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

Background: Meningiomas are the most frequent primary intracranial tumor. While histological grade and grade of excision are established predictors of recurrence, the predictive ability of other clinical features, such as the role of radical excision of dural attachment and postoperative radiation therapy in intermediate-risk groups, remains unknown., Methods: Clinical and radiological features and surgical details were analyzed in 451 World Health Organization (WHO) grade 1 intracranial meningiomas and 248 WHO grade 2 meningiomas operated on between 2010 and 2015. Outcomes were assessed in 352 WHO grade 1 and 208 WHO grade 2 meningiomas, studying the effect of extent of resection and use of radiation therapy. Kaplan-Meier analysis was used to determine differences in survival by extent of resection and use of postoperative radiation therapy in the treatment of the meningiomas., Results: The mean age of the cohort was 46.3 years, with a female predominance. On univariate analysis, sex, WHO grade, and Simpson grade were significant predictors of recurrence. On multivariate analysis, WHO grade and Simpson grade remained significant predictors of recurrence. Recurrence was significantly associated with poor performance status and mortality. Postoperative radiation significantly improved progression-free survival among patients with grade 2 meningiomas who underwent gross total resection, but not among patients with grade 1 and grade 2 meningiomas who underwent subtotal resection., Conclusions: WHO grade and Simpson grade are independent predictors of recurrence in meningiomas. Regardless of WHO grade, gross total resection must be performed when possible, and postoperative radiation therapy may be recommended in grade 2 meningiomas., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To identify the risk factors and management of the multiple recurrences and reoperations for intracranial meningiomas., Methods: Data of a neurosurgical series of 35 patients reoperated on for recurrent intracranial meningiomas were reviewed. Analyzed factors include patient age and sex, tumor location, extent of resection, WHO grade, Ki67-MIB1 and PR expression at initial diagnosis, time to recurrence; pattern of regrowth, extent of resection, WHO grade and Ki67-MIB1 at first recurrence were also analyzed. All these factors were stratified into two groups based on single (Group A) and multiple reoperations (Group B)., Results: Twenty-four patients (69%) belonged to group A and 11 (31%) to group B. The age < 65 years, male sex, incomplete resection at both initial surgery and first reoperation, and multicentric-diffuse pattern of regrowth at first recurrence are risk factors for multiple recurrences and reoperations. In group B, the WHO grade and Ki67-MIB1 increased in further recurrences in 54% and 64%, respectively. The time to recurrence was short in 7 cases (64%), whereas 4 patients (36%) further recurred after many years. Eight patients (73%) are still alive after 7 to 22 years and 2 to 4 reoperations., Conclusion: The extent of resection and the multicentric-diffuse pattern of regrowth at first recurrence are the main risk factors for multiple recurrences and reoperations. Repeated reoperations might be considered even in patients with extensive recurrent tumors before the anaplastic transformation occurs. In such cases, even partial tumor resections followed by radiation therapy may allow long survival in good clinical conditions., (© 2024. The Author(s).)

Objective: This study was based on MRI features and number of tumor-infiltrating CD8 + T cells in post-operative pathology, in predicting meningioma recurrence risk., Methods: Clinical, pathological, and imaging data of 102 patients with surgically and pathologically confirmed meningiomas were retrospectively analyzed. Patients were divided into recurrence and non-recurrence groups based on follow-up. Tumor-infiltrating CD8 + T cells in tissue samples were quantitatively assessed with immunohistochemical staining. Apparent diffusion coefficient (ADC) histogram parameters from preoperative MRI were quantified in MaZda. Considering the high correlation between ADC histogram parameters, we only chose ADC histogram parameter that had the best predictive efficacy for COX regression analysis further. A visual nomogram was then constructed and the recurrence probability at 1- and 2-years was determined. Finally, subgroup analysis was performed with the nomogram., Results: The risk factors for meningioma recurrence were ADCp1 (hazard ratio [HR] = 0.961, 95% confidence interval [95% CI]: 0.937 ~ 0.986, p = 0.002) and CD8 + T cells (HR = 0.026, 95%CI: 0.001 ~ 0.609, p = 0.023). The resultant nomogram had AUC values of 0.779 and 0.784 for 1- and 2-years predicted recurrence rates, respectively. The survival analysis revealed that patients with low CD8 + T cells counts or ADCp1 had higher recurrence rates than those with high CD8 + T cells counts or ADCp1. Subgroup analysis revealed that the AUC of nomogram for predicting 1-year and 2-year recurrence of WHO grade 1 and WHO grade 2 meningiomas was 0.872 (0.652) and 0.828 (0.751), respectively., Conclusions: Preoperative ADC histogram parameters and tumor-infiltrating CD8 + T cells may be potential biomarkers in predicting meningioma recurrence risk., Clinical Relevance Statement: The findings will improve prognostic accuracy for patients with meningioma and potentially allow for targeted treatment of individuals who have the recurrent form., (© 2024. The Author(s).)

Background: Giant meningiomas may show special features in terms of biological behavior and management. We aimed to research recurrence and mortality of giant meningiomas., Methods: Medical files of patients with meningioma with at least 1 dimension of ≥5 cm in any plane in radiological investigations between December 2012 and January 2022 were retrospectively reviewed. Tumor dimensions were measured on magnetic resonance images except 1. All patients except two underwent clinical follow-up at a mean of 27.19 ± 29.87 (range, 4-112) months., Results: There were 42 patients, 26 (61.9%) women and 16 (38.1%) men who ranged in age from 31 to 85 (mean, 60.31 ± 14.86) years. Headache (57.1%) was the most common symptom. The mean tumor size was 70.14 ± 19.03 (range, 50-152) mm. Tumors were most located at the frontal convexity (40.5%). Simpson grade I resection was achieved in 19% of the cases. The tumors were World Health Organization grade 1 in 74% and grade 2 in 26% of the cases. Major complications developed in 26.1% of the patients. Recurrence happened in 5 (11.9%) cases. The number of World Health Organization grade 2 tumors (P = 0.013; P < 0.05) and tumor size (P = 0.006; P < 0.01) were significantly higher in the recurrent cases. Mortality was % 11.9 and statistically significantly higher in the recurrence group (P = 0.025; P < 0.05)., Conclusions: Giant intracranial meningiomas are challenging because of surgical experience, tumor size, peritumoral edema, blood supply, anatomical changes, and limited visibility. They have a high risk of recurrence and mortality., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Re-irradiation (re-RT) for recurrent intracranial meningiomas is hindered by the limited radiation tolerance of surrounding tissue and the risk of side effects. This study aimed at assessing outcomes, toxicities and prognostic factors in a cohort of patients with recurrent meningiomas re-treated with different RT modalities., Materials and Methods: A multi-institutional database from 8 Italian centers including intracranial recurrent meningioma (RM) patients who underwent re-RT with different modalities (SRS, SRT, PT, EBRT) was collected. Biologically Equivalent Dose in 2 Gy-fractions (EQD2) and Biological Effective Dose (BED) for normal tissue and tumor were estimated for each RT course (α/β = 2 for brain tissue and α/β = 4 for meningioma). Primary outcome was second progression-free survival (s-PFS). Secondary outcomes were overall survival (OS) and treatment-related toxicity. Kaplan-Meier curves and Cox regression models were used for analysis., Results: Between 2003 and 2021 181 patients (pts) were included. Median age at re-irradiation was 62 (range 20-89) and median Karnofsky Performance Status (KPS) was 90 (range 60-100). 78 pts were identified with WHO grade 1 disease, 65 pts had grade 2 disease and 10 pts had grade 3 disease. 28 pts who had no histologic sampling were grouped with grade 1 patients for further analysis. Seventy-five (41.4 %) patients received SRS, 63 (34.8 %) patients SRT, 31 (17.1 %) PT and 12 (6.7 %) EBRT. With a median follow-up of 4.6 years (interquartile range 1.7-6.8), 3-year s-PFS was 51.6 % and 3-year OS 72.5 %. At univariate analysis, SRT (HR 0.32, 95 % CI 0.19-0.55, p < 0.001), longer interval between the two courses of irradiation (HR 0.37, 95 % CI 0.21-0.67, p = 0.001), and higher tumor BED (HR 0.45 95 % CI 0.27-0.76, p = 0.003) were associated with longer s-PFS; in contrast, Ki67 > 5 % (HR 2.81, 95 % CI 1.48-5.34, p = 0.002) and WHO grade > 2 (HR 3.08, 95 % CI 1.80-5.28, p < 0.001) were negatively correlated with s-PFS. At multivariate analysis, SRT, time to re-RT and tumor BED maintained their statistically significant prognostic impact on s-PFS (HR 0.36, 95 % CI 0.21-0.64, p < 0.001; HR 0.38, 95 % CI 0.20-0.72, p = 0.003 and HR 0.31 95 % CI 0.13-0.76, p = 0.01, respectively). Acute and late adverse events (AEs) were reported in 38 (20.9 %) and 29 (16 %) patients. Larger tumor GTV (≥10 cc) was significantly associated with acute and late toxicity (p < 0.001 and p = 0.009, respectively)., Conclusions: In patients with recurrent meningiomas, reirradiation is a feasible treatment option associated with acceptable toxicity profile. Prognostic factors in the decision-making process have been identified and should be incorporated in daily practice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Meningiomas are the most common primary intracranial tumors in adults. Although benign in a majority of cases, they have a variable clinical course and may recur even after a thorough surgical resection. Ki-67, a nuclear protein involved in cell cycle regulation, has been widely studied as a marker of cellular proliferation in various cancers. However, the prognostic significance of Ki-67 in meningiomas remains controversial. Here, we investigate the Ki-67 index, as a predictive marker of meningioma recurrence following surgical resection and compare it to established prognostic markers such as WHO grade and degree of resection., Methods: The medical records of 451 patients with previously untreated cranial meningiomas who underwent resections from January 2011 to January 2021 at North Shore University Hospital (NSUH) were reviewed. Collected data included WHO grade, Ki-67 proliferative index, degree of resection - gross (GTR) vs subtotal (STR) - as judged by the surgeon, tumor location, and meningioma recurrence. This study was approved by the NSUH Institutional Review Board IRB 21-1107., Results: There were 290 patients with grade I, 154 with grade II, and 7 with grade III meningiomas. The average post-resection follow-up period was 4 years, and 82 tumors (18 %) recurred. Higher WHO grades were associated with higher rates of recurrence, with rates of 11.4 %, 27.9 %, and 71.4 % for grades 1, 2, and 3, respectively, and subtotal resection corresponded to a higher rate of recurrence than total resection (34.3 % and 13.4 %, respectively). Higher WHO grades also correlated with higher Ki-67 scores (2.59, 10.01, and 20.71) for grades 1, 2, and 3, respectively. A multivariate logistic regression model identified Ki-67 and degree of resection as independent predictive variables for meningioma recurrence, with Ki-67 specifically predicting recurrence in the WHO grade II subset when analyzed separately for WHO grades I and II., Conclusion: Our 10-year retrospective study suggests that the Ki-67 index is an important predictive marker for recurrence of intracranial meningiomas following surgical resection, particularly among patients with WHO grade II tumors. Our findings add to a growing body of data that support inclusion of Ki-67 index in the WHO grading criteria for patients with meningiomas., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: To study each atypical feature in atypical meningioma versus other grade 2 meningiomas and its possible relation to recurrence., Methods: This is a retrospective study of patients with WHO grade 2 meningioma operated in our institution between 01/2008 and 12/2020. The rate of recurrence, reoperation and readmission were recorded during the follow-up period. A statistical analysis was done to determine the significance of each pathological feature in regard to recurrence., Results: A total of 74 patients were included as WHO grade 2 meningioma with 60 (81%) patients having an AM and 14 (19%) patients with chordoid or clear cell meningioma. The mean age was 51 years±14. The most common location was meningioma abutting the frontal lobe (convexity). Major atypical features were more noted in the AM, however, there was no significant difference between AM and other types of meningioma. Increased Nuclear cytoplasmic ratio and cellularity were found significantly more in AM. The recurrence rate was 16.2%. No specific pathology feature (major or minor) nor the type of Grade 2 meningioma was significantly related to recurrence., Conclusion: The types of WHO grade 2 meningiomas have similar prognosis and recurrence rates. There is no significant difference between the atypical features in indicating a more aggressive nature or risk of recurrence in grade 2 meningiomas., (Copyright: © Neurosciences.)

