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ObjectTumors in the temporo-mesial region often extend into the insula and vice versa. The present study investigated the results of a surgical strategy that combines principles of tumor and epilepsy surgery.MethodsWe retrospectively analyzed 157 consecutive patients with intrinsic brain tumors in the temporo-mesial region, with varying degrees of extensions into the insula (44 patients, 28.0%). The surgical strategy utilized “anatomy-guided resection,” targeting specific anatomical compartments infiltrated by the tumor (e.g., temporal pole, anterior temporo-mesial region = uncus and hippocampal head, posterior temporo-mesial, insula) rather than treating the tumor as a single mass.ResultsThe most frequent histologies were ganglioglioma CNS WHO grade 1 (55 patients, 35.0%) and IDH1 wildtype glioblastoma (36 patients, 22.9%). Tumor infiltration was most commonly found in the anterior temporo-mesial compartment (145 patients, 92.4%). An anterior temporal lobectomy was part of the surgical strategy in 131 cases (83.4%). Seventy-six patients (48.4%) with drug-resistant epilepsy underwent a formal presurgical epilepsy work-up, including depth electrode placement in three cases. Complete resections were achieved in 117 patients (74.5%), with supramarginal resections performed in 89 cases (56.7%). Four patients experienced non-temporary neurological complications (CTCAE grade 3–5). At 6 months, 127 of 147 assessable patients (86.4%) were free from seizures or auras (ILAE class 1), excluding early postoperative seizures (

Abstract Hedgehog signaling mediates embryologic development of the central nervous system and other tissues and is frequently hijacked by neoplasia to facilitate uncontrolled cellular proliferation. Meningiomas, the most common primary brain tumor, exhibit Hedgehog signaling activation in 6.5% of cases, triggered by recurrent mutations in pathway mediators such as SMO. In this study, we find 35.6% of meningiomas that lack previously known drivers acquired various types of somatic structural variations affecting chromosomes 2q35 and 7q36.3. These cases exhibit ectopic expression of Hedgehog ligands, IHH and SHH, respectively, resulting in Hedgehog signaling activation. Recurrent tandem duplications involving IHH permit de novo chromatin interactions between super-enhancers within DIRC3 and a locus containing IHH. Our work expands the landscape of meningioma molecular drivers and demonstrates enhancer hijacking of Hedgehog ligands as a route to activate this pathway in neoplasia.

Introduction: The appropriate surgical management of insular gliomas is controversial. Management strategies vary considerably between centers. Research question: To provide robust resection, functional and epilepsy outcome figures, study growth patterns and tumor classification paradigms, analyze surgical approaches, mapping/monitoring strategies, surgery for insular glioblastoma, as well as molecular findings, and to identify open questions for future research. Material and methods: On behalf of the EANS Neuro-oncology Section we performed a systematic review and meta-analysis (using a random-effects model) of the more current (2000–2023) literature in accordance with the PRISMA guidelines. Results: The pooled postoperative motor and speech deficit rates were 6.8% and 3.6%. There was a 79.6% chance for postoperative epilepsy control. The postoperative KPI was 80–100 in 83.5% of cases. Functional monitoring/mapping paradigms (which may include awake craniotomies) seem mandatory. (Additional) awake surgery may result in slightly better functional but also worse resection outcomes. Transcortical approaches may carry a lesser rate of (motor) deficits than transsylvian surgeries. Discussion and conclusions: This paper provides an inclusive overview and analysis of current surgical management of insular gliomas. Risks and complication rates in experienced centers do not necessarily compare unfavorably with the results of routine neuro-oncological procedures. Limitations of the current literature prominently include a lack of standardized outcome reporting. Questions and issues that warrant more attention include surgery for insular glioblastomas and how to classify the various growth patterns of insular gliomas.

CNS invasion has been included as an independent criterion for the diagnosis of a high-grade (WHO and CNS grade 2 and 3) meningioma in the 2016 and more recently in the 2021 WHO classification. However, the prognostic role of brain invasion has recently been questioned. Also, surgical treatment for brain invasive meningiomas may pose specific challenges. We conducted a systematic review of the 2016–2022 literature on brain invasive meningiomas in Pubmed, Scopus, Web of Science and the Cochrane Library. The prognostic relevance of brain invasion as a stand-alone criterion is still unclear. Additional and larger studies using robust definitions of histological brain invasion and addressing the issue of sampling errors are clearly warranted. Although the necessity of molecular profiling in meningioma grading, prognostication and decision making in the future is obvious, specific markers for brain invasion are lacking for the time being. Advanced neuroimaging may predict CNS invasion preoperatively. The extent of resection (e.g., the Simpson grading) is an important predictor of tumor recurrence especially in higher grade meningiomas, but also – although likely to a lesser degree – in benign tumors, and therefore also in brain invasive meningiomas with and without other histological features of atypia or malignancy. Hence, surgery for brain invasive meningiomas should follow the principles of maximal but safe resections. There are some data to suggest that safety and functional outcomes in such cases may benefit from the armamentarium of surgical adjuncts commonly used for surgery of eloquent gliomas such as intraoperative monitoring, awake craniotomy, DTI tractography and further advanced intraoperative brain tumor visualization.

