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

Synchronous or metachronous growth of multiple tumors (≥ 2) is found in up to 20% of meningioma patients. However, biological as well as histological features and prognosis are largely unexplored. Clinical and histological characteristics were retrospectively investigated in 95 patients harboring 226 multiple meningiomas (MMs) and compared with 135 cases of singular meningiomas (SM) using uni- and multivariate analyses. In MM, tumors occurred synchronously and metachronously in 62% and 38%, respectively. WHO grade was intra-individually constant in all but two MMs, and histological subtype varied in 13% of grade 1 tumors. MM occurred more commonly in convexity/parasagittal locations, while SM were more frequent at the skull base (p < .001). In univariate analyses, gross total resection (p = .014) and high-grade histology in MM were associated with a prolonged time to progression (p < .001). Most clinical characteristics and rates of high-grade histology were similar in both groups (p ≥ .05, each). Multivariate analyses showed synchronous/metachronous meningioma growth (HR 4.50, 95% CI 2.26-8.96; p < .001) as an independent predictor for progression. Compared to SM, risk of progression was similar in cases with two (HR 1.56, 95% CI .76-3.19; p = .224), but exponentially raised in patients with 3-4 (HR 3.25, 1.22-1.62; p = .018) and ≥ 5 tumors (HR 13.80, 4.06-46.96; p < .001). Clinical and histological characteristics and risk factors for progression do not relevantly differ between SM and MM. Although largely constant, histology and WHO grade occasionally intra-individually vary in MM. A distinctly higher risk of disease progression in MM as compared to SM might reflect different underlying molecular alterations., (© 2023. The Author(s).)

Background: About 25% of patients with intracranial meningioma display seizures at the time of initial presentation. Hence, identification of risk factors for preoperative seizures is crucial during perioperative care of meningioma patients., Methods: Associations of preoperative seizures with clinical, radiological and histological variables were analyzed in 945 patients (689 females, 73% and 256 males, 27%; median age: 58 years) who underwent surgery for primary diagnosed intracranial meningioma., Results: Preoperative seizures were found in 189 patients (20%). In univariate analyses, male gender (OR=1.91, 95% CI: 1.37-2.68; P<0.001), grade II/III histology (OR=2.24, 95% CI: 1.46-3.46; P<0.001), brain invasion (OR=2.59, 95% CI: 1.45-4.63; P=001), non-skull base tumor location (OR=3.07, 95% CI: 2.13-4.41; P<0.001), heterogeneous contrast-enhancement (OR=1.60, 95% CI: 1.04-2.46; P=0.031), intratumoral calcifications (OR=1.91, 95% CI: 1.17-3.10; P=0.009), an irregular shape (OR=2.07, 95% CI: 1.32-3.26; P=0.002) as well as tumor (OR=1.01 per ccm, 95% CI: 1.00-1.02; P=0.001) and edema volumes (OR=1.01 per ccm, 95% CI: 1.00-1.01; P<0.001) were correlated with seizures. Semiology was not related to any of the analyzed variables (P>0.05, each). No associations were found between seizures and histological subtype of 832 grade I meningiomas (P=0.391). In multivariate analyses, only non-skull base tumor location (OR=3.12, 95% CI: 1.74-5.59; P<0.001) and a rising peritumoral edema volume (OR=1.01 per ccm, 95% CI: 1.00-1.01; P<0.001) were identified as independent predictors for preoperative seizures., Conclusions: Several mostly radiological variables were identified as risk factors for epilepsy. However, multivariate analyses confirmed only peritumoral edema and non-skull base tumor location as independent predictors for preoperative seizures. None of the variables predicts semiology.

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

Risk factors to predict late-onset tumor recurrence in meningioma patients are urgently needed to schedule control intervals during long-term follow-up. We therefore analyzed the value of established risk factors for postoperative meningioma recurrence for the prediction of long-term prognosis. Correlations of clinical and histopathological variables with tumor relapse after 3, 5, and 10 years following microsurgery were analyzed in uni- and multivariate analyses, and compared to findings in the entire cohort. In the entire cohort (N = 1218), skull base location (HR: 1.51, 95%CI 1.05-2.16; p = .026), Simpson ≥ IV resections (HR: 2.41, 95%CI 1.52-3.84; p < .001), high-grade histology (HR: 3.70, 95%CI 2.50-5.47; p < .001), and male gender (HR: 1.46, 95%CI 1.01-2.11; p = .042) were independent risk factors for recurrence. Skull base location (HR: 1.92, 95%CI 1.17-3.17; p = .010 and HR: 2.02, 95%CI 1.04-3.95; p = .038) and high-grade histology (HR: 1.87, 95%CI 1.04-3.38; p = .038 and HR: 2.29, 95%CI 1.07-4.01; p = .034) but not subtotal resection (HR: 1.53, 95%CI .68-3.45; p = .303 and HR: 1.75, 95%CI .52-5.96; p = .369) remained correlated with recurrence after a recurrence-free follow-up of ≥ 3 and ≥ 5 years, respectively. Postoperative tumor volume was related with recurrence in general (p < .001) but not beyond a follow-up of ≥ 3 years (p > .05). In 147 patients with a follow-up of ≥ 10 years, ten recurrences occurred and were not correlated with any of the analyzed variables. Skull base tumor location and high-grade histology but not the extent of resection should be considered when scheduling the long-term follow-up after meningioma surgery. Recurrences ≥ 10 years after surgery are rare, and predictors are lacking., (© 2021. The Author(s).)

Classification of the extent of resection into gross and subtotal resection (GTR and STR) after meningioma surgery is derived from the Simpson grading. Although utilized to indicate adjuvant treatment or study inclusion, conflicting definitions of STR in terms of designation of Simpson grade III resections exist. Correlations of Simpson grading and dichotomized scales (Simpson grades I-II vs ≥ III and grade I-III vs ≥ IV) with postoperative recurrence/progression were compared using Cox regression models. Predictive values were further compared by time-dependent receiver operating curve (tdROC) analyses. In 939 patients (28% males, 72% females) harboring WHO grade I (88%) and II/III (12%) meningiomas, Simpson grade I, II, III, IV, and V resections were achieved in 29%, 48%, 11%, 11%, and < .5%, respectively. Recurrence/progression was observed in 112 individuals (12%) and correlated with Simpson grading (p = .003). The risk of recurrence/progression was increased after STR in both dichotomized scales but higher when subsuming Simpson grade ≥ IV than grade ≥ III resections (HR: 2.49, 95%CI 1.50-4.12; p < .001 vs HR: 1.67, 95%CI 1.12-2.50; p = .012). tdROC analyses showed moderate predictive values for the Simpson grading and significantly (p < .05) lower values for both dichotomized scales. AUC values differed less between the Simpson grading and the dichotomization into grade I-III vs ≥ IV than grade I-II vs ≥ III resections. Dichotomization of the extent of resection is associated with a loss of the prognostic value. The value for the prediction of progression/recurrence is higher when dichotomizing into Simpson grade I-III vs ≥ IV than into grade I-II vs ≥ III resections.

