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Matthew E Eagles,1 Farshad Nassiri,2,3 Jetan H Badhiwala,2 Suganth Suppiah,2 Saleh A Almenawer,4 Gelareh Zadeh,3,5 Kenneth D Aldape3,6 1Section of Neurosurgery, Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada; 2Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada; 3MacFeeters-Hamilton Neuro-Oncology Program, University Health Network, Toronto, ON, Canada; 4Division of Neurosurgery, Department of Surgery, McMaster University, Hamilton, ON, Canada; 5Division of Neurosurgery, University Health Network, Toronto, ON, Canada; 6Division of Pathology, University Health Network, Toronto, ON, Canada Abstract: Glioblastoma (GBM) is the most common and fatal primary adult brain tumor. To date, various promising chemotherapeutic regimens have been trialed for use in GBM; however, temozolomide (TMZ) therapy remains the only US Food and Drug Administration-approved first-line chemotherapeutic option for newly diagnosed GBM. Despite maximal therapy with surgery and combined concurrent chemoradiation and adjuvant TMZ therapy, the median overall survival remains approximately 14 months. Given the failure of conventional chemotherapeutic strategies in GBM, there has been renewed interest in the role of immunotherapy in GBM. Dendritic cells are immune antigen-presenting cells that play a role in both the innate and adaptive immune system, thereby making them prime vehicles for immunotherapy via dendritic cell vaccinations (DCVs) in various cancers. There is great enthusiasm surrounding the use of DCVs for GBM with multiple ongoing trials. In this review, we comprehensively summarize the safety, efficacy, and quality of life results from 33 trials reporting on DCV for high-grade gliomas. Keywords: glioma, vaccine, dendritic cells, glioblastoma

In order to evaluate the effectiveness of the Iranian made charcoal tubes in the field , 60 local made and 60 imported ones (SKC type) were randomly selected and placed side by side for sampling aromatic hydrocarbons (including Benzene, Toluene, Xylene) in workers breathing zone in a paint factory. The results indicated that there were no statistically significant differences between the mean concentrations of aromatic hydrocarbons measured in studied groups. The ratios of pressure drop to flow rate of Iranian made tubes were statistically higher than the SKC ones (P

Background: Our group and others have recently identified four molecular groups of meningioma, with unique underlying biology and outcomes. The relevance of group-specific metabolite profiles (particularly among hypermetabolic tumours), has not been explored., Methods: We performed untargeted metabolic profiling of meningiomas representing each molecular group and WHO grade. Prognostic biochemicals were identified using Cox regression and their biological importance was explored using RNA and protein-based pathway analyses. Validation was performed using targeted high performance liquid chromatography-mass spectrometry (HPLC-MS/MS)., Results: Global metabolic profiling identified 560 unique biochemicals. We identified a 21-metabolite outcome signatures which is strongly predictive of outcome after adjusting for WHO grade, extent of resection, and receipt of adjuvant radiotherapy (HR 326.49, 95%CI 16.72-6375.48, p < 0.0001). The abundance of N6-trimethyllysine was associated with earlier time to recurrence on our whole cohort (log-rank p = 0.009) and within hypermetabolic and WHO grade 2 tumours specifically; this was validated using targeted HPLC-MS/MS on two cohorts. Consensus RNA and protein expression analysis demonstrated as association between N6-trimethyllysine abundance and activation of oxidative phosphorylation pathways, which portended worse outcomes in the hypermetabolic subgroup but, interestingly, better outcomes in the proliferative subgroup. By contrast, upregulated pyruvate and lactate transporters were associated with worse outcomes in proliferative meningiomas specifically., Conclusions: This is the first study to demonstrate a subgroup-specific prognostic role of N6-trimethyllysine in hypermetabolic meningiomas, offering increasingly granular outcome predictions using a widely accessible technique (HPLC-MS/MS). We also suggest fundamental differences in preferred energy utilization between and a potential need for subgroup-specific therapies., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Meningiomas exhibit considerable clinical and biological heterogeneity. We previously identified four distinct molecular groups (immunogenic, NF2-wildtype, hypermetabolic, proliferative) that address much of this heterogeneity. Despite the utility of these groups, the stochasticity of clustering methods and the use of multi-omics data for discovery limits the potential for classifying prospective cases. We sought to address this with a dedicated classifier., Methods: Using an international cohort of 1698 meningiomas, we constructed and rigorously validated a machine learning-based molecular classifier using only DNA methylation data as input. Original and newly-predicted molecular groups were compared using DNA