other cortical or white matter locations can disrupt this task remains undetermined.

Glioma-Induced Alterations in Excitatory Neurons are Reversed by mTOR Inhibition.

Gliomas are highly aggressive brain tumors characterized by poor prognosis and composed of diffusely infiltrating tumor cells that intermingle with non-neoplastic cells in the tumor microenvironment, including neurons. Neurons are increasingly appreciated as important reactive components of the glioma microenvironment, due to their role in causing hallmark glioma symptoms, such as cognitive deficits and seizures, as well as their potential ability to drive glioma progression. Separately, mTOR signaling has been shown to have pleiotropic effects in the brain tumor microenvironment, including regulation of neuronal hyperexcitability. However, the local cellular-level effects of mTOR inhibition on glioma-induced neuronal alterations are not well understood. Here we employed neuron-specific profiling of ribosome-bound mRNA via 'RiboTag,' morphometric analysis of dendritic spines, and in vivo calcium imaging, along with pharmacological mTOR inhibition to investigate the impact of glioma burden and mTOR inhibition on these neuronal alterations. The RiboTag analysis of tumor-associated excitatory neurons showed a downregulation of transcripts encoding excitatory and inhibitory postsynaptic proteins and dendritic spine development, and an upregulation of transcripts encoding cytoskeletal proteins involved in dendritic spine turnover. Light and electron microscopy of tumor-associated excitatory neurons demonstrated marked decreases in dendritic spine density. In vivo two-photon calcium imaging in tumor-associated excitatory neurons revealed progressive alterations in neuronal activity, both at the population and single-neuron level, throughout tumor growth. This in vivo calcium imaging also revealed altered stimulus-evoked somatic calcium events, with changes in event rate, size, and temporal alignment to stimulus, which was most pronounced in neurons with high-tumor burden. A single acute dose of AZD8055, a combined mTORC1/2 inhibitor, reversed the glioma-induced alterations on the excitatory neurons, including the alterations in ribosome-bound transcripts, dendritic spine density, and stimulus evoked responses seen by calcium imaging. These results point to mTOR-driven pathological plasticity in neurons at the infiltrative margin of glioma - manifested by alterations in ribosome-bound mRNA, dendritic spine density, and stimulus-evoked neuronal activity. Collectively, our work identifies the pathological changes that tumor-associated excitatory neurons experience as both hyperlocal and reversible under the influence of mTOR inhibition, providing a foundation for developing therapies targeting neuronal signaling in glioma.

Brain tumor-related epilepsy management: A Society for Neuro-oncology (SNO) consensus review on current management.

Tumor-related epilepsy (TRE) is a frequent and major consequence of brain tumors. Management of TRE is required throughout the course of disease and a deep understanding of diagnosis and treatment is key to improving quality of life. Gross total resection is favored from both an oncologic and epilepsy perspective. Shared mechanisms of tumor growth and epilepsy exist, and emerging data will provide better targeted therapy options. Initial treatment with antiseizure medications (ASM) in conjunction with surgery and/or chemoradiotherapy is typical. The first choice of ASM is critical to optimize seizure control and tolerability considering the effects of the tumor itself. These agents carry a potential for drug-drug interactions and therefore knowledge of mechanisms of action and interactions is needed. A review of adverse effects is necessary to guide ASM adjustments and decision-making. This review highlights the essential aspects of diagnosis and treatment of TRE with ASMs, surgery, chemotherapy, and radiotherapy while indicating areas of uncertainty. Future studies should consider the use of a standardized method of seizure tracking and incorporating seizure outcomes as a primary endpoint of tumor treatment trials.

MGMT Promoter Methylation Predicts Overall Survival after Chemotherapy for 1p/19q-Codeleted Gliomas.