Risk factors for prediction of prognosis in meningiomas derivable from routine preoperative magnetic resonance imaging (pMRI) remain elusive. Correlations of tumor and edema volume, disruption of the arachnoid layer, heterogeneity of contrast enhancement, enhancement of the capsule, T2-intensity, tumor shape, and calcifications on pMRI with tumor recurrence and high-grade (WHO grade II/III) histology were analyzed in 565 patients who underwent surgery for WHO grade I (N = 516, 91%) or II/III (high-grade histology, N = 49, 9%) meningioma between 1991 and 2018. Edema volume (OR, 1.00; p = 0.003), heterogeneous contrast enhancement (OR, 3.10; p < 0.001), and an irregular shape (OR, 2.16; p = 0.015) were associated with high-grade histology. Multivariate analyses confirmed edema volume (OR, 1.00; p = 0.037) and heterogeneous contrast enhancement (OR, 2.51; p = 0.014) as risk factors for high-grade histology. Tumor volume (HR, 1.01; p = 0.045), disruption of the arachnoid layer (HR, 2.50; p = 0.003), heterogeneous contrast enhancement (HR, 2.05; p = 0.007), and an irregular tumor shape (HR, 2.57; p = 0.001) were correlated with recurrence. Multivariate analyses confirmed tumor volume (HR, 1.01; p = 0.032) and disruption of the arachnoid layer (HR, 2.44; p = 0.013) as risk factors for recurrence, independent of histology. Subgroup analyses revealed disruption of the arachnoid layer (HR, 9.41; p < 0.001) as a stronger risk factor for recurrence than high-grade histology (HR, 5.15; p = 0.001). Routine pMRI contains relevant information about the risk of recurrence or high-grade histology of meningioma patients. Loss of integrity of the arachnoid layer on MRI had a higher prognostic value than the WHO grading, and underlying histological or molecular alterations remain to be determined.

Introduction: Seizures after meningioma surgery are common, with a distinct impact on postoperative life quality. Sufficient risk factors for seizure development are sparsely known but needed to improve perioperative patient counseling and, eventually, antiepileptic treatment., Materials and Methods: Correlations between clinical, radiological and histological variables and the onset of new seizures following surgery for initially diagnosed cranial meningioma were retrospectively analyzed in uni- and multivariate analyses., Results: 752 preoperatively seizure-naïve patients (569 females, 76 % and 183 males, 24 %) with a median age of 57 years were included. Postoperative seizures occurred in 69 cases (9 %). In univariate analyses, seizures were correlated with preoperative Karnofsky Score < 80 (OR: 1.91, 95 % CI 1.01-3.59; p = .045), convexity/parasagittal tumor location (OR: 1.77, 95 % CI 1.06-2.95; p = .030), heterogenous contrast-enhancement of the tumor (OR: 2.24, 95 % CI 1.14-4.39; p = .019) and intratumoral calcifications (OR: 3.35, 95 % CI 1.59-7.05; p = .001). Multivariable analyses revealed age at the time of surgery (OR: 1.04, 95 % CI 1.01-1.07; p = .009) and intratumoral calcifications on preoperative imaging (OR: 3.70, 95 % CI 1.73-7.92; p = .001) as risk factors for postoperative seizures. Based on multivariate analyses, a score for discrimination of patients at low (3 %), intermediate (11 %) and high risk (17 %) of postoperative seizures (AUC: 0.7, p < .001) was conducted. In subgroup analyses, postoperative hemorrhage (OR: 2.90, 95 % CI 1.13-7.46; p = .028) and hydrocephalus (OR: 3.65, 95 % CI 1.48-9.01; p = .005) were correlated with postoperative seizures., Conclusion: Risk factors for postoperative seizures after meningioma surgery are sparse and can be basically taken from preoperative imaging. Among surgical complications, postoperative hemorrhage and hydrocephalus are strong seizure predictors., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The usefulness of 5-aminolevulinic acid (5-ALA)-mediated fluorescence-guided surgery (FGS) in meningiomas is intensely discussed. However, data about kinetics of 5-ALA and protoporphyrin (Pp) IX in meningiomas are lacking., Methods: As the first study so far, we performed longitudinal intraoperative real-time ex situ measurements of fluorescence intensity and PpIX concentrations during FGS of ten benign and two atypical meningiomas. Kinetics were subsequently compared with data from 229 glioblastomas., Results: Spectroscopy revealed fluorescence (median 2945.65 a.u.) and PpIX accumulation (median 18.31 μg/ml) in all 43 analyzed samples. Fluorescence intensity (2961.50 a.u. vs 118.41 a.u.; p < .001) and PpIX concentrations (18.72 μg/ml vs .98 μg/ml; p < .001) were higher in samples with (N = 30) than without (N = 2) visible intraoperative tumor fluorescence. ROC curve analyses revealed a PpIX cut-off concentration of 3.85 μg/ml (AUC = .992, p = .005) and a quantitative fluorescence cut-off intensity of 286.73 a.u. (AUC = .983, p = .006) for intraoperative visible tumor fluorescence. Neither fluorescence intensity (p = .356) nor PpIX (p = .631) differed between atypical and benign meningiomas. Fluorescence and PpIX peaked 7-8 h following administration of 5-ALA. Meningiomas displayed a higher fluorescence intensity (p = .012) and PpIX concentration (p = .005) than glioblastomas 5-6 h after administration of 5-ALA. Although fluorescence was basically maintained, PpIX appeared to be cleared faster in meningiomas than in glioblastomas., Conclusions: Kinetics of PpIX and fluorescence intensity differ between meningiomas and glioblastomas in the early phase after 5-ALA administration. Modification of the timing of drug administration might impact visibility of intraoperative fluorescence and helpfulness of FGS and should be investigated in future analyses.

