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Simple Summary: Is the resection of spinal meningiomas in asymptomatic patients or patients with mild neurological symptoms justified? In this study, we compare the neurological outcome, quality of life, and quality of care of these patients to patients with more severe neurological symptoms. The results show that early neurosurgical intervention leads to better neurological outcomes and quality of life, contradicting a watch-and-see regime. Background: The main treatment modality for spinal meningiomas (SM) is gross total resection (GTR). However, the optimal timing of surgery, especially in cases with absent or mild neurological symptoms, remains unclear. The aim of this study is to assess the impact of early-stage resection on neurological outcome, quality of life (QoL), and quality of care. The primary objective is a favorable neurological outcome (McCormick scale 1). Methods: We retrospectively analyzed data from patients who underwent operations for SM between 2011 and 2021. Patients with mild neurological symptoms preoperatively (McCormick scale 1 and 2) were compared to those with more severe neurological symptoms (McCormick scale 3–5). Disabilities and QoL were assessed according to validated questionnaires (SF-36, ODI, NDI). Results: Age, spinal cord edema, thoracic localization, and spinal canal occupancy ratio were associated with more severe neurological symptoms (all p < 0.05). Patients presenting with mild symptoms were associated with favorable neurological outcomes (OR: 14.778 (95%CI 3.918–55.746, p < 0.001)), which is associated with shorter hospitalization, better QoL, and fewer disabilities (p < 0.05). Quality of care was comparable in both cohorts. Conclusions: Early surgical intervention for SM, before the development of severe neurological deficits, should be considered as it is associated with a favorable neurological outcome and quality of life. [ABSTRACT FROM AUTHOR]

Background: The risk of recurrence is overestimated by the Kaplan–Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan–Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated. Methods: We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan–Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions. Results: Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan–Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions). Conclusion: The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Although frozen section pathology (FSP) is commonly performed during surgery for glioma-suspicious lesions, confounders of accuracy are largely unknown. FSP and final diagnosis were compared in 398 surgeries for glioma-suspicious lesions. Diagnostic accuracy, risk factors for diagnostic shift from neoplastic to non-neoplastic tissue and vice versa according to the final diagnosis, and the impact on intraoperative and postoperative decision-making were analyzed. Diagnostic shift occurred in 70 cases (18%), and sensitivity, specificity, and the positive (PPV) and negative (NPV) predictive value of FSP were 82.5%, 77.8%, 99.4%, and 9.3%, respectively. No correlations between shift and patients' age and sex, sample fluorescence or volume, tumor location, correct information on the pathology form, final high- or low-grade histology, or molecular alterations were found (p >.05, each). Shift was more common after irradiation (25% vs 15%; p =.025) or chemotherapy (26% vs 15%; p =.022) than in treatment naïve cases and correlated with the type of surgery (p =.002). FSP altered intraoperative decision-making in 25 cases (6%). Postoperative shift led to repeated surgery in 12 patients (3%). In 45 cases, in which FSP and final diagnosis based on the same tissue, shift occurred in only 5 patients (11%), and sensitivity, specificity, PPV, and NPV for FSP were 77.4%, 78.6%, 88.9%, and 61.1%, respectively. No correlations between diagnostic shift and any of the analyzed variables were found (p >.05, each). Although accuracy of FSP during glioma surgery is sufficient, moderate NPV should be considered during intraoperative decision-making. While confounders are sparse, accuracy might be increased by repeated sampling. Diagnostic shift rarely alters postoperative treatment strategy. [ABSTRACT FROM AUTHOR]

