Survival In Meningioma Research Articles

A 16 year-retrospective study of refractory meningiomas: Prognostic factors and systemic treatments.

2085 Background: Meningiomas are the most common brain tumors, with no established standard systemic treatment for refractory cases after surgical and radiotherapeutic interventions. This study aims to identify prognostic factors for overall survival in refractory meningioma and document patient evolution with systemic treatments. Methods: In a retrospective study, we identified patients with meningioma initially followed at CHUM university hospital between 2006 and 2022. Patients with progression after first-line treatment and over 6 months of follow-up were included. The population was divided into two: group 1 received surgery and/or radiotherapy for progression, and group 2 received additional systemic treatments. Survival analysis with Kaplan-Meier curves and group comparisons (Log-Rank, Fisher's Exact Tests) were conducted. Results: A total of750 patients with meningioma were identified. 99 (13%) progressed after first-line treatment. Among them, 70 (9%) were categorized in group 1 and 29 (4%), in group 2. The median follow-up time from diagnosis was 7.5 years. The overall 10-year survival rate was higher in group 1 compared to group 2 (88% vs 62%). Prognostic factors affecting survival were identified as the following: disease progression after second-line treatment, age ≥ 65 years, and grade 2 or 3. When comparing PFS-1 after first-line treatment, they were similar between group 1 and group 2 (mPFS-1: 2.63 vs 3.49 years; p = 0.421). However, PFS-2 after second-line treatment was significantly shorter in group 2 (mPFS-2 : 12.6 vs 2.3 years ; p < 0.001). Age of ≥ 65 years (10-year survival: 57% vs 89%; p < 0.001) and higher grades (10 year survival: 90% grade 1 vs 58% - grade 2 vs 75% - grade 3; p = 0.027) were associated with lower survival rates. The number of lesions (unique or multiple) and localization (supra or infratentorial) of tumors had no significant impact on survival (p=0.257; p = 0.482). Regarding systemic treatments, 7 patients (25%) received Bevacizumab. It was the treatment associated with the longest PFS (mPFS = 22.5 months) when compared to Hydroxyurea (n=18 [62%], mPFS = 4 months), Somatostatin (n = 5 [17%], mPFS = 8 months), a combination of Hydroxyurea and Somatostatin (n=7 [24%], mPFS = 8 months) and Sunitinib (n=3 [10%], mPFS = 14 months). For patients discontinuing systemic treatment, median survival was 5 months. Systemic treatments were well-tolerated. Among moderate to severe side effects (grade ≥ 2), we documented bradycardia (Somatostatin, n=1), elevated liver enzymes (Sunitinib, n=1), anemia and neutropenia (Hydroxyurea, n=3) and proteinuria (Bevacizumab, n=1). Conclusions: Prognostic factors for survival in meningioma include age ≥ 65 years, grades 2 and 3, and the occurrence of a second progression. Our study highlights Bevacizumab in systemic treatment strategies which was well tolerated in our patients.

Association of county-level socioeconomic status with meningioma incidence and outcomes.