Abstract Interleukin 6 (IL-6) is a prominent proinflammatory cytokine and has been discussed as a potential biomarker for delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage. In the present study we have analyzed the time course of serum and cerebrospinal fluid (CSF) IL-6 levels in 82 patients with severe aneurysmal subarachnoid hemorrhage (SAH) requiring external ventricular drains in correlation to angiographic vasospasm, delayed cerebral ischemia, secondary infarctions and other clinical parameters. We observed much higher daily mean IL-6 levels (but also large interindividual variations) in the CSF than the serum of the patients with a peak between days 4 and 14 including a maximum on day 5 after SAH. Individual CSF peak levels correlated significantly with DCI (mean day 4–14 peak, DCI: 26,291 ± 24,159 pg/ml vs. no DCI: 16,184 ± 13,163 pg/ml; P = 0.023). Importantly, CSF IL-6 levels differed significantly between cases with DCI and infarctions and patients with DCI and no infarction (mean day 4–14 peak, DCI with infarction: 37,209 ± 26,951 pg/ml vs. DCI, no infarction: 15,123 ± 11,239 pg/ml; P = 0.003), while findings in the latter patient group were similar to cases with no vasospasm (mean day 4–14 peak, DCI, no infarction: 15,123 ± 11,239 vs. no DCI: 15,840 ± 12,979; P = 0.873). Together, these data support a potential role for elevated CSF IL-6 levels as a biomarker for DCI with infarction rather than for DCI in general. This fits well with a growing body of evidence linking neuroinflammation to ischemia and infarction, but (together with the large interindividual variations observed) limits the diagnostic usefulness of CSF IL-6 levels in SAH patients.

Background and PurposeSurgical decompression of the posterior fossa is often performed in cases with a space-occupying cerebellar infarction to prevent coma and death. In this study, we analyzed our institutional experience with this condition. We specifically attempted to address timing issues and investigated the role of cerebellar necrosectomy using imaging data and conducting volumetric analyses.MethodsWe retrospectively studied pertinent clinical and imaging data, including computerized volumetric analyses (preoperative/postoperative infarction volume, necrosectomy volume, and posterior fossa volume), from all 49 patients who underwent posterior fossa decompression surgery for cerebellar infarction in our department from January 2012 to January 2021.ResultsThirty-five (71%) patients had a Glasgow Coma Scale (GCS) of 14–15 at admission vs. only 14 (29%) before vs. 41 (84%) following surgery. Seven (14%) patients had preventive surgery (initial GCS 14–15, preoperative GCS change ≤ 1). Only 18 (37%) patients had an mRS score of 0–3 at discharge. Estimated overall survival was 70.5% at 1 year. Interestingly, 18/20 (90%) surviving cases had a modified Rankin Scale (mRS) outcome of 0–3 (mRS 0–2: 12/20 [60%]) 1 year after surgery. Surgical timing, including preventive surgery and mass effect of the infarct, in the posterior fossa assessed semi-quantitatively (Kirollos grade) and with volumetric parameters that were not predictive of the patients' (functional) outcomes.ConclusionPosterior fossa decompression for cerebellar infarction is a life-saving procedure, but rapid recovery of the GCS after surgery does not necessarily translate into good functional outcome. Many patients died during follow-up, but long-term mRS outcomes of 4–5 are rare. Surgery should probably aim primarily at pressure relief, and our clinical as well as volumetric data suggest that the impact of removing an infarcted tissue may be limited. It is presumably relatively safe to initially withhold surgery in cases with a GCS of 14–15.

