High-grade Meningiomas Research Articles

EXTH-41. COMBINATION TREATMENT OF CALCIUM CHANNEL ANTAGONIST MIBEFRADIL ENHANCES THE EFFECT OF HYDROXYUREA AT THERAPEUTIC RANGES IN HIGH-GRADE MENINGIOMA IN VITRO

Abstract High-grade meningiomas (MNs), WHO Grade II- III, are highly aggressive brain tumors that are difficult to treat. Standard chemotherapy agents are, at best, moderately effective in treating high-grade MNs. There is great interest in developing combinatorial drug treatment regimens to enhance the effects of standard chemotherapy. Many cancer types, including brain tumors, have an increase in the expression of voltage-gated calcium channels (VGCCs). These channels are involved in the regulation of cell cycle, proliferation, and apoptosis, among other functions. FDA-approved VGCC antagonists nimodipine (NIMO) and mibefradil (MIB) target two different VGCCs, L- and T-type channels, and have been of great interest for their use in combination therapy in other cancers. We sought to determine the efficacy of chemotherapy agents tested at clinically relevant concentrations for the treatment of high-grade MNs alone or in combination with NIMO or MIB. We cultured CH-157MN and IOMM-Lee MN cells and assessed their cell survival, apoptosis, and proliferation in the presence of temozolomide, octreotide, sunitinib, or hydroxyurea (HU). We confirmed that HU (150 µM) was the most efficacious chemotherapy agent, decreasing cell viability at therapeutic ranges. Monotherapy treatment with 2 or 4 µM MIB significantly decreased cell viability in both cell lines, whereas 1 µM NIMO only affected IOMM-Lee cells. The combination of HU and MIB further decreased cell viability but only in the most aggressive cell line, IOMM-Lee, whereas NIMO did not enhance HU’s ability to decrease cell survival. Remarkably, we detect an enhancement of HU’s effect by MIB when both agents are used within therapeutic ranges, as reported by pharmacokinetic studies. Here we demonstrate for the first time that T-type calcium channels play an important role in MN survival. The combination of HU and MIB suggests their use could be a promising treatment for high-grade MN.

EPID-24. CAPTURING EVOLVING DEFINITIONS OF 12 SELECT RARE CNS TUMORS: A TIMELY REPORT FROM CBTRUS AND NCI-CONNECT

Abstract BACKGROUND Incidence, prevalence, and survival are population-based cancer statistics that describe cancer burden. The National Cancer Institute’s Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) specializes in research of 12 rare CNS tumor types to improve approaches to care and treatment. These tumors include atypical teratoid/rhabdoid tumors, brainstem and midline glioma, choroid plexus tumors, ependymoma, high grade meningioma, gliomatosis cerebri, medulloblastoma, oligodendroglioma/anaplastic oligodendroglioma, pineal region tumors, pleomorphic xanthoastrocytoma, CNS embryonal tumors, not elsewhere classified (NEC)/not otherwise specified (NOS), and primary CNS sarcoma. This study aimed to update incidence, prevalence, and survival statistics for these tumors. METHODS The Central Brain Tumor Registry of the United States (CBTRUS) database, a combined dataset of CDC’s National Program of Cancer Registries (NPCR) and NCI’s Surveillance, Epidemiology and End RESULTS (SEER) data, was used to calculate average annual age-adjusted incidence rates (AAAIR) per 100,000 population overall and by sex, race-ethnicity, and age (2008-2019). NPCR data were used to calculate relative survival (RS) estimates (2008-2018). Prevalence on December 31, 2019 was estimated using annual age-specific incidence and survival from CBTRUS and SEER, respectively. RESULTS AAAIR was 1.51 per 100,000 for these tumors combined, with highest incidence in ependymomas (AAAIR=0.41/100,000). Most tumor types were more common in males, adults (ages 40+ years) or children ages < 15 years, and non-Hispanic White individuals. Ependymomas were most prevalent (19,339 cases) followed by oligodendrogliomas (15,070 cases). RS for all subtypes combined at 1-, 5-, and 10-years was 86.6%, 71.9%, and 65.3%, respectively. Ependymomas had the highest RS (5-years=90.6%) and primary CNS sarcomas had the lowest RS (5-years=7.7%). CONCLUSIONS Incidence, prevalence, and survival patterns for these 12 selected rare cancer subtypes varied significantly by type. Population-based data are critical to guiding effective design of and accrual expectations for clinical trials in rare cancers.