Background Risk stratification based on standardized quality measures has become crucial in neurosurgery. Contemporary quality indicators have often been developed for a wide range of neurosurgical procedures collectively. The accuracy of tumor-inherent characteristics of patients diagnosed with meningioma remains questionable. The objective of this study was the analysis of currently applied quality indicators in meningioma surgery and the identification of potential new measures. Methods Data of 133 patients who were operated on due to intracranial meningiomas were subjected to a retrospective analysis. The primary outcomes of interest were classical quality indicators such as the 30-day readmission, 30-day reoperation, 30-day mortality, 30-day nosocomial infection, and the 30-day surgical site infection rate. Uni- and multivariate analyses were performed. The occurrence of a new postoperative neurologic deficit was analyzed as a potential new quality indicator. Results The overall unplanned readmission rate was 3.8%; 13 patients were reoperated within 30 days (9.8%). The 30-day nosocomial infection and surgical site infection rates were 6.8 and 1.5%, respectively. A postoperative new neurologic deficit or neurologic deterioration as a currently assessed quality feature was observed in 12 patients (9.2%). The edema volume on preoperative scans proved to have a significant impact on the occurrence of a new postoperative neurologic deficit (p = 0.023). Conclusions Classical quality indicators in neurosurgery have proved to correlate with considerable deterioration of the patient's health in meningioma surgery and thus should be taken into consideration for application in meningioma patients. The occurrence of a new postoperative neurologic deficit is common and procedure specific. Thus, this should be elucidated for application as a complementary quality indicator in meningioma surgery. [ABSTRACT FROM AUTHOR]

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]

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. [ABSTRACT FROM AUTHOR]

Petroleum is commonly used as a solvent, and primary intrathecal administration or secondary diffusion and subsequent clinical management has not been reported. We report the case of a male patient with intrathecal petroleum diffusion following accidental lumbar infiltration. After the onset of secondary myeloencephalopathy with coma and tetraparesis, continuous cranio-lumbar irrigation using an external ventricular and a lumbar drain was established. Cranial imaging revealed distinct supra- and infratentorial alterations. The patient improved slowly and was referred to rehabilitation. Intrathecal petroleum leads to myeloencephalopathy and continuous cranio-lumbar irrigation might be a safe treatment option. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop a magnetic resonance imaging (MRI) based radiomics model to predict mitosis cycles in intracranial meningioma grading prior to surgery. Preoperative contrast-enhanced T1-weighted (T1CE) cerebral MRI data of 167 meningioma patients between 2015 and 2020 were obtained, preprocessed and segmented using the 3D Slicer software and the PyRadiomics plugin. In total 145 radiomics features of the T1CE MRI images were computed. The criterion on the basis of which the feature selection was made is whether the number of mitoses per 10 high power field (HPF) is greater than or equal to zero. Our analyses show that machine learning algorithms can be used to make accurate predictions about whether the number of mitoses per 10 HPF is greater than or equal to zero. We obtained our best model using Ridge regression for feature pre-selection, followed by stepwise logistic regression for final model construction. Using independent test data, this model resulted in an AUC (Area under the Curve) of 0.8523, an accuracy of 0.7941, a sensitivity of 0.8182, a specificity of 0.7500 and a Cohen's Kappa of 0.5576. We analyzed the performance of this model as a function of the number of mitoses per 10 HPF. The model performs well for cases with zero mitoses as well as for cases with more than one mitosis per 10 HPF. The worst model performance (accuracy = 0.6250) is obtained for cases with one mitosis per 10 HPF. Our results show that MRI-based radiomics may be a promising approach to predict the mitosis cycles in intracranial meningioma prior to surgery. Specifically, our approach may offer a non-invasive means of detecting the early stages of a malignant process in meningiomas prior to the onset of clinical symptoms. [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]

