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Purpose: Interactions with tumor-associated microglia and macrophages (TAM) are critical for glioblastoma progression. Polysialic acid (polySia) is a tumor-associated glycan, but its frequency of occurrence and its prognostic value in glioblastoma are disputed. Through interactions with the opposing immune receptors Siglec-11 and Siglec-16, polySia is implicated in the regulation of microglia and macrophage activity. However, due to a nonfunctional SIGLEC16P allele, SIGLEC16 penetrance is less than 40%. Here, we explored possible consequences of SIGLEC16 status and tumor cell–associated polySia on glioblastoma outcome. Experimental Design: Formalin-fixed paraffin-embedded specimens of two independent cohorts with 70 and 100 patients with newly diagnosed glioblastoma were retrospectively analyzed for SIGLEC16 and polySia status in relation to overall survival. Inflammatory TAM activation was assessed in tumors, in heterotypic tumor spheroids consisting of polySia-positive glioblastoma cells and Siglec-16–positive or Siglec-16–negative macrophages, and by exposing Siglec-16–positive or Siglec-16–negative macrophages to glioblastoma cell–derived membrane fractions. Results: Overall survival of SIGLEC16 carriers with polySia-positive tumors was increased. Consistent with proinflammatory Siglec-16 signaling, levels of TAM positive for the M2 marker CD163 were reduced, whereas the M1 marker CD74 and TNF expression were increased, and CD8+ T cells enhanced in SIGLEC16/polySia double-positive tumors. Correspondingly, TNF production was elevated in heterotypic spheroid cultures with Siglec-16–expressing macrophages. Furthermore, a higher, mainly M1-like cytokine release and activating immune signaling was observed in SIGLEC16-positive as compared with SIGLEC16-negative macrophages confronted with glioblastoma cell–derived membranes. Conclusions: Collectively, these results strongly suggest that proinflammatory TAM activation causes the better outcome in patients with glioblastoma with a functional polySia-Siglec-16 axis.

Supplementary Table S1.Demographic and clinical parameters of GB patient cohorts.Supplementary Table S2.Characteristics of the two cohorts of n = 70 (MHH) and n = 100 (UMG) GB patients stratified for the presence of a functional SIGLEC16 allele (A) or for the occurrence of polySia on tumor cells (B).Supplementary Table S3.Cox proportional hazards regression analysis of covariates for SIGLEC16 and polySia status in relation to OS (MHH and UMG cohorts combined).Supplementary Table S4.Median age of GB cases stratified for SIGLEC16 genotype and polySia on tumor cells.Supplementary Table S5.OS analysis of GB cases receiving (A) or not receiving gross total resection (B) stratified for SIGLEC16 genotype and polySia on tumor cells (MHH and UMG cohorts combined).Supplementary Table S6.OS analysis of GB cases receiving (A) or not receiving chemotherapy (B) stratified for SIGLEC16 genotype and polySia on tumor cells (MHH cohort only).Supplementary Table S7.OS analysis of GB cases receiving gross total resection and chemotherapy stratified for SIGLEC16 genotype and polySia on tumor cells (MHH and UMG cohorts combined, n=101).Supplementary Table S8.OS analysis of IDH-wildtype GB cases (UMG cohort) stratified for SIGLEC16 genotype and polySia on tumor cells.Supplementary Table S9.OS analysis of UMG cohort stratified for MGMT gene promoter methylation and SIGLEC16 genotype, polySia on tumor cells, CD163 and CD74 status.Supplementary Table S10.Characteristics of the two cohorts of n = 70 (MHH) and n = 100 (UMG) GB patients stratified for CD74low and CD74high.Supplementary Table S11. Median age at resection of GB cases stratified for CD163 to CD68 (A) or CD74 to IBA1 ratios (B) alone or in combination with the SIGLEC16 genotype.Supplementary Table S12. OS analysis of GB cases receiving (A) or not receiving gross total resection (B) stratified for CD163 to CD68 or CD74 to IBA1 ratios alone or in combination with the SIGLEC16 genotype (MHH and UMG cohorts combined).Supplementary Table S13. OS analysis of GB cases receiving (A) or not receiving chemotherapy (B) stratified for CD163 to CD68 or CD74 to IBA1 ratios alone or in combination with the SIGLEC16 genotype (MHH cohort only).Supplementary Table S14.OS analysis of GB cases receiving both gross total resection and chemotherapy stratified for CD163 to CD68 or CD74 to IBA1 ratios alone or in combination with the SIGLEC16 genotype (MHH and UMG cohorts combined, n=101).

Purpose:Interactions with tumor-associated microglia and macrophages (TAM) are critical for glioblastoma progression. Polysialic acid (polySia) is a tumor-associated glycan, but its frequency of occurrence and its prognostic value in glioblastoma are disputed. Through interactions with the opposing immune receptors Siglec-11 and Siglec-16, polySia is implicated in the regulation of microglia and macrophage activity. However, due to a nonfunctional SIGLEC16P allele, SIGLEC16 penetrance is less than 40%. Here, we explored possible consequences of SIGLEC16 status and tumor cell–associated polySia on glioblastoma outcome.Experimental Design:Formalin-fixed paraffin-embedded specimens of two independent cohorts with 70 and 100 patients with newly diagnosed glioblastoma were retrospectively analyzed for SIGLEC16 and polySia status in relation to overall survival. Inflammatory TAM activation was assessed in tumors, in heterotypic tumor spheroids consisting of polySia-positive glioblastoma cells and Siglec-16–positive or Siglec-16–negative macrophages, and by exposing Siglec-16–positive or Siglec-16–negative macrophages to glioblastoma cell–derived membrane fractions.Results:Overall survival of SIGLEC16 carriers with polySia-positive tumors was increased. Consistent with proinflammatory Siglec-16 signaling, levels of TAM positive for the M2 marker CD163 were reduced, whereas the M1 marker CD74 and TNF expression were increased, and CD8+ T cells enhanced in SIGLEC16/polySia double-positive tumors. Correspondingly, TNF production was elevated in heterotypic spheroid cultures with Siglec-16–expressing macrophages. Furthermore, a higher, mainly M1-like cytokine release and activating immune signaling was observed in SIGLEC16-positive as compared with SIGLEC16-negative macrophages confronted with glioblastoma cell–derived membranes.Conclusions:Collectively, these results strongly suggest that proinflammatory TAM activation causes the better outcome in patients with glioblastoma with a functional polySia-Siglec-16 axis.