Prior literature suggests that individual socioeconomic status (SES) may influence incidence, treatments, and survival of brain tumor cases. We aim to conduct the first national study to evaluate the association between US county-level SES and incidence, treatment, and survival in meningioma. The Central Brain Tumor Registry of the United States analytic dataset, which combines data from CDC's National Program of Cancer Registries (NPCR) and National Cancer Institute's Surveillance, Epidemiology, and End Results Program, was used to identify meningioma cases from 2006 to 2019. SES quintiles were created using American Community Survey data. Logistic regression models were used to evaluate associations between SES and meningioma. Cox proportional hazard models were constructed to assess the effect of SES on survival using the NPCR analytic dataset. A total of 409 681 meningioma cases were identified. Meningioma incidence increased with higher county-level SES with Q5 (highest quintile) having a 12% higher incidence than Q1 (incidence rate ratios (IRR) = 1.12, 95%CI: 1.10-1.14; P < .0001). The Hispanic group was the only racial-ethnic group that had lower SES associated with increased meningioma incidence (Q5: age-adjusted incidence ratio (AAIR) = 9.02, 95%CI: 8.87-9.17 vs. Q1: AAIR = 9.33, 95%CI: 9.08-9.59; IRR = 0.97, 95%CI: 0.94-1.00; P = .0409). Increased likelihood of surgical treatment was associated with Asian or Pacific Islander non-Hispanic individuals (compared to White non-Hispanic (WNH)) (OR = 1.28, 95%CI: 1.23-1.33, P < .001) and males (OR = 1.31, 95%CI: 1.29-1.33, P < .001). Black non-Hispanic individuals (OR = 0.90, 95%CI: 0.88-0.92, P < .001) and those residing in metropolitan areas (OR = 0.96, 95%CI: 0.96-0.96, P < .001) were less likely to receive surgical treatment compared to WNH individuals. Overall median survival was 137 months, and survival was higher in higher SES counties (Q5 median survival = 142 months). Higher county-level SES was associated with increased meningioma incidence, surgical treatment, and overall survival. Racial-ethnic stratification identified potential disparities within the meningioma population. Further work is needed to understand the underpinnings of socioeconomic and racial disparities for meningioma patients.

NIMG-75. POSTOPERATIVE68GA-DOTATATE/PET-CT IMAGING IS PROGNOSTIC FOR PROGRESSION-FREE SURVIVAL IN MENINGIOMA WHO GRADE 1: A PROSPECTIVE SINGLE-CENTER STUDY

Abstract PURPOSE Microsurgical tumor resection represents the first-line treatment for symptomatic meningiomas, and extent of resection has been shown to be of prognostic importance. Assessment of tumor remnants with somatostatin receptor PET proves to be superior to intraoperative estimation with Simpson grading or MRI. However, prognostic relevance of postoperative PET for progression-free survival in meningiomas remains unclear. METHODS We conducted a prospective study including patients with surgically removed meningioma WHO grade 1 and collected clinical and imaging data. All patients received postoperative MRI and 68Gallium-DOTATATE/PET, and were followed regularly with MRI surveillance scans for detection of tumor recurrence/progression. RESULTS We included 46 patients with 49 tumors. Mean age at diagnosis was 57.8 ± 1.7 years with a male-to-female ratio of 1:1.7. Local tumor progression occurred in 7/49 patients (14%) after a median follow-up of 52 months. Positive PET was associated with an increased risk for progression (*p = 0.015) and a lower progression-free survival (*p = 0.029) whereas MRI was not. 20/20 patients (100%) with negative PET findings remained recurrence-free. Location of recurrence/progression on MRI was adjacent to regions where postoperative PET indicated tumor remnants in all cases. Gross tumor volumes were higher on PET compared to MRI (*p = 0.032). CONCLUSION Our data show that 68Ga-DOTATATE/PET is highly sensitive in revealing tumor remnants in patients with meningioma WHO grade 1. Negative PET findings were associated with a higher progression-free survival, thus improving surveillance. In patients with tumor remnants, additional PET can optimize adjuvant radiotherapy target planning of surgically resected meningiomas.

Unveiling a Biomarker Signature of Meningioma: The Need for a Panel of Genomic, Epigenetic, Proteomic, and RNA Biomarkers to Advance Diagnosis and Prognosis.

