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Meningiomas are the most common intracranial lesions and constitute one-third of diagnoses. Surgical resection is the gold-standard treatment option. In case of treatment failure, therapeutic options are limited. Bevacizumab is a vascular endothelial growth factor ligand-binding monoclonal antibody that prevents angiogenesis. This study aims to investigate the efficacy and feasibility of bevacizumab in meningiomas On December 30, 2023, a systematic search was conducted according to PRISMA guidelines using the PubMed, Scopus, Web of Science, and Embase databases. This study is conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart. Our study included 12 studies, comprising 243 individuals and 310 tumors. Most of the studies were retrospective (80%). Most of the patients were male (47.9%). The bevacizumab was mostly administered intravenously at 10 mg/kg every two weeks (77.8%). The mean progression-free survival (PFS) and overall survival (OS) were 19.1 ± 4.7 and 23.9 ± 8.4 months, respectively. The response rate was 0.33 (95%CI: 0.14-0.60). The PFS-6, PFS-12, and PFS-24 were 0.80 (95% CI: 0.64-0.89), 0.66 (95%CI: 0.46-0.82), and 25% (95%CI: 0.16-0.37), respectively. The OS-6, OS-12, and OS-24 were 0.89 (95% CI: 0.80-0.96), 0.86 (95%CI: 0.65-0.95), and 0.48 (95%CI: 0.16-0.82), respectively. The meta-regression identified the total number of individuals, number of tumors, gender, WHO II/III, and prior resection as a possible source of heterogeneity for outcomes. This study highlights the effectiveness of bevacizumab in meningiomas, especially in refractory, high-grade, or neurofibromatosis patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The study by Canisius et al. (2022) explores the expression of decitabine-targeted oncogenes (TRIM58, FAM84B, ELOVL2, DIO3) in meningiomas, aiming to evaluate decitabine's therapeutic potential for high-grade tumors. Using immunohistochemical staining and RT-PCR in over 100 patient samples, the authors found significant correlations between oncogene expression and tumor grade, with elevated ELOVL2 levels being linked to tumor recurrence. This work highlights the role of decitabine in modulating oncogene expression and suggests its potential in treating refractory meningiomas. Despite the robust methodology, limitations such as the small sample size and the lack of comprehensive molecular data were noted. Future research should incorporate larger sample sizes and advanced genomic techniques like RNA sequencing to better understand oncogenic mechanisms. The study emphasizes the need for further in situ analyses of decitabine's efficacy, setting the foundation for future neuro-oncological treatments., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: World Health Organization grade II/III meningiomas frequently recur despite maximal safe surgical resection and adjuvant radiation. Notoriously resistant to medical therapy, no well-established guidelines for pharmacologic treatment currently exist. In recent years, a small number of clinical trials have investigated immune checkpoint inhibitors (ICIs) for patients with recurrent grade II/III meningiomas. We reviewed the existing literature to 1) summarize the clinical responses that have been observed and 2) identify tumor genomic characteristics that may predict a better response to ICI therapy., Methods: PubMed was searched following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to include studies reporting clinical data for recurrent grade II or grade III meningiomas treated with ICIs. Clinical features, available tumor genomics, and outcomes were analyzed., Results: Four studies were included comprising 59 patients; 74.6% had World Health Organization grade II meningiomas and 25.4% had grade III meningiomas. Thirt-two patients (54%) received nivolumab, 26 (44%) received pembrolizumab, and 1 (2%) received an ICI not named. While tumor genomic data was not consistently reported across studies, favorable response was most associated with mismatch repair deficiency and high tumor mutational burden. Common adverse effects included liver/pancreas enzyme elevations (11.5%), fatigue (11.5%), and leukopenia/infection (9%)., Conclusions: Checkpoint inhibitors represent a promising investigational therapy for patients with recurrent grade II/III meningiomas. These drugs may be more efficacious for tumors with mismatch repair deficiency or high tumor mutational burden. Future investigations would benefit from research consortia with prospective enrollments of patients, descriptive characterization of tumor genomics, and standardized assessment of radiographic response., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: We previously reported that tumor 3D volume growth rate (3DVGR) classification could help in the assessment of drug activity in patients with meningioma using 3 main classes and a total of 5 subclasses: class 1: decrease; 2: stabilization or severe slowdown; 3: progression. The EORTC-BTG-1320 clinical trial was a randomized phase II trial evaluating the efficacy of trabectedin for recurrent WHO 2 or 3 meningioma. Our objective was to evaluate the discriminative value of 3DVGR classification in the EORTC-BTG-1320., Methods: All patients with at least 1 available MRI before trial inclusion were included. 3D volume was evaluated on consecutive MRI until progression. 2D imaging response was centrally assessed by MRI modified Macdonald criteria. Clinical benefit was defined as neurological or functional status improvement or steroid decrease or discontinuation., Results: Sixteen patients with a median age of 58.5 years were included. Best 3DVGR classes were: 1, 2A, 3A, and 3B in 2 (16.7%), 4 (33.3%), 2 (16.7%), and 4 (33.3%) patients, respectively. All patients with progression-free survival longer than 6 months had best 3DVGR class 1 or 2. 3DVGR classes 1 and 2 (combined) had a median overall survival of 34.7 months versus 7.2 months for class 3 (P = .061). All class 1 patients (2/2), 75% of class 2 patients (3/4), and only 10% of class 3 patients (1/10) had clinical benefit., Conclusions: Tumor 3DVGR classification may be helpful to identify early signals of treatment activity in meningioma clinical trials., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Meningiomas constitute the most common primary tumors of the central nervous system. Despite maximum treatment, grade 2/3 meningiomas are associated with a high risk of recurrence. Stereotactic radiosurgery is the treatment of choice as adjuvant treatment for grade 2/3 meningiomas. Currently, pharmacotherapies, including molecular targeted therapy for various growth factors, their receptors, and the associated pathways, have shown limited effectiveness for management of refractory or recurrent meningiomas. Therefore, novel systemic treatment approaches are urgently required in such cases. Recent advances in genetics and epigenetics and the identification of specific genetic alterations have led to new classifications of these tumors and the development of therapeutic targets. Identification of targeted gene mutations may lead to precision-based medicine. Other therapeutic approaches such as immune checkpoint inhibitors rarely elicit a significant response in meningiomas with a high tumor mutation burden. Combination therapies that affect these multiple targets are also considered adjuvant therapeutic options. Comprehensive/in-depth research is warranted to investigate the safety and efficacy of other treatment strategies, including chimeric antigen receptor T-cells, oncolytic virus immunotherapy, and gene therapy. In this article, we review the current evidence regarding the efficacy of systemic treatments available in the literature and discuss recent and ongoing trials for meningiomas.

