Radio-resistance poses a significant challenge in meningioma treatment. This study aimed to establish radio-resistant meningioma cell lines and uncover molecular mechanisms driving radio-resistance to identify potential biomarkers and therapeutic targets. Radio-resistant meningioma cell lines (IOMM-Lee-RR, CH157-RR) were developed using a progressive radiation dose (cumulative 90 Gy). Cell morphology, radiosensitivity, apoptosis, viability, migration, invasion, cell cycle, and DNA damage repair were analyzed via clonogenic assays, flow cytometry, and Western blotting. Transcriptome sequencing was performed to identify differentially expressed genes (DEGs), followed by KEGG and GO enrichment analyses. Protein-protein interaction (PPI) analysis was conducted to identify hub genes. TK1 expression was further validated in a cohort of 350 meningiomas and the GSE189672 dataset. Radio-resistant meningioma cell lines exhibited enhanced survival, reduced apoptosis, increased cell viability, and superior migratory and invasive abilities compared to parental cells. Under radiation, these cells showed G0/G1 phase accumulation and reduced G2/M phase arrest, along with enhanced DNA repair capacity, as evidenced by lower γ-H2AX expression and fewer DNA damage foci. Transcriptome analysis revealed significant enrichment in metabolic pathways, DNA repair, and cell cycle regulation. Among 34 hub genes identified, TK1 emerged as a key gene, being highly expressed in recurrent and high-grade meningiomas and positively correlated with Ki67. Analysis of the GSE189672 dataset confirmed TK1 as a poor prognostic factor associated with tumor recurrence. Radio-resistant meningioma cells exhibit enhanced DNA repair, migration, invasion, and altered cell cycle dynamics. TK1 was identified as a promising biomarker and therapeutic target for overcoming radio-resistance in meningiomas.

Meningioma is one of the most common primary neoplasms in the central nervous system,whereas there is still no specific molec-ularly targeted therapy that has been approved for the clinical treatment of aggressive meningiomas.There is therefore an urgent demand to decrypt the biological and molecular landscape of malignant meningioma.Here,through the in-silica prescreening and 10-year follow-up of 445 meningioma patients,we uncovered that CBX7 is progressively decreased with malignancy grade and neoplasia stage in meningioma and a high CBX7 expression level predicts a favorable prognosis in meningioma patients.CBX7 restoration significantly induces cell cycle arrest and inhibits meningioma cell proliferation.iTRAQ-based proteomics analysis indicated that CBX7 restoration triggers the metabolic shift from glycolysis to oxidative phosphorylation.The mechanistic study demonstrated that CBX7 promotes the proteasome-dependent degradation of c-MYC proteins by transcriptionally inhibiting the expression of a c-MYC deubiquitinase,USP44,which attenuates c-MYC-mediated transactivation of LDHA transcripts and further inhibits glycolysis and subsequent cellular proliferation.More importantly,the functional role of CBX7 was further confirmed in both subcutaneous and orthotopic meningioma xenografts mouse models and human meningioma patients.Together,our results shed light on the critical role of CBX7 during meningioma malignancy progression and identified the CBX7/USP44/c-MYC/LDHA axis as a promising therapeutic target against meningioma progression.

OBJECTIVE Psammomatous meningiomas (PMs) are a rare histological subtype of meningioma but are rather frequent in spinal meningiomas. The authors aimed to analyze the incidence, clinical features, molecular alterations, long-term outcomes, and prognostic factors of PMs. METHODS In total, 151 patients with PMs were included in this study. Clinical characteristics, molecular alterations, and progression-free survival (PFS) were analyzed in PMs. Clinical characteristics were compared between PMs and other WHO grade 1 meningiomas. Targeted sequencing of meningioma-relevant genes was performed to determine the molecular alterations in PMs. RESULTS PMs accounted for 1.34% of all meningiomas. Clinically, spinal location (p < 0.001) and female predominance (p < 0.001) were statistically significant in PMs when compared with the other grade 1 subtypes. Radiologically, calcification was frequently found in PMs (88.24%). Genetically, NF2 was the most frequently mutated gene in PMs (59.7%), followed by TRAF7 and AKT1. Ten patients experienced recurrence during the long-term follow-up. Multivariate analysis demonstrated that age (p = 0.009), extent of resection (p < 0.001), Ki-67 index (p = 0.007), and NF2 status (p < 0.001) were independent prognostic factors in the cohort of PMs. Interestingly, NF2 mutation was detected in all (48/48) spinal PMs (SPMs) but in only 38.46% (35/91) of cranial PMs (CPMs), revealing a significant difference (p < 0.001). The mean Ki-67 index (p = 0.044) and proportion of PMs with PR-positive expression (p = 0.048) were significantly higher in SPMs than in CPMs. The frequent NF2 mutations are associated with spinal location predominance and worse PFS in PMs. CONCLUSIONS Female sex and spinal location predominance were statistically significant in PMs. NF2 mutation was an independent predictor for worse PFS of PMs. Of note, NF2 mutation was detected in all SPMs but in only 38.46% of CPMs, revealing a significant difference.