Objective: In meningiomas, the Simpson grading system is applied to estimate the risk of postoperative recurrence, but might suffer from bias and limited overview of the resection cavity. In contrast, the value of the postoperative tumor volume as an objective predictor of recurrence is largely unexplored. The objective of this study was to compare the predictive value of residual tumor volume with the intraoperatively assessed extent of resection (EOR)., Methods: The Simpson grade was determined in 939 patients after surgery for initially diagnosed intracranial meningioma. Tumor volume was measured on initial postoperative MRI within 6 months after surgery. Correlation between both variables and recurrence was compared using a tree-structured Cox regression model., Results: Recurrence correlated with Simpson grading (p = 0.003). In 423 patients (45%) with available imaging, residual tumor volume covered a broad range (0-78.5 cm3). MRI revealed tumor remnants in 8% after gross-total resection (Simpson grade I-III, range 0.12-33.5 cm3) with a Cohen's kappa coefficient of 0.7153. Postoperative tumor volume was correlated with recurrence in univariate analysis (HR 1.05 per cm3, 95% CI 1.02-1.08 per cm3, p < 0.001). A tree-structured Cox regression model revealed any postoperative tumor volume > 0 cm3 as a critical cutoff value for the prediction of relapse. Multivariate analysis confirmed the postoperative tumor volume (HR 1.05, p < 0.001) but not the Simpson grading (p = 0.398) as a predictor for recurrence., Conclusions: EOR according to Simpson grading was overrated in 8% of tumors compared to postoperative imaging. Because the predictive value of postoperative imaging is superior to the Simpson grade, any residual tumor should be carefully considered during postoperative care of meningioma patients.

Background: Despite considerable rates of recurrence and mortality in atypical meningiomas, reliable predictors for estimating postoperative long-term prognosis remain elusive., Methods: Clinical, histopathological, and radiological variables from 138 patients, including 64 females and 74 males (46% and 54%, median age 62 years), who underwent surgery for intracranial atypical meningioma were retrospectively analyzed. Associations between variables and recurrence and mortality were investigated using uni- and multivariate analyses., Results: Gross total (GTR) and subtotal resection (STR) was achieved in 81% and 19% of cases, respectively. Within a median follow-up of 62 months, recurrence occurred in 52 (38%) and mortality in 22 (16%) cases. In patients who did not receive adjuvant irradiation, recurrence rates were higher after STR than after GTR (32% vs 63%, p = 0.025). In univariate analyses, only intratumoral calcifications on preoperative MRI (p = 0.012) and the presence of brain invasion in the absence of other histological grading criteria (p = 0.010) were correlated with longer progression-free intervals (PFI). In multivariate analyses, patient age was positively (HR 1.03, 95%CI 1.04-1.05; p = 0.018) and the presence of brain invasion as the only grading criterion (HR 0.37, 95%CI 0.19-0.74; p = 0.005) was negatively related with progression, while rising age at the time of surgery (HR 1.07, 95%CI 1.03-1.12; p = 0.001) was prognostic for mortality., Conclusions: PFI was longer in brain invasive but otherwise histological benign meningiomas and in tumors displaying calcifications on preoperative MRI. Advancing patient age and lower Karnofsky Performance Score were associated with higher overall mortality.

Objective: Identification of risk factors for perioperative epilepsy remains crucial in the care of patients with meningioma. Moreover, associations of brain invasion with clinical and radiological variables have been largely unexplored. The authors hypothesized that invasion of the cortex and subsequent increased edema facilitate seizures, and they compared radiological data and perioperative seizures in patients with brain-invasive or noninvasive meningioma., Methods: Correlations of brain invasion with tumor and edema volumes and preoperative and postoperative seizures were analyzed in univariate and multivariate analyses., Results: Totals of 108 (61%) females and 68 (39%) males with a median age of 60 years and harboring totals of 92 (52%) grade I, 79 (45%) grade II, and 5 (3%) grade III tumors were included. Brain invasion was found in 38 (22%) patients and was absent in 138 (78%) patients. The tumors were located at the convexity in 72 (41%) patients, at the falx cerebri in 26 (15%), at the skull base in 69 (39%), in the posterior fossa in 7 (4%), and in the ventricle in 2 (1%); the median tumor and edema volumes were 13.73 cm3 (range 0.81-162.22 cm3) and 1.38 cm3 (range 0.00-355.80 cm3), respectively. As expected, edema volume increased with rising tumor volume (p < 0.001). Brain invasion was independent of tumor volume (p = 0.176) but strongly correlated with edema volume (p < 0.001). The mean edema volume in noninvasive tumors was 33.0 cm3, but in invasive tumors, it was 130.7 cm3 (p = 0.008). The frequency of preoperative seizures was independent of the patients' age, sex, and tumor location; however, the frequency was 32% (n = 12) in patients with invasive meningioma and 15% (n = 21) in those with noninvasive meningioma (p = 0.033). In contrast, the probability of detecting brain invasion microscopically was increased more than 2-fold in patients with a history of preoperative seizures (OR 2.57, 95% CI 1.13-5.88; p = 0.025). In univariate analyses, the rate of preoperative seizures correlated slightly with tumor volume (p = 0.049) but strongly with edema volume (p = 0.014), whereas seizure semiology was found to be independent of brain invasion (p = 0.211). In multivariate analyses adjusted for age, sex, tumor location, tumor and edema volumes, and WHO grade, rising tumor volume (OR 1.02, 95% CI 1.00-1.03; p = 0.042) and especially brain invasion (OR 5.26, 95% CI 1.52-18.15; p = 0.009) were identified as independent predictors of preoperative seizures. Nine (5%) patients developed new seizures within a median follow-up time of 15 months after surgery. Development of postoperative epilepsy was independent of all clinical variables, including Simpson grade (p = 0.133), tumor location (p = 0.936), brain invasion (p = 0.408), and preoperative edema volume (p = 0.081), but was correlated with increasing preoperative tumor volume (p = 0.004). Postoperative seizure-free rates were similar among patients with invasive and those with noninvasive meningioma (p = 0.372)., Conclusions: Brain invasion was identified as a new and strong predictor for preoperative, but not postoperative, seizures. Although also associated with increased peritumoral edema, seizures in patients with invasive meningioma might be facilitated substantially by cortical invasion itself. Consideration of seizures in consultations between the neurosurgeon and neuropathologist can improve the microscopic detection of brain invasion.