methylation, RNA sequencing, copy number profiles, whole exome sequencing, and clinical outcomes., Results: We show that group-specific outcomes in the validation cohort are nearly identical to those originally described, with median PFS of 7.4 (4.9-Inf) years in hypermetabolic tumors and 2.5 (2.3-5.3) years in proliferative tumors (not reached in the other groups). Tumors classified as NF2-wildtype had no NF2 mutations, and 51.4% had canonical mutations previously described in this group. RNA pathway analysis revealed upregulation of immune-related pathways in the immunogenic group, metabolic pathways in the hypermetabolic group and cell-cycle programs in the proliferative group. Bulk deconvolution similarly revealed enrichment of macrophages in immunogenic tumours and neoplastic cells in hypermetabolic and proliferative tumours with similar proportions to those originally described., Conclusions: Our DNA methylation-based classifier, which is publicly available for immediate clinical use, recapitulates the biology and outcomes of the original molecular groups as assessed using multiple metrics/platforms that were not used in its training., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Brain metastases (BMs) are the most common and among the deadliest brain tumors. Currently, there are no reliable predictors of BM development from primary cancer, which limits early intervention. Lung adenocarcinoma (LUAD) is the most common BM source and here we obtained 402 tumor and plasma samples from a large cohort of patients with LUAD with or without BM (n = 346). LUAD DNA methylation signatures were evaluated to build and validate an accurate model predicting BM development from LUAD, which was integrated with clinical factors to provide comprehensive patient-specific BM risk probabilities in a nomogram. Additionally, immune and cell interaction gene sets were differentially methylated at promoters in BM versus paired primary LUAD and had aligning dysregulation in the proteome. Immune cells were differentially abundant in BM versus LUAD. Finally, liquid biomarkers identified from methylated cell-free DNA sequenced in plasma were used to generate and validate accurate classifiers for early BM detection. Overall, LUAD methylomes can be leveraged to predict and noninvasively identify BM, moving toward improved patient outcomes with personalized treatment., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: The last decade has seen major international research efforts focus on better understanding disease heterogeneity in meningioma. Multiple molecular platforms have generated significant biological and clinical utility, and there is a need to translate these findings into routine clinical practice. Here we review the role of DNA methylation profiling in meningioma and advocate for its widespread adoption., Methods: We review modern DNA methylation-based classification and outcome prediction tools in meningioma. Biological classifiers, which were constructed agnostic to outcome using unsupervised approaches, outcome predictors, and liquid biopsy models are discussed in detail., Results: DNA methylation has been used for biological classification and outcome in meningioma with considerable success. Several groups have proposed novel molecular classification systems which share similar features with one another and outperform WHO grade in their ability to predict outcome and explain subgroup-specific biological processes. In addition, recent studies have suggested a role for methylation-based liquid-biopsy in meningioma, which represents an exciting avenue for further exploration., Conclusions: DNA methylation profiling has been revolutionary in meningioma. There is a need for widespread adoption of these approaches to personalize care and inform clinical trial design., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: We previously developed a DNA methylation-based risk predictor for meningioma, which has been used locally in a prospective fashion since its original publication. As a follow-up, we validate this model using a large prospective cohort and introduce a streamlined next-generation predictor compatible with newer methylation arrays., Methods: Genome-wide methylation profiles were generated with the Illumina EPICArray. The performance of our next-generation predictor was compared with our original model and standard-of-care 2021 WHO grade using time-dependent receiver operating characteristic curves. An nomogram was generated by incorporating our methylation predictor with WHO grade and extent of resection., Results: A total of 1347 meningioma cases were utilized in the study, including 469 prospective cases from 3 institutions and an external cohort of 100 WHO grade 2 cases for model validation. Both the original and next-generation models significantly outperform 2021 WHO grade in predicting early postoperative recurrence. Dichotomizing patients into grade-specific risk subgroups was predictive of outcome within both WHO grades 1 and 2 tumours (p<0.05), while all WHO grade 3 tumours were considered high-risk. Multivariable Cox regression demonstrated benefit of adjuvant