Integrative spatial analysis reveals a multi-layered organization of glioblastoma.

Glioma contains malignant cells in diverse states. Here, we combine spatial transcriptomics, spatial proteomics, and computational approaches to define glioma cellular states and uncover their organization. We find three prominent modes of organization. First, gliomas are composed of small local environments, each typically enriched with one major cellular state. Second, specific pairs of states preferentially reside in proximity across multiple scales. This pairing of states is consistent across tumors. Third, these pairwise interactions collectively define a global architecture composed of five layers. Hypoxia appears to drive the layers, as it is associated with a long-range organization that includes all cancer cell states. Accordingly, tumor regions distant from any hypoxic/necrotic foci and tumors that lack hypoxia such as low-grade IDH-mutant glioma are less organized. In summary, we provide a conceptual framework for the organization of cellular states in glioma, highlighting hypoxia as a long-range tissue organizer.

Single-Cell Mapping of Human Brain Cancer Reveals Tumor-Specific Instruction of Tissue-Invading Leukocytes.

Brain malignancies can either originate from within the CNS (gliomas) or invade from other locations in the body (metastases). A highly immunosuppressive tumor microenvironment (TME) influences brain tumor outgrowth. Whether the TME is predominantly shaped by the CNS micromilieu or by the malignancy itself is unknown, as is the diversity, origin, and function of CNS tumor-associated macrophages (TAMs). Here, we have mapped the leukocyte landscape of brain tumors using high-dimensional single-cell profiling (CyTOF). The heterogeneous composition of tissue-resident and invading immune cells within the TME alone permitted a clear distinction between gliomas and brain metastases (BrM). The glioma TME presented predominantly with tissue-resident, reactive microglia, whereas tissue-invading leukocytes accumulated in BrM. Tissue-invading TAMs showed a distinctive signature trajectory, revealing tumor-driven instruction along with contrasting lymphocyte activation and exhaustion. Defining the specific immunological signature of brain tumors can facilitate the rational design of targeted immunotherapy strategies.

Microbial peptides activate tumour-infiltrating lymphocytes in glioblastoma.

Microbial organisms have key roles in numerous physiological processes in the human body and have recently been shown to modify the response to immune checkpoint inhibitors1,2. Here we aim to address the role of microbial organisms and their potential role in immune reactivity against glioblastoma. We demonstrate that HLA molecules of both glioblastoma tissues and tumour cell lines present bacteria-specific peptides. This finding prompted us to examine whether tumour-infiltrating lymphocytes (TILs) recognize tumour-derived bacterial peptides. Bacterial peptides eluted from HLA class II molecules are recognized by TILs, albeit very weakly. Using an unbiased antigen discovery approach to probe the specificity of a TIL CD4+ T cell clone, we show that it recognizes a broad spectrum of peptides from pathogenic bacteria, commensal gut microbiota and also glioblastoma-related tumour antigens. These peptides were also strongly stimulatory for bulk TILs and peripheral blood memory cells, which then respond to tumour-derived target peptides. Our data hint at how bacterial pathogens and bacterial gut microbiota can be involved in specific immune recognition of tumour antigens. The unbiased identification of microbial target antigens for TILs holds promise for future personalized tumour vaccination approaches.

Role of microsurgical tumor burden reduction in patients with breast cancer brain metastases considering molecular subtypes: a two-center volumetric survival analysis.

BACKGROUND: Advancements in metastatic breast cancer (BC) treatment have enhanced overall survival (OS), leading to increased rates of brain metastases (BM). This study analyzes the association between microsurgical tumor reduction and OS in patients with BCBM, considering tumor molecular subtypes and perioperative treatment approaches. METHODS: Retrospective analysis of surgically treated patients with BCBM from two tertiary brain tumor Swiss centers. The association of extent of resection (EOR), gross-total resection (GTR) achievement, and postoperative residual tumor volume (RV) with OS and intracranial progression-free survival (IC-PFS) was evaluated using Cox proportional hazard model. RESULTS: 101 patients were included in the final analysis, most patients (38%) exhibited HER2-/HR + BC molecular subtype, followed by HER2 + /HR + (25%), HER2-/HR- (21%), and HER2 + /HR- subtypes (13%). The majority received postoperative systemic treatment (75%) and radiotherapy (84%). Median OS and intracranial PFS were 22 and 8 months, respectively. The mean pre-surgery intracranial tumor volume was 26 cm3, reduced to 3 cm3 post-surgery. EOR, GTR achievement and RV were not significantly associated with OS or IC-PFS, but higher EOR and lower RV correlated with extended OS in patients without extracranial metastases. HER2-positive tumor status was associated with longer OS, extracranial metastases at BM diagnosis and symptomatic lesions with shorter OS and IC-PFS. CONCLUSIONS: Our study found that BC molecular subtypes, extracranial disease status, and BM-related symptoms were associated with OS in surgically treated patients with BCBM. Additionally, while extensive resection to minimize residual tumor volume did not significantly affect OS across the entire cohort, it appeared beneficial for patients without extracranial metastases.