PolySia on GB tumor cells is associated with NCAM

Supplementary Methods

PolySia on CD11c-positive and on CD45-positive, IBA1-negative cells

Antibody array detection of cytokines and chemokines

PolySia is not associated with CD3- or CD34-positive cells

OS analysis of the two GB cohorts individually stratified for CD163 to CD68 or CD74 to IBA1 ratios

PolySia is associated with GFAP-positive cells

BackgroundHomozygous loss of CDKN2A/B is a genetic alteration found in many cancer types including meningiomas, where it is associated with poor clinical outcome. It is now also a diagnostic criterion for grade 3 meningiomas in the 2021 WHO classification for central nervous system tumors. However, as in other cancers, the relationship between copy number loss of CDKN2A/B and expression of its gene product is unclear and may be either commensurate or paradoxical in nature. Therefore, we aimed to investigate the association of CDKN2A mRNA expression with clinical prognosis, WHO grade, and other molecular biomarkers in meningiomas such as DNA methylation, molecular group, and proteomics.MethodsWe used multidimensional molecular data of 490 meningioma samples from 4 independent cohorts to examine the relationship between mRNA expression of CDKN2A and copy number status, its correlation to clinical outcome, the transcriptomic pathways altered in differential CDKN2A expression, and its relationship with DNA methylation, and proteomics using an integrated molecular approach.ResultsMeningiomas without any copy number loss were dichotomized into high (CDKN2Ahigh) and low (CDKN2Alow) CDKN2A mRNA expression groups. Patients with CDKN2Ahighmeningiomas had poorer progression free survival (PFS) compared to those with CDKN2Alowmeningiomas. CDKN2A mRNA expression was increased in more aggressive molecular groups, and in higher WHO grade meningiomas across all cohorts. CDKN2Ahighmeningiomas and meningiomas with CDKN2A copy number loss shared common up-regulated cell cycling pathways. CDK4 mRNA expression was increased in CDKN2Ahighmeningiomas and both p16 and CDK4 protein were more abundant in CDKN2Ahighmeningiomas. CDKN2Ahighmeningiomas were frequently hypermethylated at the gene body and UTR compared to CDKN2Alowmeningiomas and found be more commonly Rb-deficient.ConclusionsAn intermediate level of CDKN2A mRNA expression appears to be optimal as significantly low (CDKN2A deleted) or high expression (CDKN2Ahigh) are associated with poorer outcomes clinically. Though CDK4 is elevated in CDKN2Ahighmeningiomas, Rb-deficiency may be more common in this group, leading to lack of response to CDK inhibitors.

Introduction Meningiomas are the most common benign intracranial neoplasms. CNS invasion in meningiomas has been integrated into the 2016 WHO classification of CNS tumors as a stand-alone criterion for atypia. Since then, its prognostic impact has been debated based on contradictory results from retrospective analyses. The aim of the study was to elucidate whether histopathological evidence of CNS invasion is associated with increased proliferative potential. Methods We have conducted a quantified measurement of the proliferation marker Ki67 and analyzed its association with CNS invasion determined by histology together with other established prognostic markers of progression. Routine, immunohistochemical staining for Ki67 were digitalized and automatic quantification was done using Image J software. Results Overall, 1718 meningiomas were assessed. Histopathological CNS invasion was seen in 108 cases (6.7%). Uni- and multivariate analysis revealed a significantly higher Ki67 proliferation rate in meningiomas with CNS invasion (p Conclusions Meningiomas with histopathological CNS invasion show a higher proliferative activity.

The expression of somatostatin receptors in meningioma is well established. First, suggestions of a prognostic impact of SSTRs in meningioma have been made. However, the knowledge is based on few investigations in small cohorts. We recently analyzed the expression of all five known SSTRs in a large cohort of over 700 meningiomas and demonstrated significant correlations with WHO tumor grade and other clinical characteristics. We therefore expanded our dataset and additionally collected information about radiographic tumor recurrence and progression as well as clinically relevant factors (gender, age, extent of resection, WHO grade, tumor location, adjuvant radiotherapy, neurofibromatosis type 2, primary/recurrent tumor) for a comprehensive prognostic multivariate analysis (n = 666). The immunohistochemical expression scores of SSTR1, 2A, 3, 4, and 5 were scored using an intensity distribution score ranging from 0 to 12. For recurrence-free progression analysis, a cutoff at an intensity distribution score of 6 was used. Univariate analysis demonstrated a higher rate of tumor recurrence for increased expression scores for SSTR2A, SSTR3, and SSTR4 (p = 0.0312, p = 0.0351, and p = 0.0390, respectively), while high expression levels of SSTR1 showed less frequent tumor recurrences (p = 0.0012). In the Kaplan–Meier analysis, a higher intensity distribution score showed a favorable prognosis for SSTR1 (p = 0.0158) and an unfavorable prognosis for SSTR2A (0.0143). The negative prognostic impact of higher SSTR2A expression remained a significant factor in the multivariate analysis (RR 1.69, p = 0.0060). We conclude that the expression of SSTR2A has an independent prognostic value regarding meningioma recurrence.

Background Despite best clinical management, meningioma patients experience tumor recurrence. Efforts have been made to improve the prognostic stratification of meningiomas. Recently, a multi-faceted molecular classification suggested that the marker S100 is associated with a favorable outcome, making a further analysis in a larger cohort interesting. Materials and methods The immunohistochemical staining for S100 was analyzed in 1669 paraffin-embedded meningioma samples. The distribution and association with clinical data and progression-free survival via radiographic tumor recurrence were assessed. Results Of 1669 cases, 218 tumors showed strong S100 expression (13.1%). A significantly higher frequency of S100 positive meningiomas was observed in meningiomas of female patients, tumors with spinal and convexity/falx location, primary tumor surgery, NF2, higher extent of resection, lower WHO CNS grade, adjuvant radiotherapy and recurrence-free tumors during follow-up. Univariate analysis revealed a favorable progression-free survival for meningiomas with S100 expression (p = 0.0059) but not in the multivariate analysis. Higher S100 frequency was independently associated with female gender (p = 0.0003), NF2 (p p p = 0.0133). Conclusions The positive prognostic impact of S100 is mostly attributed to the confounding clinical factors gender, tumor location, NF2 status and WHO CNS grade.

Background A loss of the trimethylation of lysine 27 of histone H3 (H3K27me3) in meningioma has been recently suggested as an adjunct to identify subsets of higher risk of recurrence. The aim of the present study was to assess the prognostic value of H3K27 histone trimethylation and its potential clinical utility in the “Tübingen meningioma cohort.” Methods Patients who underwent meningioma resection between October 2003 and December 2015 at the University Hospital Tübingen were included. Immunohistochemical stainings for H3K27me3 and the proliferation marker MIB1 were assessed and correlated with clinical parameters using univariate and multivariate Cox regressions as well as Pearson's chi-squared and log-rank test. Results Overall, 1268 meningiomas were analyzed with a female to male ratio of 2.6 and a mean age of 58.7 years (range 8.3–91.0). With 163 cases lost to follow up, 1103 cases were available for further analysis with a mean follow-up of 40.3 months (range 1.1–186.3). Male gender, younger age, intracranial tumor localization, progressive tumor, subtotal resection, higher WHO grade, increased MIB1 rate, and loss of H3K27me3 were significant negative prognostic factors in the univariate analysis. H3K27me3 status and all other prognostic factors, except age and tumor location, remained significant in the multivariate model. Furthermore, adjuvant radiotherapy was an independent positive prognostic factor. Conclusions Loss of H3K27me3 combined with MIB1 labeling index are independent prognostic factors in meningioma. These data from the Tübingen meningioma cohort support the clinical utility of H3K27me3 immunohistochemical staining in meningioma and its integration into the routine histopathological workup.