Purpose: Several retrospective studies and meta-analyses of Peptide Radionuclide Radiation Therapy in meningiomas suggest six-month progression-free survival improvement for WHO grade 1 and 2 meningiomas. In the present study, we aimed to evaluate the impact of such treatment on three-dimensional volume growth rate (3DVGR) in nonanaplastic meningiomas., Methods: The authors performed a retrospective study including eight patients treated with Lutathera®. Millimetric 3D T1-weighted with gadolinium enhancement magnetic resonance imaging sequences were requested for volume measurement. Then, tumor growth rate was classified following a previously described 3DVGR classification (Graillon et al.)., Results: Patients harbored seven WHO grade 2 meningiomas and one aggressive WHO grade 1. All patients, except one, underwent four treatment cycles. 3DVGR significantly decreased at 3, 6, and 12 months after treatment initiation analyzing each lesion separately. Mean and median 3DVGR from all patients were respectively at 29.5% and 44.5%/6 months before treatment initiation, then at 16.5% and 25%/6 months at three months post-treatment initiation, 9.5% and 4.5%/6 months after 6 months, as well as 9.5% and 10.5%/6 months after 12 months. At 3, 6, and 12 months after treatment initiation, 4/8, 6/7, and 5/6 patients were class 2 (stabilization or severe 3DVGR slowdown), respectively. No patient was class 1 at 6 and 12 months, suggesting a lack of drug response., Conclusion: In nonanaplastic meningiomas, Lutathera®'s antitumoral activity appeared delayed and more likely observed at six months, while no major response was observed under treatment. Moreover, its antitumoral activity persisted for 12-18 months following treatment initiation., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Rationale and Objectives: Tumor progression and recurrence（P/R）after surgical resection are common in meningioma patients and can indicate poor prognosis. This study aimed to investigate the values of clinicopathological information and preoperative magnetic resonance imaging (MRI) radiomics in predicting P/R and progression-free survival (PFS) in meningioma patients., Methods and Materials: A total of 169 patients with pathologically confirmed meningioma were included in this study, 54 of whom experienced P/R. Clinicopathological information, including age, gender, Simpson grading, World Health Organization (WHO) grading, Ki-67 index, and radiotherapy history, as well as preoperative traditional radiographic findings and radiomics features for each MRI modality (T1-weighted, T2-weighted, and enhanced T1-weighted images) were initially extracted. After feature selection, the optimal performance was estimated among the models established using different feature sets. Finally, Cox survival analysis was further used to predict PFS., Results: Ki-67 index, Simpson grading, WHO grading, and radiotherapy history were found to be independent predictors for P/R in the multivariate regression analysis. This clinicopathological model had an area under the curve (AUC) of 0.865 and 0.817 in the training and testing sets, respectively. The performance of the combined radiomics model reached 0.85 and 0.84, respectively. A clinicopathological-radiomics model was then established, which significantly improved the prediction of meningioma P/R (AUC = 0.93 and 0.88, respectively). Finally, the risk ratio was estimated for each selected feature, and the C-index of 0.749 was obtained., Conclusion: Radiomics signatures of preoperative MRI have the ability to predict meningioma at the risk of P/R. By integrating clinicopathological information, the best performance was achieved., Competing Interests: Declaration of Competing Interest The authors C.H., F.L., and H.D. were employed by Beijing Deepwise & League of PHD Technology Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: Meningiomas show variable tendency to recur. While risk factors of recurrence have been largely investigated in literature, a paucity of data is available on the time to recurrence. Our purpose was to identify main factors affecting the time to recurrence to assist preoperative treatment decision-making strategy and to define a tailored clinical and neuroradiological follow-up., Methods: Data of 35 patients with intracranial meningioma recurrences have been retrospectively reviewed. Demographic (patient age at initial diagnosis and sex), radiologic (meningioma location, pattern of regrowth and topography of recurrences at first reoperation), pathologic (WHO grade and Ki67-MIB1 at initial surgery and at first reoperation, progesterone receptor [PR] expression), and surgical (extent of resection at initial surgery according to Simpsons grading system, number of reoperations) factors were analyzed., Results: Time to recurrence ranged from 20 to 120 months. Extent of resection at initial surgery was Simpson grade I in 7 patients (20%), grade II in 10 (28.5%), grade III in 14 (40%), and grade IV in 4 (11.5%). Longer median time to recurrence was observed for skull base localization (P < 0.01), Simpson grades I and II versus grades III (P = 0.01) and IV (P = 0.02), values of Ki67-MIB1 ≤ 4% (P = 0.001), and PR > 60% (P = 0.03); conversely, sex, age, number of reoperations, unchanged/progression of Ki67, and/or World Health Organization grade between first surgery and reoperation did not correlate in statistically significant way with time to recurrence., Conclusions: The extent of resection and the Ki67-MIB1 represent the most important factors predicting shorter recurrence time of intracranial meningiomas. Patients with incomplete (Simpson grades III and IV) resection and high Ki67-MIB1 values, especially at non-skull base localization and with low PR values, require a closer short-term clinical and radiologic follow-up in the first years after surgery., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