PURPOSE: While MGMT promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy and guides treatment decisions in glioblastoma, its role in grade 2 and 3 glioma remains unclear. Recent data suggest that mMGMT is prognostic of progression-free survival in 1p/19q-codeleted oligodendrogliomas, but an effect on overall survival (OS) has not been demonstrated. EXPERIMENTAL DESIGN: We identified patients with newly diagnosed 1p/19q-codeleted gliomas and known MGMT promoter status in the National Cancer Database from 2010 to 2019. Multivariable Cox proportional hazards regression modeling was used to assess the effect of mMGMT on OS after adjusting for age, sex, race, comorbidity, grade, extent of resection, chemotherapy, and radiotherapy. RESULTS: We identified 1,297 eligible patients, 938 (72.3%) of whom received chemotherapy in their initial course of treatment. The MGMT promoter was methylated in 1,009 (77.8%) patients. Unmethylated MGMT (uMGMT) was associated with worse survival compared with mMGMT [70% {95% confidence interval (CI), 64%-77%} vs. 81% (95% CI, 78%-85%); P < 0.001; adjusted HR (aHR), 2.35 (95% CI, 1.77-3.14)]. uMGMT was associated with worse survival in patients who received chemotherapy [63% (95% CI, 55-73%) vs. 80% (95% CI, 76%-84%); P < 0.001; aHR, 2.61 (95% CI, 1.89-3.60)] but not in patients who did not receive chemotherapy [P = 0.38; HR, 1.31 (95% CI, 0.71-2.42)]. Similar results were observed regardless of World Health Organization grade and after single- or multiagent chemotherapy. CONCLUSIONS: Our study demonstrates an association between mMGMT and OS in 1p/19q-codeleted gliomas. MGMT promoter status should be considered as a stratification factor in future clinical trials of 1p/19q-codeleted gliomas that use OS as an endpoint.

Long-term outcomes of mesial temporal laser interstitial thermal therapy for drug-resistant epilepsy and subsequent surgery for seizure recurrence: a multi-centre cohort study.

BACKGROUND: Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive alternative to surgical resection for drug-resistant mesial temporal lobe epilepsy (mTLE). Reported rates of seizure freedom are variable and long-term durability is largely unproven. Anterior temporal lobectomy (ATL) remains an option for patients with MRgLITT treatment failure. However, the safety and efficacy of this staged strategy is unknown. METHODS: This multicentre, retrospective cohort study included 268 patients consecutively treated with mesial temporal MRgLITT at 11 centres between 2012 and 2018. Seizure outcomes and complications of MRgLITT and any subsequent surgery are reported. Predictive value of preoperative variables for seizure outcome was assessed. RESULTS: Engel I seizure freedom was achieved in 55.8% (149/267) at 1 year, 52.5% (126/240) at 2 years and 49.3% (132/268) at the last follow-up ≥1 year (median 47 months). Engel I or II outcomes were achieved in 74.2% (198/267) at 1 year, 75.0% (180/240) at 2 years and 66.0% (177/268) at the last follow-up. Preoperative focal to bilateral tonic-clonic seizures were independently associated with seizure recurrence. Among patients with seizure recurrence, 14/21 (66.7%) became seizure-free after subsequent ATL and 5/10 (50%) after repeat MRgLITT at last follow-up≥1 year. CONCLUSIONS: MRgLITT is a viable treatment with durable outcomes for patients with drug-resistant mTLE evaluated at a comprehensive epilepsy centre. Although seizure freedom rates were lower than reported with ATL, this series represents the early experience of each centre and a heterogeneous cohort. ATL remains a safe and effective treatment for well-selected patients who fail MRgLITT.

Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states.

Glioblastoma (GBM) diffusely infiltrates the brain and intermingles with non-neoplastic brain cells, including astrocytes, neurons and microglia/myeloid cells. This complex mixture of cell types forms the biological context for therapeutic response and tumor recurrence. We used single-nucleus RNA sequencing and spatial transcriptomics to determine the cellular composition and transcriptional states in primary and recurrent glioma and identified three compositional 'tissue-states' defined by cohabitation patterns between specific subpopulations of neoplastic and non-neoplastic brain cells. These tissue-states correlated with radiographic, histopathologic, and prognostic features and were enriched in distinct metabolic pathways. Fatty acid biosynthesis was enriched in the tissue-state defined by the cohabitation of astrocyte-like/mesenchymal glioma cells, reactive astrocytes, and macrophages, and was associated with recurrent GBM and shorter survival. Treating acute slices of GBM with a fatty acid synthesis inhibitor depleted the transcriptional signature of this pernicious tissue-state. These findings point to therapies that target interdependencies in the GBM microenvironment.