Background: Primary central nervous system lymphoma (PCNSL) is a rare lymphoma of the central nervous system, usually of diffuse large B cell phenotype. Stereotactic biopsy followed by histopathology is the diagnostic standard. However, limited material is available from CNS biopsies, thus impeding an in-depth characterization of PCNSL. Methods: We performed flow cytometry, single-cell RNA sequencing, and B cell receptor sequencing of PCNSL cells released from biopsy material, blood, and cerebrospinal fluid (CSF), and spatial transcriptomics of biopsy samples. Results: PCNSL-released cells were predominantly activated CD19+CD20+CD38+CD27+ B cells. In single-cell RNA sequencing, PCNSL cells were transcriptionally heterogeneous, forming multiple malignant B cell clusters. Hyperexpanded B cell clones were shared between biopsy- and CSF- but not blood-derived cells. T cells in the tumor microenvironment upregulated immune checkpoint molecules, thereby recognizing immune evasion signals from PCNSL cells. Spatial transcriptomics revealed heterogeneous spatial organization of malignant B cell clusters, mirroring their transcriptional heterogeneity across patients, and pronounced expression of T cell exhaustion markers, co-localizing with a highly malignant B cell cluster. Conclusions: Malignant B cells in PCNSL show transcriptional and spatial intratumor heterogeneity. T cell exhaustion is frequent in the PCNSL microenvironment, co-localizes with malignant cells, and highlights the potential of personalized treatments. [ABSTRACT FROM AUTHOR]

Our aim is to predict possible gross total and subtotal resections of skull meningiomas from pre-treatment T1 post contrast MR-images using radiomics and machine learning in a representative patient cohort. We analyse the accuracy of our model predictions depending on the tumor location within the skull and the postoperative tumor volume. In this retrospective, IRB-approved study, image segmentation of the contrast enhancing parts of the tumor was semi-automatically performed using the 3D Slicer open-source software platform. Imaging data were split into training data and independent test data at random. We extracted a total of 107 radiomic features by hand-delineated regions of interest on T1 post contrast MR images. Feature preselection and model construction were performed with eight different machine learning algorithms. Each model was estimated 100 times on new training data and then tested on a previously unknown, independent test data set to avoid possible overfitting. Our cohort included 138 patients. A gross total resection of the meningioma was performed in 107 cases and a subtotal resection in the remaining 31 cases. Using the training data, the mean area under the curve (AUC), mean accuracy, mean kappa, mean sensitivity and mean specificity were 0.901, 0.875, 0.629, 0.675 and 0.933 respectively. We obtained very similar results with the independent test data: mean AUC = 0.900, mean accuracy = 0.881, mean kappa = 0.644, mean sensitivity = 0.692 and mean specificity = 0.936. Thus, our model exposes good and stable predictive performance with both training and test data. Our radiomics approach shows that with machine learning algorithms and comparatively few explanatory factors such as the location of the tumor within the skull as well as its shape, it is possible to make accurate predictions about whether a meningioma can be completely resected by surgery. Complete resections and resections with larger postoperative tumor volumes can be predicted with very high accuracy. However, cases with very small postoperative tumor volumes are comparatively difficult to predict correctly. [ABSTRACT FROM AUTHOR]