EPID-20. SEX-SPECIFIC DIFFERENCES IN MENINGIOMA SUBTYPES AND MUTATIONS – A RETROSPECTIVE ANALYSIS

Abstract A variety of intrinsic and extrinsic factors are known to influence and promote the development of cancer. Although the patients’ gender can influence extrinsic factors, biological sex is an important intrinsic factor. Here, it must also be considered that hormone levels change over the lives of patients. To further investigate these aspects, meningioma can serve as a prototype tumor. Differences are already obvious when analyzing the epidemiology and outcomes: Females are more frequently diagnosed with meningioma, but high-grade meningiomas and fatal outcomes are more frequently observed in males. To further resolve sex and potentially hormone-specific differences, we retrospectively examined a dataset of 798 patients (females n=541, males n=257). Additionally, we arbitrarily set a cut-off of 58 years to stratify for females between pre- and post-menopause. The male cohort was analyzed accordingly to exclude an age-dependent effect. Further, the female cohort was subdivided into “45-55 years” and “other” to analyze the impact of high hormone fluctuations within menopause. When examining the histological data, we found that women displayed the chordoid subtype more frequently than men (6.3% vs. 1.6%). In the age-dependent analyses, there may be a signal for a hormone-dependent effect, as for females this subtype was diagnosed more frequently < 58 than > 58 years of age (10.6% vs. 1.9%; males: 0% vs. 3.0%) and within the menopause (15.5% vs. 3.2%). The same pattern was noted for the TRAF7 mutation, which was detected more frequently in females (20.2% vs. 7.7%), females < 58 years (23.9% vs. 15.6%, males: 6.2% vs. 9.1%) and females within the menopause (27.9% vs. 17.6%) than in the respective other subgroups. This preliminary data warrants further research in larger, comprehensively annotated cohorts and analysis for hormone levels and receptor expression.

DDDR-32. EVALUATING THE THERAPEUTIC EFFECTS OF SMALL MOLECULE INHIBITORS OF CDK4/6 AND FAK IN PRECLINICAL MENINGIOMA MODELS

Abstract BACKGROUND New therapies are needed for meningioma since treatment options are limited once patients have exhausted surgery and radiation. FAK, CDK4/6 and RAF/MEK represent potential targets because of synthetic lethality with NF2, loss of CDKN2A, and activation of MAPK signaling pathway in meningioma, respectively. The objective of this study was to evaluate the efficacy of targeting FAK, CDK4/6 and RAF/MEK as monotherapies and combination therapies in traditional and patient-derived cell lines and xenografts. METHODS In vitro, cell viability and proliferation assays were used to test abemaciclib (CDK4/6 inhibitor), defactinib (FAK inhibitor) and VS-6766 (RAF/MEK inhibitor) as monotherapy and in combination. To better recapitulate the meningioma microenvironment, targeted agents were evaluated with Matrigel, an artificial extracellular matrix. The efficacy of VS-4718 (in vivo formulation of defactinib) and abemaciclib were evaluated in a subcutaneous IOMM-lee meningioma model (having CDKN2A loss) in nude mice. Furthermore, we are establishing cell cultures and patient-derived cell and xenograft (PDX) models using freshly-resected tissue from patients with recurrent or high-grade (WHO grade 2-3) meningiomas. RESULTS In vitro evaluation identified the combination of defactinib with abemaciclib resulted in a synergistic decrease in cell viability relative to each monotherapy alone, while the combination of defactinib+VS-6766 was not beneficial. The presence of Matrigel enhanced the sensitivity of all three agents. In vivo, we observed improved survival in mice treated with abemaciclib vs control (45 days vs 26 days; p=0.03), as well as combination of VS-4718 + abemaciclib vs control (44 days vs 26 days; p=0.04, Gehan-Breslow-Wilcoxon test). We did not observe survival extension with VS-4718 monotherapy. Lastly, we successfully established an orthotopic meningioma PDX using a WHO Grade 3 tumor for evaluation of novel therapies in meningioma. CONCLUSION Abemaciclib showed promising efficacy in preclinical meningioma xenografts with CDKN2A loss. Studies to evaluate these therapies in other orthotopic models are underway.