Meningiomas are the most prevalent primary intracranial tumors. The majority are benign but can undergo dedifferentiation into advanced grades classified by World Health Organization (WHO) into Grades 1 to 3. Meningiomas' tremendous variability in tumor behavior and slow growth rates complicate their diagnosis and treatment. A deeper comprehension of the molecular pathways and cellular microenvironment factors implicated in meningioma survival and pathology is needed. This review summarizes the known genetic and epigenetic aberrations involved in meningiomas, with a focus on neurofibromatosis type 2 (NF2) and non-NF2 mutations. Novel potential biomarkers for meningioma diagnosis and prognosis are also discussed, including epigenetic-, RNA-, metabolomics-, and protein-based markers. Finally, the landscape of available meningioma-specific animal models is overviewed. Use of these animal models can enable planning of adjuvant treatment, potentially assisting in pre-operative and post-operative decision making. Discovery of novel biomarkers will allow, in combination with WHO grading, more precise meningioma grading, including meningioma identification, subtype determination, and prediction of metastasis, recurrence, and response to therapy. Moreover, these biomarkers may be exploited in the development of personalized targeted therapies that can distinguish between the 15 diverse meningioma subtypes.

Increased expression of leucine-rich α-2 glycoprotein 1 as a predictive biomarker of favorable progression-free survival in meningioma.

Most meningiomas, which are frequent central nervous system tumors, are classified as World Health Organization (WHO) grade 1 because of their slow-growing nature. However, the recurrence rate varies and is difficult to predict using conventional histopathological diagnoses. Leucine-rich α-2 glycoprotein 1 (LRG1) is involved in cell signal transduction, cell adhesion, and DNA repair and is a predictive biomarker in different malignant tumors; however, such a relationship has not been reported in meningiomas. We examined tissue microarrays of histological samples from 117 patients with grade 1 and 2 meningiomas and assessed their clinical and pathological features, including expression of LRG1 protein. LRG1-high meningiomas showed an increased number of vessels with CD3-positive cell infiltration (P = 0.0328) as well as higher CD105-positive vessels (P = 0.0084), as compared to LRG1-low cases. They also demonstrated better progression-free survival (hazard ratio [HR] 0.11, 95% confidence interval [CI] 0.016-0.841) compared to LRG1-low patients (P = 0.033). Moreover, multivariate analysis indicated that high LRG1 expression was an independent prognostic factor (HR, 0.13; 95% CI, 0.018-0.991; P = 0.049). LRG1 immunohistochemistry may be a convenient tool for estimating the prognosis of meningiomas in routine practice. Further studies are required to elucidate the key role of LRG1 in meningioma progression.

P15.11.B POSTOPERATIVE68GA-DOTATATE/PET-CT IMAGING IS PROGNOSTIC FOR PROGRESSION-FREE SURVIVAL IN MENINGIOMA WHO GRADE 1: A PROSPECTIVE SINGLE-CENTER STUDY

Abstract BACKGROUND Microsurgical tumor resection represents the first-line treatment for symptomatic meningiomas, and extent of resection has been shown to be of prognostic importance. Assessment of tumor remnants with somatostatin receptor PET proves to be superior to intraoperative estimation with Simpson grading or MRI. However, prognostic relevance of postoperative PET for progression-free survival in meningiomas remains unclear. METHODS We conducted a prospective study including patients with surgically removed meningioma WHO grade 1 and collected clinical and imaging data. All patients received postoperative MRI and 68Gallium-DOTATATE/PET, and were followed regularly with MRI surveillance scans for detection of tumor recurrence/progression. RESULTS We included 46 patients with 49 tumors. Mean age at diagnosis was 57.8 ± 1.7 years with a male-to-female ratio of 1:1.7. Local tumor progression occurred in 7/49 patients (14%) after a median follow-up of 52 months. Positive PET was associated with an increased risk for progression (*p = 0.015) and a lower progression-free survival (*p = 0.029) whereas MRI was not. 20/20 patients (100%) with negative PET findings remained recurrence-free. Location of recurrence/progression on MRI was adjacent to regions where postoperative PET indicated tumor remnants in all cases. Gross tumor volumes were higher on PET compared to MRI (*p = 0.032). CONCLUSION Our data show that 68Ga-DOTATATE/PET is highly sensitive in revealing tumor remnants in patients with meningioma WHO grade 1. Negative PET findings were associated with a higher progression-free survival, thus improving surveillance. In patients with tumor remnants, additional PET can optimize adjuvant radiotherapy target planning of surgically resected meningiomas.