Meningiomas are the most common primary intracranial tumors. The majority of patients can be cured by surgery, or tumor growth can be stabilized by radiation. However, the management of recurrent and more aggressive tumors remains difficult because no established alternative treatment options exist. Therefore, innovative therapeutic approaches are needed. Studies have shown that meningiomas express somatostatin receptors. It is well known from treating neuroendocrine tumors that peptide radioreceptor therapy that targets somatostatin receptors can be effective. As yet, this therapy has been used for treating meningiomas only within individual curative trials. However, small case series and studies have demonstrated stabilization of the disease. Therefore, we see potential for optimizing this therapeutic option through the development of new substances and specific adaptations to the different meningioma subtypes. The current review provides an overview of this topic.

ObjectiveThe role of resection in progressive glioblastoma (GBM) to prolong survival is still controversial. The aim of this study was to determine 1) the predictors of post-progression survival (PPS) in progressive GBM and 2) which subgroups of patients would benefit from recurrent resection.MethodsWe have conducted a retrospective bicentric cohort study on isocitrate dehydrogenase (IDH) wild-type GBM treated in our hospitals between 2006 and 2015. Kaplan-Maier analyses and univariable and multivariable Cox regressions were performed to identify predictors and their influence on PPS.ResultsOf 589 patients with progressive IDH wild-type GBM, 355 patients were included in analyses. Median PPS of all patients was 9 months (95% CI 8.0-10.0), with complete resection 12 months (95% CI 9.7-14.3, n=81), incomplete resection 11 months (95% CI 8.9-13.1, n=70) and without resection 7 months (95% CI 06-08, n=204). Multivariable Cox regression demonstrated a benefit for PPS with complete (HR 0.67, CI 0.49-0.90) and incomplete resection (HR 0.73, 95% CI 0.51-1.04) and confirmed methylation of the O6-methylguanine-DNA-methyltransferase (MGMT) gene promoter, lower age at diagnosis, absence of deep brain and multilocular localization, higher Karnofsky Performance Status (KPS) and recurrent therapies to be associated with longer PPS. In contrast, traditional eloquence and duration of progression-free survival had no effect on PPS. Subgroup analyses showed that all subgroups of confirmed predictors benefited from resection, except for patients in poor condition with a KPS

ObjectiveThe exact role of the extent of resection or residual tumor volume on overall survival in glioblastoma patients is still controversial. Our aim was to create a statistical model showing the association between resection extent/residual tumor volume and overall survival and to provide a nomogram that can assess the survival benefit of individual patients and serve as a reference for non-randomized studies.MethodsIn this retrospective multicenter cohort study, we used the non-parametric Cox regression and the parametric log-logistic accelerated failure time model in patients with glioblastoma. On 303 patients (training set), we developed a model to evaluate the effect of the extent of resection/residual tumor volume on overall survival and created a score to estimate individual overall survival. The stability of the model was validated by 20-fold cross-validation and predictive accuracy by an external cohort of 253 patients (validation set).ResultsWe found a continuous relationship between extent of resection or residual tumor volume and overall survival. Our final accelerated failure time model (pseudo R2 = 0.423; C-index = 0.749) included residual tumor volume, age, O6-methylguanine-DNA-methyltransferase methylation, therapy modality, resectability, and ventricular wall infiltration as independent predictors of overall survival. Based on these factors, we developed a nomogram for assessing the survival of individual patients that showed a median absolute predictive error of 2.78 (mean: 1.83) months, an improvement of about 40% compared with the most promising established models.ConclusionsA continuous relationship between residual tumor volume and overall survival supports the concept of maximum safe resection. Due to the low absolute predictive error and the consideration of uneven distributions of covariates, this model is suitable for clinical decision making and helps to evaluate the results of non-randomized studies.

The authors would like to make a correction to their published paper [...]

Purpose Low-grade gliomas (LGG) and mixed neuronal-glial tumors (MNGT) show frequent MAPK pathway alterations. Oncogenic fibroblast growth factor receptor 1 (FGFR1) tyrosinase kinase domain has been reported in brain tumors of various histologies. We sought to determine the frequency of FGFR1 hotspot mutations N546 and K656 in driver-unknown LGG/MNGT and examined FGFR1 immunohistochemistry as a potential tool to detect those alterations. Methods We analyzed 476 LGG/MNGT tumors for KIAA-1549-BRAF fusion, IDH1/2, TERT promotor, NF1, H3F3A and the remaining cases for FGFR1 mutation frequency and correlated FGFR1 immunohistochemistry in 106 cases. Results 368 of 476 LGG/MNGT tumors contained non-FGFR1 alterations. We identified 9 FGFR1 p.N546K and 4 FGFR1 p.K656E mutations among the 108 remaining driver-unknown samples. Five tumors were classified as dysembryoplastic neuroepithelial tumor (DNT), 4 as pilocytic astrocytoma (PA) and 3 as rosette-forming glioneuronal tumor (RGNT). FGFR1 mutations were associated with oligodendroglia-like cells, but not with age or tumor location. FGFR1 immunohistochemical expression was observed in 92 cases. FGFR1 immunoreactivity score was higher in PA and DNT compared to diffuse astrocytoma, but no correlation between FGFR1 mutation in tumors and FGFR1 expression level was observed. Conclusion FGFR1 hotspot mutations are the fifth most prevailing alteration in LGG/MNGT. Performing FGFR1 sequencing analysis in driver-unknown low-grade brain tumors could yield up to 12% FGFR1 N546/K656 mutant cases.