RADT-38. DOSE ESCALATED RADIOTHERAPY IS ASSOCIATED WITH IMPROVED OUTCOMES FOR HIGH GRADE MENINGIOMA

Abstract BACKGROUND The optimal modern radiotherapy (RT) approach after surgery for atypical and malignant meningioma is unclear. We present results of dose-escalation. METHODS Consecutive patients with histopathologic grade 2 or 3 meningioma treated with RT were reviewed. A dose-escalation cohort [≥ 66Gy equivalent dose in 2 Gy fractions using an a/b = 10 (EQD2)], was compared to a standard dose cohort (< 66Gy). Outcomes were progression-free survival (PFS), cause-specific survival (CSS), overall survival (OS), local failure (LF) and radiation necrosis. RESULTS 118 patients (111 Grade 2, 94.1%) were identified; 54/118 (45.8%) received dose-escalation and 64/118 (54.2%) standard dose. Median follow-up was 45.4 months (IQR: 24.0 - 80.0 months) and median OS was 9.7 years (Q1: 4.6 years, Q3: not reached). All dose-escalated patients had residual disease vs. 65.6% in the standard dose cohort (p < 0.001). PFS at 3-, 4- and 5-years in the dose-escalated vs. standard dose cohort were 78.9%, 72.2% and 64.6% vs. 57.2%, 49.1% and 40.8%, respectively, (p = 0.030). On multivariable (MVA) analysis, dose-escalation (HR: 0.544,p = 0.042) was associated with improved PFS, whereas ≥ 2 surgeries (HR: 1.989, p = 0.035) and older age (HR: 1.035, p < 0.001) were associated with worse PFS. The cumulative risk of LF was reduced with dose-escalation (p = 0.016). MVA confirmed dose-escalation protective for LF (HR: 0.483, p = 0.019), whereas ≥ 2 surgeries prior to RT predicted for LF (HR: 2.145, p = 0.008). A trend was observed for improved CSS and OS in the dose-escalation cohort (p < 0.1). Seven patients (5.9%) developed symptomatic radiation necrosis (RN) with no significant difference between the two cohorts. CONCLUSIONS Dose-escalated radiotherapy with ≥ 66Gy for high grade meningioma is associated with improved local control and PFS with an acceptable risk of RN.

RADT-37. INTERIM RESULTS OF ACCELERATOR-BASED BORON NEUTRON CAPTURE THERAPY, RANDOMIZED CONTROLLED TRIAL FOR RECURRENT AND REFRACTORY HIGH-GRADE MENINGIOMAS

Abstract BACKGROUND High-grade meningiomas (HGMs) recurred after X-ray treatment showed 5.2 months as median progression free survival (mPFS) and only 24.6 months as median overall survival (mOS) from the literatures. Recently, we showed much more excellent OS and PFS using reactor-based boron neutron capture therapy (BNCT) (Neuro-Oncology 24:90-98, 2022). Based on these data, we started “A phase II investigator-lead RCT using accelerator-based BNCT system for refractory recurrent high-grade meningioma”, with the aid of Japanese governmental financial support. METHODS We prepared 2 study arms, BNCT test treatment arm (12 subjects) and control best supportive care arm (6 subjects) in RCT fashion. PFS judged by third party committee was set-up as primary endpoint and PFS judged by investigators themselves and OS of BNCT arm were set-up as secondary endpoints. To diminish ethical problems of this RCT, rescue BNCT is permitted for control group patients, if they showed progress disease during the observation period. Macdonald criteria was adopted for assessment. The first patient-in was August 2019 and the last patient-in was August 2021. Interim results of this trial: Three and two grade 3 subjects were included in BNCT and control arm, respectively. Others were grade 2 subjects. As of April 20, 2023, mPFS judged by investigators showed 90 weeks and 8 weeks for BNCT and control arm, respectively (P = 0.0004). OS-2 year rates of BNCT and control arms are 91.7% and 25%, respectively (p = 0.01) CONCLUSION Primary endpoint, mPFS judged by third party committee is still being closed and unknown, so far, until the end of the trial (August 2024). With regard to secondary endpoints, there are marked differences in both arms in mPFS judged by investigators. Also, OS in BNCT arm is extremely excellent in comparison with EORTC RCT of “trabectedine” and PD-1 blockade reports, just recently appeared.

Hemorrhagic meningioma with pulmonary metastasis: Case report and literature review

Abstract Meningiomas are extra-axial neoplasms that originate from the arachnoid cap cells located on the inner surface of the meninges. Approximately 36% of central nervous system tumors are meningiomas. Based on earlier findings to be benign in most cases, they are categorized as slow-growing tumors that form gradually over time. Meningiomas are usually asymptomatic and discovered inadvertently. They rarely present with immediate clinical symptoms or abrupt hemorrhagic strokes. However, tumor hemorrhage can be fatal in high-grade meningiomas, particularly those with vascularization. We describe a 58-year-old man who was hospitalized after experiencing an unexpectedly acute headache. The right cerebellar hemisphere and vermis cerebellar hemorrhage were detected on computed tomography (CT), and the cerebellar hemorrhage was explained by a diagnosis of hypertension. When additional analysis of the patient’s chest CT indicated lung mass lesions, we assumed that the lung cancer had spread to the brain. However, the pathological outcomes of a guided definite pulmonary aspiration biopsy, in conjunction with resection of the cerebellar tumor, suggested a subtentorial meningioma with ruptured hemorrhage and pulmonary meningioma metastasis. The patient was transferred to a hospital closer to home for ongoing follow-up and, after 2 months, he had recovered well.

Integrated Meta-Omics Analysis Unveils the Pathways Modulating Tumorigenesis and Proliferation in High-Grade Meningioma.