Objective: We analyzed the applicability of the Simpson grading system to estimate the risk of tumor recurrence after microsurgery for recurrent meningiomas., Methods: Correlations between the Simpson grade and the extent of resection (EOR) (gross total resection [Simpson grade I and II] vs. subtotal resection [Simpson grade ≥III]) with tumor relapse after microsurgery for meningioma recurrence were investigated compared with the findings in primary diagnosed tumors. Location-specific differences were further elucidated in subgroup analyses., Results: A total of 829 individuals (88% in group A) with primary diagnosed meningioma and 109 patients with first postoperative recurrence (12% in group B) who underwent surgery were included. In group A, both Simpson grade (P = 0.003) and EOR (P < 0.001) correlated strongly with recurrence. In group B, Simpson grade correlated with tumor location (P = 0.030), and the risk of subtotal resection was greater in the posterior fossa (odds ratio, 5.26; P = 0.018) and skull base (odds ratio, 6.16; P = 0.002) meningiomas. Older age at tumor relapse (hazard ratio [HR], 1.05; P = 0.001), male sex (HR, 2.19; P = 0.02), and grade 2/3 histologic findings (HR, 2.18; P = 0.02). However, neither the Simpson grade nor dichotomized EOR correlated with further tumor recurrence. The frequency of postoperative complications was similar in both groups., Conclusions: Surgery for recurrent meningiomas is not generally associated with an increased risk of postoperative complications compared with resection of primary diagnosed tumors. However, the Simpson grade and EOR in recurrent meningiomas correlated poorly with further tumor relapse. The lower prognostic value of the tumor remnants left behind during microsurgery for recurrent meningiomas should be considered when operating on lesions that can be surgically challenging., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Although the majority of surgeries for spinal meningiomas are performed in geriatric patients, age-related analyzes of preoperative symptoms and functional outcome are sparse. Clinical, neuropathological and radiological data of 88 patients who underwent surgery for spinal meningiomas were reviewed. Correlations between the patients' age and preoperative symptoms as well as functional outcome were investigated. 14 males (16%) and 74 females (84%) with a median age of 67 years were included. Age at the time of surgery was independent of the tumor location and volume, intra-/extradural tumor location, spinal cord compression or signal change on T2-weighted MRI (p > 0.05, each). Preoperative McCormick score (p = 0.001), motor (p = 0.005) and sensory (p = 0.025) deficits and incontinence (p = 0.010) increased, while frequency of radicular pain decreased with increasing age (p = 0.020). Multivariate analyses confirmed an increasing risk of motor (OR: 1.05, p = 0.017) and, with borderline significance, of sensory deficits (OR: 1.04, 95%CI 1.00-1.10; p = 0.056) with rising age. Simpson grades I, II, III and IV were achieved in 12 (14%), 54 (64%), 14 (17%) and 4 (5%) individuals, respectively. Only 3 of 12 patients (25%) with perioperative complications were younger than 65 years. Rising age was associated with improvement of motor (p = 0.006) and sensory deficits (p = 0.045). In multivariate analyzes, probability of improvement of preoperative motor weakness (OR = 1.05, p = 0.031) and sensory deficits (OR = 1.07, p = 0.014) increased with rising age. Despite more frequent preoperative neurological deficits, older patients with spinal meningiomas recover most noticeably after surgery. However, stratification of the medical condition is urgent to reduce complications., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: There have been major developments in diagnostic and surgical and non-surgical techniques used in the management of meningiomas over last three decades. We set out to describe these changes in a systematic manner., Method: Clinical and radiological data, surgical procedures, complications, and outcome of 817 patients who underwent surgery for primarily diagnosed meningioma between 1991 and 2015 were investigated., Results: Median age at diagnosis increased significantly from 56 to 59 years (p = .042), while tumor location and preoperative Karnofsky performance status did not change during the observation period. Availability of preoperative MRI increased, and rates of angiography and tumor embolization decreased (p < .001, each). Median duration of total, pre-, and postoperative stay was 13, 2, and 9 days, respectively, and decreased between 1991 and 2015 (p < .001, each). Median incision-suture time varied annually (p < .001) but without becoming clearly longer or shorter during the entire observation period. The use of intraoperative neuronavigation and neuromonitoring increased, while the rates of Simpson grade I and III surgeries decreased (p < .001). Rates of postoperative hemorrhage (p = .997), hydrocephalus (p = .632), and wound infection (p = .126) did not change, while the frequency of early postoperative neurological deficits decreased from 21% between 1991 and 1995 to 13% between 2011 and 2015 (p = .003). During the same time, the rate of surgeries for postoperative cerebrospinal fluid leakage slightly increased from 2 to 3% (p = .049). Within a median follow-up of 62 months, progression was observed in 114 individuals (14%). Progression-free interval did not significantly change during observation period (p > .05). Multivariate analyses confirmed the lack of correlation between year of surgery and tumor relapse (HR: 1.1, p > .05)., Conclusions: Preoperative diagnosis and surgery of meningiomas have been substantially evolved. Although early neurological outcome has improved, long-term prognosis remains unchanged.

In meningiomas, location-specific differences of the prognostic value of the Simpson classification are sparsely investigated but can influence strategy of surgery. We therefore compared the prognostic value of the Simpson classification in different tumor locations. Progression was compared with Simpson grade in 826 meningioma patients (median age 58 years, female:male ratio 2.4) in location-specific uni- and multivariate analyses. Simpson grade strongly correlated with tumor location (p < .001). Within a median follow-up of 50 months, recurrence was observed in 107 of 803 patients (13%). In general, increasing Simpson grade (p = .002) and subtotal resection (STR, ≥grade III) were correlated with tumor recurrence [hazard ratio (HR): 1.87; p = .004]. In 268 convexity meningiomas, frequency of tumor recurrence correlated with Simpson grade (p = .034). Risk of recurrence was similar after grade I and II resections, tended to increase after grade III (HR: 2.35; p = .087) but was higher after grade IV resections (HR: 7.35; p = .003). Risk of recurrence was higher after STR (HR: 4.21; p = .001) than after gross total resection (GTR, ≤grade II). Contrarily, increasing Simpson grade and STR were not correlated with progression in 102 falx, 38 posterior fossa and nine intraventricular meningiomas. In 325 skull base lesions, risk of recurrence was similar after GTR and STR (p = .198) and was only increased after grade IV resections (HR: 3.26; p = .017). Simpson grading and extent of resection were not equally prognostic in all locations. Lower impact of extent of resection should be considered during surgery for skull base, posterior fossa and falx meningiomas.