Atypical meningiomas could manifest early recurrence after surgery and even adjuvant radiotherapy. We aimed to construct a clinico-radiomics model to predict post-operative recurrence of atypical meningiomas based on clinicopathological and radiomics features. The study cohort was comprised of 224 patients from two neurosurgical centers. 164 patients from center I were divided to the training cohort for model development and the testing cohort for internal validation. 60 patients from center II were used for external validation. Clinicopathological characteristics, radiological semantic, and radiomics features were collected. A radiomic signature was comprised of four radiomics features. A clinico-radiomics model combining the radiomics signature and clinical characteristics was constructed to predict the recurrence of atypical meningiomas. 1920 radiomics features were extracted from the T1 Contrast and T2-FLAIR sequences of patients in center I. The radiomics signature was able to differentiate post-operative patients into low-risk and high-risk groups based on tumor recurrence (P < 0.001). A clinic-radiomics model was established by combining age, extent of resection, Ki-67 index, surgical history and the radiomics signature for recurrence prediction in atypical meningiomas. The model achieved a good prediction performance with the integrated AUC of 0.858 (0.802−0.915), 0.781 (0.649−0.912) and 0.840 (0.747−0.933) in the training, internal validation and external validation cohort, respectively. The present study established a radiomics signature and a clinico-radiomics model with a favorable performance in predicting tumor recurrence for atypical meningiomas.

Abstract Purpose Psammomatous meningiomas (PMs) is a rare histological subtype of meningioma, but is rather frequent in spinal meningiomas. We are aimed to analyze the incidence, clinical features, molecular alterations, long-term outcomes, and prognostic factors of PMs. Methods We enrolled 151 patients with PMs, including 98 cranial PMs (CPMs) and 53 spinal PMs (SPMs), in this study. Clinical characteristics, molecular alterations, and progression-free survival (PFS) were analyzed in PMs. Targeted sequencing of meningioma-relevant genes was performed to determine the molecular alterations in PMs. Results PMs had a significant spinal location (p < 0.001) and female (p < 0.001) predominance, compared with the other grade 1 subtypes, and frequently associated with calcification (88.24%) and NF2 mutation (59.7%). During the long-term follow-up, 10 PMs (4 CPMs and 6 SPMs) recurred. Mutant NF2 was a significant predictor for worse PFS. Interestingly, SPMs exhibited distinct characteristics from CPMs. NF2 mutation was detected in all SPMs (48/48) but only in 38.46% (35/91) of CPMs, revealing a striking difference. Of note, SPMs showed a strong trend towards worse PFS than CPMs (p = 0.067) in all patients but not in patients with NF2 mutation (p = 0.65). The frequent NF2 mutation may have contributed to the spinal location predominance of PMs and worse PFS of SPMs. Conclusion PMs had significant female and spinal location predominance. NF2 mutation was an independent predictor for worse PFS of PMs. Of note, we discovered a striking difference in the rate of NF2 mutation in SPMs vs CPMs, which may have contributed to the spinal location predominance worse PFS of PMs.