To investigate the applicability and performance of automated machine learning (AutoML) for potential applications in diagnostic neuroradiology. In the medical sector, there is a rapidly growing demand for machine learning methods, but only a limited number of corresponding experts. The comparatively simple handling of AutoML should enable even non-experts to develop adequate machine learning models with manageable effort. We aim to investigate the feasibility as well as the advantages and disadvantages of developing AutoML models compared to developing conventional machine learning models. We discuss the results in relation to a concrete example of a medical prediction application. In this retrospective IRB-approved study, a cohort of 107 patients who underwent gross total meningioma resection and a second cohort of 31 patients who underwent subtotal resection were included. Image segmentation of the contrast enhancing parts of the tumor was performed semi-automatically using the open-source software platform 3D Slicer. A total of 107 radiomic features were extracted by hand-delineated regions of interest from the pre-treatment MRI images of each patient. Within the AutoML approach, 20 different machine learning algorithms were trained and tested simultaneously. For comparison, a neural network and different conventional machine learning algorithms were trained and tested. With respect to the exemplary medical prediction application used in this study to evaluate the performance of Auto ML, namely the pre-treatment prediction of the achievable resection status of meningioma, AutoML achieved remarkable performance nearly equivalent to that of a feed-forward neural network with a single hidden layer. However, in the clinical case study considered here, logistic regression outperformed the AutoML algorithm. Using independent test data, we observed the following classification results (AutoML/neural network/logistic regression): mean area under the curve = 0.849/0.879/0.900, mean accuracy = 0.821/0.839/0.881, mean kappa = 0.465/0.491/0.644, mean sensitivity = 0.578/0.577/0.692 and mean specificity = 0.891/0.914/0.936. The results obtained with AutoML are therefore very promising. However, the AutoML models in our study did not yet show the corresponding performance of the best models obtained with conventional machine learning methods. While AutoML may facilitate and simplify the task of training and testing machine learning algorithms as applied in the field of neuroradiology and medical imaging, a considerable amount of expert knowledge may still be needed to develop models with the highest possible discriminatory power for diagnostic neuroradiology. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Killer cell immunoglobulin-like receptors (KIRs) comprise a group of highly polymorphic inhibitory receptors which are specific for classical HLA class-I molecules. Peripheral blood and freshly prepared tumor cell suspensions (n = 60) as well as control samples (n = 32) were investigated for the distribution, phenotype, and functional relevance of CD158ab/KIR2DL1,-2/3 expressing NK-cells in glioblastoma (GBM) patients. We found that GBM were scarcely infiltrated by NK-cells that preferentially expressed CD158ab/KIR2DL1,-2/3 as inhibitory receptors, displayed reduced levels of the activating receptors CD335/NKp46, CD226/DNAM-1, CD159c/NKG2C, and showed diminished capacity to produce IFN-γ and perforin. Functional hypoactivity of GBM-derived NK-cells persisted despite IL-2 preactivation. Blockade with a specific KIR2DL-1,2/3 monoclonal antibody reversed NK-cell inhibition and significantly enhanced degranulation and IFN-γ production of IL-2 preactivated NK-cells in the presence of primary GBM cells and HLA-C expressing but not HLA class-I deficient K562 cells. Additional analysis revealed that significant amounts of IL-2 could be produced by tumor-derived CD4+ and CD8+CD45RA- memory T-cells after combined anti-CD3/anti-CD28 stimulation. Our data indicate that both blockade of inhibitory KIR and IL-2 triggering of tumor-derived NK-cells are necessary to enhance NK-cell responsiveness in GBM. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Invasion of brain tissue by meningiomas has been identified as one key factor for meningioma recurrence. The identification of meningioma tumor tissue surrounded by brain tissue in neurosurgical samples has been touted as a criterion for atypical meningioma (CNS WHO grade 2), but is only rarely seen in the absence of other high‐grade features, with brain‐invasive otherwise benign (BIOB) meningiomas remaining controversial. While post‐surgery irradiation therapy might be initiated in brain‐invasive meningiomas to prevent recurrences, specific treatment approaches targeting key molecules involved in the invasive process are not established. Here we have compiled the current knowledge about mechanisms supporting brain tissue invasion by meningiomas and summarize preclinical models studying targeted therapies with potential inhibitory effects. [ABSTRACT FROM AUTHOR]