Subarachnoid hemorrhage due to pituitary adenoma apoplexy-case report and review of the literature.

Pituitary apoplexy (PA) may be complicated by development of subarachnoid hemorrhage (SAH). We conducted a literature review to evaluate the rate of PA-associated tumor rupture and SAH. We conducted a systematic literature search (PubMed, Web of Science, Medline) for patients with PA-associated SAH and report a case SAH following PA. Suitable articles, case series, and case reports were selected based on predefined criteria following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). We reviewed included publications for clinical, radiological, surgical, and histopathological parameters.We present the case of a patient with PA developing extensive SAH whilst on the MRI who underwent delayed transsphenoidal resection. According to our literature review, we found 55 patients with a median age of 46 years; 18 (32.7%) were female. Factors associated with PA-related SAH were hypertension, diabetes mellitus, prior trauma, anticoagulant, and/or antiplatelet therapy. The most common presenting symptoms included severe headache, nausea and/or vomiting, impaired consciousness, and meningeal irritation. Acute onset was described in almost all patients. Twenty-two of the included patients underwent resection. In patients with available outcome, 45.1% had a favorable outcome, 10 (19.6%) had persisting focal neurological deficits, 7 developed cerebral vasospasms (12.7%), and 18 (35.3%) died. Mortality greatly differed between surgically (9.1%) and non-surgically (44.8%) treated patients. PA-associated SAH is a rare condition developing predominantly in males with previously unknown macroadenomas. Timely surgery often prevents aggravation or development of severe neuro-ophthalmological defects and improves clinical outcome.

A T-cell antigen atlas for meningioma: novel options for immunotherapy.

Meningiomas are the most common primary intracranial tumors. Although most symptomatic cases can be managed by surgery and/or radiotherapy, a relevant number of patients experience an unfavorable clinical course and additional treatment options are needed. As meningiomas are often perfused by dural branches of the external carotid artery, which is located outside the blood-brain barrier, they might be an accessible target for immunotherapy. However, the landscape of naturally presented tumor antigens in meningioma is unknown. We here provide a T-cell antigen atlas for meningioma by in-depth profiling of the naturally presented immunopeptidome using LC-MS/MS. Candidate target antigens were selected based on a comparative approach using an extensive immunopeptidome data set of normal tissues. Meningioma-exclusive antigens for HLA class I and II are described here for the first time. Top-ranking targets were further functionally characterized by showing their immunogenicity through in vitro T-cell priming assays. Thus, we provide an atlas of meningioma T-cell antigens which will be publicly available for further research. In addition, we have identified novel actionable targets that warrant further investigation as an immunotherapy option for meningioma.

Anatomical phenotyping and staging of brain tumours.

