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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.)

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.)

Homozygous deletion of CDKN2A/B was recently incorporated into the World Health Organization classification for grade 3 meningiomas. While this marker is overall rare in meningiomas, its relationship to other CDKN2A alterations on a transcriptomic, epigenomic, and copy number level has not yet been determined. We therefore utilized multidimensional molecular data of 1577 meningioma samples from 6 independent cohorts enriched for clinically aggressive meningiomas to comprehensively interrogate the spectrum of CDKN2A alterations through DNA methylation, copy number variation, transcriptomics, and proteomics using an integrated molecular approach. Homozygous CDKN2A/B deletions were identified in only 7.1% of cases but were associated with significantly poorer outcomes compared to tumors without these deletions. Heterozygous CDKN2A/B deletions were identified in 2.6% of cases and had similarly poor outcomes as those with homozygous deletions. Among tumors with intact CDKN2A/B (without a homozygous or heterozygous deletion), we found a distinct difference in outcome based on mRNA expression of CDKN2A, with meningiomas that had elevated mRNA expression (CDKN2A high ) having a significantly shorter time to recurrence. The expression of CDKN2A was independently prognostic after accounting for copy number loss and consistently increased with WHO grade and more aggressive molecular and methylation groups irrespective of cohort. Despite the discordant and mutually exclusive status of the CDKN2A gene in these groups, both CDKN2A high meningiomas and meningiomas with CDKN2A deletions were enriched for similar cell cycle pathways but at different checkpoints. High mRNA expression of CDKN2A was also associated with gene hypermethylation, Rb-deficiency, and lack of response to CDK inhibition. p16 immunohistochemistry could not reliably differentiate between meningiomas with and without CDKN2A deletions but appeared to correlate better with mRNA expression. These findings support the role of CDKN2A mRNA expression as a biomarker of clinically aggressive meningiomas with potential therapeutic implications., (© 2023. The Author(s).)

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406)., (© 2023. The Author(s).)

There is considerable variability in the management of diffuse low-grade gliomas (LGGs). To characterize treatment paradigms, a survey of Canadian neurosurgeons was performed with forty neurosurgeons responding. Their responses show that the management of patients with LGGs has evolved in the past decade and findings from the RTOG9802 trial have been integrated into the practice of Canadian neurosurgeons. Most respondents stated that the patient selection and treatment strategy advocated by the RTOG9802 trial needs further evaluation. Overall, there is a trend toward more aggressive surgical resections, and future investigations will have to more accurately stratify patient risk profiles.

Background : Our group previously developed an upper extremity repositioning (Sup-ER) protocol for brachial plexus birth injuries (BPBIs) that may improve supination and external rotation (ER) at 2 years of age. Questions were raised about the potential for the protocol to cause internal rotation (IR) deficits. The goal of this study was to explore the longer-term outcomes of the Sup-ER protocol and investigate IR/ER function. Methods : This prospective cross-sectional cohort study examined 16 children older than 4 years of age with significant enough BPBI to be treated with the Sup-ER protocol. Total shoulder and elbow function were assessed, including passive and active ranges of motion and strength of IR and ER. Results : Range of motion (ROM) for most active movements was decreased in the affected compared to unaffected arm. Notably, IR passive ROM was similar in the affected (78.7°) and unaffected arm (82.8°). External rotation strength of the affected arm was weaker (42.8 N) compared to the unaffected arm (57.9 N). IR strength had a greater deficit in the affected (43.2 N) arm compared to the unaffected arm (72.2 N), but both ER and IR showed less deficit than described in the literature. Conclusions : Despite differences in ranges of motion between the affected and unaffected arms, ROMs for the affected arm were comparable to the functional limits as reported in the literature. The Sup-ER protocol shows potential to optimize long-term shoulder rotation function in children with BPBI without compromising IR.

Purpose: This study aims to compare the prevalence and outcomes of surgically correctable congenital anomalies between sexes., Methods: Upon registration on PROSPERO (CRD42019120165), a librarian aided in conducting a systematic review using PRISMA guidelines. The five largest relevant studies were included for each anomaly. Cumulative prevalence differences and confidence intervals were calculated, and the Cochran-Mantel-Haenszel test was performed., Results: Of 42,722 identified studies, 68 were included in our analysis. All included anomalies had greater than 1000 patients except duodenal atresia (n = 787) and intestinal duplication (n = 148). Males had a significantly higher prevalence than females in 10/14 anomalies (Hirschsprung's disease, omphalomesenteric duct, congenital diaphragmatic hernia, anorectal malformation, malrotation, esophageal atresia, congenital pulmonary airway malformation, intestinal atresia, omphalocele, and gastroschisis; p < 0.001). There was no difference in the prevalence of duodenal atresia or intestinal duplication between sexes (p = 0.88 and 0.65, respectively). Females had a significantly higher prevalence of biliary anomalies (atresia and choledochal cyst)., Conclusion: Our study indicates that males have higher prevalence rates of most congenital anomalies. Further investigations are required to illuminate the embryology underlying this sex distribution and whether sex influences outcomes., Type of Study: Systematic review and meta-analysis., Level of Evidence: Prognostic study, level II., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD), the amyloid β (Aβ) peptide deposits along the vascular lumen, leading to degeneration and dysfunction of surrounding tissues. Activated coagulation factor XIIIa (FXIIIa) covalently cross-links proteins in blood and vasculature, such as in blood clots and on the extracellular matrix. Although FXIIIa co-localizes with Aβ in CAA, the ability of FXIIIa to cross-link Aβ has not been demonstrated. Using Western blotting, kinetic assays, and microfluidic analyses, we show that FXIIIa covalently cross-links Aβ40 into dimers and oligomers ( k cat / K m = 1.5 × 10 5 m -1 s -1 ), as well as to fibrin, platelet proteins, and blood clots under flow in vitro Aβ40 also increased the stiffness of platelet-rich plasma clots in the presence of FXIIIa. These results suggest that FXIIIa-mediated cross-linking may contribute to the formation of Aβ deposits in CAA and Alzheimer's disease., (© 2019 Hur et al.)