Background There is a pressing demand for more accurate, disease-specific quality measures in the field of neurosurgery. Aiming at most adequately measuring and reflecting the quality of glioma therapy, we developed a novel quality indicator bundle in form of a checklist for all patients that are treated operatively for glioma. Methods On the basis of possible glioma-specific quality indicators retrieved from the literature and quality guidelines, a multidisciplinary team developed a checklist containing 13 patient-need-specific outcome measures. Subsequently, the checklist was prospectively applied to a total of 78 patients compared with a control group consisting of 322 patients. A score was generated based on the maximum of quality measures achieved. Results Significant improvements in quality after prospectively introducing the checklist were achieved for supplemental physical and occupational therapy during inpatient stay (89.4% vs 100%, P =.002), consultation of a social worker during inpatient stay (64% vs 92.3%, P <.001), psycho-oncological screening (14.3% vs 70.5%, P <.001), psycho-oncological consultation (31.1% vs 82.1%, P <.001), and consultation of the palliative care team (20% vs 40%, P =.031). Overall, after introduction of the checklist one-third (n = 23) of patients reached best-practice measures in all categories, and over half of the patients (n = 44) achieved above 90% with respect to the outcome measures. Conclusions Aiming at ensuring comprehensive, consistent, and timely care of glioma patients, the implementation of the checklist for routine use in glioma surgery represents an efficient, easily reproducible, and powerful tool for significant improvements. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Although the utility 5-aminolevulinic acid (5-ALA)-mediated fluorescence-guided surgery (FGS) in meningiomas is increasingly discussed, data about the kinetics of protoporphyrin IX (PpIX) and tumor fluorescence are sparse. Methods: PpIX kinetics after exposition to varying 5-ALA doses (12.5–150 µg/ml) was analyzed in two immortalized as well as primary WHO grade I and II meningioma and U87 high-grade glioma cell lines. Expression of FECH, ABCB6 and ABCG2 was investigated by quantitative real-time PCR. Results: Fluorescence in Ben-Men 1 and primary WHO grade I/II meningioma increased with rising 5-ALA doses up to 100 µg/ml but then showed a saturation effect. However, decrease of fluorescence was slower after 150 than after 100 µg/ml 5-ALA. Fluorescence in U87 cells marginally increased with rising 5-ALA doses. Kinetics of the fluorescence in Ben-Men 1 cells did not differ from primary meningioma cells after 25–150 µg/ml 5-ALA (p >.05, each). No difference was found when comparing the fluorescence between primary grade I and II meningiomas after any 5-ALA dosage (p >.05, each). No relevant fluorescence was found in IOMM-Lee cells. Expression of FECH, ABCB6 and ABCG2 as well as PpIX export differed between all analyzed cell lines but were not connected to fluorescence. Conclusions: Eligibility of established meningioma cell lines for in-vitro analyzes of tumor fluorescence significantly differs. Fluorescence in Ben-Men 1 and primary meningioma cell lines but less in IOMM Lee cells is 5-ALA dose-dependent, encouraging in-situ trials to encounter currently discussed shortcomings of FGS in meningiomas. Fluorescence is not related to expression of FECH, ABCB6 and ABCG2. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Telomerase activity and (human) Telomerase Reverse Transcriptase (hTERT) expression are considered hallmarks in oncogenesis of neoplasms and are upregulated by alterations of the hTERT promoter. In meningiomas, numerous studies investigated hTERT expression, telomerase activity, promoter mutations, and methylations. Moreover, reports about hTERT-targeted chemotherapy in meningiomas have recently been published. We provide a systematic review of the literature about the role of hTERT in meningiomas. TERT expression and telomerase activity is found in benign and high-grade meningiomas and increase with WHO grade. Remarkably, rates of TERT expression/telomerase activity usually exceed mutation frequency and both telomerase activity and TERT expression have also been found in hTERT promoter wildtype meningiomas, indicating further mechanisms of TERT upregulation. Although hTERT promoter methylation has been reported in the vast majority of meningiomas, correlation with TERT expression remains controversial. Rates of promoter mutations, and methylation were shown to increase with rising WHO grade. Moreover, promoter methylation and mutations strongly correlate with prognosis. Although mutations predicted malignant progression, de novo mutations in high-grade recurrences of former benign lesions were also observed. Retroviral transduction of the TERT gene enabled immortalization in several grade I–III meningioma cell lines. In vitro analyses revealed significant effects on viability in hTERT-mutated meningioma cells after targeted treatment. Alternative mechanisms of telomere lengthening are usually absent in meningiomas. TERT and hTERT promoter alterations play a major role during oncogenesis of meningiomas with implications for prognosis and potentially treatment. [ABSTRACT FROM AUTHOR]