Purpose: There are no effective medical therapies for patients with meningioma who progress beyond surgical and radiotherapeutic interventions. Somatostatin receptor type 2 (SSTR2) represents a promising treatment target in meningiomas. In this multicenter, single-arm phase II clinical study (NCT03971461), the SSTR2-targeting radiopharmaceutical 177Lu-DOTATATE is evaluated for its feasibility, safety, and therapeutic efficacy in these patients., Patients and Methods: Adult patients with progressive intracranial meningiomas received 177Lu-DOTATATE at a dose of 7.4 GBq (200 mCi) every eight weeks for four cycles. 68Ga-DOTATATE PET-MRI was performed before and six months after the start of the treatment. The primary endpoint was progression-free survival (PFS) at 6 months (PFS-6). Secondary endpoints were safety and tolerability, overall survival (OS) at 12 months (OS-12), median PFS, and median OS., Results: Fourteen patients (female = 11, male = 3) with progressive meningiomas (WHO 1 = 3, 2 = 10, 3 = 1) were enrolled. Median age was 63.1 (range 49.7-78) years. All patients previously underwent tumor resection and at least one course of radiation. Treatment with 177Lu-DOTATATE was well tolerated. Seven patients (50%) achieved PFS-6. Best radiographic response by modified Macdonald criteria was stable disease (SD) in all seven patients. A >25% reduction in 68Ga-DOTATATE uptake (PET) was observed in five meningiomas and two patients. In one lesion, this corresponded to >50% reduction in bidirectional tumor measurements (MRI)., Conclusions: Treatment with 177Lu-DOTATATE was well tolerated. The predefined PFS-6 threshold was met in this interim analysis, thereby allowing this multicenter clinical trial to continue enrollment. 68Ga-DOTATATE PET may be a useful imaging biomarker to assess therapeutic outcome in patients with meningioma., (©2023 American Association for Cancer Research.)

Meningioma is the most common central nervous system (CNS) tumor. In recent decades, several efforts have been made to eradicate this disease. Surgery and radiotherapy remain the standard treatment options for these tumors. Drug therapy comes to play its role when both surgery and radiotherapy fail to treat the tumor. This mostly happens when the tumors are close to vital brain structures and are nonbenign. Although a wide variety of chemotherapeutic drugs and molecular targeted drugs such as tyrosine kinase inhibitors, alkylating agents, endocrine drugs, interferon, and targeted molecular pathway inhibitors have been studied, the roles of numerous drugs remain unexplored. Recent interest is growing toward studying and engineering exosomes for the treatment of different types of cancer including meningioma. The latest studies have shown the involvement of exosomes in the theragnostic of various cancers such as the lung and pancreas in the form of biomarkers, drug delivery vehicles, and vaccines. Proper attention to this new emerging technology can be a boon in finding the consistent treatment of meningioma., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Drug repositioning (DR) is the process of identifying novel therapeutic potentials for already-approved drugs and discovering new therapies for untreated diseases. DR can play an important role in optimizing the pre-clinical process of developing novel drugs by saving time and cost compared with the process of de novo drug discovery. Although the number of publications related to DR has rapidly increased, most therapeutic approaches were reported for malignant tumors. Surgical resection represents the definitive treatment for benign tumors of the central nervous system (BTCNS). However, treatment options remain limited for surgery-, chemotherapy- and radiation-refractory BTCNS, as well as malignant tumors. Meningioma, pituitary neuroendocrine tumor (PitNET), and schwannoma are the most common BTCNS. The treatment strategy using DR may be applied for refractory BTCNS, such as Grade 2 meningiomas, neurofibromatosis type 2-related schwannomatosis, and PitNETs with cavernous sinus invasion. In the setting of BTCNS, stable disease can provide significant benefit to the patient. DR may provide a longer duration of survival without disease progression for patients with refractory BTCNS. This article reviews the utility of DR for refractory BTCNS.

Purpose: Effective chemotherapeutical agents for the treatment of meningiomas are still lacking. Previous in-vitro analyses revealed efficacy of decitabine (DCT), a DNA methyltransferase (DNMT) inhibitor established in the treatment of leukemia, in a yet undefined subgroup of meningiomas., Methods: Effects of DCT on proliferation and viability was analyzed in primary meningioma cells by immunofluorescence and MTT assays, and cases were classified as drug responders and non-responders. Molecular preconditions for efficacy were analyzed using immunofluorescence for Ki67, DNMT1, and five oncogenes (TRIM58, FAM84B, ELOVL2, MAL2, LMO3) previously found to be differentially methylated after DCT exposition, as well as by genome-wide DNA methylation analyses., Results: Efficacy of DCT (10µM) was found in eight (62%) of 13 meningioma cell lines 48 h after drug exposition (p < .05). DCT significantly reduced DNMT1 expression in all but two cell lines, and median ΔDNMT1 reduction 48 h after drug exposition was lower in DCT-resistant (-11.1%) than in DCT-sensitive (-50.5%, p = .030) cells. Rates of cell lines responsive to DCT exposition distinctly decreased to 25% after 72 h. No significant correlation of the patients´ age, sex, histological subtype, location of the paternal tumor, expression of Ki67, DNMT1 or the analyzed oncogenes with treatment response was found (p > .05, each). DCT efficacy was further independent of the methylation class and global DNA methylation of the paternal tumor., Conclusion: Early effects of DCT in meningiomas are strongly related with DNMT1 expression, while clinical, histological, and molecular predictors for efficacy are sparse. Kinetics of drug efficacy might indicate necessity of repeated exposition and encourage further analyses., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Meningiomas represent the most common primary neoplasms of the central nervous system (CNS). 20% present with atypical (WHO grade II) or malignant (grade III) meningiomas, which show aggressive biologic behavior and high recurrence. Although surgical resection and radiation therapy are the primary treatment options for these tumors, there is a subgroup of patients who do not respond well to or are poor candidates for these approaches, leading to the exploration of systemic therapies as an alternative., Areas Covered: The literature on different therapeutic groups of systemic drugs for recurrent meningiomas is reviewed, with a focus on the different molecular targets. Past and current ongoing clinical trials are also discussed., Expert Opinion: To date, there is no recognized treatment that has demonstrated a substantial increase in progression-free or overall survival rates. Nonetheless, therapies targeting anti-VEGF have exhibited more encouraging results in general. The examination of genomic and epigenomic traits of meningiomas, along with the integration of molecular markers into the latest WHO tumor grading system, has provided valuable insights. This has opened avenues for exploring numerous intracellular and extracellular pathways, as well as mutations, that have been targeted in ongoing clinical trials.