Background: The WHO classification of brain tumours describes 15 subtypes of meningioma. Nine of these subtypes are allotted to WHO grade I, and three each to grade II and grade III. Grading is based solely on histology, with an absence of molecular markers. Although the existing classification and grading approach is of prognostic value, it harbours shortcomings such as ill-defined parameters for subtypes and grading criteria prone to arbitrary judgment. In this study, we aimed for a comprehensive characterisation of the entire molecular genetic landscape of meningioma to identify biologically and clinically relevant subgroups., Methods: In this multicentre, retrospective analysis, we investigated genome-wide DNA methylation patterns of meningiomas from ten European academic neuro-oncology centres to identify distinct methylation classes of meningiomas. The methylation classes were further characterised by DNA copy number analysis, mutational profiling, and RNA sequencing. Methylation classes were analysed for progression-free survival outcomes by the Kaplan-Meier method. The DNA methylation-based and WHO classification schema were compared using the Brier prediction score, analysed in an independent cohort with WHO grading, progression-free survival, and disease-specific survival data available, collected at the Medical University Vienna (Vienna, Austria), assessing methylation patterns with an alternative methylation chip., Findings: We retrospectively collected 497 meningiomas along with 309 samples of other extra-axial skull tumours that might histologically mimic meningioma variants. Unsupervised clustering of DNA methylation data clearly segregated all meningiomas from other skull tumours. We generated genome-wide DNA methylation profiles from all 497 meningioma samples. DNA methylation profiling distinguished six distinct clinically relevant methylation classes associated with typical mutational, cytogenetic, and gene expression patterns. Compared with WHO grading, classification by individual and combined methylation classes more accurately identifies patients at high risk of disease progression in tumours with WHO grade I histology, and patients at lower risk of recurrence among WHO grade II tumours (p=0·0096) from the Brier prediction test). We validated this finding in our independent cohort of 140 patients with meningioma., Interpretation: DNA methylation-based meningioma classification captures clinically more homogenous groups and has a higher power for predicting tumour recurrence and prognosis than the WHO classification. The approach presented here is potentially very useful for stratifying meningioma patients to observation-only or adjuvant treatment groups. We consider methylation-based tumour classification highly relevant for the future diagnosis and treatment of meningioma., Funding: German Cancer Aid, Else Kröner-Fresenius Foundation, and DKFZ/Heidelberg Institute of Personalized Oncology/Precision Oncology Program., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

OBJECTIVE The purpose of this study was to compare long-term prognosis after meningioma surgery in elderly and younger patients as well as to compare survival of elderly patients with surgically treated meningioma to survival rates for the general population. METHODS Five hundred meningioma patients (median follow-up 90 months) who underwent surgery between 1994 and 2009 were subdivided into "elderly" (age ≥ 65 years, n = 162) and "younger" (age < 65 years, n = 338) groups for uni- and multivariate analyses. Mortality was compared with rates for the age- and sex-matched general population. RESULTS The median age at diagnosis was 71 in the elderly group and 51 years in the younger group. Sex, intracranial tumor location, grade of resection, radiotherapy, and histopathological subtypes were similar in the 2 groups. High-grade (WHO Grades II and III) and spinal tumors were more common in older patients than in younger patients (15% vs 8%, p = 0.017, and 12% vs 4%, p = 0.001, respectively). The progression-free interval (PFI) was similar in the 2 groups, whereas mortality at 3 months after surgery was higher and median overall survival (OS) was shorter in older patients (7%, 191 months) than in younger patients (1%, median not reached; HR 4.9, 95% CI 2.75-8.74; p < 0.001). Otherwise, the median OS in elderly patients did not differ from the anticipated general life expectancy (HR 1.03, 95% CI 0.70-1.50; p = 0.886). Within the older patient group, PFI was lower in patients with high-grade meningiomas (HR 24.74, 95% CI 4.23-144.66; p < 0.001) and after subtotal resection (HR 10.57, 95% CI 2.23-50.05; p = 0.003). Although extent of resection was independent of perioperative mortality, the median OS was longer after gross-total resection than after subtotal resection (HR 2.7, 95% CI 1.09-6.69; p = 0.032). CONCLUSIONS Elderly patients with surgically treated meningioma do not suffer from impaired survival compared with the age-matched general population, and their PFI is similar to that of younger meningioma patients. These data help mitigate fears concerning surgical treatment of elderly patients in an aging society.

In meningiomas, prognostic impact of mutations in the human telomerase reverse transcriptase (hTERT) promoter region was recently shown, while studies of promoter methylation and analyses of hemangiopericytomas are lacking. hTERT promoter methylation was analyzed in 78 meningioma and 38 meningeal hemangiopericytoma samples by methylation-specific polymerase chain reaction (MS-PCR) and compared with histopathological and clinical variables and with immunohistochemical hTERT expression. Promoter methylation was found in 62 samples (53 %) and tended to be higher in meningiomas (N = 19/41, 46 %) than in hemangiopericytomas (N = 8/33, 24 %, p = .057). In meningiomas, methylation was 16, 60 and 77 % in grade I, II and III tumors (p < .001) and higher in recurrent (N = 33/37, 89 %) than in primary diagnosed (N = 19/41, 46 %) tumors (OR 5.14, 95 % CI 1.34-19.71, p = .017). Univariate analyses showed shorter mean progression free and overall survival in methylated than in unmethylated individuals (26 vs. 100 months; p = .045 and 110 vs. 113 months; p = .025, respectively). Moreover, hTERT expression was found in 70 % (N = 53) and was more frequent in methylated than in unmethylated samples (78 vs. 52 %, OR 3.36, 95 % CI 1.20-9.40, p = .021). In hemangiopericytomas, methylation was similar in grade II (24 %) and III (25 %, p > .05) and in primary (24 %) and recurrent tumors (40 %, p > .05). hTERT expression was similar as compared to meningiomas (74 %, N = 28, p > .05) but was independent of promoter methylation (OR 4.26, 95 % CI 0.47-39.0, p = .199). In meningeal tumors, hTERT promoter methylation is more common than mutations and in meningiomas but not in hemangiopericytomas positively correlated with WHO grade and hTERT expression.