Meningioma, a primary brain tumor, is commonly encountered and accounts for 39% of overall CNS tumors. Despite significant progress in clinical research, conventional surgical and clinical interventions remain the primary treatment options for meningioma. Several proteomics and transcriptomics studies have identified potential markers and altered biological pathways; however, comprehensive exploration and data integration can help to achieve an in-depth understanding of the altered pathobiology. This study applied integrated meta-analysis strategies to proteomic and transcriptomic datasets comprising 48 tissue samples, identifying around 1832 common genes/proteins to explore the underlying mechanism in high-grade meningioma tumorigenesis. The in silico pathway analysis indicated the roles of extracellular matrix organization (EMO) and integrin binding cascades in regulating the apoptosis, angiogenesis, and proliferation responsible for the pathobiology. Subsequently, the expression of pathway components was validated in an independent cohort of 32 fresh frozen tissue samples using multiple reaction monitoring (MRM), confirming their expression in high-grade meningioma. Furthermore, proteome-level changes in EMO and integrin cell surface interactions were investigated in a high-grade meningioma (IOMM-Lee) cell line by inhibiting integrin-linked kinase (ILK). Inhibition of ILK by administrating Cpd22 demonstrated an anti-proliferative effect, inducing apoptosis and downregulating proteins associated with proliferation and metastasis, which provides mechanistic insight into the disease pathophysiology.

Multi-parametric MRI-based machine learning model for prediction of WHO grading in patients with meningiomas

ObjectiveThe purpose of this study was to develop and validate a nomogram combined multiparametric MRI and clinical indicators for identifying the WHO grade of meningioma.Materials and methodsFive hundred and sixty-eight patients were included in this study, who were diagnosed pathologically as having meningiomas. Firstly, radiomics features were extracted from CE-T1, T2, and 1-cm-thick tumor-to-brain interface (BTI) images. Then, difference analysis and the least absolute shrinkage and selection operator were orderly used to select the most representative features. Next, the support vector machine algorithm was conducted to predict the WHO grade of meningioma. Furthermore, a nomogram incorporated radiomics features and valuable clinical indicators was constructed by logistic regression. The performance of the nomogram was assessed by calibration and clinical effectiveness, as well as internal validation.ResultsPeritumoral edema volume and gender are independent risk factors for predicting meningioma grade. The multiparametric MRI features incorporating CE-T1, T2, and BTI features showed the higher performance for prediction of meningioma grade with a pooled AUC = 0.885 (95% CI, 0.821–0.946) and 0.860 (95% CI, 0.788–0.923) in the training and test groups, respectively. Then, a nomogram with a pooled AUC = 0.912 (95% CI, 0.876–0.961), combined radiomics score, peritumoral edema volume, and gender improved diagnostic performance compared to radiomics model or clinical model and showed good calibration as the true results. Moreover, decision curve analysis demonstrated satisfactory clinical effectiveness of the proposed nomogram.ConclusionsA novel nomogram is simple yet effective in differentiating WHO grades of meningioma and thus can be used in patients with meningiomas.Clinical relevance statementWe proposed a nomogram that included clinical indicators and multi-parameter radiomics features, which can accurately, objectively, and non-invasively differentiate WHO grading of meningioma and thus can be used in clinical work.Key Points• The study combined radiomics features and clinical indicators for objectively predicting the meningioma grade.• The model with CE-T1 + T2 + brain-to-tumor interface features demonstrated the best predictive performance by investigating seven different radiomics models.• The nomogram potentially has clinical applications in distinguishing high-grade and low-grade meningiomas.

Dose-Escalated Radiation Therapy Is Associated With Improved Outcomes for High-Grade Meningioma

The optimal modern radiation therapy (RT) approach after surgery for atypical and malignant meningioma is unclear. We present results of dose escalation in a single-institution cohort spanning 2000 to 2021. Consecutive patients with histopathologic grade 2 or 3 meningioma treated with RT were reviewed. A dose-escalation cohort (≥66 Gy equivalent dose in 2-Gy fractions using an α/β=10) was compared with a standard-dose cohort (<66 Gy). Outcomes were progression-free survival (PFS), cause-specific survival, overall survival (OS), local failure (LF), and radiation necrosis. One hundred eighteen patients (111 grade 2, 94.1%) were identified; 54 (45.8%) received dose escalation and 64 (54.2%) standard dose. Median follow-up was 45.4 months (IQR, 24.0-80.0 months) and median OS was 9.7 years (Q1: 4.6 years, Q3: not reached). All dose-escalated patients had residual disease versus 65.6% in the standard-dose cohort (P < .001). PFS at 3, 4, and 5 years in the dose-escalated versus standard-dose cohort was 78.9%, 72.2%, and 64.6% versus 57.2%, 49.1%, and 40.8%, respectively, (P=.030). On multivariable analysis, dose escalation (hazard ratio [HR], 0.544; P=.042) was associated with improved PFS, whereas ≥2 surgeries (HR, 1.989; P=.035) and older age (HR, 1.035; P < .001) were associated with worse PFS. The cumulative risk of LF was reduced with dose escalation (P=.016). Multivariable analysis confirmed that dose escalation was protective for LF (HR, 0.483; P=.019), whereas ≥2 surgeries before RT predicted for LF (HR, 2.145; P=.008). A trend was observed for improved cause-specific survival and OS in the dose-escalation cohort (P < .1). Seven patients (5.9%) developed symptomatic radiation necrosis with no significant difference between the 2 cohorts. Dose-escalated RT with ≥66 Gy for high-grade meningioma is associated with improved local control and PFS with an acceptable risk of radiation necrosis.