Background: The current literature on meningioma reveals a gap in knowledge regarding the impact of genetic factors on patient survival. Furthermore, there is a lack of data on the relationship between the perioperative use of corticosteroids and patient survival in meningioma patients. Our study aims to overcome these gaps by investigating the correlation between genetic factors and overall survival and the effect of postoperative corticosteroids and other clinical characteristics on patient outcomes in meningioma patients., Methods: A retrospective analysis of the medical records of 85 newly diagnosed meningioma patients treated from 2016 to 2017 with follow-up until December 2022 was performed., Results: NF2 mutations occurred in 60% of tumors, AKT1 mutations in 8.2%, and TRAF7 mutations in 3.6%. Most tumors in the parasagittal region had the NF2 mutation. On the other hand, almost all tumors in the sphenoid ridge area did not have the NF2 mutation. AKT-1-mutated meningiomas had more frequent peritumoral edema. Patients who received steroids perioperatively had worse overall survival (OS) than those without steroids (p = 0.034). Moreover, preoperative peri-meningioma edema also was associated with worse OS (p < 0.003). Contrarily, NF2 mutations did not influence survival., Conclusions: The combination of clinical, pathomorphological, and genetic data allows us to characterize the tumor better and assess its prognosis. Corticosteroids perioperatively and peri-meningioma edema were associated with shorter OS, according to our study. Glucocorticoids should be used judiciously for the shortest time required to achieve symptomatic relief., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Response Evaluation Criteria in Solid Tumors (RECIST)-based response rates are commonly used as efficacy endpoints in phase II clinical trials for solid tumors. However, no consensus has been reached concerning adequate efficacy endpoints for phase II clinical trials targeting meningioma. Irregularity of lesions after resection, and varying degrees of dysplasia and histologic subtypes make establishing an appropriate efficacy evaluation difficult., Methods: We analyzed primary efficacy endpoints (PEEs) and background factors from 48 trials retrieved from ClinicalTrials.gov ( https://clinicaltrials.gov/ ) using the search criteria "meningioma," "interventional," "phase II," and "study start 4/1/2001 to 3/31/2021." Primary purpose of the study was efficacy endpoint setting in overall population and three subgroups., Results: Among 45 PEEs set in the 39 trials included; 33 trials with single PEE, and six trials with double PEEs, 17/45 (38%) trials adopted progression-free survival (PFS) rate, 15/45 (33%) trials response rate (seven Macdonald criteria or modified, three RECIST, three volumetric estimation, one RANO criteria, one unknown), 10/45 (22%) PFS, 1/45 (2%) OS, and 2/45 (4%) other endpoints. Although 26 PEEs were time-to-event endpoints, 19 of the 26 PEEs were single-arm studies., Conclusions: Time-to-event efficacy endpoints were often compared to historical data, and two-dimensional evaluation is more suitable than one-dimensional one. Accumulation of prognostic data is essential to standardize time-to-event efficacy endpoints. Considering the difficulty of setting design for phase II clinical studies targeting meningioma, evaluation might be done with multiple efficacy endpoints., (© 2023. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Meningioma was the most primary intracranial tumor, but the molecular characteristics and the treatment of malignant meningioma were still unclear. Nine malignant progression-related genes based prognostic signatures were identified by transcriptome analysis between benign meningioma and malignant meningioma. The external dataset GEO136661 and quantitative Real-time Polymerase Chain Reaction were used to verify the prognostic factors. has-miR-3605-5p, hsa-miR-664b-5p, PNRC2, BTBD8, EXTL2, SLFN13, DGKD, NSD2, and BVES were closed with malignant progression. Moreover, Doxorubicin was identified by Connectivity Map website with the differential malignant progression-related genes. CCK-8 assay, Edu assay, wound healing assay, and trans-well experiment were used to reveal that Doxorubicin could inhibit proliferation, migration and invasion of IOMM-Lee Cells., (© 2023. The Author(s).)

Background: Meningioma is the most common primary intracranial tumor in adults. A subset of these tumors recur and invade the brain, even after surgery and radiation, resulting in significant disability. There is currently no standard-of-care chemotherapy for meningiomas. As genomic DNA methylation profiling can prognostically stratify these lesions, we sought to determine whether any existing chemotherapies might be effective against meningiomas with high-risk methylation profiles., Methods: A previously published dataset of meningioma methylation profiles was used to screen for clinically significant CpG methylation events and associated cellular pathways. Based on these results, patient-derived meningioma cell lines were used to test candidate drugs in vitro and in vivo, including efficacy in conjunction with radiotherapy., Results: We identified 981 genes for which methylation of mapped CpG sites was related to progression-free survival in meningiomas. Associated molecular pathways were cross-referenced with FDA-approved cancer drugs, which nominated Docetaxel as a promising candidate for further preclinical analyses. Docetaxel arrested growth in 17 meningioma cell sources, representing all tumor grades, with a clinically favorable IC50 values ranging from 0.3 nM to 10.7 mM. The inhibitory effects of this medication scaled with tumor doubling time, with maximal benefit in fast-growing lesions. The combination of Docetaxel and radiation therapy increased markers of apoptosis and double-stranded DNA breaks, and extended the survival of mice engrafted with meningioma cells relative to either modality alone., Conclusions: Global patterns of DNA methylation may be informative for the selection of chemotherapies against meningiomas, and existing drugs may enhance radiation sensitivity in high-risk cases., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: WHO grade II and III meningiomas are more invasive than grade I malignancies and determine patients' shorter overall survival. Their tendency to recur after treatment has represented an important therapeutic challenge because of the limited treatment strategies at recurrence. Angiogenesis and mechanistic target of rapamycin (mTOR) activation are two of the main features of higher grade meningiomas, determining invasiveness and tendency to relapse. While these options prove promising, available clinical data on mTOR inhibitors' efficacy are somewhat limited., Case Study: We report a case of a 25-year-old female patient diagnosed with a right parasagittal occipital anaplastic meningioma (grade III WHO) in 2013. The patient underwent multiple treatments and, in 2019, a further recurrence occurred. The patient reported an mTOR mutation, and it is for this reason that the MTB approved treatment with everolimus and bevacizumab. Therapy was administered in May 2019, and partial response and prolonged disease control was obtained in November 2021, when progression took place. The patient's death occurred in March 2022., Conclusions: This case report provides evidence on the efficacy of mTOR inhibitors as a treatment option in recurrent meningiomas. Furthermore, it highlights the importance of performing a molecular analysis as a preliminary step towards targeting the mTOR pathway., (© 2022. Fondazione Società Italiana di Neurologia.)

Purpose: Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas., Patients and Methods: Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy., Results: Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events., Conclusion: GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2 -mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

Purpose: To date, there are no systemic treatment options for patients with recurrent or refractory meningioma., Experimental Design: To identify effective drugs, we performed a large-scale drug screening using FDA-approved drugs on several meningioma cell lines. The impact of the top four compounds was assessed on cell viability, proliferation, colony formation, migration, and apoptosis. In addition, the antineoplastic effects of the selected drugs were validated in a heterotopic xenograft mouse model., Results: Analyses of the viability of meningioma cells treated with 119 antineoplastic FDA-approved drugs resulted in categorization into sensitive and resistant drug-response groups based on the mean IC50 values and peak serum concentrations (Cmax) in patients. Eighty drugs, including 15 alkylating agents, 14 antimetabolites, and 13 tyrosine kinase inhibitors, were classified as resistant (IC50 > Cmax). The sensitive drug-response group (n = 29, IC50 < Cmax) included RNA/protein synthesis inhibitors, proteasome inhibitors, topoisomerase, tyrosine-kinase, and partial histone deacetylase and microtubule inhibitors. The IC50 value of the four most effective compounds (carfilzomib, omacetaxine, ixabepilone, and romidepsin) ranged from 0.12 to 9.5 nmol/L. Most of them caused cell-cycle arrest in the G2-M-phase and induced apoptosis. Furthermore, all drugs except romidepsin significantly inhibited tumor growth in vivo. The strongest antineoplastic effect was observed for ixabepilone, which reduced tumor volume by 86%., Conclusions: In summary, a large-scale drug screening provides a comprehensive insight into the anti-meningioma activities of FDA-approved drugs, and identified carfilzomib, omacetaxine, ixabepilone, and romidepsin as novel potent antineoplastic agents for the treatment of aggressive meningiomas. The most pronounced effects were observed with ixabepilone mandating for further clinical investigation., (©2022 American Association for Cancer Research.)