radiotherapy in high-risk cases specifically, reinforcing its informative role in clinical decision making. Finally, our next-generation predictor contains nearly 10-fold fewer features than the original model, allowing for targeted arrays., Conclusions: This next-generation DNA methylation-based meningioma outcome predictor significantly outperforms 2021 WHO grading in predicting time to recurrence. We make this available as a point-and-click tool which will improve prognostication, inform patient selection for RT, and allow for molecularly-stratified clinical trials., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Treatment of the tumor and dural margin with surgery and sometimes radiation are cornerstones of therapy for meningioma. Molecular classifications have provided insights into the biology of disease; however, response to treatment remains heterogeneous. In this study, we used retrospective data on 2,824 meningiomas, including molecular data on 1,686 tumors and 100 prospective meningiomas, from the RTOG-0539 phase 2 trial to define molecular biomarkers of treatment response. Using propensity score matching, we found that gross tumor resection was associated with longer progression-free survival (PFS) across all molecular groups and longer overall survival in proliferative meningiomas. Dural margin treatment (Simpson grade 1/2) prolonged PFS compared to no treatment (Simpson grade 3). Molecular group classification predicted response to radiotherapy, including in the RTOG-0539 cohort. We subsequently developed a molecular model to predict response to radiotherapy that discriminates outcome better than standard-of-care classification. This study highlights the potential for molecular profiling to refine surgical and radiotherapy decision-making., Competing Interests: Competing interests S.Y. is a member of advisory boards and has received honoraria from AstraZeneca, Amgen, Bayer, Janssen, Pfizer, Roche and Servier. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Introduction: Subdural haematomas (SDHs), acute or chronic, are common neurosurgical diagnoses. These problems can occur among patients requiring direct oral anticoagulation (DOAC) for atrial fibrillation. There are currently no guidelines regarding the optimal timing to resume anticoagulation for these patients after SDH. The objective of this study is to evaluate the feasibility of conducting a future large randomised controlled trial (RCT) evaluating the safety and efficacy of resuming DOACs early (ie, at 30 days) vs late (ie, at 3 months) for patients with atrial fibrillation following diagnosis of SDH., Methods and Analysis: This is a pilot, open-label, multicentre RCT that will enrol adults with newly diagnosed acute or chronic SDH with or without other intracranial bleeding who were receiving therapeutic anticoagulation with a DOAC as stroke prophylaxis for atrial fibrillation. Patients will be randomly allocated to resume a DOAC at standard dosing starting either days 30+7 or days 90±14. The primary outcomes for the pilot RCT are recruitment rate, protocol adherence and patient compliance with the randomly allocated interventions. Secondary outcomes are patient functional outcomes and safety and effectiveness outcomes, which will comprise key endpoints for the future planned RCT. This pilot RCT will provide important data to inform the feasibility of conducting a future, large RCT of early versus late resumption of DOACs for atrial fibrillation stroke prophylaxis in patients newly diagnosed with SDH. The future RCT will help inform management of a commonly encountered clinical dilemma with high associated morbidity and mortality., Ethics and Dissemination: This study has been approved by the research ethics board of record. It will be conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines and regulatory requirements. Informed consent will be obtained from eligible patients or substitute decision-makers. Data from this study will inform the design of future, larger RCTs., Trial Registration Number: NCT05472766., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Meningiomas are the most common primary intracranial tumors in adults and are increasing in incidence due to the aging population and increased access to neuroimaging. While most exhibit nonmalignant behavior, a subset of meningiomas are biologically aggressive and are associated with treatment resistance, resulting in significant neurologic morbidity and even mortality. In recent years, meaningful advances in our understanding of the biology of these tumors have led to the incorporation of molecular biomarkers into their grading and prognostication. However, unlike other central nervous system (CNS) tumors, a unified molecular taxonomy for meningiomas has not yet been established and remains an overarching goal of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official World Health Organization (cIMPACT-NOW) working group. Additionally, clinical equipoise still remains on how specific meningioma cases and patient populations should be optimally managed. To address these existing gaps, members of the International Consortium