Abstract A signalling pathway involving PLEKHG5 (guanine exchange factor) for the Ras superfamily member RAB26 to transcription factor NF-κB was discovered in autophagy. PLEKHG5 was reported in glioblastoma multiforme (GBM) and correlates with patient survival. Thus, the generation of a cellular model for understanding PLEKHG5 signalling is the study purpose. We generated a CRISPR/Cas9-mediated knockout of PLEKHG5 in U251-MG glioblastoma cells and analysed resulting changes. Next, we used a mRFP-GFP-LC3+ reporter for visualisation of autophagic defects and rescued the phenotype of PLEKHG5 wildtype via transduction of a constitutively active RAB26QL-plasmid. Effects of overexpressing RAB26 were investigated and correlated with the O6-methylguanine-DNA methyltransferase (MGMT) and cellular survival. PLEKHG5 knockout showed changes in morphology, loss of filopodia and higher population doubling times. Accumulation of autolysosomes was resulted by decreased LAMP-1 in PLEKHG5-deficient cells. Rescue of PLEKHG5 −/− restored the downregulation of RhoA activity, showed faster response to tumour necrosis factor and better cellular fitness. MGMT expression was activated after RAB26 overexpression compared to non-transduced cells. Survival of PLEKHG5 knockout was rescued together with sensitivity to temozolomide by RAB26QL. This study provides new insights in the PLEKHG5/RAB26 signalling within U251-MG cells, which suggests potential therapeutic strategies in other glioma cells and further in primary GBM.

Abstract A curved image sensor on plastic foil has been developed for cone beam computed tomography (CBCT) X-ray imaging. The image sensor of about 6 × 8 cm2 size has been built on a thin polyimide foil with an indium gallium zinc oxide (IGZO) backplane and an organic photodetectors (OPD) frontplane. A flexible cesium iodide (CsI) scintillator has been attached to the optical sensor with 480 × 640 pixels of 126 µm size. Dark current density of the OPD was low with less than 10−7 mA/cm2 at −2 V, while an external quantum efficiency (EQE) of about 50% was reached in the visible wavelength range matched to the scintillator output. The image quality of the digital X-ray detector allowed for 3D reconstruction images of a bone phantom on a rotating stage with a lab setup. The curved detector with 32 cm curvature radius opens up the path for very compact CBCT gantries with largely reduced footprint.

Abstract Background We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

Abstract Background Molecularly targeted therapies using receptor inhibitors, small molecules or monoclonal antibodies are routinely applied in oncology. Verification of target expression should be mandatory prior to initiation of therapy, yet, determining the expression status is most challenging in recurrent glioblastoma (GBM) where most patients are not eligible for second-line surgery. Because very little is known on the consistency of expression along the clinical course we here explored common drug targets in paired primary vs. recurrent GBM tissue samples. Methods Paired surgical tissue samples were derived from a homogeneously treated cohort of 34 GBM patients. All patients received radiotherapy and temozolomide chemotherapy. Verification of common drug targets included immunohistological analysis of PDGFR-β, FGFR-2, FGFR-3, and mTOR-pathway component (phospho-mTORSer2448) as well as molecular, MLPA-based analysis of specific copy number aberrations at the gene loci of ALK, PDGFRA, VEGFR2/KDR, EGFR, MET, and FGFR1. Results Paired tumor tissue exhibited significant changes of expression in 9 of the 10 investigated druggable targets (90%). Only one target (FGFR1) was found “unchanged”, since dissimilar expression was observed in only one of the 34 paired tumor tissue samples. All other targets were variably expressed with an 18–56% discordance rate between primary and recurrent tissue. Conclusions The high incidence of dissimilar target expression status in clinical samples from primary vs. recurrent GBM suggests clinically relevant heterogeneity along the course of disease. Molecular target expression, as determined at primary diagnosis, may not necessarily present rational treatment clues for the clinical care of recurrent GBM. Further studies need to analyze the therapeutic impact of longitudinal heterogeneity in GBM.

Cells of glioblastoma, the most frequent primary malignant brain tumor, are characterized by their rapid growth and infiltration of adjacent healthy brain parenchyma, which reflects their aggressive biological behavior. In order to maintain their excessive proliferation and invasion, glioblastomas exploit the innate biological capacities of the patients suffering from this tumor. The pathways involved in cell cycle regulation and apoptosis are the mechanisms most commonly affected. The following work reviews the regulatory pathways of cell growth in general as well as the dysregulated cell cycle and apoptosis relevant mechanisms observed in glioblastomas. We then describe the molecular targeting of the current established adjuvant therapy and present ongoing trials or completed studies on specific promising therapeutic agents that induce cell cycle arrest and apoptosis of glioblastoma cells.