Association of MGMT Promoter Methylation With Survival in Low-grade and Anaplastic Gliomas After Alkylating Chemotherapy.

Importance: O6-methylguanine-DNA methyltransferase (MGMT [OMIM 156569]) promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy for glioblastomas and is routinely used to guide treatment decisions. However, the utility of MGMT promoter status for low-grade and anaplastic gliomas remains unclear due to molecular heterogeneity and the lack of sufficiently large data sets. Objective: To evaluate the association of mMGMT for low-grade and anaplastic gliomas with chemotherapy response. Design, Setting, and Participants: This cohort study aggregated grade II and III primary glioma data from 3 prospective cohort studies with patient data collected from August 13, 1995, to August 3, 2022, comprising 411 patients: MSK-IMPACT, EORTC (European Organization of Research and Treatment of Cancer) 26951, and Columbia University. Statistical analysis was performed from April 2022 to January 2023. Exposure: MGMT promoter methylation status. Main Outcomes and Measures: Multivariable Cox proportional hazards regression modeling was used to assess the association of mMGMT status with progression-free survival (PFS) and overall survival (OS) after adjusting for age, sex, molecular class, grade, chemotherapy, and radiotherapy. Subgroups were stratified by treatment status and World Health Organization 2016 molecular classification. Results: A total of 411 patients (mean [SD] age, 44.1 [14.5] years; 283 men [58%]) met the inclusion criteria, 288 of whom received alkylating chemotherapy. MGMT promoter methylation was observed in 42% of isocitrate dehydrogenase (IDH)-wild-type gliomas (56 of 135), 53% of IDH-mutant and non-codeleted gliomas (79 of 149), and 74% of IDH-mutant and 1p/19q-codeleted gliomas (94 of 127). Among patients who received chemotherapy, mMGMT was associated with improved PFS (median, 68 months [95% CI, 54-132 months] vs 30 months [95% CI, 15-54 months]; log-rank P < .001; adjusted hazard ratio [aHR] for unmethylated MGMT, 1.95 [95% CI, 1.39-2.75]; P < .001) and OS (median, 137 months [95% CI, 104 months to not reached] vs 61 months [95% CI, 47-97 months]; log-rank P < .001; aHR, 1.65 [95% CI, 1.11-2.46]; P = .01). After adjusting for clinical factors, MGMT promoter status was associated with chemotherapy response in IDH-wild-type gliomas (aHR for PFS, 2.15 [95% CI, 1.26-3.66]; P = .005; aHR for OS, 1.69 [95% CI, 0.98-2.91]; P = .06) and IDH-mutant and codeleted gliomas (aHR for PFS, 2.99 [95% CI, 1.44-6.21]; P = .003; aHR for OS, 4.21 [95% CI, 1.25-14.2]; P = .02), but not IDH-mutant and non-codeleted gliomas (aHR for PFS, 1.19 [95% CI, 0.67-2.12]; P = .56; aHR for OS, 1.07 [95% CI, 0.54-2.12]; P = .85). Among patients who did not receive chemotherapy, mMGMT status was not associated with PFS or OS. Conclusions and Relevance: This study suggests that mMGMT is associated with response to alkylating chemotherapy for low-grade and anaplastic gliomas and may be considered as a stratification factor in future clinical trials of patients with IDH-wild-type and IDH-mutant and codeleted tumors.

A Transcriptome-Based Precision Oncology Platform for Patient-Therapy Alignment in a Diverse Set of Treatment-Resistant Malignancies.