P.104 Grade 3 meningioma survival, recurrence and functional outcomes in an international multicenter cohort

Background: Meningiomas are the most common intracranial tumor, graded from 1 (benign) to 3 (malignant). The aim of this study was to identify clinical features associated with overall survival (OS), progression-free survival (PFS) and functional status for malignant meningiomas. Methods: Demographic, clinical and histopathological data from grade 3 intracranial meningioma cases were identified in the clinical databases from seven sites in North America and Europe from 1991-2022. Summary statistics and Kaplan-Meier OS and PFS curves were generated. Results: We identified 108 patients, with a median age 65 years (IQR: 52, 72) and 53.7% were female. Median OS was 109 months (95% CIs: 88, 227), and 5-year OS rate was 65% (95% CIs: 56, 76). Median PFS was 38 months (95% CIs: 24, 56) and 5-year PFS rate was 37% (95% CIs: 28, 49). OS and PFS were significantly lower in patients aged ≥65 years. Median preoperative KPS score was 80 (IQR: 70, 90), postoperatively KPS was 90 (IQR: 70, 98) and 1-year follow-up KPS was 70 (IQR: 50, 80). Conclusions: This study provides robust survival, recurrence and functional data for grade 3 meningiomas in North America and Europe over a 30-year period.

Docetaxel targets aggressive methylation profiles and serves as a radiosensitizer in high-risk meningiomas.

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. 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. 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. 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.

Preoperative hematological inflammatory markers associated with grade and survival in Meningiomas

Meningiomas represent the most frequently diagnosed intracranial tumors. Inflammatory cells present in the tumor can modulate both antitumor and protumor functions, and modify the therapeutic response. Hematological inflammatory parameters have provided prognostic information useful in the treatment and clinical evaluation of several tumors. The aim of this study was to evaluate preoperative hematological markers of patients with meningiomas and to relate them to clinical variables and recurrence-regrowth free survival. Eighty-nine patients without corticosteroid therapy were included. Blood test results and tumor characteristics were collected from medical records. Associations between clinical characteristics and the recurrence-regrowth free survival (RFS) were evaluated using Cox proportional hazard analysis and Kaplan-Meier curves. The receiver operating characteristic (ROC) curves were constructed. Of the 89 cases, 73 (82%) were grade I and 16 (18%) grade II. The mean age was 53 ± 13.9 years, with higher frequency in women. Anemia was observed in 23.6% and neutrophilia in 42% of the patients. In univariate analysis, anemia (p = 0.04), neutrophilia (p = 0.02) and neutrophil/lymphocyt ratio (NLR) (p = 0.02) were associated with an increased risk of recurrence-regrowth and shorter RFS. In multivariate analysis, anemia and NLR > 4.1 represented a higher risk of recurrence-regrowth (p = 0.003). The ROC curve analysis showed that only the lymphocyte/monocyte (L/M) > 2.5 was able to predict the tumor grade. The preoperative presence of anemia, neutrophilia, NLR > 4.1 and L/M > 2.5 were associated with a worse prognosis in meningiomas. The use of preoperative hematological inflammatory parameters as prognostic factors can be promissing for evaluation and follow-up of meningiomas.

The effect of socioeconomic status on age at diagnosis and overall survival in patients with intracranial meningioma