-BACKGROUND: Dysregulation of immune infiltration critically contributes to the tumorigenesis and progression of meningiomas. However, the landscape of immune microenvironment and key genes correlated with immune cell infiltration remains unclear. -METHODS: Four Gene Expression Omnibus data sets were included. CIBERSORT algorithm was utilized to analyze the immune cell infiltration in samples. Wilcoxon test, Random Forest algorithm, and Least Absolute Shrinkage and Selection Operator regression were adopted in identifying significantly different infiltrating immune cells and differentially expressed genes (DEGs). Functional enrichment analysis was performed by Kyoto Encyclopedia of Genes and Genomes and Gene Ontology. The correlation between genes and immune cells was evaluated via Spearman's correlation analysis. Receiver Operator Char-acteristic curve analysis evaluated the markers' diagnostic effectiveness. The mRNA-miRNA and Drug-Gene-Immune cell interaction networks were constructed to identify potential diagnostic and therapeutic targets. -CONCLUSIONS: ADCY1 can be identified as a diagnostic marker; ADCY1, BMX, KCNA5, SLCO4A1, and TTR are po-tential therapeutic targets, and their associations with macrophages, neutrophils, NK cells, and plasma cells might impact the tumorigenesis of meningiomas.

OBJECTIVE:Benefits of adjuvant radiotherapy (ART) after gross-total resection (GTR) of de novo atypical meningiomas (AMs) are controversial, and factors predictive of radiotherapy benefits in patients with de novo AMs after GTR are unknown. The authors aimed to evaluate the benefits of ART and explore potential factors sensitizing AMs to ART.METHODS:A total of 231 consecutive patients who were pathologically diagnosed with de novo AMs and treated with GTR (Simpson class I-III resections) from 2010 to 2018 were enrolled in the study. Clinicopathological and prognostic information was collected and analyzed. Univariate and multivariate Cox analyses were used to evaluate prognostic predictors and compare the response to radiotherapy. Propensity score matching (PSM) was used to balance the confounding bias in subgroups.RESULTS:A total of 138 patients (59.74%) received ART. Progesterone receptor (PR) expression was positive in 157 patients (67.97%). During the mean follow-up period of 76.25 months, 65 patients (28.14%) experienced recurrence and 38 (16.45%) died of tumor progression. For disease-specific survival (DSS), ART was a better prognostic factor via univariate (p = 0.003) and multivariate (p = 0.025) analyses. For progression-free survival (PFS), univariate Cox analysis showed that ART improved PFS (p = 0.013), but multivariate analysis did not (p = 0.068). Positive PR expression (p = 0.019), age 53.5 years or younger (p = 0.012), and Ki-67 7.5% or lower (p = 0.025) were independent prognostic predictors for better PFS. In the subcohort analysis, the beneficial impact of ART was observed in the PR-negative cohort (p = 0.002) but not in the PR-positive cohort (p = 0.86). The heterogeneity analysis demonstrated that the PR-negative cohort was more sensitive to ART than the PR-positive cohort (p = 0.036). ART was not found to be associated with better PFS in younger patients (≤ 53.5 years, p = 0.14), older patients (> 53.5 years, p = 0.085), those with a Ki-67 index ≤ 7.5% (p = 0.068), or those with a Ki-67 > 7.5% (p = 0.13). The contrasting effects of ART in the PR-negative versus PR-positive cohorts remained true even after PSM, confirming that PR-negative, but not PR-positive, de novo AMs benefited from ART after GTR.CONCLUSIONS:ART was an independent prognostic factor for DSS of patients with de novo AMs treated with GTR (p = 0.025), but not for PFS (p = 0.068). Negative PR expression was a radiosensitive biomarker on PFS for de novo AM patients after GTR.

Malignant meningiomas often show invasive growth that makes complete tumor resection challenging, and they are more prone to recur after radical resection. Invasive meningioma associated transcript 1 (IMAT1) is a long noncoding RNA located on Homo sapiens chromosome 17 that was identified by our team based on absolute expression differences in invasive and non-invasive meningiomas. Our studies indicated that IMAT1 was highly expressed in invasive meningiomas compared with non-invasive meningiomas. In vitro studies showed that IMAT1 promoted meningioma cell invasion through the inactivation of the Krüppel-like factor 4 (KLF4)/hsa-miR22-3p/Snai1 pathway by acting as a sponge for hsa-miR22-3p, and IMAT1 knockdown effectively restored the tumor suppressive properties of KLF4 by preserving its tumor suppressor pathway. In vivo experiments confirmed that IMAT1 silencing could significantly inhibit the growth of subcutaneous tumors and prolong the survival period of tumor-bearing mice. Our findings demonstrated that the high expression of IMAT1 is the inherent reason for the loss of the tumor suppressive properties of KLF4 during meningioma progression. Therefore, we believe that IMAT1 may be a potential biological marker and treatment target for meningiomas.