Predicting in vivo response to antineoplastics remains an elusive challenge. We performed a first-of-kind evaluation of two transcriptome-based precision cancer medicine methodologies to predict tumor sensitivity to a comprehensive repertoire of clinically relevant oncology drugs, whose mechanism of action we experimentally assessed in cognate cell lines. We enrolled patients with histologically distinct, poor-prognosis malignancies who had progressed on multiple therapies, and developed low-passage, patient-derived xenograft models that were used to validate 35 patient-specific drug predictions. Both OncoTarget, which identifies high-affinity inhibitors of individual master regulator (MR) proteins, and OncoTreat, which identifies drugs that invert the transcriptional activity of hyperconnected MR modules, produced highly significant 30-day disease control rates (68% and 91%, respectively). Moreover, of 18 OncoTreat-predicted drugs, 15 induced the predicted MR-module activity inversion in vivo. Predicted drugs significantly outperformed antineoplastic drugs selected as unpredicted controls, suggesting these methods may substantively complement existing precision cancer medicine approaches, as also illustrated by a case study. SIGNIFICANCE: Complementary precision cancer medicine paradigms are needed to broaden the clinical benefit realized through genetic profiling and immunotherapy. In this first-in-class application, we introduce two transcriptome-based tumor-agnostic systems biology tools to predict drug response in vivo. OncoTarget and OncoTreat are scalable for the design of basket and umbrella clinical trials. This article is highlighted in the In This Issue feature, p. 1275.

Seizure onset patterns predict outcome after stereo-electroencephalography-guided laser amygdalohippocampotomy.

OBJECTIVE: Stereotactic laser amygdalohippocampotomy (SLAH) is an appealing option for patients with temporal lobe epilepsy, who often require intracranial monitoring to confirm mesial temporal seizure onset. However, given limited spatial sampling, it is possible that stereotactic electroencephalography (stereo-EEG) may miss seizure onset elsewhere. We hypothesized that stereo-EEG seizure onset patterns (SOPs) may differentiate between primary onset and secondary spread and predict postoperative seizure control. In this study, we characterized the 2-year outcomes of patients who underwent single-fiber SLAH after stereo-EEG and evaluated whether stereo-EEG SOPs predict postoperative seizure freedom. METHODS: This retrospective five-center study included patients with or without mesial temporal sclerosis (MTS) who underwent stereo-EEG followed by single-fiber SLAH between August 2014 and January 2022. Patients with causative hippocampal lesions apart from MTS or for whom the SLAH was considered palliative were excluded. An SOP catalogue was developed based on literature review. The dominant pattern for each patient was used for survival analysis. The primary outcome was 2-year Engel I classification or recurrent seizures before then, stratified by SOP category. RESULTS: Fifty-eight patients were included, with a mean follow-up duration of 39 ± 12 months after SLAH. Overall 1-, 2-, and 3-year Engel I seizure freedom probability was 54%, 36%, and 33%, respectively. Patients with SOPs, including low-voltage fast activity or low-frequency repetitive spiking, had a 46% 2-year seizure freedom probability, compared to 0% for patients with alpha or theta frequency repetitive spiking or theta or delta frequency rhythmic slowing (log-rank test, p = .00015). SIGNIFICANCE: Patients who underwent SLAH after stereo-EEG had a low probability of seizure freedom at 2 years, but SOPs successfully predicted seizure recurrence in a subset of patients. This study provides proof of concept that SOPs distinguish between hippocampal seizure onset and spread and supports using SOPs to improve selection of SLAH candidates.

Risk Stratification for Management of Solitary Fibrous Tumor/Hemangiopericytoma of the Central Nervous System.