Background Intracranial meningiomas are the most common primary tumors of the central nervous system. How socioeconomic status (SES) impacts treatment access and outcomes for brain tumor subtypes is an emerging area of research. Few studies have examined the relationship between SES and meningioma survival and management with reference to relevant clinical factors, including age at diagnosis. We studied the independent effects of SES on receiving surgery and survival probability in patients with intracranial meningioma Methods 54,282 patients diagnosed with intracranial meningioma between 2003 and 2012 from the Surveillance, Epidemiology, and End Results (SEER) Program at the National Cancer Institute database were included. Patient SES was divided into tertiles. Patient age groups included ‘older’ (>65, the median patient age) and ‘younger’. Multivariable linear regression and Cox proportional hazards model were used with SAS v9.4. Results were adjusted for race, sex, and tumor grade. Kaplan–Meier survival curves were constructed according to SES tertiles and age groups. Results Meningioma prevalence increased with higher SES tertile. Higher SES tertile was also associated with younger age at diagnosis (OR = 0.890, p < 0.05), an increased likelihood of undergoing gross total resection (GTR) (OR = 1.112, p < 0.05), and a trend toward greater 5-year survival probability (HR = 1.773, p = 0.0531). Survival probability correlated with younger age at diagnosis (HR = 2.597, p < 0.001), but not with GTR receipt. Conclusion The findings from this national longitudinal study on patients with meningioma suggest that SES affects age at diagnosis and treatment access for intracranial meningiomas patients. Further studies are required to understand and address the mechanisms underlying these disparities.

Programmed death ligand-1 (PD-L1) expression in meningioma; prognostic significance and its association with hypoxia and NFKB2 expression

Management of clinically aggressive meningiomas is a considerable challenge. PD-L1 induced immune suppression has increasingly gained attention in clinical management of cancer; however, to date, the clinical significance and regulatory mechanisms of PD-L1 in meningioma is not yet fully characterized. We sought to characterize PD-L1 expression in meningioma and elucidate its regulatory mechanisms. Immunohistochemical staining of PD-L1 expression in meningiomas showed 43% positivity in both tumor and immune cells and we observed intra and inter tumoral heterogeneity. Univariate and multivariate analyses confirmed that PD-L1 protein expression is an independent prognostic marker for worse recurrence free survival in meningioma. Furthermore, our transcriptomic analysis revealed a strong association between PD-L1 expression and that of NFKB2 and carbonic anhydrase 9 (CA9). We also demonstrated that both of these markers, when co-expressed with PD-L1, predict tumor progression. Our studies on several meningioma cell lines cultured in hypoxic conditions validated the association of CA9 and PD-L1 expression. Here we show the clinical significance of PD-L1 in meningioma as a marker that can predict tumor recurrence. We also show an association PD-L1 expression with NFKB2 expression and its induction under hypoxic conditions. These findings may open new avenues of molecular investigation in pathogenesis of meningioma.

STK11 mutation status is associated with decreased survival in meningiomas.

Emerging evidence suggests that STK11 mutations may influence clinical outcome and response to immunotherapy in cancer. Next-generation targeted sequencing of STK11 mutation status in a large cohort of 188 meningiomas. STK11 loss-of-function mutations were identified in 3.7% of meningiomas. STK11 mutations were found in both low- and high-grade lesions and samples from primary and recurrent disease. There was a 2.8-fold increased risk of death for patients whose meningioma harbored an STK11 mutation, after controlling for lesion grade and occurrence status. The median overall survival for patients with STK11-mutated meningiomas was 4.4years compared with 16.8years. These data identify recurrent STK11 mutations in a subset of meningiomas. Genotyping of STK11 is encouraged for meningioma patients undergoing immunotherapy-based therapy.

Inequalities in Meningioma Survival: Results from the National Cancer Database.

BackgroundMeningiomas are the second most common primary tumors of the central nervous system. However, there is a paucity of literature examining how healthcare, demographic, and socioeconomic factors impact patient outcomes.MethodsWe conducted a retrospective study of 65,812 patients from the National Cancer Database (NCDB; 2004-2012) who received treatment for their meningioma. Univariate and multivariate analyses were performed with the overall five-year survival as the primary outcome, and the following factors: facility type, geography, housing area, patient insurance, sex, ethnicity, race, income, and education. The multivariate model was adjusted for patient age, co-morbidity, tumor size, behavior, and treatment strategy.ResultsDiagnosis and treatment at an academic/research program, private insurance, female sex, Hispanic ethnicity, and high school diploma conferred a survival advantage on both univariate and multivariate analyses.ConclusionsDisparities in survival outcomes in patients with meningiomas exist across multiple healthcare, demographic, and socioeconomic factors. Additional research is needed to elucidate the genetic and environmental factors driving these inequalities.