Brain invasion (BI) is a new criterion for atypia in meningiomas and therefore potentially impacts adjuvant treatment. However, it remains unclear whether surgical practice and specimen characteristics influence histopathological analyses and the accuracy of detecting BI. Tumor location, specimen characteristics, and rates of BI were compared in meningioma samples obtained from 2938 surgeries in different neurosurgical departments but diagnosed in a single neuropathological institute. Non-skull base tumor location was associated with CNS tissue on the microscopic slides (OR 1.45; p <.001), increasing specimen weight (OR 1.01; p <.001), and remaining tissue not subjected to neuropathological analyses (OR 2.18; p <.001) but not with BI (OR 1.29; p =.199). Specimen weight, rates of residual tissue not subjected to histopathological analyses, of BI and of brain tissue, on the microscopic slides differed among the neurosurgical centers (p <.001, each). Frequency of BI was increased in one department (OR 2.07; p =.002) and tended to be lower in another (OR.61; p =.088). The same centers displayed the highest and lowest rates of brain tissue in the specimen, respectively (p <.001). Moreover, the correlation of BI with the neurosurgical center was not confirmed when only analyzing specimen with evidence of brain tissue in microscopic analyses (p =.223). Detection of BI was not correlated with the intraoperative use of CUSA in subgroup analyses. Rates of brain invasion in neuropathological analyses are not associated with tumor location but differ among some neurosurgical centers. Evidence raises that surgical nuances impact specimen characteristics and therefore the accuracy of the detection of BI. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The aim of the study was to determine pre-operative factors associated with adverse events occurring within 30 days after neurosurgical tumor treatment in a German center, adjusting for their incidence in order to prospectively compare different centers.Methods: Adult patients that were hospitalized due to a benign or malignant brain were retrospectively assessed for quality indicators and adverse events. Analyses were performed in order to determine risk factors for adverse events and reasons for readmission and reoperation.Results: A total of 2511 cases were enrolled. The 30 days unplanned readmission rate to the same hospital was 5.7%. The main reason for readmission was tumor progression. Every 10th patient had an unplanned reoperation. The incidence of surgical revisions due to infections was 2.3%. Taking together all monitored adverse events, male patients had a higher risk for any of these complications (OR 1.236, 95%CI 1.025-1.490, p = 0.027). Age, sex, and histological diagnosis were predictors of experiencing any complication. Adjusted by incidence, the increased risk ratios greater than 10.0% were found for male sex, age, metastatic tumor, and hemiplegia for various quality indicators.Conclusions: We found that most predictors of outcome rates are based on preoperative underlying medical conditions and are not modifiable by the surgeon. Comparing our results to the literature, we conclude that differences in readmission and reoperation rates are strongly influenced by standards in decision making and that comparison of outcome rates between different health-care providers on an international basis is challenging. Each health-care system has to develop own metrics for risk adjustment that require regular reassessment. [ABSTRACT FROM AUTHOR]

The article offers information on the Chordoid meningiomas topics including information on DNA methylation pattern for chordoid meningioma; genetic variation of meningioma; and significant enrichment for deletions of chromosomal arm 2p.

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. [ABSTRACT FROM AUTHOR]

Background: The advantages of 5-aminolevulinacid (5-ALA)-induced fluorescence-guided surgery in meningiomas are increasingly discussed. In this context, despite detectable tumor tissue in histopathologial analyses, no fluorescence was shown at the dura tail using the standard operating microscope. Thus, 5-ALA metabolism in this surgically important site remains unknown but needs to be elucidated when further evaluating indications of fluorescence-guided surgery in meningiomas.Method: We here present the spatially resolved identification of protoporphyrin IX (PpIX) in sphenoid ridge meningioma cryosections from a patient who underwent fluorescence-guided microsurgery using molecular imaging analysis by matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS/MS).Results: Despite a strong fluorescence of the main tumor, no fluorescence could be detected at the dura tail using the standard operating microscope (blue-light, 405 nm). However, histopathological analyses clearly showed meningioma tissue. Remarkably, MALDI-MS/MS analysis revealed PpIX formation also at the non-fluorescing dura tail. However, no PpIX was detected in the tumor free dura mater.Conclusion: MALDI-MS/MS visualized a selective accumulation of PpIX within the tumor tissue including the dura tail. Thus, absence of fluorescence in the dura tail as visualized by the operating microscope is not caused by the lack of PpIX formation. [ABSTRACT FROM AUTHOR]