WHO grade I meningiomas occasionally show regrowth after radiosurgical treatment, which cannot be predicted by clinical features. There is increasing evidence that certain biomarkers are associated with regrowth of meningiomas. The aim of this retrospective study was to asses if these biomarkers could be of value to predict regrowth of WHO grade I meningiomas after additive radiosurgery. Forty-four patients with WHO grade I meningiomas who underwent additive radiosurgical treatment between 2002 and 2015 after Simpson IV resection were included in this study, of which 8 showed regrowth. Median follow-up time was 64 months (range 24-137 months). Tumors were analyzed for the proliferation marker Ki-67 by immunohistochemistry and for deletion of 1p36 by fluorescence in situ hybridization (FISH). Furthermore, genomic DNA was analyzed for promoter hypermethylation of the genes NDRG1-4, SFRP1, HOXA9 and MGMT. Comparison of meningiomas with and without regrowth after radiosurgery revealed that loss of 1p36 (p = 0.001) and hypermethylation of NDRG1 (p = 0.046) were correlated with regrowth free survival. Loss of 1p36 was the only parameter that was significantly associated with meningioma regrowth after multivariate analysis (p = 0.01). Assessment of 1p36 loss in tumor tissue prior to radiosurgery might be considered an indicator of prognosis/regrowth. However, this finding has to be validated in an independent larger set of tumors., (© 2021. The Author(s).)

Background: Atypical meningiomas exhibit a high tendency for tumor recurrence even after multimodal therapy. Information regarding recurrence patterns after additive radiotherapy is scarce but could improve radiotherapy planning and therapy decision. We conducted an analysis of recurrence patterns with regard to target volumes and dose coverage assessing target volume definition and postulated areas of tumor re-growth origin. Prognostic factors contributing to relapse were evaluated., Methods: The clinical outcome of patients who had completed additive, somatostatin receptor (SSTR)-PET/CT-based fractionated intensity-modulated radiotherapy for atypical meningioma between 2007 and 2017 was analyzed. In case of tumor recurrence/progression, treatment planning was evaluated for coverage of the initial target volumes and the recurrent tumor tissue. We proposed a model evaluating the dose distribution in postulated areas of tumor re-growth origin. The median of proliferation marker MIB-1 was assessed as a prognostic factor for local progression and new distant tumor lesions., Results: Data from 31 patients who had received adjuvant (n = 11) or salvage radiotherapy (n = 20) were evaluated. Prescribed dose ranged from 54.0 to 60.0 Gy. Local control at five years was 67.9%. Analysis of treatment plans of the eight patients experiencing local failure proved sufficient extent of target volumes and coverage of the prescribed dose of at least 50.0 Gy as determined by mean dose, D98, D2, and equivalent uniform dose (EUD) of all initial target volumes, postulated growth-areas, and areas of recurrent tumor tissue. In all cases, local failure occurred in high-dose volumes. Tumors with a MIB-1 expression above the median (8%) showed a higher tendency for re-growth., Conclusions: The model showed adequate target volume and relative dose distribution but absolute dose appears lower in recurrent tumors without reaching statistical significance. This might provide a rationale for dose escalation studies. Biological factors such as MIB-1 might aid patients' stratification for dose escalation.

Simpson grading of resection has been used as a predictor of intracranial meningioma (IM) recurrence. Histopathological findings, like the Ki-67/MIB-1 labeling index, may be useful in the assessment risk of recurrence. Our objective was to analyze the predictive value of meningioma recurrence using both parameters. We retrospectively studied 322 consecutive patients with histopathological diagnosis of IM WHO grade I and 43 patients with IM WHO grade II in a 13-year period. Multivariate survival analysis was performed. In the WHO grade I IM group, recurrence was observed in 28 patients (8.69%). The Cox regression model for WHO grade I IM, provided a significative hazard ratio (HR) for Ki-67/MIB-1 index ≥3 (HR = 36.35, p < 0.001) and Simpson's grading resection, grade II (HR = 2.03, p = 0.045), grade III (HR = 3.41, p = 0.034) and grade IV (HR = 19.75, p ≥ 0.001). In the WHO grade II IM group, recurrence was observed in 10 patients (23.25%). The Cox regression model for WHO grade II IM, provided a significative hazard ratio (HR) for Ki-67/MIB-1 index ≥3% (HR = 1.66, p < 0.001) and Simpson's grading resection grade III (HR = 3.96, p = 0.027). The Kaplan-Meier survival curve showed a similar distribution of survival between WHO grade I IM with Ki-67/MIB-1 ≥3% and WHO grade II IM. In WHO grade I meningiomas, the Ki-67/MIB-1 index and Simpson grading were both independent predictors of recurrence. A similar management protocol should be advisable for WHO grade I with Ki-67/MIB-1 ≥3% and WHO grade II meningiomas., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Despite optimal surgical resection, meningiomas may recur, with increasing grade and the degree of resection being predictive of risk. We hypothesize that an increasing Ki67 correlates with a higher risk of recurrence of resected WHO grade I meningiomas., Methods: The study population consisted of patients with resected WHO grade 1 meningiomas in locations outside of the base of skull. Digitally scanned slides stained for Ki67 were analyzed using automatic image analysis software in a standardized fashion., Results: Recurrence was observed in 53 (17.7%) of cases with a median follow up time of 25.8 months. Ki67 ranged from 0 to 30%. Median Ki67 was 5.1% for patients with recurrence and 3.5% for patients without recurrence. In unadjusted analyses, high Ki-67 (≥ 5 vs. < 5) vs. ≥ 5) was associated with over a twofold increased risk of recurrence (13.1% vs. 27% respectively; HR 2.1731; 95% CI [1.2534, 3.764]; p = 0.006). After Adjusting for patient or tumor characteristics, elevated Ki-67 remained significantly correlated with recurrence. Grade 4 Simpson resection was noted in 71 (23.7%) of patients and it was associated with a significantly increased risk of recurrence (HR 2.56; 95% CI [1.41, 4.6364]; p = 0.002)., Conclusions: WHO grade 1 meningiomas exhibit a significant rate of recurrence following resection. While Ki-67 is not part of the WHO grading criteria of meningiomas, a value greater than 5% is an independent predictor for increased risk of local recurrence following surgical resection.

Objective: Meningiomas of the anterior clinoid process (ACP) present significant surgical challenges given their anatomic relation to critical neurovascular structures. Routine anterior clinoidectomy is often described as a critical step in the resection of these tumors to reduce recurrence and improve visual outcomes. Anterior clinoidectomy, however, is not without risk and its benefits have not been clearly delineated. We present the outcomes of our series of surgically managed ACP meningiomas in which an anterior clinoidectomy was not routinely employed., Methods: A retrospective review of all ACP meningiomas operated on between August 1997 and March 2019 was conducted. Patients with a recurrent tumor or with <6 months of follow-up were excluded. Resection was typically carried out via a frontotemporal craniotomy followed by intradural removal of the tumor. Anterior clinoidectomy was only performed if hyperostosis of the ACP caused mass effect on the optic nerve., Results: Twenty-nine patients were included in this study. Anterior clinoidectomy was performed in 3 patients (10.3%). Gross total resection was achieved in 22 patients (75.9%). Of the 21 patients (72.4%) who presented with visual deficits, vision improved in 18 patients (85.7%) and worsened in 2 (9.5%). Tumor recurrence occurred in 5 patients (17.2%) at a mean follow-up of 64.9 months. Perioperative morbidity was 10.3%. Permanent morbidity and mortality were 6.9% (vision deterioration) and 0%, respectively., Conclusions: Resection of ACP meningiomas without routine anterior clinoidectomy minimizes potential risk while achieving gross total resection, recurrence, and visual improvement rates comparable with those in previously reported series., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Traditionally patient owners express their concerns that surgical or diagnostic procedures on a tumor may induce metastasis. In pets, this has been documented in only very rare occasions, e. g. needle path metastases after diagnostic fine needle biopsies of urinary bladder or prostatic tumors. Here, we describe a case of subcutaneous seeding of a feline intracranial grade 1 meningioma 6 months after surgical resection. A 10-year-old male neutered domestic shorthaired cat with typical neurological signs was diagnosed with an extra-axial contrast enhancing mass in the dorsal frontotemporal lobes using magnetic resonance imaging (MRI). Transfronto-parietal bone craniotomy was performed and the 24 × 19 × 22 mm large tumor was largely removed. Tumor recurrence after 12 months resulted in a second surgical tumor removal. In addition, 2 subcutaneous masses of 10 × 4 × 4 mm in size were removed at the site of the original surgical site which were fully separated from the recurring meningeal tumor by the intact frontal bone. Histology and immunohistochemistry suggested the same tumor growth in all 4 masses. Most likely the tumor seeding had been caused during the first surgery. After all, the risk of surgical seeding of a benign tumor seems very low., Competing Interests: The authors confirm that they do not have any conflict of interest., (Thieme. All rights reserved.)