The prognostic role of Ki-67/MIB-1 in meningioma: A systematic review with meta-analysis.

Ki-67 is a typical immunohistochemical marker for cell proliferation. Higher expression of Ki-67 is correlated with poor clinical outcomes in several cancers. However, the prognostic value of Ki-67 on the prognosis of meningiomas is still controversial. The purpose of this meta-analysis was to evaluate the prognostic value of Ki-67 in meningiomas. We searched Medline and EMBASE from inception to December 31, 2018, to identify relevant articles. Using a fixed or random effects model, pooled hazard ratios (HRs) for overall survival (OS) and disease/progression/recurrence-free survival (D/P/RFS) were estimated. A total of 43 studies, comprising 5012 patients, were included in this analysis. Higher Ki-67 expression levels were significantly associated with worse OS (HR = 1.565; 95% CI: 1.217-2.013) and D/P/RFS (HR = 2.644; 95% CI: 2.264-3.087) in meningiomas. Subgroup analysis revealed that all the included factors (ethnicity, tumor grade, HR sources, definition of cutoffs, cutoff values) for heterogeneity investigation can affect the pooled results. Among them, the definitions of cutoffs and cutoff values factor are the two main contributors toward heterogeneity. Multivariable meta-regression analysis also showed that methodologies used for cutoff value definition contributed to the high inner-study heterogeneity. Higher Ki-67 expression levels negatively influenced survival in meningiomas. A higher cutoff value (>4%) is more appropriate for prognosis prediction. It is highly recommended that Ki-67 expression profile could be assessed in meningiomas treatment for predicting survival. And patients with elevated expression of Ki-67 need to have close follow-ups.

Inequalities in Meningioma Survival: Results from the National Cancer Database

Background: Meningiomas are the second most common primary tumor of the central nervous system, with an incidence of approximately 30,000 new cases per year. However, there is a paucity of literature examining how healthcare, demographic, and socioeconomic factors impact patient survival outcomes. Methods: We conducted a retrospective study of patients from the National Cancer Database (NCDB) diagnosed with meningioma between 2004 and 2012. Univariate and multivariate analysis was performed to investigate the impact of patient, tumor, and treatment factors on overall survival: age, comorbidities, tumor behavior and size, and treatment strategy. Results: Diagnosis and treatment at an academic/research program, private insurance, female sex, Hispanic ethnicity, Asian race, higher median household income, and high school diploma conferred a survival advantage on both univariate and multivariate analyses of the 162,222 patients in the NCDB. Black race was associated with decreased survival on multivariate analysis. Conclusions: Disparities in survival outcomes in patients with meningiomas exist across multiple healthcare, demographic, and socioeconomic factors. Additional research is needed to elucidate the genetic and environmental factors driving these inequalities.

Prognostic significance of preoperative neutrophilia on recurrence-free survival in meningioma.