BACKGROUND: WHO grade 2 meningiomas, including atypical, chordoid, and clear cell subtypes, form a heterogenous group of meningiomas with varying aggressiveness and clinical behavior. OBJECTIVE: To demonstrate the differences of clinical-histopathological characteristics and long-term outcomes among these 3 subtypes. METHODS: A total of 609 consecutive patients diagnosed with WHO grade 2 meningiomas (543 atypical meningiomas [AMs], 36 chordoid meningiomas [CMs], and 30 clear cell meningiomas [CCMs]) from 2010 to 2018 were enrolled in this study. We compared the clinical-histopathological characteristics and long-term outcomes in these 3 subtypes and assessed survival differences among the subtypes. Targeted panel sequencing of meningioma-relevant genes was performed in the cases of CM. RESULTS: The patients with CCM were significantly younger than those with AM (P < .001) and CM (P = .016). CMs were more likely to receive gross total resection than AMs and CCMs (P = .033). The Ki-67 index was lower (P < .001) while the progesterone receptors-positive rate was higher (P = .034) in CM than in AM and CCM. Importantly, survival analysis demonstrated that CM had better progression-free survival (P = .022) and overall survival (P = .0056) than non-CM tumors. However, the PFS of CM was still worse than WHO grade 1 meningiomas (P < .001). Alterations in NF2 (20.6%) and KMT2C (26.5%) were associated with poorer PFS in CM (P = .013 for NF2; P = .021 for KMT2C). CONCLUSION: Patients with CM had better long-term postoperative outcomes than the other WHO grade 2 subtypes. A lower Ki-67 index, higher PR status, higher extent of resection, and lower frequency of NF2 alteration might contribute to favorable clinical outcomes of CM.

Objective: The aim is to evaluate the clinical, radiological features and long-term outcomes of microcystic meningiomas (MM) in a single neurosurgical center.Methods: A total of 87 consecutive patients underwent surgical resection of MM between 2005 to 2016 were enrolled for analysis. Clinical, pathological, radiological and prognostic information was collected and analyzed; Univariate and multivariate COX analysis was conducted to select factors affected the progression-free survival (PFS). PFS was compared among other Grade 1 subtypes in our center as well.Results: 56 females and 31 males were identified. 12 patients (13.8%) experienced tumor progression. The median PFS was unavailable, and the 5-, 10-, and 15-year PFS rates were 96.9%, 84.0%, and 73.9%, respectively. Peri-tumor brain edema (PTBE) was frequent in MMs (85%). Univariate COX analysis demonstrated that skull base location, STR, and higher Ki-67 were significant negative prognostic factors for PFS (P < 0.05), while tumor location and Ki-67 were independent factors (P < 0.01). MM had a worse prognosis when compared to other WHO Grade 1 subtypes diagnosed in our neurosurgical center during the same time period (P = 0.0087).Conclusions: MM is a rare subtype of grade 1 meningioma, PTBE and reticular enhancement were characteristic in MMs. skull base location and higher Ki-67 labeling index were independent negative prognostic factors. MMs had a shorter PFS than the other WHO Grade 1 subtypes.

To evaluate the clinicopathological characteristics, radiology, and long-term outcomes of microcystic meningiomas (MM) and compare it with other subtypes of meningiomas managed at a single neurosurgical center. A total of 87 consecutive patients who underwent surgical resection and were diagnosed as MM between 2005 and 2016 were enrolled for analysis. Clinicopathological, radiology, and prognostic information was collected and analyzed. Progression free survival (PFS) was compared with 659 patients with other subtypes of WHO grade 1 meningiomas and 167 patients with atypical meningiomas treated during the same period. Fifty six females and 31 males with MM were analyzed. Peri-tumor brain edema was frequent on T2 WI (85%).12 patients (13.8%) experienced tumor progression during the mean follow-up of 101.66 ± 40.92 months. The median PFS was unavailable, and the 5, 10, and 15 year progression-free rates were 96.9%, 84.0%, and 73.9%, respectively. Univariate COX analysis demonstrated skull base location and higher Ki-67 index as significant negative prognostic factors for PFS (P < 0.05); multivariate analysis identified tumor location and Ki-67 index as independent factors (P < 0.01), as well. Of note, the PFS of MM was worse than other WHO grade 1 subtypes (P < 0.001), but better than atypical meningiomas (P < 0.001), and the PFS differences were retained even when the analysis was limited to the patients receiving GTR (P < 0.05). The PFS of MM was worse than other WHO grade 1 subtypes and better than atypical meningiomas. Skull base location and higher Ki-67 index were independent negative prognostic factors in MM.