Background: Patients with WHO grade III meningioma have a poor prognosis with a median survival of less than two years and a high risk of recurrence. However, traditional treatment options have failed to improve prognosis. Therefore, development of novel immunotherapy targets is urgently needed. CD47 acting as a "don't eat me" signal to macrophages can trigger tumor immune escape. However, the role of CD47 in malignant meningioma is not well understood., Methods: We collected 190 clinical meningioma samples and detected the expression of CD47 and immune infiltration in WHO grade I-III by immunohistochemistry, western blot, qPCR. We also examined the functional effects of anti-CD47 on cell proliferation, migration and invasion, macrophagemediated phagocytosis and tumorigenicity both in vitro and in vivo ., Results: We found that the expression of CD47 was increased in malignant meningioma along with a decreased number of T cells and an increase in CD68 + macrophages. Blocking CD47 with anti-CD47 antibody (B6H12) suppressed tumor cell growth, motility and promoted macrophage-mediated phagocytosis in IOMM-Lee cells in vitro . In vivo experiments showed that anti-CD47 antibody (B6H12 or MIAP301) significantly inhibited the tumor growth and this effect was partly blocked by the depletion of macrophages. Finally, p-ERK and EGFR showed higher expression in malignant meningioma with high expression of CD47, which was verified by western blot., Conclusion: Our results demonstrated that CD47 maybe involved in the meningioma progression and prognosis and offered a novel therapeutic option by targeting CD47 in malignant meningioma., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Meningiomas are associated with several gonadal steroid hormone-related risk factors and demonstrate a predominance in females. These associations led to investigations of the role that hormones may have on meningioma growth and development. While it is now accepted that most meningiomas express progesterone and somatostatin receptors, the conclusion for other receptors has been less definitive., Methods: We performed a review of what is known regarding the relationship between hormones and meningiomas in the published literature. Furthermore, we reviewed clinical trials related to hormonal agents in meningiomas using MEDLINE PubMed, Scopus, and the NIH clinical trials database., Results: We identify that all steroid-hormone trials lacked receptor identification or positive receptor status in the majority of patients. In contrast, four out of five studies involving somatostatin analogs used positive receptor status as part of the inclusion criteria., Conclusions: Several clinical trials have recently been completed or are now underway using somatostatin analogs in combination with other therapies that appear promising, but a reevaluation of hormone-based monotherapy is warranted. Synthesizing this evidence, we clarify the remaining questions and present future directions for the study of the biological role and therapeutic potential of hormones in meningioma and discuss how the stratification of patients using features such as grade, receptor status, and somatic mutations, might be used for future trials to select patients most likely to benefit from specific therapies., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Meningiomas are the most frequently diagnosed intracranial neoplasms. Usually, they are treated by surgical resection in curative intent. Radiotherapy and stereotactic radiosurgery are commonly applied in the adjuvant setting in newly diagnosed atypical (CNS WHO grade 2), and anaplastic (CNS WHO grade 3) meningioma, especially if gross total resection is not feasible, and in recurrent cases. Conversely, the evidence for pharmacotherapy in meningioma is scarce., Methods: The available literature of systemic treatment in meningioma was screened using PubMed, and ongoing clinical trials were explored using ClinicalTrials.gov., Results: Classical cytotoxic agents, somatostatin analogs, and antihormone treatments have shown only limited efficacy. In contrast, tyrosine kinase inhibitors and monoclonal antibodies, especially those targeting angiogenic signaling such as sunitinib and bevacizumab, have shown promising antitumoral activity in small phase 2 trials. Moreover, results of recent landmark studies on (epi-)genetic alterations in meningioma revealed potential therapeutic targets which are currently under investigation. These include inhibitors of mammalian target of rapamycin (mTOR), focal adhesion kinase (FAK), cyclin-dependent kinases (CDK), phosphoinositide-3-kinase (PI3K), sonic hedgehog signaling, and histone deacetylases. In addition, clinical trials evaluating immune checkpoint inhibitors such as ipilimumab, nivolumab, pembrolizumab and avelumab are currently being conducted and early results suggest clinically meaningful responses in a subset of patients., Conclusions: There is a paucity of high-level evidence on systemic treatment options in meningioma. However, interesting novel treatment targets have been identified in the last decade. Positive signals of anti-angiogenic agents, genomically targeted agents and immunotherapy in early phase trials should be confirmed in large prospective controlled trials., (© 2022. The Author(s).)

Meningiomas are the most common primary brain tumor in adults and have been historically managed with surgery and radiation therapy. However, in patients with inoperable, recurrent or high-grade tumors, medical therapy is often needed. Traditional chemotherapy and hormone therapy have been largely ineffective. However, with improved understanding of the molecular drivers in meningioma, there has been increasing interest in targeted molecular and immune therapies. In this chapter, we will discuss recent advances in meningioma genetics and biology and review current clinical trials with targeted molecular treatment and other novel therapies., (© 2023. Springer Nature Switzerland AG.)

Purpose: During intracranial meningioma surgery, surgeons experience considerable blood loss. Tranexamic acid (TXA) is used to minimize blood loss in several neurosurgical settings. However, evidence and trials are lacking. Our objective is to establish the most recent evidence on TXA safety and efficacy in intracranial meningioma surgery., Methodology: Based upon Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), the authors collected fully published English literature on the administration of tranexamic acid for patients undergoing intracranial meningioma surgery using the keywords ["tranexamic acid" and "meningioma"] and its synonyms from Cochrane Central Database, the WHO International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov, and PubMed. The primary outcome of the current study was total blood loss. The secondary outcomes include individuals requiring blood transfusion, anesthesia duration, surgical duration, and complication rate. Each included studies' quality was assessed using the JADAD scale., Results: For qualitative and quantitative data synthesis, we included five RCTs (n = 321) with the mean age was 47.5 ± 11.9 years for the intervention group and 47.2 ± 11.9 years for the control group. Our meta-analysis showed that the administration of TXA is associated with decreased total blood loss of standardized mean difference (SMD) of -1.40 (95% CI [-2.49, -0.31]), anesthetic time SMD -0.36 (95% CI [-0.63, -0.09]), and blood transfusion requirements RR 0.58 (95% CI [0.34, 0.99])., Conclusions: The current study showed that TXA was associated with reduced intraoperative blood loss and intra- and postoperative blood transfusion. However, the studies are small. More RCT studies with a greater sample size are favorable., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