Objective: In meningioma, correlation of brain invasion with prognosis and clinical variables remains controversial., Methods: Correlation of brain invasion with clinical and histopathologic variables was investigated in 467 patients with primary intracranial meningioma., Results: Diffuse (n = 3; 10%), clusterlike (n = 11; 34%) or fingerlike (n = 18; 56%) invasion was detected in 32 patients (7%). Brain invasion was more common in males than in females (13% vs. 5%; odds ratio, 2.75; 95% confidence interval, 1.29-5.89; P = 0.009) and pattern of invasion differed between genders (P = 0.037). Brain invasion was absent in 401 benign meningiomas and present in 48% of 60 atypical (n = 29) and 50% of 6 anaplastic (n = 3) meningiomas (P < 0.001) but was independent of tumor location and extent of resection. Progression occurred in 11% and was more frequent (31% vs. 15%; P = 0.036) in invasive than in noninvasive tumors, but only after gross total resection and in univariate analyses, and independent of invasion pattern. In atypical meningiomas, frequency of adjuvant irradiation was similar comparing invasive and noninvasive tumors and grading solely based on brain invasion (n = 20; 33%), other World Health Organization (WHO) criteria (n = 31; 52%) or a combination of both (n = 9; 15%). Risk of recurrence was lower (hazard ratio, 0.258, 95% confidence interval, 0.09-0.734; P = 0.011) when grading exclusively based on brain invasion than when further WHO criteria were in addition present and the progression-free interval among the first was similar to benign tumors., Conclusions: Brain invasion and its patterns are correlated to gender. In contrast to the current WHO classification, invasion was associated with recurrence only after gross total resection and not independent of further histopathologic criteria of atypia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The World Health Organization (WHO) classification and grading system attempts to predict the clinical course of meningiomas based on morphological parameters. However, because of high interobserver variation of some criteria, more reliable prognostic markers are required. Here, we assessed the TERT promoter for mutations in the hotspot regions C228T and C250T in meningioma samples from 252 patients. Mutations were detected in 16 samples (6.4% across the cohort, 1.7%, 5.7%, and 20.0% of WHO grade I, II, and III cases, respectively). Data were analyzed by t test, Fisher's exact test, log-rank test, and Cox proportional hazard model. All statistical tests were two-sided. Within a mean follow-up time in surviving patients of 68.1 months, TERT promoter mutations were statistically significantly associated with shorter time to progression (P < .001). Median time to progression among mutant cases was 10.1 months compared with 179.0 months among wild-type cases. Our results indicate that the inclusion of molecular data (ie, analysis of TERT promoter status) into a histologically and genetically integrated classification and grading system for meningiomas increases prognostic power. Consequently, we propose to incorporate the assessment of TERT promoter status in upcoming grading schemes for meningioma., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Dramatic growth of meningiomas is occasionally encountered during pregnancy. While cell proliferation is often assumed, hemodynamic changes have also been touted as a cause., Objective: We identified 17 meningiomas resected during pregnancy or within 3 weeks post-partum and characterized them to determine the cause of occasional rapid growth in pregnancy., Methods: Seventeen tumors were identified from searches at 4 university centers. All available clinical records, radiology images, and tissue specimens were reviewed, with immunohistochemical studies performed as needed., Results: Sixteen patients underwent tumor resection and 1 died of complications prior to surgery. Average patient age was 32 years. Nine experienced onset of symptoms in the third trimester or within 8 days post-partum. Principle physical findings included visual complaints (59%) and cranial nerve palsies (29%). Ten tumors (59%) were located in the skull base region. The Ki-67 labeling index was low (0.5-3.6%) in 11 of 13 benign (grade I) tumors and elevated (11-23.2%) in 3 of 4 atypical (grade II) meningiomas. Eight (50%) tumors featured hypervascularity with at least focal CD34-positive hemangioma-like microvasculature. Fourteen (82%) showed evidence of intra- and/or extracellular edema, 1 so extensive that its meningothelial nature was not apparent. Five tumors (29%) exhibited intratumoral hemorrhage and/or necrosis., Conclusion: Our series suggests that pregnancy-associated meningiomas located in the skull base are likely to require surgical intervention for visual complaints and cranial nerve palsies. The rapid tumor growth is more often due to potentially reversible hemodynamic changes rather than hormone-induced cellular proliferation.

High levels of fatty acid synthase (FAS) expression have been reported in hormone receptor-positive tumors, including prostate, breast, and ovarian cancers, and its inhibition reduces tumor growth in vitro and in vivo. Similar to other hormone receptor-positive tumor types, meningiomas are progesterone receptor- and estrogen receptor-immunoreactive brain tumors. To define the role of FAS in human meningioma growth control, we first analyzed the FAS expression using a tissue microarray containing 38 meningiomas and showed increased FAS expression in 70% of atypical WHO grade II and anaplastic WHO grade III meningiomas compared with 10% of benign WHO grade I tumors. We next confirmed this finding by real-time PCR and Western blotting. Second, we demonstrated that treatment with the FAS inhibitor, cerulenin (Cer), significantly decreased meningioma cell survival in vitro. Third, we showed that Cer treatment reduced FAS expression by modulating Akt phosphorylation (activation). Fourth, we demonstrated that Cer treatment of mice bearing meningioma xenografts resulted in significantly reduced tumor volumes associated with increased meningioma cell death. Collectively, our data suggest that the increased FAS expression in human meningiomas represents a novel therapeutic target for the treatment of unresectable or malignant meningioma.

Meningiomas are the second most common brain tumors in adults, and meningiomas exhibit a tendency to invade adjacent structures. Compared with high-grade gliomas, little is known about the molecular changes that potentially underlie the invasive behavior of meningiomas. In this study, we examined the expression and function of the membrane alanyl-aminopeptidase [mAAP, aminopeptidase N (APN), CD13, EC3.4.11.2] zinc-dependent ectopeptidase in meningiomas and meningioma cell lines, based on its prior association with tumor invasion in colorectal and renal carcinomas. We found a significant reduction of APNmRNA and protein expression, as well as enzymatic activity, in high-grade meningiomas. While meningioma tumor cell proliferation was not affected by either pharmacologic APN inhibition or siRNA-mediated APN silencing, APN pharmacologic and siRNA knockdown significantly reduced meningioma cell invasion in vitro. Next, we employed pathway-specific cDNA microarray analyses to identify extracellular matrix and adhesion molecules regulated by APN, and found that APN-siRNA knockdown substantially increased the expression of secreted protein, acidic and rich in cysteine (SPARC)/osteonectin. Finally, we demonstrated that SPARC, which has been previously associated with meningioma invasiveness, was increased in aggressive meningiomas. Collectively, these results suggest that APN expression and enzymatic function is reduced in aggressive meningiomas, and that alterations in the balance between APN and SPARC might favor meningioma invasion.

