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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.

Aim: Atypical teratoid rhabdoid tumor (ATRT) is a rare and highly aggressive primary CNS neoplasm, predominantly observed in children. The use of autologous stem cell transplantation (ASCT) in pediatric ATRT has shown promise; however, its utility in adult ATRT remains unclear. Patients & methods: This study presents the case of an adult patient with ATRT who is in remission after ASCT and reviews the literature on ASCT in adults with ATRT. Four cases of ATRT in adults who underwent ASCT were identified, with pertinent data summarized. Results: All five patients survived longer than the historical average survival rate, four of whom had no clinical or radiographic evidence of disease at the final follow-up. Conclusion: Based on limited data, there may be a role for ASCT in the treatment of adults with ATRT.

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 (CDKN2Ahigh) 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 CDKN2Ahigh 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.

Glioblastoma (GBM) poses a significant challenge in oncology and stands as the most aggressive form of brain cancer. A primary contributor to its relentless nature is the stem‐like cancer cells, called glioblastoma stem cells (GSCs). GSCs have the capacity for self‐renewal and tumorigenesis, leading to frequent GBM recurrences and complicating treatment modalities. While natural killer (NK) cells exhibit potential in targeting and eliminating stem‐like cancer cells, their efficacy within the GBM microenvironment is limited due to constrained infiltration and function. To address this limitation, novel investigations focusing on boosting NK cell activity against GSCs are imperative. This study presents two streamlined image‐based assays assessing NK cell migration and cytotoxicity towards GSCs. It details protocols and explores the strengths and limitations of these methods. These assays could aid in identifying novel targets to enhance NK cell activity towards GSCs, facilitating the development of NK cell‐based immunotherapy for improved GBM treatment.

IntroductionMeningioma is the most common primary intracranial tumour in adults. The majority are non-malignant, but a proportion behave more aggressively. Incidental/minimally symptomatic meningioma are often managed by serial imaging. Symptomatic meningioma, those that threaten neurovascular structures, or demonstrate radiological growth, are usually resected as first-line management strategy. For patients in poor clinical condition, or with inoperable, residual or recurrent disease, radiotherapy is often used as primary or adjuvant treatment. Effective pharmacotherapy treatments do not currently exist. There is heterogeneity in the outcomes measured and reported in meningioma clinical studies. Two 'Core Outcome Sets' (COS) will be developed: (COSMIC: Intervention) for use in meningioma clinical effectiveness trials and (COSMIC: Observation) for use in clinical studies of incidental/untreated meningioma.Methods and analysisTwo systematic literature reviews and trial registry searches will identify outcomes measured and reported in published and ongoing (1) meningioma clinical effectiveness trials, and (2) clinical studies of incidental/untreated meningioma. Outcomes include those that are clinician reported, patient reported, caregiver reported and based on objective tests (eg, neurocognitive tests), as well as measures of progression and survival. Outcomes will be deduplicated and categorised to generate two long lists. The two long lists will be prioritised through two, two-round, international, modified eDelphi surveys including patients with meningioma, healthcare professionals, researchers and those in caring/supporting roles. The two final COS will be ratified through two 1-day online consensus meetings, with representation from all stakeholder groups.Ethics and disseminationInstitutional review board (University of Liverpool) approval was obtained for the conduct of this study. Participant eConsent will be obtained prior to participation in the eDelphi surveys and consensus meetings. The two systematic literature reviews and two final COS will be published and freely available.Trial registration numberCOMET study ID 1508.

Summary: Stereotactic radiosurgery (SRS) has been shown to be efficacious for the treatment of limited brain metastasis (BM); however, the effects of SRS on human brain metastases have yet to be studied. We performed genomic analysis on resected brain metastases from patients whose resected lesion was previously treated with SRS. Our analyses demonstrated for the first time that patients possess a distinct genomic signature based on type of treatment failure including local failure, leptomeningeal spread, and radio-necrosis. Examination of the center and peripheral edge of the tumors treated with SRS indicated differential DNA damage distribution and an enrichment for tumor suppressor mutations and DNA damage repair pathways along the peripheral edge. Furthermore, the two clinical modalities used to deliver SRS, LINAC and GK, demonstrated differential effects on the tumor landscape even between controlled primary sites. Our study provides, in human, biological evidence of differential effects of SRS across BM’s.