INTRODUCTION: Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) of the central nervous system (CNS) is a rare meningeal tumor. Given the absence of prospective or randomized data, there are no standard indications for radiotherapy. Recently, the NRG Oncology and EORTC cooperative groups successfully accrued and completed the first prospective trials evaluating risk-adapted adjuvant radiotherapy strategies for meningiomas. Using a similar framework, we sought to develop prognostic risk categories that may predict the survival benefit associated with radiotherapy, using two large national datasets. METHODS: We queried the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) databases for all newly diagnosed cases of SFT/HPC within the CNS. Risk categories were created, as follows: low risk-grade 1, with any extent of resection (EOR) and grade 2, with gross-total resection; intermediate risk-grade 2, with biopsy/subtotal resection; high risk-grade 3 with any EOR. The Kaplan-Meier method and Cox proportional hazards regressions were used to determine the association of risk categories with overall and cause-specific survival. We then determined the association of radiotherapy with overall survival in the NCDB, stratified by risk group. RESULTS: We identified 866 and 683 patients from the NCDB and SEER databases who were evaluated, respectively. In the NCDB, the 75% survival times for low- (n = 312), intermediate- (n = 239), and high-risk (n = 315) patients were not reached, 86 months (HR 1.60 (95% CI 1.01-2.55)), and 55 months (HR 2.56 (95% CI 1.68-3.89)), respectively. Our risk categories were validated for overall and cause-specific survival in the SEER dataset. Radiotherapy was associated with improved survival in the high- (HR 0.46 (0.29-0.74)) and intermediate-risk groups (HR 0.52 (0.27-0.99)) but not in the low-risk group (HR 1.26 (0.60-2.65)). The association of radiotherapy with overall survival remained significant in the multivariable analysis for the high-risk group (HR 0.55 (0.34-0.89)) but not for the intermediate-risk group (HR 0.74 (0.38-1.47)). Similar results were observed in a time-dependent landmark sensitivity analysis. CONCLUSION: Risk stratification based on grade and EOR is prognostic of overall and cause-specific survival for SFT/HPCs of the CNS and performs better than any individual clinical factor. These risk categories appear to predict the survival benefit from radiotherapy, which is limited to the high-risk group and, potentially, the intermediate-risk group. These data may serve as the basis for a prospective study evaluating the management of meningeal SFT/HPCs.

Synaptic hyperexcitability of cytomegalic pyramidal neurons contributes to epileptogenesis in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a developmental disorder associated with epilepsy, autism, and cognitive impairment. Despite inactivating mutations in the TSC1 or TSC2 genes and hyperactive mechanistic target of rapamycin (mTOR) signaling, the mechanisms underlying TSC-associated neurological symptoms remain incompletely understood. Here we generate a Tsc1 conditional knockout (CKO) mouse model in which Tsc1 inactivation in late embryonic radial glia causes social and cognitive impairment and spontaneous seizures. Tsc1 depletion occurs in a subset of layer 2/3 cortical pyramidal neurons, leading to development of cytomegalic pyramidal neurons (CPNs) that mimic dysplastic neurons in human TSC, featuring abnormal dendritic and axonal overgrowth, enhanced glutamatergic synaptic transmission, and increased susceptibility to seizure-like activities. We provide evidence that enhanced synaptic excitation in CPNs contributes to cortical hyperexcitability and epileptogenesis. In contrast, astrocytic regulation of synapse formation and synaptic transmission remains unchanged after late embryonic radial glial Tsc1 inactivation, and astrogliosis evolves secondary to seizures.

Single unit analysis and wide-field imaging reveal alterations in excitatory and inhibitory neurons in glioma.

While several studies have attributed the development of tumour-associated seizures to an excitatory-inhibitory imbalance, we have yet to resolve the spatiotemporal interplay between different types of neuron in glioma-infiltrated cortex. Herein, we combined methods for single unit analysis of microelectrode array recordings with wide-field optical mapping of Thy1-GCaMP pyramidal cells in an ex vivo acute slice model of diffusely infiltrating glioma. This enabled simultaneous tracking of individual neurons from both excitatory and inhibitory populations throughout seizure-like events. Moreover, our approach allowed for observation of how the crosstalk between these neurons varied spatially, as we recorded across an extended region of glioma-infiltrated cortex. In tumour-bearing slices, we observed marked alterations in single units classified as putative fast-spiking interneurons, including reduced firing, activity concentrated within excitatory bursts and deficits in local inhibition. These results were correlated with increases in overall excitability. Mechanistic perturbation of this system with the mTOR inhibitor AZD8055 revealed increased firing of putative fast-spiking interneurons and restoration of local inhibition, with concomitant decreases in overall excitability. Altogether, our findings suggest that diffusely infiltrating glioma affect the interplay between excitatory and inhibitory neuronal populations in a reversible manner, highlighting a prominent role for functional mechanisms linked to mTOR activation.

Somatic variants in diverse genes leads to a spectrum of focal cortical malformations.

Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signalling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n = 16), focal cortical dysplasia type I and related phenotypes (n = 48), focal cortical dysplasia type II (n = 44), or focal cortical dysplasia type III (n = 15). We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1 and NIPBL, genes previously associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that focal cortical dysplasia types I, II and III are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.