Purpose To determine if loss of H3K27me3 could predict higher risk of re-recurrence in recurrent meningiomas. Methods A retrospective, single-center cohort study was performed for patients who underwent resection of recurrent grade 1 (N = 132) &2 (N = 32) meningiomas from 2009 to 2013. Association of H3K27me3 staining and clinical parameters was analyzed. Additionally, H3K27me3 staining was performed from 45 patients whose tumors recurred and were resected during the follow-up, to evaluate H3K27me3 change during tumor progression. Survival analysis was performed as well. Results Loss of H3K27me3 expression was observed in 83 patients, comprising 63 grade 1 (47.7%) and 20 grade 2 patients (62.5%). Both grade 1 (p < 0.001) and grade 2 recurrent meningiomas (p < 0.001) had a higher frequency of H3K27me3 loss, compared to de novo meningiomas. 8 of 27 tumors with retained H3K27me3 lost H3K27me3 during re-recurrence (29.6%), while no gain of H3K27me3 was observed in progressive disease from 18 tumors with H3K27me3 loss. Loss of H3K27me3 expression was associated with an earlier re-recurrence in recurrent meningiomas grade 1 and 2 (p < 0.001), and was an independent prognostic factor for PFS in recurrent grade 1 meningiomas (p = 0.005). Conclusion Compared to primary meningiomas, recurrent meningiomas more predominantly had loss of H3K27me3 expression, and further loss can occur during the progression of recurrent tumors. Our results further demonstrated that loss of H3K27me3 predicted shorter PFS in recurrent grade 1 and grade 2 meningiomas. Our work thus supports clinical testing of H3K27me3 in recurrent meningiomas WHO grade 1 and 2.

PurposeThis study aimed to investigate the feasibility of predicting NF2 mutation status based on the MR radiomic analysis in patients with intracranial meningioma. MethodsThis retrospective study included 105 patients with meningiomas, including 60 NF2-mutant samples and 45 wild-type samples. Radiomic features were extracted from magnetic resonance imaging scans, including T1-weighted, T2-weighted, and contrast T1-weighted images. Student's t-test and LASSO regression were performed to select the radiomic features. All patients were randomly divided into training and validation cohorts in a 7:3 ratio. Five linear models (RF, SVM, LR, KNN, and xgboost) were trained to predict the NF2 mutational status. Receiver operating characteristic curve and precision-recall analyses were used to evaluate the model performance. Student's t-tests were then used to compare the posterior probabilities of NF2 mut/loss prediction for patients with different NF2 statuses. ResultsNine features had nonzero coefficients in the LASSO regression model. No significant differences was observed in the clinical features. Nine features showed significant differences in patients with different NF2 statuses. Among all machine learning algorithms, SVM showed the best performance. The area under curve and accuracy of the predictive model were 0.85; the F1-score of the precision-recall curve was 0.80. The model risk was assessed by plotting calibration curves. The p-value for the H-L goodness of fit test was 0.411 (p> 0.05), which indicated that the difference between the obtained model and the perfect model was statistically insignificant. The AUC of our model in external validation was 0.83. ConclusionA combination of radiomic analysis and machine learning showed potential clinical utility in the prediction of preoperative NF2 status. These findings could aid in developing customized neurosurgery plans and meningioma management strategies before postoperative pathology.

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.