As a type of central nervous system tumor, meningioma usually compresses the nerve center due to its local expansion, further causing neurological deficits. However, there are limited therapeutic approaches for meningiomas. ITF2357, a potent class I and II histone deacetylase inhibitor (HDACi), has been shown to inhibit cell proliferation, promote apoptosis, and block the cell cycle in various sarcoma cells, including glioblastoma and peripheral T-cell lymphoma. Here, we investigated the potential role of ITF2357 on meningioma cancer cells (IOMM-Lee cells). First, we demonstrated that the half-maximal inhibitory concentration (IC50) of ITF2357 was 1.842 μM by MTT assay. In addition, ITF2357 effectively inhibited the proliferation and colonization ability of IOMM-Lee cells. Flow cytometry analysis showed that ITF2357 induced G0/G1 and G2/M phase cell cycle arrest and cell apoptosis. Mechanically, the RNA sequencing data revealed that ITF2357 could affect the PI3K-Akt signaling pathway and the cell cycle progression. Furthermore, the expression levels of Akt, PI3K, p-Akt, and p-PI3K were determined by western blotting. Collectively, our data revealed that ITF2357 induces G0 G1 and G2/M phase arrest and apoptosis by inhibiting hyperactivation of the PI3K-Akt pathway, ultimately inhibiting cell viability and proliferation of meningioma cells, which developed a new approach to the treatment of meningioma., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Approximately 20% of meningiomas are not benign (higher grade) and tend to relapse after surgery and radiation therapy. Malignant (anaplastic) meningioma (MM) is a minor subset of high-grade meningioma that is lethal with no effective treatment options currently. Oncolytic herpes simplex virus (oHSV) is a powerful anti-cancer modality that induces both direct cell death and anti-tumor immunity, and has shown activity in preclinical models of MM. However, clinically meaningful efficacy will likely entail rational mechanistic combination approaches. We here show that epigenome modulator histone deacetylase inhibitors (HDACi) increase anti-cancer effects of oHSV in human MM models, IOMM-Lee (NF2 wild-type) and CH157 (NF2 mutant). Minimally toxic, sub-micromolar concentrations of pan-HDACi, Trichostatin A and Panobinostat, substantively increased the infectability and spread of oHSV G47Δ within MM cells in vitro, resulting in enhanced oHSV-mediated killing of target cells when infected at low multiplicity of infection (MOI). Transcriptomics analysis identified selective alteration of mRNA processing and splicing modules that might underlie the potent anti-MM effects of combining HDACi and oHSV. In vivo, HDACi treatment increased intratumoral oHSV replication and boosted the capacity of oHSV to control the growth of human MM xenografts. Thus, our work supports further translational development of the combination approach employing HDACi and oHSV for the treatment of MM., Competing Interests: Conflict of interest statement SDR and RLM are co-inventors on patents relating to oncolytic herpes simplex viruses, owned and managed by Georgetown University and Massachusetts General Hospital, which have received royalties from Amgen and ActiVec Inc. SDR acted as a consultant and received honoraria from Replimune, Cellinta, and Greenfire Bio, and honoraria and equity from EG 427. RLM. is on the S.A.B. and receives payment from Virogin Biotech Ltd., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Meningioma is the most common type of primary intracranial tumor with 0.1-1% of all primary meningiomas have been reported to develop into metastases. However, there is no proven therapeutic strategy for multiple metastases of meningiomas., Case Presentation: A 60-year-old female accepted total tumor resection of a right frontal lobe meningioma in September 2018, In October 2021, the patient was admitted to hospital because of cough and shortness of breath and diagnosed with metastatic meningiomas. The computed tomography (CT) scan revealed the presence of large masses in the right thoracic and abdominal cavity. After two cycles of anti-PD-1 and anti-VEGF treatment, the symptoms were relieved and the tumor was necrotic. Follow up to June 21, 2022, the patient has been given eleven cycles of the treatment every 3 weeks without tumor progression., Conclusions: This case showed combined anti-PD-1 and anti-VEGF treatment stimulates peripheral blood immune cells to kill metastatic meningioma cells. Whether combined immunotherapy is more effective for metastatic meningioma needs further exploration., (© 2022. The Author(s).)

Treatment-refractory meningiomas have a dismal prognosis and limited treatment options. Meningiomas express high-densities of somatostatin receptors (SSTR), thus potentially susceptible to antitumorigenic effects of somatostatin analogues (SSA). Evidence for SSA in meningiomas is scarce, and it is unclear if published literature would either (1) support wider use of SSA, if (2) more evidence is desirable, or if (3) available evidence is sufficient to discard SSA. We addressed the need for more evidence with a systematic review and meta-analysis. We performed an individual patient data (IPD) meta-analysis. Main outcomes were toxicity, best radiological response, progression-free survival, and overall survival. We applied multivariable logistic regression models to estimate the effect of SSA on the probability of obtaining radiological disease control. The predictive performance was evaluated using area under the curve and Brier scores. We included 16 studies and compiled IPD from 8/9 of all previous cohorts. Quality of evidence was overall ranked "very low." Stable disease was reported in 58% of patients as best radiological response. Per 100 mg increase in total SSA dosage, the odds ratios for obtaining radiological disease control was 1.42 (1.11 to 1.81, P = 0.005) and 1.44 (1.00 to 2.08, P = 0.05) for patients treated with SSA as monodrug therapy vs SSA in combination with everolimus, respectively. Low quality of evidence impeded exact quantification of treatment efficacy, and the association between response and treatment may represent reverse causality. Yet, the SSA treatment was well tolerated, and beneficial effect cannot be disqualified. A prospective trial without bias from inconsistent study designs is warranted to assess SSA therapy for well-defined meningioma subgroups., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Treatment of meningiomas refractory to surgery and irradiation is challenging and effective chemotherapies are still lacking. Recently, in vitro analyses revealed decitabine (DCT, 5-aza-2'-deoxycytidine) to be effective in high-grade meningiomas and, moreover, to induce hypomethylation of distinct oncogenes only sparsely described in meningiomas in vivo yet.Expression of the corresponding onco- and tumor suppressor genes TRIM58, FAM84B, ELOVL2, MAL2, LMO3, and DIO3 were analyzed and scored by immunohistochemical staining and RT-PCR in samples of 111 meningioma patients. Correlations with clinical and histological variables and prognosis were analyzed in uni- and multivariate analyses.All analyzed oncogenes were highly expressed in meningiomas. Expression scores of TRIM58 tended to be higher in benign than in high-grade tumors 20 vs 16 (p = .002) and all 9 samples lacking TRIM58 expression displayed WHO grade II/III histology. In contrast, median expression scores for both FAM84B (6 vs 4, p ≤ .001) and ELOVL2 (9 vs 6, p < .001) were increased in high-grade as compared to benign meningiomas. DIO3 expression was distinctly higher in all analyzed samples as compared to the reference decitabine-resistant Ben-Men 1 cell line. Increased ELOVL2 expression (score ≥ 8) correlated with tumor relapse in both uni- (HR: 2.42, 95%CI 1.18-4.94; p = .015) and multivariate (HR: 2.09, 95%CI 1.01-4.44; p = .046) analyses.All oncogenes involved in DCT efficacy in vitro are also widely expressed in vivo, and expression is partially associated with histology and prognosis. These results strongly encourage further analyses of DCT efficiency in meningiomas in vitro and in situ., (© 2022. The Author(s).)