Background Various prognostic factors have been suggested in meningioma patients including WHO grading, brain invasion and bone involvement, for instance. Brain invasion was included as an independent criterion in the recent WHO classification. However, assessability of brain or bone involvement is often limited or varies between histopathologic, operative and imaging reports. Objective of our study was to investigate prognostic values including brain and bone involvement according to different clinical approaches. Methods A cohort of 111 patients was treated with primary, adjuvant or salvage irradiation between 2008 and 2017 using intensity-modulated radiotherapy. Positron-emission tomography (PET) was available for treatment planning in 81% of patients. Clinical data were extracted from the medical reports. Brain and bone involvement were stratified separately according to histopathologic, operative and imaging reports as well as judged in synopsis. Results WHO grade I tumours, lower estimated proliferation index, primary versus recurrence treatment and localization (i.e. skull base, optic nerve sheath) were beneficial prognostic factors for local control. Judgement of brain and bone invasion partly differed between diagnostic modalities. In synopsis, brain or bone invasion did not show a significant influence on local control rates. Conclusions Several previously described prognostic factors could be reproduced. However, partly divergent histopathological, surgical and image-based judgements could be found in regard to brain and bone invasion and all methods imply limitations. Therefore, we suggest a particular, complemental synopsis judgement. In synopsis, brain or bone involvement did not coherently impair local control in our irradiated patients. This might be explained by elaborate radiation techniques and PET-based treatment planning. Electronic supplementary material The online version of this article (10.1186/s13014-019-1341-x) contains supplementary material, which is available to authorized users.

PURPOSE Satisfaction with work-life balance (WLB) is an essential factor for persistent motivation of early career researchers. However, WLB satisfaction in the neuro-oncological landscape is not well characterized. We present the results of an interdisciplinary survey focusing on WLB satisfaction among neuro-oncologists in Germany. METHODS The questionnaire was sent to 351 physicians, all of whom were members of the Neuro-oncology Working Group “Neuroonkologische Arbeitsgemeinschaft” (NOA) of the German Cancer Society (Deutsche Krebsgesellschaft, DKG). The participants were asked for personal information, individual motivations, scientific interests, activities, individual workload, and job satisfaction. The questionnaire was accessible from 18 March 2021 to 1 April 2021. RESULTS Ninety-six physicians (36 female, 60 male) participated in this survey. Age, gender and relationship status were significantly different between participants who were satisfied and those not satisfied with their WLB. Female participants were less likely to be satisfied with their WLB than male participants (25% vs 75%, p = 0.005). In a logistic regression model, the finding that female participants were less likely to be satisfied with their WLB than male participants remained statistically significant (odds ratio [OR] 0.32; 95% confidence interval [CI] 0.21–0.84, p = 0.023) after accounting for possible confounding variables such as age (OR 1.06; 95% CI 1.01–1.11, p = 0.025), childlessness (children available vs not available, OR 0.40; 95% CI 0.10–1.35, p = 0.156), and relationship status (unmarried vs single, OR 2.49; 95% CI 0.50–13.98, p = 0.275; married vs single, OR 6.18; 95% CI 1.29–35.46, p = 0.029). CONCLUSIONS This survey demonstrates that WLB satisfaction is significantly decreased among female neuro-oncologists in Germany. It highlights the importance of programs such as “Diversity in Neurooncology” (DivINe), founded by the NOA and aiming to address gender disparities.

Conclusions: Meningiomas with histopathological CNS invasion show a higher proliferative activity.

The role of resection in progressive glioblastoma (GBM) to prolong survival is still controversial. The aim of this study was to determine 1) the predictors of post-progression survival (PPS) in progressive GBM and 2) which subgroups of patients would benefit from recurrent resection.We have conducted a retrospective bicentric cohort study on isocitrate dehydrogenase (Of 589 patients with progressiveOut data suggest a role for complete and incomplete recurrent resection in progressive GBM patients regardless of methylation of

Purpose: To investigate the diagnostic performance of in vivo ADC-based stratification of integrated molecular glioma grades. Materials and methods: Ninety-seven patients with histopathologically confirmed glioma were evaluated retrospectively. All patients underwent pre-interventional MRI-examination including diffusion-weighted imaging (DWI) with implemented b-values of 500, 1000, 1500, 2000, and 2500 s/mm2. Apparent Diffusion Coefficient (ADC), Mean Kurtosis (MK), and Mean Diffusivity (MD) maps were generated. The average values were compared among the molecular glioma subgroups of IDH-mutant and IDH-wildtype astrocytoma, and 1p/19q-codeleted oligodendroglioma. One-way ANOVA with post-hoc Games-Howell correction compared average ADC, MD, and MK values between molecular glioma groups. A Receiver Operating Characteristic (ROC) analysis determined the area under the curve (AUC). Results: Two b-value-dependent ADC-based evaluations presented statistically significant differences between the three molecular glioma sub-groups (p &lt, 0.001, respectively). Conclusions: High-b-value ADC from preoperative DWI may be used to stratify integrated molecular glioma subgroups and save time compared to diffusion kurtosis imaging. Higher b-values of up to 2500 s/mm2 may present an important step towards increasing diagnostic accuracy compared to standard DWI protocol.

The expression of somatostatin receptors in meningioma is well established. First, suggestions of a prognostic impact of SSTRs in meningioma have been made. However, the knowledge is based on few investigations in small cohorts. We recently analyzed the expression of all five known SSTRs in a large cohort of over 700 meningiomas and demonstrated significant correlations with WHO tumor grade and other clinical characteristics. We therefore expanded our dataset and additionally collected information about radiographic tumor recurrence and progression as well as clinically relevant factors (gender, age, extent of resection, WHO grade, tumor location, adjuvant radiotherapy, neurofibromatosis type 2, primary/recurrent tumor) for a comprehensive prognostic multivariate analysis (n = 666). The immunohistochemical expression scores of SSTR1, 2A, 3, 4, and 5 were scored using an intensity distribution score ranging from 0 to 12. For recurrence-free progression analysis, a cutoff at an intensity distribution score of 6 was used. Univariate analysis demonstrated a higher rate of tumor recurrence for increased expression scores for SSTR2A, SSTR3, and SSTR4 (p = 0.0312, p = 0.0351, and p = 0.0390, respectively), while high expression levels of SSTR1 showed less frequent tumor recurrences (p = 0.0012). In the Kaplan-Meier analysis, a higher intensity distribution score showed a favorable prognosis for SSTR1 (p = 0.0158) and an unfavorable prognosis for SSTR2A (0.0143). The negative prognostic impact of higher SSTR2A expression remained a significant factor in the multivariate analysis (RR 1.69, p = 0.0060). We conclude that the expression of SSTR2A has an independent prognostic value regarding meningioma recurrence.

Most meningiomas are slow growing tumors arising from the arachnoid cap cells and can be cured by surgical resection or radiation therapy in selected cases. However, recurrent and aggressive cases are also quite common and challenging to treat due to no established treatment alternatives. Assessment of the risk of recurrence is therefore of utmost importance and several prognostic clinical and molecular markers have been established. Additionally, the identification of invasive growth of meningioma cells into CNS tissue was demonstrated to lead to a higher risk of recurrence and was therefore integrated into the WHO classification of CNS tumors. However, the evidence for its prognostic impact has been questioned in subsequent studies and its exclusion from the next WHO classification proposed. We were recently able to show the prognostic impact of CNS invasion in a large comprehensive retrospective meningioma cohort including other established prognostic factors. In this review we discuss the growing experiences that have been gained on this matter, with a focus on the currently nonuniform histopathological assessment, imaging characteristics and intraoperative sampling as well as the overall outlook on the future role of this potential prognostic factor.