The systematic adoption of the histopathologic criteria provided by the 2016 update of the WHO classification of brain tumors has markedly increased the relative proportion of atypical and anaplastic meningiomas. These tumors exhibit a much greater recurrence rate compared to benign meningiomas, which negatively impacts survival. In recent years, the publication of numerous retrospective case series, yet no randomized controlled trials, on the impact of radiation therapy in non-benign meningioma, has yielded conflicting evidence. At present, maximum safe resection, including the dural attachment, is the preferred primary treatment modality for all types of meningiomas. Adjuvant radiotherapy is currently recommended for subtotally resected grade II and for all grade III meningiomas. However, in grade II meningiomas achieving complete resection, close radiologic and clinical observation is a feasible option. Despite the great amount of non-benign meningiomas available and eligible for trials, there is a striking lack of prospective studies testing adjuvant therapies against observation for this subset of patients. An updated and systematic literature review is provided on the effectiveness and indications of radiotherapy on grade II and III meningiomas.

Background: For meningiomas, complete resection is recommended as first-line treatment while stereotactic radiosurgery (SRS) is established for meningiomas of smaller size considered inoperable. If the patient´s medical condition or preference excludes surgery, SRS remains a treatment option. We evaluated the efficacy and safety of SRS in a cohort comprising these cases., Methods: In this retrospective single-centre analysis we included patients receiving single fraction SRS either by modified LINAC or robotic guidance by Cyberknife for potentially resectable intracranial meningiomas. Treatment-related adverse events as well as local and regional control rates were determined from follow-up imaging and estimated by the Kaplan-Meier method., Results: We analyzed 188 patients with 218 meningiomas. The median radiological, and clinical follow-up periods were 51.4 (6.2-289.6) and 55.8 (6.2-300.9) months. The median tumor volume was 4.2 ml (0.1-22), and the mean marginal radiation dose was 13.0 ± 3.1 Gy, with reference to the 80.0 ± 11.2% isodose level. Local recurrence was observed in one case (0.5%) after 239 months. The estimated 2-, 5-, 10- and 15-year regional recurrence rates were 1.5%, 3.0%, 6.6% and 6.6%, respectively. Early adverse events (≤ 6 months after SRS) occurred in 11.2% (CTCEA grade 1-2) and resolved during follow-up in 7.4% of patients, while late adverse events were documented in 14.4% (grade 1-2; one case grade 3). Adverse effects (early and late) were associated with the presence of symptoms or neurological deficits prior to SRS (p < 0.03) and correlated with the treatment volume (p < 0.02)., Conclusion: In this analysis SRS appears to be an effective treatment for patients with meningiomas eligible for complete resection and provides reliable long-term local tumor control with low rates of mild morbidity.

Purpose: TERT promoter mutation (TERTp Mut ) has a strong association to recurrence and has been suggested to act as a driver mutation for malignant transformation of WHO grade I and II meningiomas. TERTp Mut has been investigated in selected high-grade meningioma samples. The existence of TERTp Mut across recurrent tumors in a population-based cohort needs to be investigated in order to identify when TERTp Mut emerges across recurrent samples and to validate prognostic impact among WHO grade III tumors., Methods: We gathered material from a consecutive single-center cohort of 40 patients with malignant meningioma (WHO grade III) treated between 2000 and 2018, including specimens from primary and secondary malignant meningiomas with the corresponding earlier benign specimens and later malignant recurrences. In total 107 tumor samples were studied by Sanger sequencing for TERT promoter mutational status., Results: Seven of 40 patients (17.5%) harbored TERTp Mut thus validating the incidence of TERTp Mut in previous non-population-based cohorts. In 6/7 patients, the TERTp Mut was present at initial surgery (WHO grade I-III) while in one patient the TERTp Mut was found de novo when the meningioma became malignant. The incidences were 2/1.000.000/year for TERTp Mut WHO grade III meningioma and 8/1.000.000/year for TERTp wt WHO grade III meningioma in our catchment area. We found a 1.7 times higher recurrence rate (CI 95% 0.65-4.44) and a 2.5 higher mortality rate per 10 person-years (CI 95% 1.01-6.19) for TERTp Mut compared to TERTp wt ., Conclusion: TERTp Mut can occur independently of malignant progression in meningioma and was most often present from the first tumor sample across recurring tumors. TERTp Mut in WHO grade III may represent a marker of an aggressive subset of tumors., (© 2020 International Society of Neuropathology.)

Background: Meningiomas are the most common tumors occurring in the central nervous system, with variable recurrence rates depending on World Health Organization grading. Atypical (Grade II) meningioma has a higher rate of recurrence than benign (Grade I) meningioma. The efficacy of adjuvant radiotherapy (RT) to improve tumor control has been questioned., Objective: To investigate clinical and histopathological predictors of tumor recurrence and radio-resistance in atypical meningiomas., Methods: This cohort study retrospectively reviewed all patients in St. Michael's Hospital CNS tumor patient database who underwent surgical resection of a Grade II meningioma from 1995 to 2015. Cases with neurofibromatosis type II, multiple satellite tumors, spinal cord meningioma, radiation-induced meningioma, and perioperative death were excluded. Patient demographics, neuropathological diagnosis, tumor location, extent of resection, radiation therapy, and time to recurrence or progression were recorded. Cox univariate regression and Kaplan-Meier survival analysis were employed to identify risk factors for recurrence and radio-resistance., Results: Among 181 patients, the combination of necrosis and brain invasion was associated with an increased recurrence risk (hazard ratio [HR] = 4.560, P = .001) and the lowest progression-free survival (PFS) relative to other pathological predictors. This trend was maintained after gross total resection (GTR, P = .001). RT was associated with decreased PFS (P = .001), even in patients who received GTR (P = .001)., Conclusion: The combination of necrosis and brain invasion is a strong predictor of tumor recurrence and radio-resistance in meningioma, regardless of EOR or adjuvant RT. Our findings question the sensibility of brain invasion as an absolute criterion for Grade II status., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Background: Prognostic markers for meningioma are needed to risk-stratify patients and guide postoperative surveillance and adjuvant therapy., Objective: To identify a prognostic gene signature for meningioma recurrence and mortality after resection using targeted gene-expression analysis., Methods: Targeted gene-expression analysis was used to interrogate a discovery cohort of 96 meningiomas and an independent validation cohort of 56 meningiomas with comprehensive clinical follow-up data from separate institutions. Bioinformatic analysis was used to identify prognostic genes and generate a gene-signature risk score between 0 and 1 for local recurrence., Results: We identified a 36-gene signature of meningioma recurrence after resection that achieved an area under the curve of 0.86 in identifying tumors at risk for adverse clinical outcomes. The gene-signature risk score compared favorably to World Health Organization (WHO) grade in stratifying cases by local freedom from recurrence (LFFR, P < .001 vs .09, log-rank test), shorter time to failure (TTF, F-test, P < .0001), and overall survival (OS, P < .0001 vs .07) and was independently associated with worse LFFR (relative risk [RR] 1.56, 95% CI 1.30-1.90) and OS (RR 1.32, 95% CI 1.07-1.64), after adjusting for clinical covariates. When tested on an independent validation cohort, the gene-signature risk score remained associated with shorter TTF (F-test, P = .002), compared favorably to WHO grade in stratifying cases by OS (P = .003 vs P = .10), and was significantly associated with worse OS (RR 1.86, 95% CI 1.19-2.88) on multivariate analysis., Conclusion: The prognostic meningioma gene-expression signature and risk score presented may be useful for identifying patients at risk for recurrence., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Meningiomas, the most common adult brain tumors, recur in up to half of cases. This requires timely intervention and therefore accurate risk assessment of recurrence is essential. Our current practice relies heavily on histological grade and extent of surgical excision to predict meningioma recurrence. However, prediction accuracy can be as poor as 50% for low or intermediate grade tumors which constitute the majority of cases. Moreover, attempts to find molecular markers to predict their recurrence have been impeded by low or heterogenous genetic signal. We therefore sought to apply systems-biology approaches to transcriptomic data to better predict meningioma recurrence. We apply gene co-expression networks to a cohort of 252 adult patients from the publicly available genetic repository Gene Expression Omnibus. Resultant gene clusters ("modules") were represented by the first principle component of their expression, and their ability to predict recurrence assessed with a logistic regression model. External validation was done using two independent samples: one merged microarray-based cohort with a total of 108 patients and one RNA-seq-based cohort with 145 patients, using the same modules. We used the bioinformatics database Enrichr to examine the gene ontology associations and driver transcription factors of each module. Using gene co-expression analysis, we were able predict tumor recurrence with high accuracy using a single module which mapped to cell cycle-related processes (AUC of 0.81 ± 0.09 and 0.77 ± 0.10 in external validation using microarray and RNA-seq data, respectively). This module remained predictive when controlling for WHO grade in all cohorts, and was associated with several cancer-associated transcription factors which may serve as novel therapeutic targets for patients with this disease. With the easy accessibility of gene panels in healthcare diagnostics, our results offer a basis for routine molecular testing in meningioma management and propose potential therapeutic targets for future research.