Abstract Background An inverse relationship between allergies with glioma risk has been reported in several but not all epidemiological observational studies. We performed an analysis of genetic variants associated with atopy to assess the relationship with glioma risk using Mendelian randomisation (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. Methods Two-sample MR was undertaken using genome-wide association study data. We used single nucleotide polymorphisms (SNPs) associated with atopic dermatitis, asthma and hay fever, IgE levels, and self-reported allergy as instrumental variables. We calculated MR estimates for the odds ratio (OR) for each risk factor with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighting (IVW), maximum likelihood estimation (MLE), weighted median estimate (WME) and mode-based estimate (MBE) methods. Violation of MR assumptions due to directional pleiotropy were sought using MR-Egger regression and HEIDI-outlier analysis. Results Under IVW, MLE, WME and MBE methods, associations between glioma risk with asthma and hay fever, self-reported allergy and IgE levels were non-significant. An inverse relationship between atopic dermatitis and glioma risk was found by IVW (OR 0.96, 95% confidence interval (CI) 0.93–1.00, P = 0.041) and MLE (OR 0.96, 95% CI 0.94–0.99, P = 0.003), but not by WME (OR 0.96, 95% CI 0.91–1.01, P = 0.114) or MBE (OR 0.97, 95% CI 0.92–1.02, P = 0.194). Conclusions Our investigation does not provide strong evidence for relationship between atopy and the risk of developing glioma, but findings do not preclude a small effect in relation to atopic dermatitis. Our analysis also serves to illustrate the value of using several MR methods to derive robust conclusions.

Meningiomas are mostly benign brain tumours with the potential for becoming atypical or malignant. Here, the authors show that primary atypical meningiomas are epigenetically and genetically distinct from benign and progressed tumours, highlighting possible therapeutic targets such as PRC2.

Epigenetic silencing by DNA methylation in brain tumors has been reported for many genes, however, their function on pathogenesis needs to be evaluated. We investigated the MTSS1 gene, identified as hypermethylated by differential methylation hybridization (DMH). Fifty-nine glioma tissue samples and seven glioma cell lines were examined for hypermethylation of the MTSS1 promotor, MTSS1 expression levels and gene dosage. GBM cell lines were treated with demethylating agents and interrogated for functional consequences of MTSS1 expression after transient transfection. Hypermethylation was significantly associated with IDH1/2 mutation. Comparative SNP analysis indicates higher incidence of loss of heterozygosity of MTSS1 in anaplastic astrocytomas and secondary glioblastomas as well as hypermethylation of the remaining allele. Reversal of promoter hypermethylation results in an increased MTSS1 expression. Cell motility was significantly inhibited by MTSS1 overexpression without influencing cell growth or apoptosis. Immunofluorescence analysis of MTSS1 in human astrocytes indicates co-localization with actin filaments. MTSS1 is down-regulated by DNA methylation in glioblastoma cell lines and is part of the G-CIMP phenotype in primary glioma tissues. Our data on normal astrocytes suggest a function of MTSS1 at focal contact structures with an impact on migratory capacity but no influence on apoptosis or cellular proliferation.

Alterations of DNA methylation play an important role in gliomas. In a genome-wide screen, we identified a CpG-rich fragment within the 5′ region of the tumor necrosis factor receptor superfamily, member 11A gene (TNFRSF11A) that showed de novo methylation in gliomas. TNFRSF11A, also known as receptor activator of NF-κB (RANK), activates several signaling pathways, such as NF-κB, JNK, ERK, p38α, and Akt/PKB. Using pyrosequencing, we detected RANK/TNFRSF11A promoter methylation in 8 (57.1%) of 14 diffuse astrocytomas, 17 (77.3%) of 22 anaplastic astrocytomas, 101 (84.2%) of 120 glioblastomas, 6 (100%) of 6 glioma cell lines, and 7 (100%) of 7 glioma stem cell-enriched glioblastoma primary cultures but not in four normal white matter tissue samples. Treatment of glioma cell lines with the demethylating agent 5-aza-2′-deoxycytidine significantly reduced the methylation level and resulted in increased RANK/TNFRSF11A mRNA expression. Overexpression of RANK/TNFRSF11A in glioblastoma cell lines leads to a significant reduction in focus formation and elevated apoptotic activity after flow cytometric analysis. Reporter assay studies of transfected glioma cells supported these results by showing the activation of signaling pathways associated with regulation of apoptosis. We conclude that RANK/TNFRSF11A is a novel and frequent target for de novo methylation in gliomas, which affects apoptotic activity and focus formation thereby contributing to the molecular pathogenesis of gliomas.

Nature Communications 8: Article number: 14433 (2017) Published online 14 February 2017; Updated 20 April 2018 In this Article, a subset of the H3K27ac ChIP-seq data (15 benign meningiomas and 2 dura samples (Sample IDs: MN-297, MN-288, MN-292, MN-163, MN-1037, MN-105, MN-201, MN-249, MN-191, MN-1066, MN-169, MN-291, MN-24, MN-79, MN-1044, CONTROL1, CONTROL2) was reported previously in a publication by the corresponding author1.