Intratumoral heterogeneity (ITH) complicates the diagnosis and treatment of glioma, partly due to the diverse metabolic profiles driven by underlying genomic alterations. While multiparametric imaging enhances the characterization of ITH by capturing both spatial and functional variations, it falls short in directly assessing the metabolic activities that underpin these phenotypic differences. This gap stems from the challenge of integrating easily accessible, colocated pathology and detailed genomic data with metabolic insights. This study presents a multifaceted approach combining stereotactic biopsy with standard clinical open-craniotomy for sample collection, voxel-wise analysis of MR images, regression-based GAM, and whole-exome sequencing. This work aims to demonstrate the potential of machine learning algorithms to predict variations in cellular and molecular tumor characteristics. This retrospective study enrolled ten treatment-naïve patients with radiologically confirmed glioma. Each patient underwent a multiparametric MR scan (T1W, T1W-CE, T2W, T2W-FLAIR, DWI) prior to surgery. During standard craniotomy, at least 1 stereotactic biopsy was collected from each patient, with screenshots of the sample locations saved for spatial registration to pre-surgical MR data. Whole-exome sequencing was performed on flash-frozen tumor samples, prioritizing the signatures of five glioma-related genes: IDH1, TP53, EGFR, PIK3CA, and NF1. Regression was implemented with a GAM using a univariate shape function for each predictor. Standard receiver operating characteristic (ROC) analyses were used to evaluate detection, with AUC (area under curve) calculated for each gene target and MR contrast combination. Mean AUC for five gene targets and 31 MR contrast combinations was 0.75 ± 0.11; individual AUCs were as high as 0.96 for both IDH1 and TP53 with T2W-FLAIR and ADC, and 0.99 for EGFR with T2W and ADC. These results suggest the possibility of predicting exome-wide mutation events from noninvasive, in vivo imaging by combining stereotactic localization of glioma samples and a semi-parametric deep learning method. The genomic alterations identified, particularly in IDH1, TP53, EGFR, PIK3CA, and NF1, are known to play pivotal roles in metabolic pathways driving glioma heterogeneity. Our methodology, therefore, indirectly sheds light on the metabolic landscape of glioma through the lens of these critical genomic markers, suggesting a complex interplay between tumor genomics and metabolism. This approach holds potential for refining targeted therapy by better addressing the genomic heterogeneity of glioma tumors.

Summary: TIGIT is a receptor on human natural killer (NK) cells. Here, we report that TIGIT does not spontaneously induce inhibition of NK cells in glioblastoma (GBM), but rather acts as a decoy-like receptor, by usurping binding partners and regulating expression of NK activating ligands and receptors. Our data show that in GBM patients, one of the underpinnings of unresponsiveness to TIGIT blockade is that by targeting TIGIT, NK cells do not lose an inhibitory signal, but gains the potential for new interactions with other, shared, TIGIT ligands. Therefore, TIGIT does not define NK cell dysfunction in GBM. Further, in GBM, TIGIT+ NK cells are hyperfunctional. In addition, we discovered that 4-1BB correlates with TIGIT expression, the agonism of which contributes to TIGIT immunotherapy. Overall, our data suggest that in GBM, TIGIT acts as a regulator of a complex network, and provide new clues about its use as an immunotherapeutic target.

