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Glioblastoma is the most common yet deadliest primary brain cancer1. The neural behavior of glioblastoma, including the formation of synaptic circuitry and tumor microtubes, is increasingly understood to be pivotal for disease manifestation2–8. Nonetheless, the few approved treatments for glioblastoma target its oncological nature, while its neural vulnerabilities remain incompletely mapped and clinically unexploited. Here, we systematically survey the neural molecular dependencies and cellular heterogeneity across glioblastoma patients and diverse model systems. In 27 patient tumour samples taken directly after surgery, we identify a spectrum of cancer cell morphologies indicative of poor prognosis and discover a set of repurposable neuroactive drugs with consistent anti-glioblastoma efficacy. Glioblastoma cells exhibit functional dependencies on highly expressed neuroactive drug targets, while interpretable molecular machine learning (COSTAR) reveals their downstream convergence on AP-1-driven tumour suppression. This drug-target connectivity signature is confirmed by highly accurate in silico drug screening on >1 million compounds using COSTAR, as well as by multi-omic profiling of drug-treated glioblastoma cells. Thus, Ca2+-driven AP-1 pathway induction represents a tumour-intrinsic vulnerability at the intersection of oncogenesis and neural activity-dependent signaling. Opportunities for clinical translation of this neural vulnerability are epitomized by the antidepressant Vortioxetine synergizing with current standard of care treatments in vivo. Together, the results presented here provide a mechanistic foundation and conceptual framework for the treatment of glioblastoma based on its neural origins.

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.

OBJECTIVE Decision-making for intracranial tumor surgery requires balancing the oncological benefit against the risk for resection-related impairment. Risk estimates are commonly based on subjective experience and generalized numbers from the literature, but even experienced surgeons overestimate functional outcome after surgery. Today, there is no reliable and objective way to preoperatively predict an individual patient’s risk of experiencing any functional impairment. METHODS The authors developed a prediction model for functional impairment at 3 to 6 months after microsurgical resection, defined as a decrease in Karnofsky Performance Status of ≥ 10 points. Two prospective registries in Switzerland and Italy were used for development. External validation was performed in 7 cohorts from Sweden, Norway, Germany, Austria, and the Netherlands. Age, sex, prior surgery, tumor histology and maximum diameter, expected major brain vessel or cranial nerve manipulation, resection in eloquent areas and the posterior fossa, and surgical approach were recorded. Discrimination and calibration metrics were evaluated. RESULTS In the development (2437 patients, 48.2% male; mean age ± SD: 55 ± 15 years) and external validation (2427 patients, 42.4% male; mean age ± SD: 58 ± 13 years) cohorts, functional impairment rates were 21.5% and 28.5%, respectively. In the development cohort, area under the curve (AUC) values of 0.72 (95% CI 0.69–0.74) were observed. In the pooled external validation cohort, the AUC was 0.72 (95% CI 0.69–0.74), confirming generalizability. Calibration plots indicated fair calibration in both cohorts. The tool has been incorporated into a web-based application available at https://neurosurgery.shinyapps.io/impairment/. CONCLUSIONS Functional impairment after intracranial tumor surgery remains extraordinarily difficult to predict, although machine learning can help quantify risk. This externally validated prediction tool can serve as the basis for case-by-case discussions and risk-to-benefit estimation of surgical treatment in the individual patient.

BackgroundMaximum safe resection followed by chemoradiotherapy as current standard of care for WHO grade III and IV gliomas can be influenced by the occurrence of perioperative adverse events (AE). The aim of this study was to determine the association of AE with the timing and choice of subsequent treatments as well as with overall survival (OS).MethodsProspectively collected data of 283 adult patients undergoing surgery for WHO grade III and IV gliomas at the University Hospital Zurich between January 2013 and June 2017 were analyzed. We assessed basic patient characteristics, KPS, extent of resection, and WHO grade, and we classified AE as well as modality, timing of subsequent treatment (delay, interruption, or non-initiation), and OS.ResultsIn 117 patients (41%), an AE was documented between surgery and the 3-month follow-up. There was a significant association of AE with an increased time to initiation of subsequent therapy (p = 0.005) and a higher rate of interruption (p < 0.001) or non-initiation (p < 0.001). AE grades correlated with time to initiation of subsequent therapy (p = 0.038). AEs were associated with shorter OS in univariate analysis (p < 0.001).ConclusionAEs are associated with delayed and/or altered subsequent therapy and can therefore limit OS. These data emphasize the importance of safety within the maximum-safe-resection concept.