Unlike other tumours, the anatomical extent of brain tumours is not objectified and quantified through staging. Staging systems are based on understanding the anatomical sequence of tumour progression and its relationship to histopathological dedifferentiation and survival. The aim of this study was to describe the spatiotemporal phenotype of the most frequent brain tumour entities, to assess the association of anatomical tumour features with survival probability and to develop a staging system for WHO grade 2 and 3 gliomas and glioblastoma. Anatomical phenotyping was performed on a consecutive cohort of 1000 patients with first diagnosis of a primary or secondary brain tumour. Tumour probability in different topographic, phylogenetic and ontogenetic parcellation units was assessed on preoperative MRI through normalization of the relative tumour prevalence to the relative volume of the respective structure. We analysed the spatiotemporal tumour dynamics by cross-referencing preoperative against preceding and subsequent MRIs of the respective patient. The association between anatomical phenotype and outcome defined prognostically critical anatomical tumour features at diagnosis. Based on a hypothesized sequence of anatomical tumour progression, we developed a three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma. This staging system was validated internally in the original cohort and externally in an independent cohort of 300 consecutive patients. While primary CNS lymphoma showed highest probability along white matter tracts, metastases enriched along terminal arterial flow areas. Neuroepithelial tumours mapped along all sectors of the ventriculocortical axis, while adjacent units were spared, consistent with a transpallial behaviour within phylo-ontogenetic radial units. Their topographic pattern correlated with morphogenetic processes of convergence and divergence of radial units during phylo- and ontogenesis. While a ventriculofugal growth dominated in neuroepithelial tumours, a gradual deviation from this neuroepithelial spatiotemporal behaviour was found with progressive histopathological dedifferentiation. The proposed three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma correlated with the degree of histological dedifferentiation and proved accurate in terms of survival upon both internal and external validation. In conclusion, this study identified specific spatiotemporal phenotypes in brain tumours through topographic probability and growth pattern assessment. The association of anatomical tumour features with survival defined critical steps in the anatomical sequence of neuroepithelial tumour progression, based on which a staging system for WHO grade 2 and 3 gliomas and glioblastoma was developed and validated.

Successful weaning versus permanent cerebrospinal fluid diversion after aneurysmal subarachnoid hemorrhage: post hoc analysis of a Swiss multicenter study.

OBJECTIVE: Acute hydrocephalus is a frequent complication after aneurysmal subarachnoid hemorrhage (aSAH). Among patients needing CSF diversion, some cannot be weaned. Little is known about the comparative neurological, neuropsychological, and health-related quality-of-life (HRQOL) outcomes in patients with successful and unsuccessful CSF weaning. The authors aimed to assess outcomes of patients by comparing those with successful and unsuccessful CSF weaning; the latter was defined as occurring in patients with permanent CSF diversion at 3 months post-aSAH. METHODS: The authors included prospectively recruited alert (i.e., Glasgow Coma Scale score 13-15) patients with aSAH in this retrospective study from six Swiss neurovascular centers. Patients underwent serial neurological (National Institutes of Health Stroke Scale), neuropsychological (Montreal Cognitive Assessment), disability (modified Rankin Scale), and HRQOL (EuroQol-5D) examinations at < 72 hours, 14-28 days, and 3 months post-aSAH. RESULTS: Of 126 included patients, 54 (42.9%) developed acute hydrocephalus needing CSF diversion, of whom 37 (68.5%) could be successfully weaned and 17 (31.5%) required permanent CSF diversion. Patients with unsuccessful weaning were older (64.5 vs 50.8 years, p = 0.003) and had a higher rate of intraventricular hemorrhage (52.9% vs 24.3%, p = 0.04). Patients who succeed in restoration of physiological CSF dynamics improve on average by 2 points on the Montreal Cognitive Assessment between 48-72 hours and 14-28 days, whereas those in whom weaning fails worsen by 4 points (adjusted coefficient 6.80, 95% CI 1.57-12.04, p = 0.01). They show better neuropsychological recovery between 48-72 hours and 3 months, compared to patients in whom weaning fails (adjusted coefficient 7.60, 95% CI 3.09-12.11, p = 0.02). Patients who receive permanent CSF diversion (ventriculoperitoneal shunt) show significant neuropsychological improvement thereafter, catching up the delay in neuropsychological improvement between 14-28 days and 3 months post-aSAH. Neurological, disability, and HRQOL outcomes at 3 months were similar. CONCLUSIONS: These results show a temporary but clinically meaningful cognitive benefit in the first weeks after aSAH in successfully weaned patients. The resolution of this difference over time may be due to the positive effects of permanent CSF diversion and underlines its importance. Patients who do not show progressive neuropsychological improvement after weaning should be considered for repeat CT imaging to rule out chronic (untreated) hydrocephalus.