A large-scale targeted proteomics of serum and tissue shows the utility of classifying high grade and low grade meningioma tumors

BackgroundMeningiomas are the most prevalent primary brain tumors. Due to their increasing burden on healthcare, meningiomas have become a pivot of translational research globally. Despite many studies in the field of discovery proteomics, the identification of grade-specific markers for meningioma is still a paradox and requires thorough investigation. The potential of the reported markers in different studies needs further verification in large and independent sample cohorts to identify the best set of markers with a better clinical perspective.MethodsA total of 53 fresh frozen tumor tissue and 51 serum samples were acquired from meningioma patients respectively along with healthy controls, to validate the prospect of reported differentially expressed proteins and claimed markers of Meningioma mined from numerous manuscripts and knowledgebases. A small subset of Glioma/Glioblastoma samples were also included to investigate inter-tumor segregation. Furthermore, a simple Machine Learning (ML) based analysis was performed to evaluate the classification accuracy of the list of proteins.ResultsA list of 15 proteins from tissue and 12 proteins from serum were found to be the best segregator using a feature selection-based machine learning strategy with an accuracy of around 80% in predicting low grade (WHO grade I) and high grade (WHO grade II and WHO grade III) meningiomas. In addition, the discriminant analysis could also unveil the complexity of meningioma grading from a segregation pattern, which leads to the understanding of transition phases between the grades.ConclusionsThe identified list of validated markers could play an instrumental role in the classification of meningioma as well as provide novel clinical perspectives in regard to prognosis and therapeutic targets.

Outcomes Following Dose Escalated Radiotherapy for High Grade Meningioma

Conventionally fractionated radiotherapy (RT) is a defined treatment following surgery for atypical and malignant meningioma. However, the optimal radiotherapeutic approach is not well defined. We present the results of our dose-escalation strategy. Consecutive patients with a histopathologic grade 2 or 3 meningioma treated with RT were retrospectively reviewed. The primary outcome was progression-free survival (PFS), and secondary outcomes included cause-specific survival (CSS), overall survival (OS), local failure and incidence of radiation necrosis. We specifically compared the dose-escalation cohort, defined as those treated with ≥66 Gy EQD2 (equivalent dose in 2 Gy fractions, a/b = 10), to the standard dose cohort receiving <66 Gy EQD2. We defined adjuvant as RT delivered within 6 months of surgery otherwise the treatment was salvage. A total of 118 patients with Grade 2 (111/118) or 3 (7/118) meningioma were identified. 54/118 (45.8%) received dose-escalation and 64/118 (54.2%) standard dosing. 34/54 (63.0%) dose-escalated and 45/64 (70.3%) standardly dosed were treated adjuvantly. The median follow-up was 45.4 months (IQR: 24.0-80.0 months) and median OS was 9.7 years. Post-operative residual disease was present in all dose-escalated patients, as compared to 65.6% in the standard dose cohort. PFS at 3-, 4- and 5-years in the dose-escalated vs. standard dose cohort were 78.9%, 72.2% and 64.6% vs. 57.2%, 49.1% and 40.8%, respectively, (p = 0.030). On multivariable (MVA) analysis, dose-escalation (HR: 0.544, 95% CI: 0.303-0.977, p = 0.042) was associated with improved PFS, whereas ≥2 surgeries (HR: 1.989, 95% CI: 1.049-3.773, p = 0.035) and older age (HR: 1.035, 95% CI:1.015-1.056, p<0.001) associated with worse PFS. The cumulative risk of local failure at 3-, 4- and 5-years in the dose-escalated vs. standard dose cohort were 16.9%, 23.8% and 31.8% vs. 39.6%, 45.6% and 53.9%, respectively, favoring dose-escalation (p = 0.016). MVA confirmed dose-escalation as predictive of a lower risk of LF (HR: 0.483, 95% CI: 0.263-0.887, p = 0.019), while ≥2 surgeries prior to RT predicted for greater LF rates (HR:2.145, 95% CI:1.220-3.771, p = 0.008). A trend was observed for prolonged CSS and OS in the dose escalation cohort (p = <0.1). Seven patients (5.9%) developed symptomatic radiation necrosis (RN) with no significant difference between the two cohorts. Dose-escalated radiotherapy for high grade meningioma to at least 66 Gy is associated with significantly improved rates of local control and PFS with an acceptable risk of RN.