Gliomas are the most frequent primary brain tumors. In a minority of cases, the differentiation between astrocytomas and oligodendrogliomas based on morphologic characteristics alone can be difficult; though it is important, as patients with oligodendrogliomas follow a more favorable clinical course. Here we report on the immunohistochemical expression pattern of the oligodendrocytic marker Nogo-A in 113 central nervous system tumors including 28 oligodendrogliomas [15, World Health Organization (WHO) grade II; 13, grade WHO III], 50 astrocytomas [10, grade WHO II; 11, grade WHO III; 29 glioblastoma multiforme (GBM)], 11 ependymomas WHO grade II, 7 central neurocytomas, 2 dysembryoplastic neuroepithelial tumors (DNTs), 5 clear cell meningiomas, and 10 metastases to the brain. The oligodendrocytic marker Nogo-A was found to be strongly expressed in 71% of oligodendrogliomas, but in 0% of ependymomas WHO grade II, astrocytomas WHO grade II or III, DNTs, central neurocytomas, or clear cell meningiomas. In GBM, a subgroup of tumors (24%) showed strong expression of Nogo-A coincidently with Ki67 positivity but glial fibrillary acidic protein-negativity. However, neither in oligodendrogliomas nor GBM was a correlation between the loss of 1p19q and the extent of Nogo-A expression observed. Our findings indicate that Nogo-A is strongly expressed in the majority of oligodendrogliomas and might be a helpful marker to distinguish oligodendrogliomas from astrocytomas WHO grades II and III as well as ependymomas. They also support the hypothesis that GBM may be a heterogeneous group of tumors derived from different progenitor cells.

The WHO classification defines different histological variants of meningiomas. Mutations of the tumor suppressor gene NF2 on 22q have been described in 30% to 60 % of sporadic meningiomas. However, the vast majority of the meningiomas that have been subject to NF2 analysis belong to the most frequent variants like transitional, fibroblastic and meningothelial meningiomas. Within these subtypes, transitional and fibroblastic meningiomas harbor significantly more NF2 mutations than meningothelial meningiomas, indicating molecular subsets of these tumors. To determine whether rare meningioma variants carry NF2 mutations we analyzed 80 tumors. NF2 mutations were detected in 5 (36%) of 14 psammomatous, 1 (11%) of 9 angiomatous, 2 (22%) of 9 clear cell, 1 (33%) of 3 chordoid and 1 (100%) of 1 papillary meningioma. In the single papillary meningioma, 2 different NF2 mutations were observed. No NF2 mutations were found in 33 secretory, 7 microcystic, 2 lymphoplasmacyte-rich, one rhabdoid and one metaplastic meningioma. In the control group of 25 fibroblastic meningiomas, 11 cases were identified to carry an NF2 mutation. These results support the concept of different molecular subgroups of meningiomas which overlap with histological variants.

Meningioma represents the most common intracranial tumor, but well-characterized cell lines derived from benign meningiomas are not available. A major reason for the lack of benign tumor cell lines is senescence of nonmalignant cells in vitro, while malignant cells are often immortal. We have developed a meningioma cell line by retrovirally transducing primary cells derived from a human WHO grade I meningothelial meningioma with the human telomerase reverse transcriptase (hTERT) gene, which enables bypassing cellular senescence. Five clones have been cultured for more than 21 months so far, while corresponding nontransfected cells ceased proliferation within 3 months. Quantitative RT-PCR and a telomeric repeat amplification protocol (TRAP) assay revealed high hTERT mRNA levels and high telomerase activity in all transduced populations, while nontransduced cells were negative. The average telomere size of transduced cells was considerably longer than that of parental cells and the biopsy specimen. One clone, designated Ben-Men-1, was characterized in more detail, and exhibited typical cytological, immunocytochemical, ultrastructural and genetical features of meningioma, including whorl formation, expression of epithelial membrane antigen, desmosomes and interdigitating cell processes, as well as -22q. Following subdural transplantation into nude mice, tumor tissue with typical histological features of meningothelial meningioma was found. We conclude that Ben-Men-1 represents an immortalized yet differentiated cell line useful for biological and therapeutical studies on meningioma.

To characterize histopathological and clinical features of angiomatous meningioma, 38 cases of angiomatous meningioma, ie, meningiomas whose vascular component exceeded 50% of the total tumor area, are reported. In addition to histologic examinations, clinical characteristics as well as follow-up data were compiled. Angiomatous meningiomas constituted 2.1% of all meningiomas. Histologic signs of atypia or anaplasia were not observed in any tumor. The mean MIB-1/Ki67 proliferation index was 2.4%. Based on vessel size, two distinct histologic subtypes were identified, which differed in localization but not with regards to sex, age, presence of peritumoral edema, MIB-1/Ki67 proliferation index, or progesterone receptor status. In patients with gross tumor resection, no recurrences occurred. To conclude, angiomatous meningiomas share histologic and clinical features of benign meningiomas. Since all angiomatous meningiomas examined here were grade 1 tumors, the diagnosis of angiomatous meningioma may have prognostic implications. Therefore, the existence of this rare subgroup of meningioma appears justified.