Simple Summary Meningiomas are benign tumors of the meninges and represent the most common primary brain tumor. Most tumors can be cured by surgical excision or stabilized by radiation therapy. However, recurrent cases are difficult to treat and alternatives to surgery and radiation are lacking. Therefore, a reliable prognostic marker is important for early identification of patients at risk. The presence of infiltrative growth of meningioma cells into central nervous system tissue has been identified as a negative prognostic factor and was therefore included in the latest WHO classification for CNS tumors. Since then, the clinical impact of CNS invasion has been questioned by different retrospective studies and its removal from the WHO classification has been suggested. There may be several reasons for the emergence of conflicting results on this matter, which are discussed in this review together with the potential and future perspectives of the role of CNS invasion in meningiomas. Abstract Most meningiomas are slow growing tumors arising from the arachnoid cap cells and can be cured by surgical resection or radiation therapy in selected cases. However, recurrent and aggressive cases are also quite common and challenging to treat due to no established treatment alternatives. Assessment of the risk of recurrence is therefore of utmost importance and several prognostic clinical and molecular markers have been established. Additionally, the identification of invasive growth of meningioma cells into CNS tissue was demonstrated to lead to a higher risk of recurrence and was therefore integrated into the WHO classification of CNS tumors. However, the evidence for its prognostic impact has been questioned in subsequent studies and its exclusion from the next WHO classification proposed. We were recently able to show the prognostic impact of CNS invasion in a large comprehensive retrospective meningioma cohort including other established prognostic factors. In this review we discuss the growing experiences that have been gained on this matter, with a focus on the currently nonuniform histopathological assessment, imaging characteristics and intraoperative sampling as well as the overall outlook on the future role of this potential prognostic factor.

Purpose: This study aimed to assess the relationship between mean kurtosis (MK) and mean diffusivity (MD) values from whole-brain diffusion kurtosis imaging (DKI) parametric maps in preoperative magnetic resonance (MR) images from 2016 World Health Organization Classification of Tumors of the Central Nervous System integrated glioma groups. Methods: Seventy-seven patients with histopathologically confirmed treatment-naïve glioma were retrospectively assessed between 1 August 2013 and 30 October 2017. The area on scatter plots with a specific combination of MK and MD values, not occurring in the healthy brain, was labeled, and the corresponding voxels were visualized on the fluid-attenuated inversion recovery (FLAIR) images. Reversely, the labeled voxels were compared to those of the manually segmented tumor volume, and the Dice similarity coefficient was used to investigate their spatial overlap. Results: A specific combination of MK and MD values in whole-brain DKI maps, visualized on a two-dimensional scatter plot, exclusively occurs in glioma tissue including the perifocal infiltrative zone and is absent in tissue of the normal brain or from other intracranial compartments. Conclusions: A unique diffusion signature with a specific combination of MK and MD values from whole-brain DKI can identify diffuse glioma without any previous segmentation. This feature might influence artificial intelligence algorithms for automatic tumor segmentation and provide new aspects of tumor heterogeneity.

OBJECTIVE: The COVID-19 pandemic may reinforce psychosocial distress of neuro-oncological patients. We aimed to (1) differentiate the burden caused by the pandemic versus the tumor and (2) establish topics relevant for brain tumor patients (BTPs) and caregivers. METHODS: Patients and caregivers were prospectively assessed from April 2020-July 2020 by a 10-item comprising interview over the phone, including qualitative and quantitative questions. They were quantitatively evaluated i.a. by the distress thermometer (DT, score 1-10). The qualitative questions were analyzed using structured content analysis: The interview questions defined the main categories. Subcategories were derived by an inductive approach assessing the frequency of patients' and caregivers' answers. RESULTS: A total of 69 patients and 20 caregivers were interviewed; n = 36 were female (49%), mean age was 53 years (range 32-81). Patients' disease-related DT scores were higher than the COVID-19-related DT scores: the median of the disease-related DT score was 7 (range 2-10) versus median of COVID-19-related distress: 5.0 (range 2-7). Caregivers perceived a higher burden due to the disease (DT median disease: 8; range 2-10 vs. DT pandemic: 3, range 0-10). A total of five main and 21 subcategories were elaborated, most frequently mentioned were "restrictions in public and private affairs" (28%), "changes in the psychological well-being" (23%), "limited social interaction by contact restriction" (25%). Subcategories relevant for caregivers were similar to those of BTPs. CONCLUSION: A considerable proportion of patients and caregivers still perceived the brain tumor disease as more burdensome than the pandemic. We established main and subcategories of interview items possibly of great relevance to patients during these difficult times, which could be implemented in the content-related adaption of the psychosocial assessment.

Beyond microsurgical resection and radiation therapy, there are currently no established treatment alternatives for meningioma patients. In selected cases, peptide radio receptor therapy (PRRT) can be implemented. For this purpose, a radionuclide is bound to a substance targeting specific receptors in meningiomas. One of them is somatostatin receptor 2, which can be found in most meningiomas. However, other somatostatin receptors (SSTR) exist, but their expressions have only been described in small case series. In this study, we analyzed the expression of SSTR1, 2A, 3, 4, and 5 in a large cohort of meningiomas in order to enable further refinement of this innovative treatment option. Overall, 726 tumor samples were processed into tissue microarrays and stained for SSTR1, 2A, 3, 4, and 5 immunohistochemically. Microscopic evaluation was done with an established semiquantitative score regarding percentual quantification and staining intensity, and results were correlated with clinical data. There was a significant lower rate of SSTR1 expression in meningiomas of male patients. Older age was associated with higher expression of SSTR1, 2A, and 5 and lower scores for SSTR3 and 4. Tumors treated with radiotherapy before resection showed lower rates of SSTR1 and 5 expression, while recurrent meningiomas had lower SSTR1 scores. Tumor tissue from patients suffering from neurofibromatosis type 2 had lower expression scores for SSTR1, 2, and 5. For SSTR3 and 4, NF2 patients showed higher scores than sporadic tumors. Spinal meningiomas had higher scores for SSTR1, 4, and 5 compared tumor location of the skull base and convexity/falx. Overall, higher WHO grade was associated with lower SSTR scores. While all SSTRs were expressed, there are marked differences of SSTR expression between meningioma subgroups. This has the potential to drive the development of more selective PRRT substances with higher treatment efficacy.