Background: Meningioma growth rates are highly variable, even within benign subgroups, with some remaining stable, whereas others grow rapidly., Objective: To identify molecular-genetic markers for more accurate prediction of meningioma recurrence and better-targeted therapy., Methods: Microarrays identified microRNA (miRNA) expression in primary and recurrent meningiomas of all World Health Organization (WHO) grades. Those found to be deregulated were further validated by quantitative real-time polymerase chain reaction in a cohort of 172 patients. Statistical analysis of the resulting dataset revealed predictors of meningioma recurrence., Results: Adjusted and nonadjusted models of time to relapse identified the most significant prognosticators to be miR-15a-5p, miR-146a-5p, and miR-331-3p. The final validation phase proved the crucial significance of miR-146a-5p and miR-331-3p, and clinical factors such as type of resection (total or partial) and WHO grade in some selected models. Following stepwise selection in a multivariate model on an expanded cohort, the most predictive model was identified to be that which included lower miR-331-3p expression (hazard ratio [HR] 1.44; P < .001) and partial tumor resection (HR 3.90; P < .001). Moreover, in the subgroup of total resections, both miRNAs remained prognosticators in univariate models adjusted to the clinical factors., Conclusion: The proposed models might enable more accurate prediction of time to meningioma recurrence and thus determine optimal postoperative management. Moreover, combining this model with current knowledge of molecular processes underpinning recurrence could permit the identification of distinct meningioma subtypes and enable better-targeted therapies., (© Congress of Neurological Surgeons 2020.)

Background: Falcine meningiomas have unique characteristics including their high rates of recurrence, association with high grade pathology, increased male prevalence, and potential for diffuse involvement of the falx., Objective: To address these issues in a substantial series of falcine meningiomas and report on the impact of extent of resection for this distinct meningioma entity., Methods: Retrospective analysis of characteristics and outcomes of 59 falcine meningioma patients who underwent surgery with the senior author. A "Grade Zero" category was used when an additional resection margin of 2 to 3 cm from the tumor insertion was achieved., Results: For de novo falcine meningiomas, gross total resection (GTR) was associated with significantly decreased recurrence incidence compared with subtotal resection (P ≤ .0001). For recurrent falcine meningiomas, median progression-free survival (PFS) was significantly improved for GTR cases (37 mo vs 12 mo; P = .017, hazard ratio (HR) .243 (.077-.774)). "Grade Zero" resection demonstrated excellent durability for both de novo and recurrent cases, and PFS was significantly improved with "Grade Zero" resection for recurrent cases (P = .003, HR 1.544 (1.156-2.062)). The PFS benefit of "Grade Zero" resection did not achieve statistical significance over Simpson grade 1 during the limited follow-up period (mean 2.8 yr) for these groups., Conclusion: The recurrence of falcine meningiomas is related to the diffuse presence of tumor between the leaflets of the falx. Increased extent of resection including, when possible, a clear margin of falx surrounding the tumor base was associated with the best long-term outcomes in our series, particularly for recurrent tumors., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Background: Atypical and anaplastic meningiomas (AAMs) are rare and comprise approximately 5% of all meningiomas. Extracranial metastases in meningioma patients occur in 0.1% of all cases, but these lesions are difficult to treat and may be a poor prognostic factor., Methods: We conducted a retrospective chart review between 1990 and 2016 of patients who had surgical resection of AAM. In a cohort of 149 patients, 6 had metastatic lesions that were histologically confirmed to be meningioma. We compared baseline characteristics between patients with and without metastasis and performed a multivariate Cox regression analysis to assess risk factors for the development of systemic metastasis., Results: Six patients had histologically confirmed meningioma metastasis. We hypothesized that the presence of scalp invasion in patients could be a potential risk factor for the development of systemic meningioma metastasis. Nine out of the 149 patients without metastasis had scalp invasion, whereas 4 out of the 6 patients with metastasis had scalp invasion. Patients with metastasis had a median age of 62 ± 20. Patients without metastasis had a median age of 59 ± 15 years. Gender distribution was similar; approximately 50% of patients in each group were female. Eighty-five percent of patients with metastatic disease were white, and 65% of patients without metastatic disease were white. Among patients without metastatic disease, 77% had World Health Organization II tumors, whereas 50% of patients with metastatic disease had World Health Organization II tumors. In multivariate analysis including age, tumor grade, size, location, extent of resection, sex, and scalp invasion, the only significant predictor of systemic metastasis was scalp invasion (odds ratio = 39.67; 95% confidence interval = 3.74-421.12; P = 0.0023). Median overall survival (OS) with metastasis was 126 months, and median OS without metastasis was 158 months. Having metastatic disease was not significantly associated with worse OS (P = 0.33)., Conclusions: Metastasis development from AAM is a rare but serious event. Because scalp invasion is a strongly associated predictive factor for development of systemic metastasis in patients with AAM, it is necessary to consider strategies to prevent and to be vigilant of the development of scalp invasion., (Published by Elsevier Inc.)

Objective: Grade 2 meningioma is more likely to recur than grade 1 meningioma. Recurrence decreases overall survival in patients with grade 2 meningioma. However, the clinical course of grade 2 meningioma with several repeated recurrences is poorly understood. The purpose of this study was to clarify the clinical characteristics of grade 2 meningioma with repeated recurrences., Methods: This study included 28 patients with grade 2 meningioma treated at our institution from January 1994 to December 2017. The relationship between survival and factors including age, sex, number of recurrences, malignant transformation, radiation therapy, tumor location, MIB-1 labeling index, Simpson grade, Karnofsky Performance Status, and surgical interval were analyzed., Results: The average age at the initial operation was 53.4 years. The number of recurrences was 3.7 times on average during the follow-up of 113.9 months after the initial operation. An increasing number of recurrences resulted in shortening of the surgical interval, increase in the MIB-1 labeling index, and decrease in Karnofsky Performance Status. In fatal cases, the average surgical interval before death was approximately 1 year. Three factors were related to poor prognosis: number of recurrences (odds ratio, 1.620; P = 0.030), malignant transformation (odds ratio, 10.625; P = 0.019), and high MIB-1 labeling index (odds ratio, 1.089; P = 0.044)., Conclusions: Shortening of the surgical interval within 1 year because of multiple recurrences led to death in patients with grade 2 meningioma. Malignant transformation was the most potent among the poor prognostic factors., (Copyright © 2020. Published by Elsevier Inc.)

Background: The role of adjuvant radiation after gross total resection (GTR) for grade II meningioma is evolving, prompting further evaluation in NRG-BN003, a phase 3 national trial. Furthermore, the relationship between facility volume and outcomes in patients with grade II meningioma after GTR has not been examined at a national level. We aim to assess overall survival (OS) of patients with grade II meningioma after GTR by surgical case volume and OS by receipt of adjuvant radiation., Methods: We used the National Cancer Database to identity 2823 patients diagnosed with grade II meningioma who underwent GTR. Propensity score matching was applied to balance covariates in patients with grade II meningioma after GTR stratified by adjuvant radiation status. Multivariable logistic regression was used to assess factors associated with radiation receipt. Kaplan-Meier and log-rank tests were used to assess OS by facility volume., Results: As facility volume increased, OS increased, with a 5-year OS of 72.8% for facilities with GTR grade II meningioma volumes of ≤8 cases per decade and 87.5% for >8 cases per decade (P < 0.0001). There was no difference in 5-year OS between GTR alone and GTR with adjuvant radiation (84.8% vs. 86.4%; P = 0.151). Covariates significantly associated with radiation receipt included facility location, facility volume, distance, and tumor size., Conclusions: Treatment at higher surgical case volume facilities is associated with improved OS for GTR grade II meningioma. These facilities also have more patients receiving adjuvant radiation. However, we observed no difference in OS between adjuvant radiation and surgery alone., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: As the predictive role of many risk factors for parasagittal meningioma (PM) recurrence remains unclear, the objective of the meta-analysis was to make a comprehensive assessment of the predictive value of selected risk factors in these lesions., Methods: Studies including data on selected risk factors, such as histology, tumor and sinus resection, sinus invasion, tumor localization, and immediate postoperative radiotherapy for PMs recurrence, were searched in the NCBI/NLM PubMed/MEDLINE, EBM Reviews/Cochrane Central, ProQuest, and Scopus databases, and analyzed using random effects modeling., Results: Thirteen observational studies involving 1243 patients met the criteria for inclusion in the meta-analysis. WHO grading of meningiomas was identified as the most powerful risk factor for recurrence. WHO grade II meningiomas (OR 11.61; 95% CI 4.43-30.43; P < .01; I 2  = 31%) or composite group of WHO grades II and III (OR 14.84; 95% CI 5.10-43.19; P < .01; I 2  = 48%) had a significantly higher risk of recurrence than benign lesions. Moreover, an advanced sinus involvement (types IV-VI according to the Sindou classification) (OR 3.49; 95% CI 1.30-9.33; P = .01; I 2  = 0%) and partial tumor resection (Simpson grades III-V) (OR 2.73; 95% CI 1.41-5.30; P = .03; I 2  = 52%) were associated with a significantly higher risk of recurrence than their counterparts., Conclusion: Among the selected risk factors, high-grade WHO lesions, advanced sinus invasion, and partial tumor resection were associated with a higher risk of PM recurrence, with WHO grading system being the most powerful risk factor.