Herniation World Federation of Neurosurgical Societies Scale Improves Prediction of Outcome in Patients With Poor-Grade Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Favorable outcomes are seen in up to 50% of patients with World Federation of Neurosurgical Societies (WFNS) grade V aneurysmal subarachnoid hemorrhage. Therefore, the usefulness of the current WFNS grading system for identifying the worst scenarios for clinical studies and for making treatment decisions is limited. We previously modified the WFNS scale by requiring positive signs of brain stem dysfunction to assign grade V. This study aimed to validate the new herniation WFNS grading system in an independent prospective cohort. METHODS: We conducted an international prospective multicentre study in poor-grade aneurysmal subarachnoid hemorrhage patients comparing the WFNS classification with a modified version-the herniation WFNS scale (hWFNS). Here, only patients who showed positive signs of brain stem dysfunction (posturing, anisocoric, or bilateral dilated pupils) were assigned hWFNS grade V. Outcome was assessed by modified Rankin Scale score 6 months after hemorrhage. The primary end point was the difference in specificity of the WFNS and hWFNS grading with respect to poor outcomes (modified Rankin Scale score 4-6). RESULTS: Of the 250 patients included, 237 reached the primary end point. Comparing the WFNS and hWFNS scale after neurological resuscitation, the specificity to predict poor outcome increased from 0.19 (WFNS) to 0.93 (hWFNS) (McNemar, P<0.001) whereas the sensitivity decreased from 0.88 to 0.37 (P<0.001), and the positive predictive value from 61.9 to 88.3 (weighted generalized score statistic, P<0.001). For mortality, the specificity increased from 0.19 to 0.93 (McNemar, P<0.001), and the positive predictive value from 52.5 to 86.7 (weighted generalized score statistic, P<0.001). CONCLUSIONS: The identification of objective positive signs of brain stem dysfunction significantly improves the specificity and positive predictive value with respect to poor outcome in grade V patients. Therefore, a simple modification-presence of brain stem signs is required for grade V-should be added to the WFNS classification. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02304328.

The BSCM score: a guideline for surgical decision-making for brainstem cavernous malformations.

Microsurgical resection of brainstem cavernous malformations (BSCMs) can be performed today with acceptable morbidity and mortality. However, in this highly eloquent location, the indication for surgery remains challenging. We aimed to elaborate a score system that may help clinicians with their choice of treatment in patients with BSCMs in this study. A single-center series of 88 consecutive BSCMs patients with 272 follow-up visits were included in this study. Univariable and multivariable generalized estimating equations (GEE) were constructed to identify the association of variables with treatment decisions. A score scale assigned points for variables that significantly contributed to surgical decision-making. Surgical treatment was recommended in 37 instances, while conservative treatment was proposed in 235 instances. The mean follow-up duration was 50.4 months, and the mean age at decision-making was 45.9 years. The mean BSCMs size was 14.3 ml. In the multivariable GEE model, patient age, lesion size, hemorrhagic event(s), mRS, and axial location were identified as significant factors for determining treatment options. With this proposed score scale (grades 0-XII), non-surgery was the first option at grades 0-III. The crossover point between surgery and non-surgery recommendations lay between grades V and VI while surgical treatment was found in favor at grades VII-X. In conclusion, the proposed BSCM operating score is a clinician-friendly tool, which may help neurosurgeons decide on the treatment for patients with BSCMs.

Collagen-bound fibrin sealant (TachoSil®) for dural closure in cranial surgery: single-centre comparative cohort study and systematic review of the literature.

Cerebrospinal fluid (CSF) leakage is a well-known complication of craniotomies and there are several dural closure techniques. One commonly used commercial product as adjunct for dural closure is the collagen-bound fibrin sealant TachoSil®. We analysed whether the addition of TachoSil has beneficial effects on postoperative complications and outcomes. Our prospective, institutional database was retrospectively queried, and 662 patients undergoing craniotomy were included. Three hundred fifty-two were treated with dural suture alone, and in 310, TachoSil was added after primary suture. Our primary endpoint was the rate of postoperative complications associated with CSF leakage. Secondary endpoints included functional, disability and neurological outcome. Systematic review according to PRISMA guidelines was performed to identify studies comparing primary dural closure with and without additional sealants. Postoperative complications associated with CSF leakage occurred in 24 (7.74%) and 28 (7.95%) procedures with or without TachoSil, respectively (p = 0.960). Multivariate analysis confirmed no significant differences in complication rate between the two groups (aOR 0.97, 95% CI 0.53-1.80, p = 0.930). There were no significant disparities in postoperative functional, disability or neurological scores. The systematic review identified 661 and included 8 studies in the qualitative synthesis. None showed a significant superiority of additional sealants over standard technique regarding complications, rates of revision surgery or outcome. According to our findings, we summarize that routinary use of TachoSil and similar products as adjuncts to primary dural sutures after intracranial surgical procedures is safe but without clear advantage in complication avoidance or outcome. Future studies should investigate whether their use is beneficial in high-risk settings.