OBJECTIVE The COVID-19 pandemic may reinforce psychosocial distress of neuro-oncological patients. We aimed to 1) differentiate the burden caused by the pandemic vs. the tumor and 2) establish topics relevant for brain tumor patients (BTPs) and caregivers. METHODS Patients and caregivers were prospectively assessed from April 2020 – July 2020 by a 10-item comprising interview over the phone, including qualitative and quantitative questions. They were quantitatively evaluated i.a. by the Distress Thermometer (DT, score 1-10). The qualitative questions were analyzed using structured content analysis: The interview questions defined the main categories. Subcategories were derived by an inductive approach assessing the frequency of patients' and caregivers' answers. RESULTS A total of 69 patients and 20 caregivers were interviewed; n= 36 were female (49%), mean age was 53 years (range 32-81). Patients' disease-related DT scores were higher than the COVID-19-related DT scores: the median of the disease-related DT score was 7 (range 2-10) vs. median of COVID-19-related distress: 5.0 (range 2-7). Caregivers perceived a higher burden due to the disease (DT median disease: 8; range 2-10 vs. DT pandemic: 3, range 0-10). A total of 5 main and 21 subcategories were elaborated, most frequently mentioned were "restrictions in public and private affairs" (28%), "changes in the psychological well-being" (23%), "limited social interaction by contact restriction" (25%). Subcategories relevant for caregivers were similar to those of BTPs. CONCLUSION A considerable proportion of patients and caregivers still perceived the brain tumor disease as more burdensome than the pandemic. We established main and subcategories of interview items possibly of great relevance to patients during these difficult times, which could be implemented in the content-related adaption of the psychosocial assessment.

Background Medical students show varying clinical practical skills when entering their final year clinical clerkship, which is the final period to acquire and improve practical skills prior to their residency. We developed a one-on-one mentoring program to allow individually tailored teaching of clinical practical skills to support final year students with varying skill sets during their neurosurgical clinical clerkship. Methods Each participating student (n = 23) was paired with a mentor. At the beginning students were asked about their expectations, teaching preferences and surgical interest. Regular meetings and evaluations of clinical practical skills were scheduled every 2 weeks together with fixed rotations that could be individually adjusted. The one-on-one meetings and evaluations with the mentor gave each student the chance for individually tailored teaching. After completion of the program each student evaluated their experience. Results The mentoring program was well received by participating students and acquisition or improvement of clinical practical skills was achieved by most students. A varying practical skill level and interest in the field of surgery was seen. Conclusions A neurosurgical one-on-one mentoring program is well received by final year medical students and allows for individually tailored learning of clinical practical skills. Supplementary Information The online version contains supplementary material available at 10.1186/s12909-021-02657-0.

Simple Summary Brain invasion has been integrated into the new WHO classification of meningiomas to improve the prognostic assessment regarding tumor recurrence. However, its role has been questioned. One of the reasons is that for complete histopathological assessment, tissue sampling of the complete brain–tumor interface is necessary, but not always surgically and technically feasible. Therefore, the additional intraoperative assessment of CNS invasion may be of value for a more precise assessment of this tumor characteristic. We therefore studied the prognostic impact of the histopathological and intraoperative assessment of CNS invasion regarding radiographic tumor recurrence and found that both factors by themselves do not reach a prognostic significance. However, if both factors are combined, CNS invasion is an independent negative prognostic factor. Our findings show the prognostic potential of a thorough assessment and underline the need for a standardization and documentation of meningioma tissue sampling for the optimal recurrence risk assessment. Abstract The detection of the infiltrative growth of meningiomas into CNS tissue has been integrated into the WHO classification as a stand-alone marker for atypical meningioma. However, its prognostic impact has been questioned. Infiltrative growth can also be detected intraoperatively. The prognostic impact of the intraoperative detection of the central nervous system tissue invasion of meningiomas was analyzed and compared to the histopathological assessment. The clinical data of 1517 cases with follow-up data regarding radiographic recurrence was collected. Histopathology and operative reports were reviewed and invasive growth was seen during resection in 23.7% (n = 345) while histopathology detected it in 4.8% (n = 73). The histopathological and intraoperative assessments were compatible in 63%. The prognostic impact of histopathological and intraoperative assessment was significant in the univariate but not in the multivariate analysis. Both methods of assessment combined reached statistical significance in the multivariate analysis (p = 0.0409). A score including all independent prognostic factors divided the cohort into three prognostic subgroups with a risk of recurrence of 33.8, 64.7 and 88.5%, respectively. The intraoperative detection of the infiltrative growth of primary meningiomas into the central nervous system tissue can complement the histopathological assessment of CNS invasion. The combined assessment is an independent prognostic factor regarding tumor recurrence and allows a risk-adapted tumor stratification.

Purpose: Median overall survival (OS) after diagnosis of glioblastoma (GBM) remains 15 months amongst patients receiving aggressive surgical resection, chemotherapy and irradiation. Treatment of patients with a poor preoperative Karnofsky Performance Status Scale (KPSS) is still controversial. Therefore, we retrospectively assessed the outcome after surgical treatment in patients with a KPSS of ≤ 60%.Methods: We retrospectively included patients with a de-novo glioblastoma WHO °IV and preoperative KPSS ≤ 60%, who underwent surgery at two neurosurgical centres between September 2006 and March 2016. We recorded pre- and postoperative tumour volume, pre- and postoperative KPSS, OS, age and MGMT promoter status.Results: 123 patients (58 females/65 males, mean age 67.4 ± 13.4 years) met the inclusion criteria. 75 of the 123 patients (61%) underwent surgical resection. 48/123 patients (39%) received a biopsy. The median preoperative and postoperative tumour volume of all patients was 33.0 ± 31.3 cm3 (IR 15.0–56.5cm3) and 3.1 ± 23.8 cm3 (IR 0.2–15.0 cm3), respectively. The median KPSS was 60% (range 20–60%) preoperatively and 50% (range 0–80%) postoperatively. The median OS was 123 ± 220 days (IR 52–395 days). Age (pConclusion: Patients with a preoperative KPSS of ≤ 60% benefit from low postoperative residual tumour volumes. Age and MGMT-methylation status were also significant prognostic parameters in this patient cohort.