Risk Factors Associated with Development of Peritumoral Edema Following Stereotactic Radiosurgery and Radiotherapy for Intracranial Meningioma

Peritumoral edema (PTE) is a potential adverse effect following radiotherapy for intracranial meningioma. The purpose of this study is to identify which baseline factors may increase risk for PTE. A retrospective chart review was conducted of 431 patients who underwent primary radiotherapy to 480 radiographically-defined intracranial meningiomas between January 2008 and December 2021 within an integrated health care system. Patients with prior surgical management were excluded. Patients were treated with frameless LINAC-based image-guided single fraction stereotactic radiosurgery (SRS) (32.9%), 5 fraction SRS (FSRS) (30.8%), or fractionated stereotactic radiotherapy (FSRT) (36.3%). Pre- and post-radiotherapy MRI studies were reviewed to evaluate for PTE following treatment. An event was defined as new or worsening PTE compared to pre-radiotherapy imaging or development of new symptoms post-radiotherapy. Univariate and stepwise logistics regression analyses were performed to compare the risk of PTE between groups. Median follow-up was 85.8 months (IQR: 49.4-125.4). Median patient age was 66 years (IQR: 56-73). Patients treated with SRS (median age: 61 years) were younger than those treated with FSRS/FSRT (median age: 68 years) (p<0.001). Lesions treated with SRS (median volume: 1.33cc) were smaller than those treated with FSRS/FSRT (median volume: 6.36cc) (p<0.001). For all-comers, 68 (14.2%) lesions developed any PTE, and 27 (5.6%) developed symptomatic PTE (SPTE). Of these, 4 patients developed symptoms post-treatment without radiographic evidence of new or worsening PTE. Incidence of PTE/SPTE by site was as follows: base of skull (BOS): 10.3%/6.1%, convexity: 22.7%/7.6%, falcine: 17.6%/4.1%, parasagittal: 27.8%/8.3%, posterior fossa/tentorium 7.0%/0.0%. Incidence of PTE/SPTE by technique was as follows: SRS: 6.3%/3.8%, FSRS: 20.9%/7.4%, FSRT: 15.5%/5.7%. On univariate analysis, age >65 (OR = 2.17 (95% CI: 1.26-3.77) p = 0.006), tumor volume (OR = 1.05 (1.02-1.08), p = 0.003), pre-treatment PTE (OR = 6.82 (95% CI: 3.59-12.94) p<0.001), and convexity/falcine/parasagittal (CFPS) location (OR = 2.52 (95% CI: 1.49-4.23) p<0.001) were associated with increased incidence of PTE. On multivariate analysis, age >65 (OR = 1.91 (95% CI: 1.05-3.45) p<0.03), tumor volume (OR = 1.04 (95% CI: 1.00-1.08) p = 0.03), pre-treatment PTE (OR = 4.64 (95% CI: 2.33-9.24) p<0.001), and CFPS location (OR = 2.53 (95% CI: 1.41-4.52) p = 0.002) were associated with increased incidence of PTE. Two patients with PTE underwent resection for local failure which revealed atypical meningioma. Age >65, larger tumor volume, presence of pre-treatment PTE, and CFPS location were associated with increased incidence of PTE following radiotherapy. Patients with these risk factors should be counseled regarding post-treatment effects. Infrequently, PTE following treatment may be an indicator of higher-grade meningioma.

Metabolomic and Lipidomic Characterization of Meningioma Grades Using LC-HRMS and Machine Learning.

Meningiomas are among the most common brain tumors that arise from the leptomeningeal cover of the brain and spinal cord and account for around 37% of all central nervous system tumors. According to the World Health Organization, meningiomas are classified into three histological subtypes: benign, atypical, and anaplastic. Sometimes, meningiomas with a histological diagnosis of benign tumors show clinical characteristics and behavior of aggressive tumors. In this study, we examined the metabolomic and lipidomic profiles of meningioma tumors, focusing on comparing low-grade and high-grade tumors and identifying potential markers that can discriminate between benign and malignant tumors. High-resolution mass spectrometry coupled to liquid chromatography was used for untargeted metabolomics and lipidomics analyses of 85 tumor biopsy samples with different meningioma grades. We then applied feature selection and machine learning techniques to find the features with the highest information to aid in the diagnosis of meningioma grades. Three biomarkers were identified to differentiate low- and high-grade meningioma brain tumors. The use of mass-spectrometry-based metabolomics and lipidomics combined with machine learning analyses to prospect and characterize biomarkers associated with meningioma grades may pave the way for elucidating potential therapeutic and prognostic targets.