Objective: Meningiomas are a common primary central nervous system tumor that lack a U.S. Food and Drug Administration-approved pharmacotherapy. Approximately 20%-35% of meningiomas are classified as higher grade with poor outcome, whereas patients with lower-grade meningiomas are known to have long-term neurologic deficits and reduced overall survival. Recent efforts to understand the epigenetic landscape of meningiomas have highlighted the importance of DNA methylation for predicting tumor outcomes and prognosis; therefore, inhibition of these pathways may present a viable therapy for these tumors., Methods: In this study, we perform dose-response curves of decitabine, a DNA methyltransferase inhibitor, on patient-cultured tumors and meningioma cell lines., Results: Thirty total samples were evaluated, including 24 patient-cultured tumors and 6 established meningioma cell lines. Meningiomas were found to have a significant reduction in cell viability after decitabine treatment in a dose dependent manner. The effect was primarily driven by 11 of the 30 tumors in our cohort, or 36.7%. Decitabine significantly reduced cell viability across all grades, tumors from different sexes, recurrent and primary tumors, as well as tumors without a history of previous radiation. Surprisingly, our single radiation-induced tumor did demonstrate greater viability after decitabine treatment., Conclusions: Our work has identified a potential drug candidate in decitabine for the treatment of meningiomas regardless of clinical subgroup. These data require further evaluation in preclinical models, and the conclusions based on clinical subgroups need to be evaluated in a larger cohort to achieve appropriate statistical power., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: No systemic treatment has been established for meningioma progressing after local therapies., Methods: This randomized, multicenter, open-label, phase II study included adult patients with recurrent WHO grade 2 or 3 meningioma. Patients were 2:1 randomly assigned to intravenous trabectedin (1.5 mg/m2 every 3 weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), objective radiological response, safety, quality of life (QoL) assessment using the QLQ-C30 and QLQ-BN20 questionnaires, and we performed tissue-based exploratory molecular analyses., Results: Ninety patients were randomized (n = 29 in LOC, n = 61 in trabectedin arm). With 71 events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] = 1.42; 80% CI, 1.00-2.03; P = .294) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) and 21.1% (95% CI, 11.3%-32.9%), respectively. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR = 0.98; 95% CI, 0.54-1.76; P = .94). Grade ≥3 adverse events occurred in 44.4% of patients in the LOC and 59% of patients in the trabectedin arm. Enrolled patients had impeded global QoL and overall functionality and high fatigue before initiation of systemic therapy. DNA methylation class, performance status, presence of a relevant co-morbidity, steroid use, and right hemisphere involvement at baseline were independently associated with OS., Conclusions: Trabectedin did not improve PFS and OS and was associated with higher toxicity than LOC treatment in patients with non-benign meningioma. Tumor DNA methylation class is an independent prognostic factor for OS., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: High-grade and recurrent meningiomas are often treatment resistant and pose a therapeutic challenge after surgical and radiation therapy (RT) failure. Temozolomide (TMZ) is a DNA alkylating agent that appears to have a radiosensitizing effect when used in combination with RT and may be worthwhile in meningioma treatment. Thus, we investigated the potential efficacy of concomitant RT plus TMZ compared to historical controls of just RT used in the treatment of high-grade and recurrent meningiomas., Methods: We performed a retrospective analysis of patients with meningioma treated at the University of Colorado with TMZ chemoradiation. Progression free survival (PFS) and overall survival (OS) were calculated from the start of chemoradiation to local recurrence or death, respectively., Results: Eleven patients (12 tumors) were treated with chemoradiation with a median follow-up of 41.5 months. There were two WHO grade 1, eight grade 2 and two grade 3 meningiomas. Three patients died during the follow-up period-one being disease related (11.1%). Two patients had meningioma recurrence-at 2.3 months (WHO grade 3), and 5.4 years (WHO grade 2). Three-year OS and PFS for grade 2 meningiomas were each 88%. Historical controls demonstrate a 3-year median OS and PFS of 83% and 75.8%, respectively., Conclusions: Treatment options are limited for meningiomas after local failure. In this study, TMZ chemoradiation demonstrated no significant difference in PFS and OS in the treatment of grade 2 meningiomas compared to historic controls. Further study is warranted to find novel methods for the treatment of malignant and recurrent meningiomas., (© 2022. The Author(s).)

High-grade meningiomas are associated with neuro-cognitive morbidity and have limited treatments. High-grade meningiomas harbor an immunosuppressive tumor microenvironment (TME) and programmed death-ligand 1 (PD-L1) expression may contribute to their aggressive phenotype. Here, we present the results of a single-arm, open-label phase 2 trial (NCT03279692) evaluating the efficacy of pembrolizumab, a PD-1 inhibitor, in a cohort of 25 evaluable patients with recurrent and progressive grade 2 and 3 meningiomas. The primary endpoint is the proportion of patients alive and progression-free at 6 months (PFS-6). Secondary endpoints include progression-free and overall survival, best intracranial response, and toxicity. Our study has met its primary endpoint and achieved a PFS-6 rate of 0.48 (90% exact CI: 0.31-0.66) and a median PFS of 7.6 months (90% CI: 3.4-12.9 months). Twenty percent of patients have experienced one (or more) grade-3 or higher treatment-related adverse events. These results suggest that pembrolizumab exerts promising efficacy on a subset of these tumors. Further studies are needed to identify the biological facets within the meningioma TME that may drive response to immune-based therapies., (© 2022. The Author(s).)

Introduction: Growing evidence recommends antifibrinolytic agent tranexamic acid (TXA) to reduce blood loss and transfusions rate in various surgical settings. However, postoperative seizure, as one of the major adverse effects of TXA infusion, has been a concern that restricts its utility in neurosurgery., Methods and Analysis: This is a randomised, placebo-controlled, non-inferiority trial. Patients with supratentorial meningiomas and deemed suitable for surgical resection will be recruited in the trial. Patients will be randomised to receive either a single administration of 20 mg/kg TXA or a placebo of the same volume with a 1:1 allocation ratio after anaesthesia induction. The primary endpoint is the cumulative incidence of early postoperative seizures within 7 days after craniotomy. Secondary outcomes include the incidence of non-seizure complications, changes of haemoglobin level from baseline, intraoperative blood loss, erythrocyte transfusion volume, Karnofsky Performance Status, all-cause mortality, and length of stay, and total hospitalisation cost., Ethics and Dissemination: This trial is registered at ClinicalTrial.gov and approved by the Chinese Ethics Committee of Registering Clinical Trials (ChiECRCT20200224). The findings will be disseminated in peer-reviewed journals and presented at national or international conferences relevant to subject fields., Trial Registration Number: NCT04595786., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Meningioma is the most common intracranial tumor, with generally favorable patient prognosis. However, patients with malignant meningioma typically experience recurrence, undergo multiple surgical resections, and ultimately have a poor prognosis. Thus far, effective chemotherapy for malignant meningiomas has not been established. We recently reported the efficacy of eribulin (Halaven) for glioblastoma with a telomerase reverse transcriptase (TERT) promoter mutation. This study investigated the anti-tumor effect of eribulin against TERT promoter mutation-harboring human malignant meningioma cell lines in vitro and in vivo. Two meningioma cell lines, IOMM-Lee and HKBMM, were used in this study. The strong inhibition of cell proliferation by eribulin via cell cycle arrest was demonstrated through viability assay and flow cytometry. Apoptotic cell death in malignant meningioma cell lines was determined through vital dye assay and immunoblotting. Moreover, a wound healing assay revealed the suppression of tumor cell migration after eribulin exposure. Intraperitoneal administration of eribulin significantly prolonged the survival of orthotopic xenograft mouse models of both malignant meningioma cell lines implanted in the subdural space (P < .0001). Immunohistochemistry confirmed apoptosis in brain tumor tissue treated with eribulin. Overall, these results suggest that eribulin is a potential therapeutic agent for malignant meningiomas., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Programmed death ligand 1 (PD-L1) contributes to tumor immunosuppression and is upregulated in aggressive meningiomas. We performed a phase II study of nivolumab, a programmed death 1 (PD-1) blocking antibody among patients with grade ≥2 meningioma that recurred after surgery and radiation therapy., Methods: Twenty-five patients received nivolumab (240 mg biweekly) until progression, voluntary withdrawal, unacceptable toxicity, or death. Tumor mutational burden (TMB) and quantification of tumor-infiltrating lymphocytes (TIL) were evaluated as potential immunocorrelative biomarkers. Change in neurologic function was prospectively assessed using the Neurologic Assessment in Neuro-Oncology (NANO) scale., Results: Enrolled patients had multiple recurrences including ≥3 prior surgeries and ≥2 prior courses of radiation in 60% and 72%, respectively. Nivolumab was well tolerated with no unexpected adverse events. Six-month progression-free survival (PFS-6) rate was 42.4% (95% CI: 22.8, 60.7) and the median OS was 30.9 months (95% CI: 17.6, NA). One patient achieved radiographic response (ongoing at 4.5 years). TMB was >10/Mb in 2 of 15 profiled tumors (13.3%). Baseline TIL density was low but increased posttreatment in 3 patients including both patients with elevated TMB. Most patients who achieved PFS-6 maintained neurologic function prior to progression as assessed by NANO., Conclusion: Nivolumab was well tolerated but failed to improve PFS-6, although a subset of patients appeared to derive benefit. Low levels of TMB and TIL density were typically observed. NANO assessment of neurologic function contributed to outcome assessment. Future studies may consider rationally designed combinatorial regimens., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: To investigate the angiogenic effects of bevacizumab and imatinib on different meningioma tissue grades., Material and Methods: In this study, in silico analysis of angiogenesis-related gene expression was carried out using previously reported datasets. Messenger ribonucleic acid expressions of VEGFA, VEGFB, PDGFRA, and PDGFRB genes were obtained from two different meningioma transcriptome datasets. The effect of antiangiogenic drugs, bevacizumab and imatinib, on meningiomainduced vascularization was assessed by using rat corneal angiogenesis assay (CAA)., Results: Bevacizumab and imatinib both significantly reduced meningioma-induced neovascularization in the CAA model., Conclusion: The angiogenic characteristics of meningiomas may be suppressed by using antiangiogenic drugs to prevent neovascularization, thus improving prognosis.