Since the introduction of the Simpson grading for the extent of resection in meningiomas in 1957, its usefulness in modern neurosurgery has been challenged. Especially, the updated WHO classification regarding brain invasion and the efficacy of radiation therapy has not been taken into account when evaluating the prognostic role of the Simpson grading in this era. We analyzed the clinical and histopathological data of 1571 meningiomas that were surgically resected in the authors’ institution between July 2003 and March 2017. Operative reports were reviewed regarding the extent of resection according to Simpson grading. Meningioma subtype according to the updated WHO classification of 2016 and clinical characteristics and time to tumor progression were analyzed. The mean follow-up was 38.4 months (range 1.2 to 195.6). A higher rate of tumor recurrence was observed for male gender, younger age, recurrent tumors, non-spinal tumor localization, higher WHO, and Simpson grades in the univariate analysis. In the multivariate analysis older age, recurrent tumors and higher WHO grades remained negative prognostic factors. Among the different Simpson grades, the relative risk for recurrence was highest for grade IV compared to all other grades (each p

Meningiomas are the most common primary tumors of the nervous system. These slow growing tumors arise from the meninges. Most patients can be cured by surgical excision. Yet, approximately 20% of patients suffer tumor recurrence. Prognostic markers are warranted to facilitate the identification of patients with an increased risk of tumor recurrence. Immunohistochemical markers are very interesting candidates in this regard and could be integrated into the routine clinical workflow as an inexpensive tool for prognostication and risk stratification. We analyzed the prognostic impact of the immunohistochemical expression of H3K27me3, somatostatin receptors 1-5 and BAP1 in the Tübingen meningioma cohort including > 1200 meningiomas. We identified an independent negative prognostic impact of the loss of H3K27me3. An increased expression score for SSTR2A was associated with a shorter progression-free survival. Higher expression of SSTR5 indicated a more favorable prognosis. The loss of BAP1 expression in meningioma cells was a negative prognostic factor with a shorter progression-free survival. Taken together, we present potential candidate prognostic markers that could be further investigated in prospective cohorts to determine their clinical utility.

Objective To show that the combined use of intraoperative high-field MRI (iMRI) and electrophysiologic monitoring (IOM) is feasible, safe, and beneficial for patients. Methods The setup, surgical, imaging, and clinical results of 110 patients with eloquent intracranial lesions with the combined use of 1.5T iMRI and IOM were analyzed. Results 187 iMRI scans were performed with IOM needles in place, resulting in a total experience of using >4000 electrodes in the iMRI. No complication (ferromagnetic or relevant heating/burning of skin) was caused by the combined use of both technologies. Surgically induced severe postoperative sensorimotor deficits were seen in 11.8%. The surgeon's estimation of a “complete resection” proved to be true postoperatively in 90.3%. If the resection was stopped due to worsening of IOM, postoperative MRI revealed residual disease to be located in direct vicinity of eloquence in 27 of 28 cases, but not in other parts of the resection cavity. Of these patients, only 7% (2 of 28) had relevant new deficits after 3 months. In 82 patients (74.5%), the resection was continued after the iMRI scan, whereas in only 18 patients (16.4%) the resection was already completed at this point. Conclusion The combined use of IOM and 1.5T iMRI is feasible and safe. The complementary use of both technologies might result in more radical resections at comparable surgically induced neurologic deficits. If available and indicated, the combined use of IOM and iMRI should be performed on a routine basis.

Objective Ventricular opening during glioblastoma (GBM) resection is controversial. Sufficient evidence regarding its prognostic role is missing. We investigated the impact of ventricular opening on overall survival (OS), hydrocephalus development, and postoperative morbidity in patients with GBM. Methods Patients who underwent primary GBM resection between 2006 and 2013 were assessed retrospectively. Established predictors for overall survival (age, Karnofsky Performance Status, extent of resection, O-6-methylguanine-DNA methyltransferase promoter methylation status, isocitrate dehydrogenase mutation status) and further clinical data (postoperative status, further treatment, preoperative tumor volume, proximity to the ventricle) were included in univariate and multivariate analyses. Results Thirteen (5.7%) of 229 patients developed a hydrocephalus. Multivariate logistic regression showed that neither ventricular opening, tumor size, proximity to the ventricle, nor extent of resection were significant risk factors for hydrocephalus. Ventricular opening did not delay postoperative therapy and was not associated with neurological morbidity. Kaplan-Meier analysis demonstrated that patients who underwent ventricular opening ( n = 114) exhibited a median OS of 14.3 months (12.9–16.5), whereas patients who did not undergo ventricular opening ( n = 115) exhibited a median OS of 18.6 months (16.1–20.8). However, multivariate Cox regression ( n = 134) did not confirm ventricular opening as an independent negative predictor of OS (risk ratio 1.09, P = 0.77). Instead, it showed that a greater preoperative tumor volume >22.8 cm 3 was a negative predictor of OS (risk ratio 1.76, P = 0.02). Conclusions Because extent of resection is a strong independent predictor of OS and ventricular opening is safe, neurosurgeons should consider ventricular opening to achieve maximal tumor resection.

Background The impact of prolonging temozolomide (TMZ) maintenance beyond six cycles in newly diagnosed glioblastoma (GBM) remains a topic of discussion. We investigated the effects of prolonged TMZ maintenance on progression-free survival (PFS) and overall survival (OS). Patients and methods In this retrospective single-center cohort study, we included patients with GBM who were treated with radiation therapy with concomitant and adjuvant TMZ. For analysis, patients were considered who either completed six TMZ maintenance cycles (group B), continued with TMZ therapy beyond six cycles (group C), or stopped TMZ maintenance therapy within the first six cycles (group A). Patients with progression during the first six TMZ maintenance cycles were excluded. Results Clinical data from 107 patients were included for Kaplan-Meier analyses and 102 for Cox regressions. Median PFS times were 8.1 months (95% confidence interval [CI] 6.1-12.4) in group A, 13.7 months (95% CI 10.6-17.5) in group B, and 20.9 months (95% CI 15.2-43.5) in group C. At first progression, response rates of TMZ/lomustine rechallenge were 47% in group B and 13% in group C. Median OS times were 12.7 months (95% CI 10.3-16.8) in group A, 25.2 months (95% CI 17.7-55.5) in group B, and 28.6 months (95% CI 24.4-open) in group C. Nevertheless, multivariate Cox regression for patients in group C compared with group B that accounted for imbalances of other risk factors showed no different relative risk (RR) for OS (RR 0.77, p = .46). Conclusion Our data do not support a general extension of TMZ maintenance therapy beyond six cycles. The Oncologist 2017;22:570-575 IMPLICATIONS FOR PRACTICE: Radiation therapy with concomitant and adjuvant temozolomide (TMZ) maintenance therapy is still the standard of care in patients below the age of 65 years in newly diagnosed glioblastoma. However, in clinical practice, many centers continue TMZ maintenance therapy beyond six cycles. The impact of this continuation is controversial and has not yet been addressed in prospective randomized clinical trials. We compared the effect of more than six cycles of TMZ in comparison with exactly six cycles on overall survival (OS) and progression-free survival (PFS) by multivariate analysis and found a benefit in PFS but not OS. Thus, our data do not suggest prolonging TMZ maintenance therapy beyond six cycles, which should be considered in neurooncological practice.