Background: Craniovertebral junction (CVJ) schwannomas are rare, with surgery and stereotactic radiosurgery (SRS) being effective yet challenging options. We systematically reviewed the literature on CVJ schwannomas. Methods: PubMed, Scopus, Web-of-Science, and Cochrane were searched following the PRISMA statement to include studies reporting CVJ schwannomas. Clinical features, management, and outcomes were analyzed. Results: We collected 353 patients from 101 included articles. Presenting symptoms were mostly neck pain (30.3%) and headache (26.3%), with most cranial neuropathies involving the XII (31.2%) and X (24.4%) nerves. Most tumors originated from C2 (30.9%) and XII (29.4%) nerves, being extracranial (45.1%) and intradural-extradural (44.2%). Erosion of C1–C2 vertebrae (37.1%), the hypoglossal canal (28.3%), and/or jugular foramen (20.1%) were noted. All tumors were operated, preferably with the retrosigmoid approach (36.5%), with the far-lateral approach (29.7%) or with the posterior approach and cervical laminectomy (26.9%), far-lateral approaches (14.2%), or suboccipital craniotomy with concurrent cervical laminectomy (14.2%). Complete tumor resection was obtained most frequently (61.5%). Adjuvant post-surgery stereotactic radiosurgery was delivered in 5.9% patients. Median follow-up was 27 months (range, 12–252). Symptom improvement was noted in 88.1% of cases, and cranial neuropathies showed improvement in 10.2%. Post-surgical complications occurred in 83 patients (23.5%), mostly dysphagia (7.4%), new cranial neuropathies (6.2%), and cerebrospinal fluid leak (5.9%). A total of 16 patients (4.5%) had tumor recurrence and 7 died (2%), with median overall survival of 2.7 months (range, 0.1–252). Conclusions: Microsurgical resection is safe and effective for CVJ schwannomas. Data on SRS efficacy and indications are still lacking, and its role deserves further evaluation.

Abstract Background After internal carotid artery (ICA) injury during endoscopic skull base surgery, the majority of patients undergo ICA embolization or stenting to treat active extravasation or pseudoaneurysm development. However, management practices when embolization or stenting is not required have not been well described. The objective of this study was to determine how patients with ICA injury but no embolization, stenting, or ligation do long‐term and ascertain the reconstruction methods utilized. Methods Twenty‐nine cases of ICA injury were identified in an international multi‐institutional retrospective review. Of these, we identified six cases that were not treated with embolization, stenting, or ICA sacrifice. Information was available for five cases. Results A muscle patch was used in the immediate repair of each case. A nasoseptal flap was used in one case. Prefabricated nasal tampons were used in all cases. Nasal packing was initially left in for a median of 7 days prior to removal. The initial muscle patch was reinforced with a second muscle graft in one case. One case demonstrated ICA bleeding at the time of packing removal and was repacked an additional week. Follow‐up for each of these cases was at least 2 years. No cases of subsequent carotid rupture were found and none of these cases ultimately underwent endovascular stenting. Radiation or proton therapy has not been subsequently used in any of these patients. Conclusions This study details the reconstruction, lessons learned, and long‐term follow‐up for five cases of ICA injury not treated with embolization, stenting, or ligation.

Background Stereotactic radiosurgery (SRS) following surgical resection is the standard of care for patients with symptomatic oligo brain metastasis (BM), however, it is associated with 10–15% local failure. Targeting a resection cavity is imprecise, thus preoperative radiosurgery where the target is well-defined may be superior, however, the efficacy of preoperative SRS has not yet been tested in a clinical trial. Methods We conducted a phase 2, single-arm trial of preoperative SRS followed by surgical resection in patients with 1–4 symptomatic oligo BMs (NCT03398694) with the primary objective of measuring 6-month local control (LC). SRS was delivered to all patients utilizing a gamma knife or linear accelerator as per RTOG-9005 dosing criteria [Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys. 2000;47(2):291–298] based on tumor diameter with the exception that the largest lesion diameter treated was 5 cm with 15 Gy with all SRS treatment given in single fraction dosing. Results The trial screened 50 patients, 48 patients were treated under the protocol and 32 patients completed the entire follow-up period. Of all the patients who completed the follow-up period, the primary endpoint of 6-month LC was 100% (95% CI: 0.891–1.000; P  = .005). Secondary endpoints, presented as medians, were overall survival (17.6 months), progression-free survival (5.3 months), distant in-brain failure (40.8% at 1 year), leptomeningeal failure (4.8% at 1 year), and radiation necrosis (7.7% at 1 year). Conclusions Our data confirms superior local control in patients who received preoperative SRS when compared to historical controls. Further study with a larger randomized cohort of patients is warranted to fully understand the benefits of preoperative SRS. [ABSTRACT FROM AUTHOR]