on Meningiomas including field-leading experts, have prepared this comprehensive consensus narrative review directed toward clinicians, researchers, and patients. Included in this manuscript are detailed overviews of proposed molecular classifications, novel biomarkers, contemporary treatment strategies, trials on systemic therapies, health-related quality-of-life studies, and management strategies for unique meningioma patient populations. In each section, we discuss the current state of knowledge as well as ongoing clinical and research challenges to road map future directions for further investigation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Spinal meningiomas comprise 25%-46% of all primary spinal tumors. While the majority are benign and slow-growing, when left untreated, they can result in significant neurological decline. Emerging clinical, imaging, and molecular data have begun to reveal spinal meningiomas as distinct tumor subtypes compared to their intracranial counterparts. Moreover, recent studies indicate molecular and genetic subtype heterogeneity of spinal meningiomas both within and across the classically defined WHO grades. In the current review, we focus on recent advances highlighting the epidemiological, pathological, molecular/genetic, and clinical characteristics of spinal meningiomas. Furthermore, we explore patient and tumor-specific factors that predict prognosis and postoperative outcomes. We highlight areas that require further investigation, specifically efforts aimed at linking unique molecular, genetic, and imaging characteristics to distinct clinical presentations to better predict and manage patient outcomes., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Meningiomas, although mostly benign, can be recurrent and fatal. World Health Organization (WHO) grading of the tumor does not always identify high-risk meningioma, and better characterizations of their aggressive biology are needed. To approach this problem, we combined 13 bulk RNA sequencing (RNA-seq) datasets to create a dimension-reduced reference landscape of 1,298 meningiomas. The clinical and genomic metadata effectively correlated with landscape regions, which led to the identification of meningioma subtypes with specific biological signatures. The time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape, where the nearest neighbors predict outcome. This study highlights the utility of combining bulk transcriptomic datasets to visualize the complexity of tumor populations. Further, we provide an interactive tool for understanding the disease and predicting patient outcomes. This resource is accessible via the online tool Oncoscape, where the scientific community can explore the meningioma landscape., Competing Interests: Declaration of interests Although the majority of Oncoscape is open source, a subset of the technology and computational algorithms presented in this paper are covered by serial no. 63/595,717, and N.N., S.A., M.J., and E.C.H. are listed as inventors., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Mutations in the pivotal metabolic isocitrate dehydrogenase (IDH) enzymes are recognized to drive the molecular footprint of diffuse gliomas, and patients with IDH mutant gliomas have overall favorable outcomes compared to patients with IDH wild-type tumors. However, survival still varies widely among patients with IDH mutated tumors. Here, we aimed to characterize molecular signatures that explain the range of IDH mutant gliomas. By integrating matched epigenome-wide methylome, transcriptome, and global metabolome data in 154 patients with gliomas, we identified a group of IDH mutant gliomas with globally altered metabolism that resembled IDH wild-type tumors. IDH-mutant gliomas with altered metabolism have significantly shorter overall survival from their IDH mutant counterparts that is not fully accounted for by recognized molecular prognostic markers of CDKN2A/B loss and glioma CpG Island Methylator Phenotype (GCIMP) status. IDH-mutant tumors with dysregulated metabolism harbored distinct epigenetic alterations that converged to drive proliferative and stem-like transcriptional profiles, providing a window to target novel dependencies in gliomas., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The foramen rotundum and anterior cavernous sinus have traditionally been accessed by transcranial approaches that are limited by the high density of critical neurovascular structures. The transmaxillary approach provides an entirely extradural route to the foramen rotundum and anterior cavernous sinus., Method: This patient with neurofibromatosis and facial pain with trigeminal schwannoma at the foramen rotundum was successfully treated by transmaxillary resection of the tumor. This approach allowed for a direct extradural access to the pathology, with bony decompression and tumor resection, avoiding transcranial routes., Conclusion: The transmaxillary approach provides a safe and entirely extradural corridor to access smaller localized skull base lesions at and surrounding the cavernous sinus., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)