Abstract: Amyloidomas are rare amyloid‐containing lesions, which may also occur in the central nervous system. Etiology, pathogenesis and clinical course are poorly understood. To gain more insight into the biology of cerebral amyloidoma, they aimed to characterize its histopathological, molecular and clinical features in a retrospective series of seven patients. FFPE tissue specimens were examined using immunohistochemistry, chromogenic in situ hybridization (CISH) for light chains kappa and lambda as well as an IgH gene clonality analysis. Follow‐up information was gathered by reviewing patient records and imaging results. Median age of the three males and four females was 50 years (range: 35–53 years). All cerebral amyloidomas were located supratentorially and were classified as lambda light chain amyloidosis (AL‐λ; n = 6) and kappa light chain amyloidosis (AL‐κ; n = 1) on immunohistochemistry and CISH. B‐cell clonality was confirmed by IgH gene clonality assay in all cases examined. After a median follow‐up of 21 months, all patients were alive and showed stable disease. No progression to systemic disease was observed. In conclusion, their data suggest that cerebral amyloidoma is a local disease characterized by B‐cell clonality and associated with a stable clinical course. [ABSTRACT FROM AUTHOR]

Background: Despite considerable advances in preoperative and intraoperative imaging and neuronavigation, resection of thalamic gliomas remains challenging. Although both endoscopic biopsy and third ventriculostomy (ETV) for the treatment of secondary hydrocephalus are commonly performed, endoscopic resection of thalamic gliomas has been very sparsely described. Method: We report and illustrate the surgical procedure and patient's outcome after full endoscopic resection of a thalamic glioma and to discuss this approach as an alternative to open microsurgery. Results: In 2016, a 56-year-old woman presented with disorientation, dysphasia and right facial hypaesthesia in our department. Cranial magnetic resonance imaging revealed a left thalamic lesion and subsequent hydrocephalus. Initially, hydrocephalus was treated by ETV but forceps biopsy was not diagnostic. However, metabolism in F-fluoroethyl- L-tyrosine positron emission tomography indicated glioma. Subsequently, endoscopic and neuronavigation-guided tumour resection was performed using a <1 cm, trans-sulcal approach through the left posterior horn of the lateral ventricle. While visibility was poor using the intraoperative microscope, neuroendoscopy provided excellent visualisation and allowed safe tumour debulking. Neither haemorrhage from the tumour or collapse of the cavity compromised endoscopic resection. Conclusions: In accordance with one previously published case of endoscopic resection of a thalamic glioma, no surgery-related complications were observed. Although this remains to be determined in larger series, endoscopic resection of these lesions might be a safe and feasible alternative to biopsy or open surgery. Future studies should also aim to identify patients specifically eligible for these approaches. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Telomerase reverse transcriptase (TERT) expression is a hallmark in tumorigenesis and upregulated due to mutations and methylation of the human (h)TERT promoter. As mutations are rare but methylation is common in pituitary adenomas (PA), we determined promoter methylation and its clinical impact in 85 primary and 15 recurrent PA by methylation-specific PCR. 40 females (47 %) and 45 males (53 %) with a median age of 53 years harboring micro-, macro-, and giant adenomas in 12, 82, and 6 % were included (prolactinomas, corticotroph, somatotroph, gonadotroph, thyreotroph, plurihormonal, and null cell adenomas in 11, 18, 10, 29, 1, 10, and 21 %, respectively). In primary diagnosed tumors, methylation rate was 27 % and higher in males than in females (40 vs. 13 %, p = 0.001) after uni- and multivariate analyses. Methylation differed among PA subtypes (0-42 %, p = n.s.) and was not significantly correlated with tumor size, cavernous sinus invasion, or serum hormone levels. Ki67 labeling index and recurrence ( N = 16, 19 %) were independent of methylation. In recurrent tumors, methylation was similar to primary PA ( N = 5/15, 33 %) and remained unchanged along follow-up. Thus, while being commonly observed in PA, hTERT promoter methylation is stable along follow-up and independent of most clinical variables, PA subtype, proliferation, and without prognostic value. [ABSTRACT FROM AUTHOR]