BackgroundMeningiomas are the most common primary intracranial tumors in adults. According to the 2021 World Health Organization (WHO) classification of central nervous system tumors, approximately 80% of meningiomas are WHO grade 1, that is, histopathologically benign, whereas about 20% are WHO grade 2 or grade 3, showing signs of atypia or malignancy. The dysregulation of N6-methylation (m6A) regulators is associated with disorders of diverse critical biological processes in human cancer. This study aimed to explore whether m6A regulator expression was associated with meningioma molecular subtypes and immune infiltration.MethodsWe evaluated the m6A modification patterns of 160 meningioma samples based on 19 m6A regulators and correlated them with immune infiltration characteristics. Novel molecular subtypes were defined based on prognostic hub gene expression.ResultsTwo meningioma clusters were identified based on the expression of 19 m6A regulators. In cluster 1, 607 differentially expressed genes (DEGs) were upregulated and 519 were downregulated. A total of 1,126 DEGs comprised three gene expression modules characterized by turquoise, blue, and gray. Functional annotation suggested that the turquoise module was involved in Wnt-related and other important cancer-related pathways. We identified 32 hub genes in this module by constructing a protein–protein interaction network. The meningioma samples were divided into two molecular subtypes. EPN1, EXOSC4, H2AX, and MZT2B not only showed significant differences between meningioma molecular subtypes but also had the potential to be the marker genes of specific meningioma subtypes.Conclusionm6A regulator gene expression may be a novel prognostic marker in meningioma.

Background Adjuvant radiotherapy (RT) is one of the most commonly used treatments for de novo high-grade meningiomas (HGMs) after surgery, but genetic determinants of clinical benefit are poorly characterized. Objective We describe efforts to integrate clinical genomics to discover predictive biomarkers that would inform adjuvant treatment decisions in de novo HGMs. Methods We undertook a retrospective analysis of 37 patients with de novo HGMs following RT. Clinical hybrid capture-based sequencing assay covering 184 genes was performed in all cases. Associations between tumor clinical/genomic characteristics and RT response were assessed. Overall survival (OS) and progression-free survival (PFS) curves were plotted using the Kaplan–Meier method. Results Among the 172 HGMs from a single institution, 42 cases (37 WHO grade 2 meningiomas and five WHO grade 3 meningiomas) were identified as de novo HGMs following RT. Only TERT mutations [62.5% C228T; 25% C250T; 12.5% copy number amplification (CN amp.)] were significantly associated with tumor progression after postoperative RT (adjusted p = 0.003). Potential different somatic interactions between TERT and other tested genes were not identified. Furthermore, TERT alterations (TERT-alt) were the predictor of tumor progression (Fisher’s exact tests, p = 0.003) and were associated with decreased PFS (log-rank test, p = 0.0114) in de novo HGMs after RT. Conclusion Our findings suggest that TERT-alt is associated with tumor progression and poor outcome of newly diagnosed HGM patients after postoperative RT.

Background:Studies have shown mitochondrial genome content (mtDNA content) varies in many malignancies. However, its distribution and prognostic values in high-grade meningioma remain largely unknown. In this retrospective study, we sought to assess a putative correlation between the mtDNA content and clinical characteristics. Methods:Mitochondrial DNA was extracted from 87 World Health Organization grade III meningioma samples using a qPCR method. The distribution of mtDNA content in WHO grade III meningioma and its correlations with clinical variables were assessed. Furthermore, we prognostic values were also determined. Results:Mean mtDNA content was 617.7 (range, 0.8-3000). There was no mtDNA distribution difference based on the histological subtypes (P= 0.07). Tumors with preoperative radiation were associated with lower mtDNA content (P= 0.041), whereas no correlations with other clinical variables were observed. A high mtDNA content was associated with significantly better PFS (P= 0.044) and OS (P= 0.019). However, in patients who received postoperative radiotherapy, low mtDNA content was associated with better PFS (P= 0.028), while no difference in OS was observed (P= 0.272). Low mtDNA content was also associated with better OS and PFS in subgroups of patients with ER negative status (PFS,P= 0.002; OS,P= 0.002). Conclusions:Consistent with other tumors, high mtDNA content was associated with better outcome in WHO grade III meningioma in our cohort. However, for patients who received post-operative radiation therapy, low mtDNA content was associated with better PFS. These findings suggest that mtDNA content may further be explored as a potential biomarker for high-grade meningioma patients and for those who received postoperative radiation therapy.