Simple Summary: Mutations in the telomerase reverse transcriptase (TERT) gene promoter are rare in meningiomas, but are associated with more aggressive forms of meningiomas as well as recurrence and progression. In this study, we analyzed data of patients who underwent meningioma surgery with neuropathologically assessed TERT promoter mutation status. Semiautomatic segmentation of the meningiomas was performed on preoperative magnetic resonance imaging (MRI). Radiomics features were extracted from T1-weighted contrast-enhanced MRI data. TERT promoter mutations were predicted using the random forest algorithm with an increasing number of radiomic features. 117 image sets were included and divided into a training group with 94 image sets and a test group with 23 image sets. Based on the test group, established five- and eight-feature models demonstrated high sensitivity, specificity, accuracy and AUC values for prediction of TERT promoter mutation status. Purpose: In meningiomas, TERT promotor mutations are rare but qualify the diagnosis of anaplasia, directly impacting adjuvant therapy. Effective screening for patients at risk for promotor mutations could enable more targeted molecular analyses and improve diagnosis and treatment. Methods: Semiautomatic segmentation of intracranial grade 2/3 meningiomas was performed on preoperative magnetic resonance imaging. Discriminatory power to predict TERT promoter mutations was analyzed using a random forest algorithm with an increasing number of radiomic features. Two final models with five and eight features with both fixed and differing radiomics features were developed and adjusted to eliminate random effects and to avoid overfitting. Results: A total of 117 image sets including training (N = 94) and test data (N = 23) were analyzed. To eliminate random effects and demonstrate the robustness of our approach, data partitioning and subsequent model development and testing were repeated a total of 100 times (each time with repartitioned training and independent test data). The established five- and eight-feature models with both fixed and different radiomics features enabled the prediction of TERT with similar but excellent performance. The five-feature (different/fixed) model predicted TERT promotor mutation status with a mean AUC of 91.8%/94.3%, mean accuracy of 85.5%/88.9%, mean sensitivity of 88.6%/91.4%, mean specificity of 83.2%/87.0%, and a mean Cohen's Kappa of 71.0%/77.7%. The eight-feature (different/fixed) model predicted TERT promotor mutation status with a mean AUC of 92.7%/94.6%, mean accuracy of 87.3%/88.9%, mean sensitivity of 89.6%/90.6%, mean specificity of 85.5%/87.5%, and a mean Cohen's Kappa of 74.4%/77.6%. Of note, the addition of further features of up to N = 8 only slightly increased the performance. Conclusions: Radiomics-based machine learning enables prediction of TERT promotor mutation status in meningiomas with excellent discriminatory performance. Future analyses in larger cohorts should include grade 1 lesions as well as additional molecular alterations. [ABSTRACT FROM AUTHOR]

Simple Summary: In meningiomas, 5-aminolevulinc acid (5-ALA)-mediated fluorescence-guided resection (FGR) has been shown to improve intraoperative tumor bone and soft tissue invasion. However, several studies reported distinct limitations of FGR, e.g., for the visualization of the dura tail or CNS invasion. Notably, correlations between fluorescence and histological findings, as well as the expression of key heme synthesis pathway molecules, have been sparsely investigated. In this study, we examined 111 samples from 44 patients after an FGR of an intracranial meningioma for the presence of histopathological evidence of tumor tissue and intraoperative fluorescence, and analyzed the expression of key transporters/enzymes involved in PpIX metabolism using immunohistochemistry and qPCR. High sensitivity and specificity for the identification of tumor tissue and correlation of fluorescence and tumor tissue with expression of the enzymes/transporters were demonstrated. However, a deviating fluorescence and expression could be observed in non-neoplastic brain tissue, whereas this was lacking in the dura. Background: The usefulness of 5-ALA-mediated fluorescence-guided resection (FGR) in meningiomas is controversial, and information on the molecular background of fluorescence is sparse. Methods: Specimens obtained during 44 FGRs of intracranial meningiomas were analyzed for the presence of tumor tissue and fluorescence. Protein/mRNA expression of key transmembrane transporters/enzymes involved in PpIX metabolism (ABCB6, ABCG2, FECH, CPOX) were investigated using immunohistochemistry/qPCR. Results: Intraoperative fluorescence was observed in 70 of 111 specimens (63%). No correlation was found between fluorescence and the WHO grade (p = 0.403). FGR enabled the identification of neoplastic tissue (sensitivity 84%, specificity 67%, positive and negative predictive value of 86% and 63%, respectively, AUC: 0.75, p < 0.001), and was improved in subgroup analyses excluding dura specimens (86%, 88%, 96%, 63% and 0.87, respectively; p < 0.001). No correlation was found between cortical fluorescence and tumor invasion (p = 0.351). Protein expression of ABCB6, ABCG2, FECH and CPOX was found in meningioma tissue and was correlated with fluorescence (p < 0.05, each), whereas this was not confirmed for mRNA expression. Aberrant expression was observed in the CNS. Conclusion: FGR enables the intraoperative identification of meningioma tissue with limitations concerning dura invasion and due to ectopic expression in the CNS. ABCB6, ABCG2, FECH and CPOX are expressed in meningioma tissue and are related to fluorescence. [ABSTRACT FROM AUTHOR]

Missense mutations of the V600E type constitute the vast majority of tumor-associated somatic alterations in the v-RAF murine sarcoma viral oncogene homolog B1 ( BRAF) gene. Initially described in melanoma, colon and papillary thyroid carcinoma, these alterations have also been observed in primary nervous system tumors albeit at a low frequency. We analyzed exon 15 of BRAF spanning the V600 locus by direct sequencing in 1,320 adult and pediatric tumors of the nervous system including various types of glial, embryonal, neuronal and glioneuronal, meningeal, adenohypophyseal/sellar, and peripheral nervous system tumors. A total of 96 BRAF mutations were detected; 93 of the V600E type and 3 cases with a three base pair insertion between codons 599 and 600. The highest frequencies of BRAF mutations were found in WHO grade II pleomorphic xanthoastrocytomas (42/64; 66%) and pleomorphic xanthoastrocytomas with anaplasia (15/23; 65%), as well as WHO grade I gangliogliomas (14/77; 18%), WHO grade III anaplastic gangliogliomas (3/6) and pilocytic astrocytomas (9/97; 9%). In pilocytic astrocytomas BRAF mutation was strongly associated with extra-cerebellar location ( p = 0.009) and was most frequent in diencephalic tumors (4/12; 33%). Glioblastomas and other gliomas were characterized by a low frequency or absence of mutations. No mutations were detected in non-glial tumors, including embryonal tumors, meningiomas, nerve sheath tumors and pituitary adenomas. The high mutation frequencies in pleomorphic xanthoastrocytomas, gangliogliomas and extra-cerebellar pilocytic astrocytomas implicate BRAF mutation as a valuable diagnostic marker for these rare tumor entities. Future clinical trials should address whether BRAF mutant brain tumor patients will benefit from BRAF-directed targeted therapies. [ABSTRACT FROM AUTHOR]