Introduction: Ever since the beginning of cerebral bypass surgery, the role of the bypass has been debated and indications have changed over the last 5 decades. This systematic literature research analysed all clinical studies on cerebral bypass that have been published from January 1959 to January 2020 for their year of publication, country of origin, citation index, role of and indication for bypass, bypass technique, revascularized territory, flow capacity, and title (for word cloud analysis per decade). Methods: A systematic literature research was conducted using PubMed, Web of Science, EMBASE, and SCOPUS databases. All studies that have been published until January 1, 2020, were included. Results: Of 6,013 identified studies, 2,585 were included in the analysis. Of these, n = 1,734 (67%) studies addressed flow-augmentation bypass and n = 701 (27%) addressed flow-preservation bypass. The most common indication reported for flow augmentation is moyamoya (n = 877, 51%), followed by atherosclerotic steno-occlusive disease (n = 753, 43%). For flow preservation, the most common indication is studies reporting on cerebral aneurysm surgery (n = 659, 94%). The increasing popularity of reporting on these bypass operations almost came to an end with the FDA approval of flow diverters for aneurysm treatment in 2011. Japan is the country with the most bypass studies (cumulatively published 933 articles), followed by the USA (630 articles) and China (232 articles). Discussion/Conclusion: Clinical studies on cerebral bypass surgery have become increasingly popular in the past decades. Since the introduction of moyamoya as a distinct pathologic entity, Asian countries in particular have a very active community regarding this disease, with an increasing number of articles published every year. Studies on bypass for chronic steno-occlusive disease peaked in the 1980s but have remained the main focus of bypass research, particularly in many European departments. The number of reports published on these bypass operations significantly decreased after the FDA approval of flow diverters for aneurysm treatment in 2011.

BackgroundThe current WHO classification integrates histological and molecular features of brain tumors. The aim of this study was to identify generalizable topological patterns with the potential to add an anatomical dimension to the classification of brain tumors.MethodsWe applied non-negative matrix factorization as an unsupervised pattern discovery strategy to the fine-grained topographic tumor profiles of 936 patients with primary and secondary brain tumors. From the anatomical features alone, this machine learning algorithm enabled the extraction of latent topological tumor patterns, termed meta-topologies. The optimal parts-based representation was automatically determined in 10,000 split-half iterations. We further characterized each meta-topology’s unique histopathologic profile and survival probability, thus linking important biological and clinical information to the underlying anatomical patternsResultsIn primary brain tumors, six meta-topologies were extracted, each detailing a transpallial pattern with distinct parenchymal and ventricular compositions. We identified one infratentorial, one allopallial, three neopallial (parieto-occipital, frontal, temporal) and one unisegmental meta-topology. Each meta-topology mapped to distinct histopathologic and molecular profiles. The unisegmental meta-topology showed the strongest anatomical-clinical link demonstrating a survival advantage in histologically identical tumors. Brain metastases separated to an infra- and supratentorial meta-topology with anatomical patterns highlighting their affinity to the cortico-subcortical boundary of arterial watershed areas.ConclusionsUsing a novel data-driven approach, we identified generalizable topological patterns in both primary and secondary brain tumors Differences in the histopathologic profiles and prognosis of these anatomical tumor classes provide insights into the heterogeneity of tumor biology and might add to personalized clinical decision making.