Objective Adjuvant radiotherapy is the main treatment modality for high grade meningioma after surgical resection; however, recurrence and survival outcomes vary. The aim of this study was to create a new “prognostic score” that allows personalized recommendations for post-operative adjuvant radiotherapy in patients with high grade meningioma. Methods Clinical data were collected from 115 patients with high grade meningioma treated with surgical resection and adjuvant radiotherapy. A prognostic model was built based on the hazards ratios of independent prognostic factors yielded by multivariate cox proportional analysis. Calibration and discrimination of the prognostic score was evaluated using good of fit test and Harrel’s C index, respectively. Results A total of 115 high grade meningioma patients (72 atypical and 43 anaplastic meningiomas) were enrolled. Three factors were independently associated with progression-free survival (PFS): extent of resection (GTR vs. STR), recurrent status (de novo vs. recurrent), and Ki-67 labeling index (<5% vs. ≥ 5%). The respective β-coefficients were used to generate the “prognostic score”. The cohort was divided into low-risk and high-risk groups based on the median prognostic score. Good of fit test showed strong calibration (P = 0.7133) and Harrel’s C index 0.766 indicated a strong discrimination capability of the prognostic score. The Harrel’s C index for OS was 0.60. Conclusions Our prognostic model using three basic clinical parameters robustly separated high grade meningioma patients who benefit vs. do not benefit from adjuvant radiotherapy. External validation of our model is warranted to help improve patient selection suitable for adjuvant radiotherapy.

Abstract Background Meningiomas with Neurofibromin 2 gene mutations (NF2-mutant meningiomas) account for ~40% of the sporadic meningiomas. However, there is still no effective drug treatment for the disease. Methods Expression profile of Merlin protein was explored through immunohistochemistry in a meningioma patient cohort (n = 346). A 20-agent library covering a wide range of meningioma relevant targets was tested using meningioma cell lines IOMM-Lee (NF2 wildtype) and CH157-MN (NF2 deficient). Therapeutic effects and biological mechanisms of the identified compound, ICG-001, in NF2-mutant meningiomas were further characterized in vitro and in patient-derived xenograft (PDX) models. Results Low Merlin expression was associated with meningioma proliferation and poor clinical outcomes in a large patient series. ICG-001, a cAMP-responsive element binding (CREB)-binding protein (CBP) inhibitor, selectively suppressed tumor growth of cells with low Merlin expression. Besides, ICG-001 mediated CH157-MN and IOMM-Lee growth inhibition primarily through robust induction of the G1 cell-cycle arrest. Treatment with ICG-001 alone significantly reduced the growth of NF2-mutant xenografts in mice, as well. We also provide further evidence that ICG-001 inhibits proliferation of NF2-mutant meningioma cells at least partly through attenuating the FOXM1-mediated Wnt/β-catenin signaling. Conclusions This study highlights the importance of ligand-mediated Wnt/β-catenin signaling as well as its drugable potency in NF2-mutant meningioma.

Purpose The aim of this study was to systematically analyze the clinical characteristics of a large cohort of parasagittal meningioma (PM) and to evaluate the patients’ outcomes and best treatment strategies based on tumor features. Methods To minimize selection bias we performed a single-institutional review of PM with restricted criteria. One hundred and ninety-two consecutive patients who met criteria for inclusion were reviewed from 2003 to 2011 in our general hospital. Results A total of 131 cases (68.2%) were with WHO grade I, while grade II and grade III PMs constituted 40 (20.8%) and 21 cases (10.9%). Higher histological grade was associated with loss of trimethylation of H3K27 (P = 0.000). For WHO grade I PMs, GTR was significantly associated with a better PFS (P = 0.023); however, adjuvant radiotherapy did not benefit patients with STR (P = 0.215). For de novo high-grade (WHO grade II and III) PMs (n = 37), adjuvant radiotherapy was associated with a significantly longer OS (P = 0.013), while no difference was observed between GTR and STR (P = 0.654). In recurrent high-grade PM patients (n = 24), GTR combined with adjuvant radiotherapy increased PFS (P = 0.005). Conclusions This study demonstrated that PMs were a heterogeneous group of tumors with a high proportion of high-grade tumors that often displayed aggressive clinical behaviors. Low-grade PM benefited from radical resection, whereas high-grade de novo PM did not. Adjuvant radiotherapy significantly prolonged OS for high-grade primary PM, but did not impact survival of patients with subtotally resected low-grade tumors. Long-term outcome of high-grade recurrent PMs was dismal. We thus show that extent of tumor resection, tumor grade and tumor recurrent status inform therapeutic decisions for PMs.