Determining the impact of postoperative complications in neurosurgery based on simulated longitudinal smartphone app-based assessment.

BACKGROUND: Complications after neurosurgical operations can have severe impact on patient well-being, which is poorly reflected by current grading systems. The objective of this work was to develop and conduct a feasibility study of a new smartphone application that allows for the longitudinal assessment of postoperative well-being and complications. METHODS: We developed a smartphone application "Post OP Tracker" according to requirements from clinical experience and tested it on simulated patients. Participants received regular notifications through the app, inquiring them about their well-being and complications that had to be answered according to their assigned scenarios. After a 12-week period, subjects answered a questionnaire about the app's functionality, user-friendliness, and acceptability. RESULTS: A total of 13 participants (mean age 34.8, range 24-68 years, 4 (30.8%) female) volunteered in this feasibility study. Most of them had a professional background in either health care or software development. All participants downloaded, installed, and applied the app for an average of 12.9 weeks. On a scale of 1 (worst) to 4 (best), the app was rated on average 3.6 in overall satisfaction and 3.8 in acceptance. The design achieved a somewhat favorable score of 3.1. One participant (7.7%) reported major technical issues. The gathered patient data can be used to graphically display the simulated outcome and assess the impact of postoperative complications. CONCLUSIONS: This study suggests the feasibility to longitudinally gather postoperative data on subjective well-being through a smartphone application. Among potential patients, our application indicated to be functional, user-friendly, and well accepted. Using this app-based approach, further studies will enable us to classify postoperative complications according to their impact on the patient's well-being.

The HLA ligandome landscape of chronic myeloid leukemia delineates novel T-cell epitopes for immunotherapy.

Antileukemia immunity plays an important role in disease control and maintenance of tyrosine kinase inhibitor (TKI)-free remission in chronic myeloid leukemia (CML). Thus, antigen-specific immunotherapy holds promise for strengthening immune control in CML but requires the identification of CML-associated targets. In this study, we used a mass spectrometry-based approach to identify naturally presented HLA class I- and class II-restricted peptides in primary CML samples. Comparative HLA ligandome profiling using a comprehensive dataset of different hematological benign specimens and samples from CML patients in deep molecular remission delineated a panel of novel frequently presented CML-exclusive peptides. These nonmutated target antigens are of particular relevance because our extensive data-mining approach suggests the absence of naturally presented BCR-ABL- and ABL-BCR-derived HLA-restricted peptides and the lack of frequent tumor-exclusive presentation of known cancer/testis and leukemia-associated antigens. Functional characterization revealed spontaneous T-cell responses against the newly identified CML-associated peptides in CML patient samples and their ability to induce multifunctional and cytotoxic antigen-specific T cells de novo in samples from healthy volunteers and CML patients. Thus, these antigens are prime candidates for T-cell-based immunotherapeutic approaches that may prolong TKI-free survival and even mediate cure of CML patients.

Mortality in Patients with Brainstem Cavernous Malformations.

OBJECTIVE: Brainstem cavernous malformations (BSCM)-associated mortality has been reported up to 20% in patients managed conservatively, whereas postoperative mortality rates range from 0 to 1.9%. Our aim was to analyze the actual risk and causes of BSCM-associated mortality in patients managed conservatively and surgically based on our own patient cohort and a systematic literature review. METHODS: Observational, retrospective single-center study encompassing all patients with BSCM that presented to our institution between 2006 and 2018. In addition, a systematic review was performed on all studies encompassing patients with BSCM managed conservatively and surgically. RESULTS: Of 118 patients, 54 were treated conservatively (961.0 person years follow-up in total). No BSCM-associated mortality was observed in our conservatively as well as surgically managed patient cohort. Our systematic literature review and analysis revealed an overall BSCM-associated mortality rate of 2.3% (95% CI: 1.6-3.3) in 22 studies comprising 1,251 patients managed conservatively and of 1.3% (95% CI: 0.9-1.7) in 99 studies comprising 3,275 patients with BSCM treated surgically. CONCLUSION: The BSCM-associated mortality rate in patients managed conservatively is almost as low as in patients treated surgically and much lower than in frequently cited reports, most probably due to the good selection nowadays in regard to surgery.

Impact of additional resection on new ischemic lesions and their clinical relevance after intraoperative 3 Tesla MRI in neuro-oncological surgery.