Objective: Although they are generally slow-growing benign tumors, meningiomas may recur after surgery with transformation into atypical meningiomas. The purpose of this study was to investigate the radiological and histopathological factors that predict the risk of tumor progression from a benign to an atypical meningioma., Patients and Methods: All patients treated for recurrent meningiomas in whom the tumor showed histopathologically confirmed high-grade transformation (HGT) from a benign to an atypical meningioma between 2001 and 2017 were included. To evaluate the predictors of transformation, patient medical records documenting the diagnosis of a benign meningioma at the first surgery prior to second surgery with HGT were reviewed. Each patient was matched with four age- and sex-matched controls who were treated for a benign meningioma. The control group comprised all patients without any recurrence for at least 60 months., Results: Fourteen patients with benign meningioma underwent HGT and were included. The median time interval of transformation was 63 months (range, 19-132 months). Multivariate analysis indicated that an increased mitotic index (odds ratio [OR], 10.409; 95 % confidence interval [CI], 1.297-83.549; P = 0.027) was a significant predictor of transformation. Prominent peritumoral edema (OR, 33.822; 95 % CI, 0.935-223.688; P = 0.054) did not reach the statistical significance., Conclusion: An increased mitotic index may be used as the predictor for HGT of benign meningiomas. Although these tumors with a high risk for transformation do not meet the diagnostic criteria for atypical meningiomas, they may require more attentive observation and management than other benign meningiomas., (Copyright © 2020. Published by Elsevier B.V.)

Atypical or malignant transformation (AT/MT) has been described in WHO grade I meningiomas. Our aim was to identify predictive factors of AT/MT at recurrence. A total of N = 15 WHO grade increases were observed in N = 13 patients (0.96% of the study population, risk of transformation of 0.12% per patient-year follow-up). Patients with and without progression at recurrence were similar regarding age, gender distribution, skull-base location, bone infiltration, and Simpson grades. Recurrence-free survival was lower in patients with transformation (5 ± 4.06 years versus 7.3 ± 5.4 years; p = 0.03). Among patient age, gender, skull base location, extent of resection or post-operative RT, no predictor of AT/MT was identified, despite a follow-up of 10,524 patient-years. The annual risk of transformation of WHO grade I meningiomas was 0.12% per patient-year follow-up. Despite the important number of patients included and their extended follow-up, we did not identify any risk factor for transformation. A total of 1,352 patients with surgically managed WHO grade I meningioma from a mixed retro-and prospective database with mean follow-up of 9.2 years ± 5.7 years (0.3-20.9 years) were reviewed. Recurring tumors at the site of initial surgery were considered as recurrence.

The objective of this study was to more fully understand the optimal neurosurgical strategy for spinal benign meningiomas from a medium to long-term perspective. This retrospective study included a cohort of 35 patients with a diagnosis of spinal meningioma who were first operated at our institute over the past 10 years and followed-up for at least 2 years after surgery. The inclusion criterion for the study was the pathological diagnosis finally verified as benign meningioma of World Health Organization (WHO) grade 1. The average follow-up duration after surgery was 61.0 months. The location of the spinal meningioma was classified into ventral or dorsal type based on the operative video record and the preoperative MR images. The extent of resection of the spinal meningioma was carefully determined based on the Simpson grade. The average neurological condition was significantly improved at the final follow-up. Simpson grade I or II resection was achieved in 31 of 35 cases (88.6%). No Simpson grade I or II cases showed local recurrence during follow-up. Tumor recurrence was noted in 2 of 4 cases of Simpson grade IV resection. One case has been followed-up without any re-operation because of no neurological deterioration, and the other case underwent stereotactic radiosurgery. This study suggested that meticulous Simpson grade II resection of spinal benign meningiomas of WHO grade 1 may be good enough from a medium to long-term follow-up perspective, though longer follow-up is absolutely necessary., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Pituicytoma is a rare; slow-growing primary tumour originating from the glial cells of the neurohypophysis. It was classed as a low-grade (grade I) central nervous system tumour by the World Health Organization in 2007. We present the case of a 71-year-old man with a previous history of sellar meningioma who underwent surgical resection of pituicytoma by transphenoidal hypophysectomy., Method: We conducted a literature search using Medline EMBASE and the Cochrane Database of Systematic Reviews using the Ovid search engines. Key words searched were 'pituitary gland', 'pituicytoma', 'neurohypophysis'. Patient records and imaging were obtained from the Royal Stoke University Hospital database., Results: A 71-year-old man with a background of sellar meningioma 16 years previously was found to have a pituitary fossa tumour on surveillance magnetic resonance imaging. Differential diagnosis was pituitary adenoma. Endoscopic transphenoidal hypophysectomy was performed. Histology was consistent with pituicytoma. As a result of this histology from his initial tumour was re-examined and was amended to pituicytoma, indicating a recurrence., Conclusion: Pituicytoma is a benign, slow growing lesion of the posterior pituitary. Brat et al diagnosed it as a distinct entity in 2000 and it was listed as a World Health Organization classification grade I tumour in 2007. It can be mistaken for pituitary adenoma owing to its similar clinical presentation. Complete excision of the tumour by transphenoidal hypophysectomy is an effective management for pituicytoma as demonstrated in this case.

Purpose: Aggressive meningiomas that progress after surgery/radiotherapy represent an unmet medical need. Strong and constant expression of SSTR2A receptors and activation of the Pi3K/Akt/mTOR pathway have been demonstrated in meningiomas. The combination of everolimus, an mTOR inhibitor, and octreotide, a somatostatin agonist, has shown additive antitumor effect in vitro . The phase II CEVOREM trial investigated the efficacy of this combination on recurrent meningiomas., Patients and Methods: Patients with documented recurrent tumor progression ineligible for further surgery/radiotherapy were eligible to receive octreotide (30 mg/d, day 1) and everolimus (10 mg/d, days 1-28). The primary endpoint was the 6-month progression-free survival rate (PFS6). The secondary endpoints were overall survival, response rate, tumor growth rate according to central review, and safety., Results: A total of 20 patients were enrolled, including 2 with World Health Organization (WHO) grade I tumors, 10 with WHO grade II tumors, and 8 with WHO grade III tumors; furthermore, 4 patients harbored NF2 germline mutation. The overall PFS6 was 55% [95% confidence interval (CI), 31.3%-73.5%], and overall 6- and 12-month survival rates were 90% (95% CI, 65.6%-97.4%) and 75% (95% CI, 50.0%-88.7%), respectively. A major decrease (>50%) was observed in the growth rate at 3 months in 78% of tumors. The median tumor growth rate decreased from 16.6%/3 months before inclusion to 0.02%/3 months at 3 months ( P < 0.0002) and 0.48%/3 months at 6 months after treatment ( P < 0.0003)., Conclusions: The combination of everolimus and octreotide was associated with clinical and radiological activity in aggressive meningiomas and warrants further studies. Decrease in the tumor volume growth rate should be considered a complementary and sensitive endpoint to select potentially effective drugs for recurrent meningiomas., (©2020 American Association for Cancer Research.)