Malignant meningioma has a poor prognosis and there are currently no effective therapies. Avenaciolide is water-insoluble natural organic product produced by Aspergillus avenaceus G. Smith that can inhibit mitochondrial function. In the present study, we investigated the anti-cancer effects of avenaciolide in an isolated human malignant meningioma cell line, HKBMM. In addition, to assess the specificity of avenaciolide, its effects on normal human neonatal dermal fibroblast HDFn cells were also examined. Avenaciolide showed effective anti-cancer activity, and its cytotoxicity in HKBMM cells was greater than that in HDFn cells. The anti-cancer effects of avenaciolide were mediated by reactive oxygen species (ROS)-induced apoptosis, which may have been caused by mitochondrial disfunction. These results suggest that avenaciolide has potential as a therapeutic drug for malignant meningioma.

Background: Meningioma arising from meninges is one among the various types of brain tumors. Others are, astrocytomas originating from astrocyte, oligodendrogliomas originating from oligodendrocyte, Ependymomas originating from ependymal cells and medulloblastomas originating from neurons. Current knowledge of molecular biology, genetics and epigenetics of meningioma is not sufficient. Therefore, In depth understanding of the mechanism of meningioma formation and progression is needed for its treatment and management. Grade I Grade I meningiomas are majorly classified as grade I, grade II and grade III. Meningioma can be indolent, slow growing or can be invasive and metastatic which can recurre. Grade I meningioma can be removed by surgery in comparison to invasive meningioma which may recurre with high propensity. This property of recurrence is responsible for high morbidity and mortality. Meningioma are majorly classified into three classes namely grade I, grade II, grade III. Protein biomarkers are considered as promising candidates for the diagnosis of meningioma., Study: Various studies done on differential expression of proteins have shown increased expression of EGFR, NEK9, EPS812, CKAP4, SET and STAT2, in all the three grades of meningioma. Additionally, some proteins like HK2 are overexpressed in grade II and grade III meningioma than in grade I meningioma. Protein Markers, found on extracellular vesicles of different grades of meningioma can serve the same purpose. A test done on a sample of any kind of body fluid like blood, tear, saliva, urine etc. for recognizing the circulating cancer cells or DNA and extracellular vesicles released from them to help detecting the early stage of cancer is known as liquid biopsy. Solid biopsy has several limitations as compared to liquid biopsy. This is because the samples can be easily collected and studied in case of liquid biopsy. Exosomes are related with liquid biopsy and hence provide platform for better diagnosis, prognosis and treatment of any type of cancer including meningioma. Exosomal tetraspanin are important example of exosomal biomarkers. The tetraspanin network is a molecular scaffold which connects various proteins for signal transduction., Conclusion: This study tells about the utility of proper knowledge of extracellular vesicle proteins and their profiles in different grades, which can help in better understanding of pathogenesis, diagnosis, prognosis and treatment of meningioma. In Addition to use of these proteins as biomarkers, role of exosomes in currently available therapeutic approaches has been discussed., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Ferroptosis, a programmed cell death characterized by lipid peroxidation, is implicated in various diseases including cancer. Although cell density-dependent E-cadherin and Merlin/Neurofibromin (NF2) loss can modulate ferroptosis, the role of ferroptosis and its potential link to NF2 status and E-cadherin expression in meningioma remain unknown., Methods: Relationship between ferroptosis modulators expression and NF2 mutational status was examined in 35 meningiomas (10 NF2 loss and 25 NF2 wild type). The impact of NF2 and E-cadherin on ferroptosis were examined by lactate dehydrogenase (LDH) release, lipid peroxidation, and western blot assays in IOMM-Lee, CH157, and patient-derived meningioma cell models. Luciferase reporter and chromatin immunoprecipitation assays were used to assess the ability of MEF2C (myocyte enhancer factor 2C) to drive expression of NF2 and CDH1 (E-cadherin). Therapeutic efficacy of Erastin-induced ferroptosis was tested in xenograft mouse models., Results: Meningioma cells with NF2 inactivation were susceptible to Erastin-induced ferroptosis. Meningioma cells grown at higher density increased expression of E-cadherin, which suppressed Erastin-induced ferroptosis. Maintaining NF2 and E-cadherin inhibited ferroptosis-related lipid peroxidation and meningioma cell death. MEF2C was found to drive the expression of both NF2 and E-cadherin. MEF2C silencing enhanced Erastin-induced ferroptotic meningioma cell death and lipid peroxidation levels in vitro, which was limited by forced expression of MEF2C targets, NF2 and E-cadherin. In vivo, anti-meningioma effect of Erastin was augmented by MEF2C knockdown and was counteracted by NF2 or E-cadherin., Conclusions: NF2 loss and low E-cadherin create susceptibility to ferroptosis in meningioma. MEF2C could be a new molecular target in ferroptosis-inducing therapies for meningioma., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose of Review: Although most meningiomas are slow growing tumors mainly controlled by surgery with or without radiotherapy, aggressive meningiomas that fail these conventional treatments constitute a rare situation, a therapeutic challenge and an unmet need in neuro-oncology., Recent Finding: Mutational landscape in recurrent high-grade meningiomas includes mainly NF2 mutation or 22q chromosomal deletion, whereas telomerase reverse transcriptase promoter, BAP-1 and CDK2NA mutations were also found in aggressive meningiomas. Pi3K-Akt-mTOR pathway is currently the most relevant intracellular signaling pathway target in meningiomas with preliminary clinical activity observed. Assessment of drug activity with progression free survival rate at 6 months is challenging in regard to meningioma growth rate heterogeneity, so that 3-dimensional growth rate before and during treatment could be considered in the future to selected new active drugs., Summary: Despite a low evidence level, some systemic therapies may be considered for patients with recurrent meningioma not amenable to further surgery or radiotherapy. In recurrent high-grade meningioma, everolimus-octreotide combination, bevacizumab, sunitinib and peptide receptor radionuclide therapy exhibit a signal of activity that may justify their clinical use. Despite a lack of clear signal of activity to date, immunotherapy may offer new perspectives in the treatment of these refractory tumors., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Malignant meningiomas are fatal and lack effective therapy. As M2 macrophages are the most prevalent immune cell type in human meningiomas, we hypothesized that normalizing this immunosuppressive population would be an effective treatment strategy., Methods: We used CIBERSORTx to examine the proportions of 22 immune subsets in human meningiomas. We targeted the colony-stimulating factor 1 (CSF1) or CSF1 receptor (CSF1R) axis, an important regulator of macrophage phenotype, using monoclonal antibodies (mAbs) in a novel immunocompetent murine model (MGS1) for malignant meningioma. RNA sequencing (RNA-seq) was performed to identify changes in gene expression in the tumor microenvironment (TME). Mass cytometry was used to delineate changes in immune subsets after treatment. We measured patients' plasma CSF1 levels using ELISA and CSF1R expression using multiplex quantitative immunofluorescence in a human meningioma tissue microarray., Results: Human meningiomas are heavily enriched for immunosuppressive myeloid cells. MGS1 recapitulates the TME of human meningiomas, including an abundance of myeloid cells, a paucity of infiltrating T cells, and low programmed death ligand 1 (PD-L1) expression. Treatment of murine meningiomas with anti-CSF1/CSF1R, but not programmed cell death receptor 1 (PD-1), mAbs abrogate tumor growth. RNA-seq and mass cytometry analyses reveal a myeloid cell reprogramming with limited effect on T cells in the TME. CSF1 plasma levels are significantly elevated in human patients, and CSF1R is highly expressed on CD163+ macrophages within the human TME., Conclusion: Our findings suggest that anti-CSF1/CSF1R antibody treatment may be an effective normalization cancer immunotherapy for malignant meningiomas., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The aim of this study was to describe progestin-associated meningiomas' characteristics, outcome and management., Material and Methods: We included 53 patients operated on and/or followed in the department for meningioma with progestin intake longer than one year and with recent drug discontinuation., Results: Cyproterone acetate (CPA), nomegestrol acetate (NomA), and chlormadinone acetate (ChlA) were involved in most cases. Mean duration of progestin drugs intake was 17.5 years. Tumors were multiple in 66% of cases and were located in the anterior and the medial skull base in 71% of cases. Transitional subtype represented 16/25 tumors; 19 meningiomas were WHO grade I and 6 were grade II. The rate of transitional subtype and skull base location was significantly higher compared to matched operated meningioma general population. No difference was observed given WHO classification. But Ki67 proliferation index tends to be lower and 5/6 of the WHO grade II meningiomas were classified as WHO grade II because of brain invasion. Strong progesterone receptors expression was observed in most cases. After progestin discontinuation, a spontaneous visual recovery was observed in 6/10 patients. Under CPA (n=24) and ChlA/NomA (n=11), tumor volume decreased in 71% and 18% of patients, was stabilized in 25% and 64% of patients, and increased in 4% and 18% of patients, respectively. Volume outcome was related to meningioma location., Conclusions: Outcome at progestins discontinuation is favorable but different comparing CPA versus ChlA-NomA and comparing tumor location. Long-term follow-up is required. In most cases, simple observation is recommended and surgery should be avoided., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: High-grade meningioma is an aggressive type of brain cancer that is often recalcitrant to surgery and radiotherapy, leading to poor overall survival. Currently, there are no FDA-approved drugs for meningioma, highlighting the need for new therapeutic options, but development is challenging due to the lack of predictive preclinical models., Methods: To leverage the known overexpression of procaspase-3 in meningioma, PAC-1, a blood-brain barrier penetrant procaspase-3 activator, was evaluated for its ability to induce apoptosis in meningioma cells. To enhance the effects of PAC-1, combinations with either hydroxyurea or temozolomide were explored in cell culture. Both combinations were further investigated in small groups of canine meningioma patients and assessed by MRI, and the novel apoptosis tracer, [18F]C-SNAT4, was evaluated in patients treated with PAC-1 + HU., Results: In meningioma cell lines in culture, PAC-1 + HU are synergistic while PAC-1 + TMZ show additive-to-synergistic effects. In canine meningioma patients, PAC-1 + HU led to stabilization of disease and no change in apoptosis within the tumor, whereas PAC-1 + TMZ reduced tumor burden in all three canine patients treated., Conclusions: Our results suggest PAC-1 + TMZ as a potentially efficacious combination for the treatment of human meningioma, and also demonstrate the utility of including pet dogs with meningioma as a means to assess anticancer strategies for this common brain tumor., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Meningiomas represent a phenotypically and genetically diverse group of tumors which often behave in ways that are not simply explained by their pathologic grade. The genetic landscape of meningiomas has become a target of investigation as tumor genomics have been found to impact tumor location, recurrence risk, and malignant potential. Additionally, targeted therapies are being developed that in the future may provide patients with personalized chemotherapy based on the genetic aberrations within their tumor. This review focuses on the most common genetic mutations found in meningiomas of all grades, with an emphasis on the impact on tumor location and clinically relevant tumor characteristics. NF-2 and the non-NF-2 family of genetic mutations are summarized in the context of low-grade and high-grade tumors, followed by a comprehensive discussion regarding the genetic and embryologic basis for meningioma location and phenotypic heterogeneity. Finally, targeted therapies based on tumor genomics currently in use and under investigation are reviewed and future avenues for research are suggested. The field of meningioma genomics has broad implications on the way meningiomas will be treated in the future, and is gradually shifting the way clinicians approach this diverse group of tumors.