Intraoperative MRI (ioMRI) has become a frequently used tool to improve maximum safe resection in brain tumor surgery. The usability of intraoperatively acquired diffusion-weighted imaging sequences to predict the extent and clinical relevance of new infarcts has not yet been studied. Furthermore, the question of whether more aggressive surgery after ioMRI leads to more or larger infarcts is of crucial interest for the surgeons' operative strategy. Retrospective single-center analysis of a prospective registry of procedures from 2013 to 2019 with ioMRI was used. Infarct volumes in ioMRI/poMRI, lesion localization, mRS, and NIHSS were analyzed for each case. A total of 177 individual operations (60% male, mean age 45.5 years old) met the inclusion criteria. In 61% of the procedures, additional resection was performed after ioMRI, which resulted in a significantly higher number of new ischemic lesions postoperatively (p < .001). The development of new or enlarged ischemic areas upon additional resection could also be shown volumetrically (mean volume in ioMRI 0.39 cm3 vs. poMRI 2.97 cm3; p < .001). Despite the surgically induced new infarcts, mRS and NIHSS did not worsen significantly in cases with additional resection. Additionally, new perilesional ischemia in eloquently located tumors was not associated with an impaired neurological outcome. Additional resection after ioMRI leads to new or enlarged ischemic areas. However, these new infarcts do not necessarily result in an impaired neurological outcome, even when in eloquent brain areas.

Preoperative risk factors associated with new focal neurological deficit and other major adverse events in first-time intracranial meningioma neurosurgery.

BACKGROUND: Neurosurgical resection is the mainstay of meningioma treatment. Adverse event (AE) rates of meningioma resections are significant, but preoperative risk factors for major AEs in patients undergoing first-time meningioma surgery are largely unknown. The aim of this study was to explore major AEs and identify preoperative risk factors in patients undergoing first-time meningioma surgery. METHODS: Data on all meningioma resections performed at the University Hospital Zurich from 1 January 2013 to 31 December 2018 were collected in a prospective registry. All AEs that occurred within 3 months of surgery were documented in detail and classified as "minor" or "major." Statistical analysis included initial individual bivariate analyses of all preoperative factors and the occurrence of major AEs. Statistically significant variables were then included in a logistic regression model to identify predictors. RESULTS: Three hundred forty-five patients were included in the study. Mean age was 58.1 years, and 77.1% of patients were female. The overall major AE rate was 20.6%; the most common of which was a new focal neurological deficit (12.8% of patients). Six preoperative factors showed a significant association with the occurrence of major AEs in bivariate analysis. All variables included in the logistic regression model showed increased odds of occurrence of major AE, but only tumor complexity as measured by the Milan Complexity Scale was a statistically significant predictor, with a score of 4 or more having twice the odds of major AEs (OR: 2.00, 95% CI: 1.15-3.48). CONCLUSION: High tumor complexity is an independent predictor of the occurrence of major AEs following meningioma resection. Preoperative assessment of tumor complexity using the Milan Complexity Scale is warranted and can aid communication with patients about AE rates and surgical decision-making.

Distinct topographic-anatomical patterns in primary and secondary brain tumors and their therapeutic potential.

PURPOSE: Understanding the topographic-anatomical patterns of brain tumors has the potential to improve our pathophysiological understanding and may allow for anatomical tailoring of surgery and radiotherapy. This study analyzed topographic-anatomical patterns underlying neuroepithelial tumors, primary CNS lymphoma and metastases. METHODS: Any histologically confirmed supra- or infratentorial parenchymal neoplasia of one institution over a 4-year period was included. Using high-resolution magnetic resonance imaging data, a detailed analysis of the topographic-anatomical tumor features was performed. Differences between neuroepithelial tumors, primary central nervous system lymphoma (PCNSL) and metastases were assessed using pairwise comparisons adjusted for multiple testing, upon significance of the omnibus test. RESULTS: Based on image analysis of 648 patients-419 (65%) neuroepithelial tumors, 28 (5%) PCNSL and 201 (31%) metastases-entity-specific topographic-anatomical patterns were identified. Neuroepithelial tumors showed a radial ventriculo-cortical orientation, inconsistent with the current belief of a growth along white matter tracts, whereas the pattern in PCNSL corresponded to a growth along such. Metastases preferentially affected the cortex and subcortical white matter of large arteries' terminal supply areas. This study provides a comprehensive anatomical description of the topography of NT, PCNSL and metastases intended to serve as a topographic reference for clinicians and neuroscientists. CONCLUSIONS: The identified distinct anatomical patterns provide evidence for a specific interaction between tumor and anatomical structures, following a pathoclitic concept. Understanding differences in their anatomical behavior has the potential to improve our pathophysiological understanding and to tailor therapy of brain tumors.