Background: In the management of meningiomas, single-fraction stereotactic radiosurgery (SRS) is an established alternative treatment to surgical resection. However, its effects on tumorigenesis and malignant transformation are still uncertain., Case Description: We have described a grade II parafalcine meningioma that was initially surgically resected (Simpson 2 clearance) and then managed with a single dose of SRS on recurrence. The tumor recurred again 7 years later, with histological features of a grade III rhabdoid-papillary lesion, with local brain invasion., Conclusion: To the best of our knowledge, this is the first report to describe malignant transformation of a grade II to grade III meningioma after SRS to date., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

High-grade spinal meningiomas (SMs) are extremely rare lesions. The true incidence, clinical features and prognosis of SMs are still unclear. To elucidate this information by using institutional data and to provide an updated review of the literature. Nineteen consecutive patients harboring 20 high-grade SMs were identified, including 15 (78.9%) female patients, with a mean age of 37.8 ± 14.9 years. The 20 tumors were most frequently located in the lumbar and lumbosacral segment (n = 6, 30.0%), followed by the cervical segment (n = 5, 25.0%), thoracolumbar junction (n = 4, 20.0%), thoracic (n = 3, 15.0%) and cervicothoracic junction (n = 2, 10.0%). The mean number of affected spinal levels was 2 ± 1. Simpson grade II and III resection were achieved for sixteen (80.0%) and four (20.0%) tumors, respectively. During a mean follow-up of 79.6 ± 39.9 months, three tumors (15.0%) recurred. Fourteen patients (73.7%) achieved excellent outcomes, three (15.7%) remained stable, one (5.3%) deteriorated, and one (5.3%) died. High-grade SMs are rare entities which consist of 5.7% SM. These lesions tend to affect young patients, with atypical meningioma being the most common pathological subtype. In our study, surgery was an effective means of treatment. Close observation is warranted after surgery because of the high recurrence rate. Recurrent patients can still benefit from a second surgery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019. Published by Elsevier Ltd.)

The incidence of meningiomas is rising and the number of incidental cases is increasing steadily. The efficiency and the safety of each treatment strategy are also improving over time. Therefore the indications to treat meningiomas are constantly changing. The aim of meningioma treatment is keeping the patient fully functional while achieving long-term relief or prevention from problems related to intracranial tumor growth. This chapter reviews the natural history and treatment results and aims to put together the information for the most objective decision-making in treating meningiomas. Factors acting on the treatment decision such as anatomical localization, symptomatology, variations in tumor biology, recurrence status, age and co-morbidities, operative gains, and patient preference are individually discussed., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Most World Health Organization (WHO) grade I meningiomas carry a favorable prognosis. Some become clinically aggressive with recurrence, invasion, and resistance to conventional therapies (grade 1.5; recurrent/progressive WHO grade I tumors requiring further treatment within 10 years). We aimed to identify biomarker signatures in grade 1.5 meningiomas where histopathology and genetic evaluation has fallen short., Experimental Design: Mass spectrometry (MS)-based phosphoproteomics and peptide chip array kinomics were used to compare grade I and 1.5 tumors. Ingenuity Pathway Analysis (IPA) identified alterations in signaling pathways with validation by Western blot analysis. The selected biomarker was evaluated in an independent cohort of 140 samples (79/140 genotyped for meningioma mutations) by tissue microarray and correlated with clinical variables., Results: The MS-based phosphoproteomics revealed differential Ser/Thr phosphorylation in 32 phosphopeptides. The kinomic profiling by peptide chip array identified 10 phosphopeptides, including a 360% increase in phosphorylation of RB1, in the 1.5 group. IPA of the combined datasets and Western blot validation revealed regulation of AKT and cell-cycle checkpoint cascades. RB1 hyperphosphorylation at the S780 site distinguished grade 1.5 meningiomas in an independent cohort of 140 samples and was associated with decreased progression/recurrence-free survival. Mutations in NF2, TRAF7, SMO, KLF4, and AKT1 E17K did not predict RB1 S780 staining or progression in grade 1.5 meningiomas., Conclusions: RB1 S780 staining distinguishes grade 1.5 meningiomas, independent of histology, subtype, WHO grade, or genotype. This promising biomarker for risk stratification of histologically bland WHO grade I meningiomas provides insight into the pathways of oncogenesis driving these outlying clinically aggressive tumors., (©2019 American Association for Cancer Research.)

Purpose: To evaluate surgical resection with brachytherapy placement as a salvage treatment in patients with recurrent high-grade meningioma who exhausted prior external beam treatment options., Methods: Single-center retrospective review of our institutional experience of brachytherapy implantation from 2012 to 2018. The primary outcome of the study was progression free survival (PFS). Secondary outcomes included overall survival (OS) and complications. A matched cohort of patients not treated with brachytherapy over the same time period was evaluated as a control group. All patients had received prior radiation treatment and underwent planned gross total resection (GTR) surgery., Results: A total of 27 cases were evaluated. Compared with prior treatment, brachytherapy implantation demonstrated a statistically significant improvement in tumor control [HR 0.316 (0.101 - 0.991), p = 0.034]. PFS-6 and PFS-12 were 92.3% and 84.6%, respectively. Compared with the matched control cohort, brachytherapy treatment demonstrated improved PFS [HR 0.310 (0.103 - 0.933), p = 0.030]. Overall survival was not statistically significantly different between groups [HR 0.381 (0.073 - 1.982), p = 0.227]. Overall postoperative complications were comparable between groups, although there was a higher incidence of radiation necrosis in the brachytherapy cohort., Conclusion: Brachytherapy with planned GTR improved PFS in recurrent high-grade meningioma patients who exhausted prior external beam radiation treatment options. Future improvement of brachytherapy dose delivery methods and techniques may continue to prolong control rates and improve outcomes for this challenging group of patients.

Aim: To analyze the correlation of clinicopathologic prognostic parameters with atypical meningiomas (AMs) and recurrence development as well as progression-free survival (PFS)., Material and Methods: The neuropathology archive and hospital records of 75 patients with AM who underwent surgery in our institution between 2010 and 2019 were retrospectively reviewed. The pathological revision was performed according to the 2016 World Health Organization (WHO) criteria. Other clinicopathological parameters, such as age, gender, tumor location, preoperative tumor size, degree of resection, Psammoma body, nuclear atypia, main histological pattern, Ki67 labeling index (LI), radiotherapy, and dura and bone invasion, were also analyzed. Statistically, univariate and multivariate analyses were assessed to determine their potential impact on recurrence-related prognostic factors., Results: Recurrence occurred in 20 patients. The mean PFS and follow-up time were 38.9 and 44.8 months, respectively. In univariate analysis, clinical and pathological features such as age of ?55 years, female sex, skull base tumor location, larger preoperative tumor size, increased mitotic count, small cells, hypercellularity, sheeting, necrosis, and dura and bone invasion were remarkable in patients with recurrence, but were not statistically significant. In multivariate analysis, increased mitotic activity and brain invasion either considered alone or combined were significantly associated with PFS. Nuclear atypia was also not associated with both tumor recurrence and PFS. However, clinical features did not significantly influence the PFS., Conclusion: This study found that recurrence could not be predicted by the presence of any of the clinicopathological features of AMs. We believe that molecular variables determined through routine neuropathological analysis will be needed in the future.

Background: Atypical meningiomas (WHO grade II) have high recurrence rate. However, data on the effect of radiotherapy (RT) is still conflicting. The aim of this study was to evaluate the influence of postoperative RT on the recurrence of primary atypical intracranial meningiomas., Methods: The medical records of all patients who underwent surgery (2007-2017 in 4 neurosurgical departments) for a histologically diagnosed primary atypical meningioma were reviewed to assess progression-free survival (PFS) and prognostic factors., Results: This analysis included 258 patients with a median age of 60 years (54.7% female). The predominant tumor locations were convexity and falx (60.9%) followed by the skull base (37.2%). Simpson grade I-II resection was achieved in 194 (75.2%) patients, Simpson grade III-IV in 53 patients (20.5%). Tumor progressed in 54 cases (20.9%). Postoperative RT was performed in 46 cases (17.8%). RT was more often applied after incomplete resection (37.7% vs. 13.4% Simpson III-IV vs. I-II). A multivariate analysis showed a significantly shorter PFS associated with Simpson III-IV [HR 1.19, (95% CI) 1.09-1.29, p < 0.001] and age > 65 years [HR 2.89, (95% CI) 1.56-5.33, p = 0.001]. A subgroup analysis with a minimal follow-up of 36 months revealed that Simpson III-IV [HR 3.01, 95% CI 1.31-6.931.03-1.24, p = 0.009] and age > 65 years [HR 2.48, 95% CI 1.20-5.13, p = 0.014] reduced PFS. The impact of postoperative RT on PFS remained statistically insignificant, even in a propensity-score matched survival analysis [n = 46; p = 0.438; OR 0.710 (0.299-1.687)]., Conclusions: In the present study, postoperative RT did not improve PFS. The most important prognostic factors remain the extent of resection and age.