P21.05.B CAPTURING EVOLVING DEFINITIONS OF 12 SELECT RARE CNS TUMORS: A TIMELY REPORT FROM CBTRUS AND NCI-CONNECT

Abstract BACKGROUND Histopathology-specific incidence, prevalence, and survival are essential population-based cancer statistics that describe cancer burden. The National Cancer Institute’s Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) aims to improve understanding of tumor biology and patient outcomes for 12 selected rare brain and other central nervous system (CNS) tumor types to improve approaches to care and treatment. These types included atypical teratoid/rhabdoid tumor, brainstem and midline gliomas, choroid plexus tumors, ependymomas, high grade meningiomas, gliomatosis cerebri, medulloblastoma, oligodendrogliomas, pineal region tumors, pleomorphic xanthoastrocytomas, CNS embryonal tumors, NEC/NOS and primary CNS sarcoma. The analysis aimed to estimate the incidence (new cases per year), prevalence (currently living cases), and survival rates for these selected rare brain and other CNS tumor types. MATERIAL AND METHODS The Central Brain Tumor Registry of the United States (CBTRUS) data, which contains data from the Centers for Disease Control and Preventions National Program of Cancer Registries (NPCR) and National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) data, from 2008-2019 were used to calculate average annual age-adjusted incidence rates (AAAIR) per 100,000 population overall and by sex, race/ethnicity, and age. Incidence time trends were calculated for diagnosis years 2004-2019. NPCR survival data from 2001-2018 were used to calculate relative survival (RS) estimates. Estimated prevalence counts as of December 31, 2019 were estimated using incidence from CBTRUS and overall survival rates from SEER. RESULTS Overall AAAIR for all 12 subtypes combined was 1.51 per 100,000 population, with the highest subtype-specific incidence in ependymomas (AAAIR=0.41/100,000). Overall, most subtypes were more common in males and people who are non-Hispanic White. Incidence of all subtypes varied by age. Ependymomas were most prevalent with 19,339 cases; followed by oligodendrogliomas with 15,070 cases. Time trends in incidence varied by subtype, with significant decreases in incidence of gliomatosis cerebri, CNS embryonal tumor, and primary CNS sarcoma. RS for all subtypes combined at 1, 5, and 10 years was 86.6%, 71.9%, and 65.3%, respectively. Ependymomas had the highest RS (1-year=96.1%, 5-years=90.6%, 10-years=86.6%) and primary CNS sarcomas had the lowest RS (1-year=48.2%, 5-years=7.7%, 10-years=5.2%). CONCLUSION Incidence, prevalence, and survival patterns for these 12 selected rare cancer subtypes varied significantly by type. Population based data are critical to guiding effective design of and accrual expectations for clinical trials in rare cancers.

Radiomics-Based Prediction of TERT Promotor Mutations in Intracranial High-Grade Meningiomas.

In meningiomas, TERT promotor mutations are rare but qualify the diagnosis of anaplasia, directly impacting adjuvant therapy. Effective screening for patients at risk for promotor mutations could enable more targeted molecular analyses and improve diagnosis and treatment. Semiautomatic segmentation of intracranial grade 2/3 meningiomas was performed on preoperative magnetic resonance imaging. Discriminatory power to predict TERT promoter mutations was analyzed using a random forest algorithm with an increasing number of radiomic features. Two final models with five and eight features with both fixed and differing radiomics features were developed and adjusted to eliminate random effects and to avoid overfitting. A total of 117 image sets including training (N = 94) and test data (N = 23) were analyzed. To eliminate random effects and demonstrate the robustness of our approach, data partitioning and subsequent model development and testing were repeated a total of 100 times (each time with repartitioned training and independent test data). The established five- and eight-feature models with both fixed and different radiomics features enabled the prediction of TERT with similar but excellent performance. The five-feature (different/fixed) model predicted TERT promotor mutation status with a mean AUC of 91.8%/94.3%, mean accuracy of 85.5%/88.9%, mean sensitivity of 88.6%/91.4%, mean specificity of 83.2%/87.0%, and a mean Cohen's Kappa of 71.0%/77.7%. The eight-feature (different/fixed) model predicted TERT promotor mutation status with a mean AUC of 92.7%/94.6%, mean accuracy of 87.3%/88.9%, mean sensitivity of 89.6%/90.6%, mean specificity of 85.5%/87.5%, and a mean Cohen's Kappa of 74.4%/77.6%. Of note, the addition of further features of up to N = 8 only slightly increased the performance. Radiomics-based machine learning enables prediction of TERT promotor mutation status in meningiomas with excellent discriminatory performance. Future analyses in larger cohorts should include grade 1 lesions as well as additional molecular alterations.