Mutational patterns and regulatory networks in epigenetic subgroups of meningioma.

DNA methylation patterns delineate clinically relevant subgroups of meningioma. We previously established the six meningioma methylation classes (MC) benign 1-3, intermediate A and B, and malignant. Here, we set out to identify subgroup-specific mutational patterns and gene regulation. Whole genome sequencing was performed on 62 samples across all MCs and WHO grades from 62 patients with matched blood control, including 40 sporadic meningiomas and 22 meningiomas arising after radiation (Mrad). RNA sequencing was added for 18 of these cases and chromatin-immunoprecipitation for histone H3 lysine 27 acetylation (H3K27ac) followed by sequencing (ChIP-seq) for 16 samples. Besides the known mutations in meningioma, structural variants were found as the mechanism of NF2 inactivation in a small subset (5%) of sporadic meningiomas, similar to previous reports for Mrad. Aberrations of DMD were found to be enriched in MCs with NF2 mutations, and DMD was among the most differentially upregulated genes in NF2 mutant compared to NF2 wild-type cases. The mutational signature AC3, which has been associated with defects in homologous recombination repair (HRR), was detected in both sporadic meningioma and Mrad, but widely distributed across the genome in sporadic cases and enriched near genomic breakpoints in Mrad. Compared to the other MCs, the number of single nucleotide variants matching the AC3 pattern was significantly higher in the malignant MC, which also exhibited higher genomic instability, determined by the numbers of both large segments affected by copy number alterations and breakpoints between large segments. ChIP-seq analysis for H3K27ac revealed a specific activation of genes regulated by the transcription factor FOXM1 in the malignant MC. This analysis also revealed a super enhancer near the HOXD gene cluster in this MC, which, together with general upregulation of HOX genes in the malignant MC, indicates a role of HOX genes in meningioma aggressiveness. This data elucidates the biological mechanisms rendering different epigenetic subgroups of meningiomas, and suggests leveraging HRR as a novel therapeutic target.

Smoking status and perioperative adverse events in patients undergoing cranial tumor surgery.

INTRODUCTION: Smoking is agreed to be a major health risk factor, but it is debated whether it has an influence on perioperative adverse events (AEs) in elective cranial tumor surgery. METHODS: We analyzed the 2013-2016 data from our prospective institutional patient registry. Consecutive patients undergoing elective microsurgical tumor surgery of a glioma or a meningioma were included. Patients were categorized as active smokers, former smokers, and non-smokers. AE were graded by the therapy-oriented Clavien-Dindo scale. Possible predictors of postoperative AE were identified with the help of a binomial logistic regression model. RESULTS: We identified 798 patients, out of which 480 were non-smokers, 193 active smokers, and 125 former smokers. The rate of AEs for active smokers (30%, 95% CI [23-37%]) was indistinguishable from the AE rate of non-smokers (32%, 95% CI [28-37%]). No difference between smoking status was found looking at all AE individually, the odds ratio of suffering from local AE and systemic AE respectively were the same between all smoking groups. The modified Rankin scale at hospital admission was a strong and significant predictor of postoperative AE (P = 0.013). CONCLUSIONS: Active smoking was not associated with an increased risk for postoperative AE, neither looking at the total number of AE nor looking at individual AE. Smoking status should therefore not be a major factor in preoperative decision making. Although not based on data of this study, doctors should always encourage patients to stop smoking due to its well-known detrimental health effect.

Clipping of a superior hypophyseal artery aneurysm during endoscopic transnasal removal of a Rathke cleft cyst: a case report.

The concomitant presence of an aneurysm in contact with a sellar lesion usually contraindicates a transsphenoidal approach (TSS). Clipping of an intracranial aneurysm is however possible in highly selected cases also through an endoscopic TSS approach, as long as the basic principles of cerebrovascular surgery are respected. We report thus on a case of a patient harboring a Rathke cleft cyst (RCC) and an aneurysm of the carotid artery (ICA) in close contact with the RCC. The anatomical characteristics of both lesions warranted an endoscopic TSS for removal of the RCC and clipping of the aneurysm during the same approach.