Despite many years of research efforts and clinical trials the prognosis of patients diagnosed with glioblastoma remains very poor. The oligodendrocyte transcription factor 2 (Olig2) was identified as a marker for glioma stem cells, which are believed to be responsible for glioma recurrence and therapy resistance. In this retrospective analysis we assessed the prognos- tic value of oligodendroglial and glioma stem cell markers in 113 IDH-wildtype glioblasto- mas. Immunohistochemical staining for Olig2, NogoA, AQP4 and Nestin was performed in combination with sequencing of IDH1 and IDH2 as well as promotor methylation analysis of the MGMT gene. Even though differences in overall survival according to Olig2 expression were observed, univariate and multivariate survival analysis did not reveal a firm significant prognostic impact of Olig2, NogoA, AQP4 or Nestin expression. Additionally, no differences in the expression of these markers depending on clinical status, age or gender were found. The established independent prognostic factors age = 70 and methylated MGMT gene promoter were significant in the multivariate analysis. In conclusion expression of oligodendroglial and glioma stem cell markers do not have an inde- pendent prognostic effect in IDH-wildtype glioblastoma. German Research Foundation/[]/DGF/Alemania Publication Fund of Hannover Medical School/[]/MHH/Alemania UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Sociales::Instituto de Investigaciones Psicológicas (IIP) UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Neurociencias (CIN)

Acetylsalicylic acid has been linked to a lower risk for different cancer types, presumably through its inhibitory effect on cyclooxygenase 2. This has also been investigated in vestibular schwannomas with promising results suggesting an antiproliferative effect and recently the intake has been recommended for vestibular schwannomas as a conservative treatment option. We constructed tissue microarrays from paraffin-embedded tissue samples of 1048 vestibular schwannomas and analyzed the expression of cyclooxygenase 2 and the proliferation marker MIB1 (Molecular Immunology Borstel) via immunohistochemistry together with clinical data (age, gender, tumor extension, prior radiotherapy, neurofibromatosis type 2, tumor recurrence, cyclooxygenase 2 responsive medication). Univariate analysis showed that cyclooxygenase 2 expression was increased with age, female gender, prior radiotherapy and larger tumor extension. MIB1 expression was also associated with higher cyclooxygenase 2 expression. Schwannomas of neurofibromatosis type 2 patients had lower cyclooxygenase 2 levels. Use of acetylsalicylic acid, non-steroidal anti-inflammatory drugs, glucocorticoids or other immunosuppressants did not show differences in cyclooxygenase 2 or MIB1 expression. Instead, cyclooxygenase 2 expression increases with tumor extension while MIB1 expression is not associated with tumor size. Overall, cyclooxygenase 2 expression is associated with proliferation but not influenced by regular intake of acetylsalicylic acid or other cyclooxygenase 2-responsive medications. Acetylsalicylic acid intake does not alter cyclooxygenase 2 expression and has no antiproliferative effect in vestibular.

The detection of IDH mutations in patients with diffusely infiltrating malignant astrocytomas resulted in substantial modifications in the concept of WHO classification of these tumors. An important underlying observation was that patients with anaplastic astrocytomas (AA) without IDH mutation had a clinical course similar to that of patients with glioblastomas (GBM). The underlying observations of the German Glioma Network and NOA-04, however, were based on mixed patient cohorts. While most GBM patients received combined radiochemotherapy, patients with AA usually had radiotherapy or chemotherapy only. This intrinsic shortcoming of the study raised the question of whether patients with AA, IDH wildtype, WHO grade III, might have better prognosis if treated with combined radiochemotherapy than patients with GBM receiving the same combination therapy. Thus, the question remains whether the established histopathological grading criteria for malignant astrocytomas in the absence of an IDH mutation are still important if neither vascular proliferation nor necrosis are detectable. All patients in the cohort investigated here with the diagnosis of AA or GBM were subjected to a combined radiochemotherapy according to the Stupp protocol independently of the histopathological diagnosis. Thus, the analysis of these patients allows to clarify whether patients with AA, IDH wildtype, WHO grade III have a prognosis similar to that of GBM, IDH wildtype, WHO grade IV, even under equivalent therapeutic conditions. We determined theIDH1andIDH2status by sequencing, theMGMTstatus by pyrosequencing after bisulfite treatment and theEGFRstatus of the patients by FISH. In fact, the patients with the histopathological diagnosis of an AA IDH wild-type under similar aggressive therapy showed a comparable and therefore no better prognosis (median overall survival (mOS) 16 months) than patients with a GBM (mOS 13 months). Instead, patients with an AA and an IDH mutation receiving the same therapy had a mOS of 54 months. Thus, it can be concluded that in the absence of an IDH mutation, the established histopathological grading criteria ‘necrosis’ and ‘vascular proliferation’ actually lose their prognostic significance. If, on the other hand, patients with malignant astrocytomas and an IDH mutation are examined, there is still a difference between patients with necrosis and/or vascular proliferation and those whose tumors do not show such characteristics. Accordingly, in patients with malignant astrocytomas with IDH mutation it can be concluded that a histological differentiation between AA IDH mutated and GBM IDH mutated remains beneficial from a prognostic perspective.

Recently, genomic patterns and methylation profiles of meningiomas were described as prognostic factors for aggressiveness and recurrence (e.g. TERT, SMO and AKT1 mutations). However, the particular molecular profiles of recurrence and malignant progression of specific meningioma subtypes remain undefined. In this regard, longitudinal molecular studies are very interesting. In this study, we characterized somatic mutations in a cohort of sporadic meningioma patients. We included 9 patients with multiple recurrences and up to 11 subsequent resections of sporadic meningiomas. We performed a comparative whole-exome sequencing (WES). Moreover, we used the whole-exome data to predict the HLA MHC class I peptides of the subsequent tumor samples in silico. Our study included patients with follow-up times accounted for up to 26 years (average: 12.6 years, range 3–26). We detected a TRAF7 mutation (c.1189G>C) in only 2 of 6 recurrent tumor samples of a female patient with a malignant progression from a WHO I to a WHO grade II meningioma. In a male patient with 9 analyzed meningioma tumor samples, recurrent somatic PLEKHG5, AGBL1, ALK, RICTOR, DEPDC5 mutations were detected. This individual pattern remained constantly evident under different treatments, even after systemic treatment with the mTOR inhibitor everolimus. Moreover, unique mutations in HLA-DQA1, OR14J1, PRH1 genes occurred after mTOR inhibition in this male patient. Furthermore, we identified somatic mutations in the tumor suppressor candidate NBPF1 in 7 of 9 patients. HLA allele types were predicted in silico, with A*02:01, B*57:01, C*03:03, C07:01 and B51:01 being most frequent. Neither ubiquitously shared somatic mutations nor shared MHC class I peptides were identified among this cohort. Taken together, our study outlines a heterogeneous molecular profile in this analysis. Since longitudinal samples in sporadic meningioma are rather rare, the ICOM consortium would be an ideal frame for studying the molecular profile of recurrence in meningioma in larger cohorts.