22 Dose Escalated Radiotherapy is Associated with Improved Outcomes for High Grade Meningioma

22 Dose Escalated Radiotherapy is Associated with Improved Outcomes for High Grade Meningioma

Meningioma

Meningioma is considered as a single type by the World Health Organization 2021 classification, encompassing 15 subtypes. These classifications are primarily based on histological attributes. However, recent advancements in understanding driver gene mutations and molecular prognostic markers are of particular importance for comprehending the clinical behavior of these tumors. Meningiomas are stratified molecularly, predominantly based on the presence of NF2 mutation. Over 50% are associated with mutations in the NF2 gene and/or monosomy of chromosome 22, whereas the remaining are associated with gene mutations in either of AKT1, SMO, KLF4, TRAF7, or the other less common ones. Importantly, these driver gene mutations are mutually exclusive and significantly associated with tumor location, histological subtype, and grading. The majority of higher-grade meningiomas is associated with multiple chromosomal aberrations, including the loss of 1p, 6q, and 14q, along with NF2 mutations. Homozygous deletion of CDKN2A/CDKN2B genes or TERT promoter mutations serves as a predictor of poor prognosis. Notably, these molecular markers are now incorporated into the criteria for anaplastic meningioma. The amalgamation of molecular insights with clinical and histological parameters, alongside patient prognosis, holds significant utility in the management of patients with meningiomas. It is anticipated to pave the way for treatments founded on molecular-clinical associations.

Usefulness and limitations of intraoperative pathological diagnosis using frozen sections for spinal cord tumors

BackgroundIntraoperative pathological diagnosis has a major influence on the intra- and postoperative management of spinal cord tumors. Thus, the aim of this study was to assess the reliability of intraoperative pathological diagnosis for spinal cord lesions by comparing it with the final pathological diagnosis and to determine its usefulness and limitations. MethodThree-hundred and three consecutive patients (mean age, 53.9 years) with neoplastic spinal cord lesions who underwent initial surgery between 2000 and 2021 were included. The anatomical locations of the spinal cord tumors and the implementation rate of intraoperative pathological diagnosis in each tumor type were evaluated. As the primary outcome, we determined the concordance rates between the intraoperative pathological diagnosis and the final diagnosis. When the intraoperative pathological diagnosis and final diagnosis were the same, the diagnosis was defined as a “match.” Otherwise, the diagnosis was defined as a “mismatch.” ResultsThe overall implementation rate of intraoperative pathological diagnosis was 53%, with implementation rates of 71%, 45%, 47%, and 50% for intramedullary, intradural extramedullary, extradural, and dumbbell tumors, respectively. The overall concordance rate was 87.6%, with concordance rates of 80%, 95%, 75%, and 90% for intramedullary, intradural extramedullary, extradural, and dumbbell tumors, respectively (p < 0.05). The diagnoses of ependymomas, low-grade astrocytomas, and high-grade astrocytomas was occasionally difficult among intramedullary tumors. Among intradural extramedullary tumors, differentiation between grade 1 meningioma and high-grade meningioma was difficult using intraoperative pathological diagnosis. ConclusionsSurgeons must recognize the lower accuracy of intraoperative pathological diagnosis for intramedullary and extradural lesions and make a final decision by considering the intraoperative gross findings, preoperative clinical course, and imaging.

Meningiomas with CNS invasion.

CNS invasion has been included as an independent criterion for the diagnosis of a high-grade (WHO and CNS grade 2 and 3) meningioma in the 2016 and more recently in the 2021 WHO classification. However, the prognostic role of brain invasion has recently been questioned. Also, surgical treatment for brain invasive meningiomas may pose specific challenges. We conducted a systematic review of the 2016-2022 literature on brain invasive meningiomas in Pubmed, Scopus, Web of Science and the Cochrane Library. The prognostic relevance of brain invasion as a stand-alone criterion is still unclear. Additional and larger studies using robust definitions of histological brain invasion and addressing the issue of sampling errors are clearly warranted. Although the necessity of molecular profiling in meningioma grading, prognostication and decision making in the future is obvious, specific markers for brain invasion are lacking for the time being. Advanced neuroimaging may predict CNS invasion preoperatively. The extent of resection (e.g., the Simpson grading) is an important predictor of tumor recurrence especially in higher grade meningiomas, but also - although likely to a lesser degree - in benign tumors, and therefore also in brain invasive meningiomas with and without other histological features of atypia or malignancy. Hence, surgery for brain invasive meningiomas should follow the principles of maximal but safe resections. There are some data to suggest that safety and functional outcomes in such cases may benefit from the armamentarium of surgical adjuncts commonly used for surgery of eloquent gliomas such as intraoperative monitoring, awake craniotomy, DTI tractography and further advanced intraoperative brain tumor visualization.