Information on the vascular supply to meningiomas is critical to the neurosurgeon. Most meningiomas are supplied by the external carotid artery, though many get pial contribution as well. Angiogenesis is critical for these neoplasms to grow. Vascular endothelial growth factor (VEGF) has been a popular target of research to decrease angiogenesis. Peritumoral brain edema (PTBE) is occasionally seen in meningiomas, which makes surgical resection more challenging. The exact cause of PTBE remains unclear, but a number of factors have been postulated to contribute. Assessment of the vascularity of meningiomas is best carried out with angiography, but noninvasive techniques are improving, diminishing the need for more invasive imaging. Embolization of tumors can be performed to minimize perioperative blood loss and potentially lower surgical morbidity. However, it has not been shown to improve outcomes, and procedural risks exist. Higher grade tumors commonly have higher vascularity. Higher vascular meningiomas are more likely to recur and have higher levels of VEGF. The vascularity of meningiomas remains a topic of interest and is the focus of many research projects., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Meningiomas are common central nervous system tumors with a wide range of morphologic variants, the pathogenesis being their complex embryogenesis. Intracranial meningiomas with heterogenous histopathology in the same lesion are common in low-grade meningiomas but less frequent in recurrent and high-grade variants., Case Description: A 75-year-old male presented elsewhere a year ago with complaints of slurred speech. Magnetic resonance imaging revealed a left frontotemporal, dural-based, extraaxial, solid cystic lesion with doubtful infiltration into the adjacent brain parenchyma. A subtotal excision was done. A diagnosis of meningioma with an aggressive biological behavior was rendered on histology, but the grade was deferred, in view of a single focus of small cell formation and no adjacent brain parenchyma to comment on invasion. The patient presented here with recurrence of his original symptoms. Magnetic resonance imaging of the brain with contrast revealed 2 dural-based, solid cystic enhancing lesions of sizes 29 mm × 25 mm × 24 mm and 25 mm × 16 mm seen at the left frontal region, indenting the adjacent brain parenchyma with diffuse meningeal thickening in the postoperative bed. Microscopy revealed a hypercellular meningeal neoplasm with increased mitosis and a pseudopapillary pattern with lipomatous changes., Conclusions: To date there are no case reports in current literature with such rare combinations in a recurrent meningioma. This highlights the multipotency of phenotypic transformation of primary meningothelial cells. The presence of papillary features, even if focal, should be quantified in the diagnosis. This is of importance because the most current literature suggests that meningioma harboring a papillary component has an increased risk of recurrence and progression to aggressive behavior., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Atypical meningioma (AM) has a high rate of local recurrence after surgery, and the role of adjuvant radiotherapy in AM remains controversial. We analysed progression-free survival (PFS) and identified the factors associated with postoperative recurrence in AM patients., Methods: Data were obtained from 263 AM patients who underwent surgery at our institution between October 2009 and September 2018. Analyses included factors such as the extent of surgical resection, MIB-1 labelling index, brain invasion and therapy modality. Univariate and multivariate analyses were used to assess recurrence-related prognostic factors., Result: The median follow-up duration was 41 months, and the median PFS was 28 months. Gross total resection (GTR) was achieved in 213 (81.0%) patients, and 86 (32.7%) patients received postoperative radiation therapy (RT). During follow-up, there were 61 (23.2%) tumour recurrences. In a Cox multivariate analysis, MIB-1 labelling index (hazard ratio = 2.637; p < 0.001), secondary tumour (hazard ratio = 3.541; p < 0.001), tumour size (hazard ratio = 1.818; p = 0.032) and extent of resection (hazard ratio = 2.861; p < 0.001) were independent significant predictors of tumour recurrence. RT was associated with reduced tumour recurrence in subtotal resection (STR) (p = 0.023) but not GTR (p = 0.923). An analysis of 6 meningioma patients who underwent more than 3 operations suggested that the recurrence time became shorter and the MIB-1 labelling index increased as the number of recurrences increased., Conclusions: MIB-1 labelling index, secondary tumour, tumour size and extent of resection were powerful predictors of recurrence in AM patients. Postoperative RT did not decrease the risk of recurrence in GTR patients.

Objective: The effectiveness of tumor control after Gamma Knife radiosurgery (GKS) for intracranial meningioma is well established. Moreover, GKS is an alternative to reduce surgical-remnant meningioma recurrence. Nevertheless, the tumor can recur even after GKS and is associated with its histologic malignancy. We here investigated the risk factors associated with recurrence from remnant lesions after GKS, assessing recurrence patterns according to histological grades., Methods: From January 2007 to January 2017, 218 patients underwent GKS for surgical-remnant lesions. To evaluate post-GKS lesion recurrence, pre-GKS magnetic resonance images were compared with those at follow-up. We retrospectively analyzed the histologic classification of meningioma and patients' clinical characteristics (sex, age, tumor location, target volume, and prescription dose)., Results: Of the 218 patients, 13 (5.9%) developed post-GKS recurrence within a mean follow-up period of 37.4 months. The recurrence patterns were as follows: adjacent to the 50% marginal-dose field (9 patients); within the 50% marginal-dose field (2 patients); and outside the field (2 patients). Six of 196 World Health Organization grade I meningioma cases, 6 of 20 grade II cases, and 1 of 2 grade III cases developed recurrence. Thus 32% of high-grade meningioma cases (grades II and III) developed recurrence during the follow-up period. Histologic grade was significantly associated (P < 0.001) with recurrence., Conclusions: The study findings indicate that the post-GKS meningioma recurrence likelihood is high when the meningioma has malignant histologic features. In addition, considering the recurrence patterns, it is important to define a precise target for GKS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Assessment of the risk of recurrence is essential to determine the therapeutic strategy of meningioma treatment. Many relapsing or aggressive meningiomas show elevated mitotic and/or Ki67 indices, reflecting cell cycle deregulation. As CDKN2A is a key tumor suppressor gene involved in cell cycle control, we investigated whether CDKN2A alterations may be involved in tumor recurrence., Methods: We carried out a comparative analysis of 17 recurrent and 13 non-recurrent meningiomas. CDKN2A single nucleotide variations (SNVs), deletions, methylation status of the promotor, and p16 expression were investigated. Results were correlated with the recurrent or non-recurrent status and clinicopathological data., Results: We identified a CDKN2A SNV (NM&#95;000077, exon2, c.G442A, p.Ala148Thr) in five meningiomas that was significantly associated with recurrence (p = 0.03). This mutation, confirmed by Sanger sequencing and referenced in the COSMIC database in various cancers, has not been reported in meningioma. The presence of one of the three following CDKN2A alterations-p.(Ala148Thr) mutation, whole homozygous or heterozygous gene loss, or promotor methylation > 8%-was observed in 13 of the 17 relapsing meningiomas and was strongly associated with recurrence (p < 0.0001) and a Ki67 labeling index > 7% (p = 0.004)., Conclusion: We report an undescribed p.(Ala148Thr) CDKN2A mutation in meningioma that was only present in relapsing tumors. In our series, CDKN2A gene alterations were only found in recurrent meningiomas. However, our results need to be evaluated on a larger series to ensure that these CDKN2A alterations can be used as biomarkers of recurrence in meningioma.

Purpose: A subset of skull base meningiomas (SBM) may show early progression/recurrence (P/R) as a result of incomplete resection. The purpose of this study is the implementation of MR radiomics to predict P/R in SBM., Methods: From October 2006 to December 2017, 60 patients diagnosed with pathologically confirmed SBM (WHO grade I, 56; grade II, 3; grade III, 1) were included in this study. Preoperative MRI including T2WI, diffusion-weighted imaging (DWI), and contrast-enhanced T1WI were analyzed. On each imaging modality, 13 histogram parameters and 20 textural gray level co-occurrence matrix (GLCM) features were extracted. Random forest algorithms were utilized to evaluate the importance of these parameters, and the most significant three parameters were selected to build a decision tree for prediction of P/R in SBM. Furthermore, ADC values obtained from manually placed ROI in tumor were also used to predict P/R in SBM for comparison., Results: Gross-total resection (Simpson Grades I-III) was performed in 33 (33/60, 55%) patients, and 27 patients received subtotal resection. Twenty-one patients had P/R (21/60, 35%) after a postoperative follow-up period of at least 12 months. The three most significant parameters included in the final radiomics model were T1 max probability, T1 cluster shade, and ADC correlation. In the radiomics model, the accuracy for prediction of P/R was 90%; by comparison, the accuracy was 83% using ADC values measured from manually placed tumor ROI., Conclusions: The results show that the radiomics approach in preoperative MRI offer objective and valuable clinical information for treatment planning in SBM.