Meningioma is the most common primary intracranial tumor and recurrence is one of the important challenges in patient management. Prognostic factors for tumor recurrences in these patients especially before surgical resection are not fully characterized. Several studies have indicated an association between changes in hematologic laboratory parameters with patient outcomes in solid malignancies. We aimed to assess the association between hematologic parameters and tumor recurrence in patients with meningioma. Preoperative complete blood count (CBC) data were analyzed in patients with newly diagnosed meningioma (n = 222). Clinical data, including history of corticosteroid therapy, tumor characteristics, and follow-up, were obtained. Recurrence-free survival (RFS) was evaluated using Cox proportional hazards models and log-rank tests. Using preoperative CBC data from patients prior to any steroid therapy, 51 (23%) patients had neutrophilia. In univariate analysis, neutrophilia was significantly associated with meningioma recurrence (hazard ratio [HR] 2.73; P < 0.01). Neither leukocytosis nor lymphocytosis was associated with RFS. In multivariate analysis, after adjusting for tumor grade, tumor size, and extent of resection, neutrophilia remained an independent prognostic factor for RFS (HR 2.23, P = 0.01). Forty-six (21%) patients had low hemoglobin levels indicative of anemia, and the presence of anemia showed a trend toward high risk for recurrence (HR 1.83; P = 0.06). The presence of neutrophilia was associated with higher rate of tumor recurrence in patients with meningioma. Validation of these results and the biologic role of neutrophilic inflammatory/immune reaction in meningioma requires further investigation.

Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma.

Meningioma is the most common primary brain tumor and carries a substantial risk of local recurrence. Methylation profiles of meningioma and their clinical implications are not well understood. We hypothesized that aggressive meningiomas have unique DNA methylation patterns that could be used to better stratify patient management. Samples (n=140) were profiled using the Illumina HumanMethylation450BeadChip. Unsupervised modeling on a training set (n=89) identified 2 molecular methylation subgroups of meningioma (MM) with significantly different recurrence-free survival (RFS) times between the groups: a prognostically unfavorable subgroup (MM-UNFAV) and a prognostically favorable subgroup (MM-FAV). This finding was validated in the remaining 51 samples and led to a baseline meningioma methylation classifier (bMMC) defined by 283 CpG loci (283-bMMC). To further optimize a recurrence predictor, probes subsumed within the baseline classifier were subject to additional modeling using a similar training/validation approach, leading to a 64-CpG loci meningioma methylation predictor (64-MMP). After adjustment for relevant clinical variables [WHO grade, mitotic index, Simpson grade, sex, location, and copy number aberrations (CNAs)] multivariable analyses for RFS showed that the baseline methylation classifier was not significant (p=0.0793). The methylation predictor, however, was significantly associated with tumor recurrence (p<0.0001). CNAs were extracted from the 450k intensity profiles. Tumor samples in the MM-UNFAV subgroup showed an overall higher proportion of CNAs compared to the MM-FAV subgroup tumors and the CNAs were complex in nature. CNAs in the MM-UNFAV subgroup included recurrent losses of 1p, 6q, 14q and 18q, and gain of 1q, all of which were previously identified as indicators of poor outcome. In conclusion, our analyses demonstrate robust DNA methylation signatures in meningioma that correlate with CNAs and stratify patients by recurrence risk.

Mitotic Index is an Independent Predictor of Recurrence-Free Survival in Meningioma.

While World Health Organization (WHO) grading of meningioma stratifies patients according to recurrence risk overall, there is substantial within-grade heterogeneity with respect to recurrence-free survival (RFS). Most meningiomas are graded according to mitotic counts per unit area on hematoxylin and eosin sections, a method potentially confounded by tumor cellularity, as well as potential limitations of accurate mitotic figure detection on routine histology. To refine mitotic figure assessment, we evaluated 363 meningiomas with phospho-histone H3 (Ser10) and determined the mitotic index (number of mitoses per 1000 tumor cells). The median mitotic indices among WHO grade I (n = 268), grade II (n = 84) and grade III (n = 11) tumors were 1, 4 and 12. Classification and regression tree analysis to categorize cut-offs identified three subgroups defined by mitotic indices of 0-2, 3-4 and ≥5, which on univariate analysis were associated with RFS (P < 0.01). In multivariate analysis, mitotic index subgrouped in this manner was significantly associated with RFS (P < 0.01) after adjustment for Simpson grade, WHO grade and MIB-1 index. Mitotic index was then examined within individual WHO grade, showing that for grade I and grade II meningiomas, mitotic index can add additional information to RFS risk. The results suggest that the use of a robust mitotic marker in meningioma could refine risk stratification.