Diffuse leptomeningeal glioneuronal tumours (DLGNT) represent rare enigmatic CNS tumours of childhood. Most patients with this disease share common radiological and histopathological features but the clinical course of this disease is variable. A radiological hallmark of this disease is widespread leptomeningeal enhancement that may involve the entire neuroaxis with predilection for the posterior fossa and spine. The classic pathologic features include low- to moderate-density cellular lesions with OLIG2 expression and evidence of 'oligodendroglioma-like' appearance. The MAPK/ERK signaling pathway has recently been reported as a potential driver of tumourigenesis in up to 80% of DLGNT with KIAA1549:BRAF fusions being the most common event seen. Until now, limited analysis of the biological drivers of tumourigenesis has been undertaken via targeted profiling, chromosomal analysis and immunohistochemistry. Our study represents the first examples of comprehensive genomic sequencing in DLGNT and shows that it is not only feasible but crucial to our understanding of this rare disease. Moreover, we demonstrate that DLGNT may be more genomically complex than single-event MAPK/ERK signaling pathway tumours., (© 2021. The Author(s).)

Epidemiological studies reported in 2016 and 2019 demonstrated that breast cancer patients under tamoxifen treatment had significantly reduced risks of meningioma development. Tamoxifen treatment duration longer than 1500 days or with cumulative dosage higher than 26 320 mg have especially lowered risk of meningioma. Clinical long-term anticancer efficacy of tamoxifen shall associate with simultaneous suppression of estrogen receptor and downregulation of certain growth factor pathways, which may associate with - but not limited to - protein kinase-C (PKC) signaling. In this study, we will put the evidence together and indicate that tamoxifen may be effective in meningioma treatment in some patients who do not express estrogen receptor but expresses PKC, yet much higher doses of tamoxifen will be needed to treat meningiomas than those applied to treat breast cancer. We underline the fact that immunohistochemical analysis of both estrogen receptor and PKC (especially α, δ, λ and ι isoenzymes) may guide in patient stratification for selective benefitting from tamoxifen in management of meningiomas. Lastly, it would also be logical to test individual responses of meningiomas to tamoxifen in primary monolayer and spheroid cultures before starting treatment in each patient as the differential distribution of PCK isoenzymes may cause also untoward effects., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)