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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.

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

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).

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.

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.

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.

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

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.

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.

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.

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 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.