Capturing adverse events reliably is paramount for clinical practice and research alike. In the era of "big data", prospective registries form the basis of clinical research and quality improvement.To present results of long-term implementation of a prospective patient registry, and evaluate the validity of the Clavien-Dindo grade (CDG) to classify complications in neurosurgery.A prospective registry for cranial and spinal neurosurgical procedures was implemented in 2013. The CDG - a complication grading focused on need for unplanned therapeutic intervention - was used to grade complications. We assess construct validity of the CDG.Data acquisition integrated into our hospital workflow permitted to include all eligible patients into the registry. We have registered 8226 patients that were treated in 11994 surgeries and 32494 consultations up until December 2020. Similarly, we have captured 1245 complications on 6308 patient discharge forms (20%) since full operational status of the registry. The majority of complications (819/6308 ​= ​13%) were treated without invasive treatment (CDG 1 or CDG 2). At discharge, there was a clear correlation of CDG and the Karnofsky Performance Status (KPS, rho ​= ​-0.29, slope -7 KPS percentage points per increment of CDG) and the length of stay (rho ​= ​0.43, slope 3.2 days per increment of CDG).Patient registries with high completeness and objective capturing of complications are central to the process of quality improvement. The CDG demonstrates construct validity as a measure of complication classification in a neurosurgical patient population.

Gliomas are the most frequent malignant primary brain tumors and continue to lack curative therapies. To aid the development of novel therapeutic approaches, a better understanding of glioma-specific molecular patterns is essential. We therefore investigate the role of the canonical point mutation in the isocitrate dehydrogenase 1 gene (IDH1R132H). Its early occurrence in oncogenesis and ubiquitous expression suggests a causative driver function; however, current literature is inconclusive on the impact of IDH1R132H, requiring innovative approaches to further elucidate the functional consequences and therapeutic potential of IDH1R132H. METHODS Clustered, regularly interspaced, short palindromic repeat (CRISPR)-Cas precision base editing systems enable the alteration of a specific base pair without suffering from off-target editing associated with previous, double strand brake-inducing systems and thus making them an ideal tool to revert the point mutation in IDH1R132H gliomas. RESULTS By selecting a CRISPR-Cas precision base editing system, the IDH1R132H site was edited with editing efficiencies of up to 50%. Primary patient derived cell lines and organoids were corrected in their IDH1R132H locus. Phenotypical changes, such as a change in IDH1R132H protein levels, 2-hydroxyglutarate concentration as well as proliferation rates were observed upon the reversal of the point mutation. Furthermore, the precision base editing system was packaged into a dual-AAV-vector split intein system and showed successful in vitro gene editing. In conclusion, this precise genetic intervention provides a methodology to create accurate patient derived models to analyze the impact of IDH1R132H on glioma biology and provides a framework for in vivo gene therapy.

This study investigates the intratumoral heterogeneity of T cell antigen presentation in 15 newly diagnosed glioblastoma patients. Our multi-omics approach includes mass spectrometry-based immunopeptidome analysis, next-generation sequencing (whole-exome and RNA sequencing), and imaging mass cytometry performed on biopsies deriving from the necrotic core (NEC), the gadolinium contrast-enhancing region (T1), and the peritumoral infiltrating zone (INF, 5-ALA positive). A total of 24493 unique HLA class I and 17394 unique HLA class II peptides were identified. Comparative profiling of peptides from our study and a benign tissue database (in-house; n = 429 donors combined with HLA ligand atlas (https://hla-ligand-atlas.org)) revealed that 20% of HLA class I ligands are glioblastoma exclusive. Of these ligands, 21%, 21%, and 15% were exclusively presented in the INF, T1, or NEC zone, respectively. Here, we focused on the INF-specific antigens as this zone is likely to remain after tumor resection and gives rise to glioblastoma recurrence. Interestingly, two INF-specific HLA ligands showed a frequency presentation of 45% in our patient cohort. One ligand originated from BAALC (Brain and acute leukemia cytoplasmic protein) and one from NCAN (Neurocan core protein), which are both known to be glioblastoma-associated proteins. Immunogenicity of pre-selected candidate antigens was assessed with autologous expanded T cells and revealed a set of novel promising targets for immunotherapy. Integrated RNA/DNA sequencing also enabled the identification of neoepitopes deriving from tumor- and region-specific mutations. Furthermore, imaging mass cytometry contributed to investigating the immune compartment of the tumor microenvironment in high dimensionality and spatial resolution. In conclusion, our approach characterized the intra-tumoral regional heterogeneity of both infiltrating immune cells and tumor antigens. This multi-omics spatial atlas of the immune landscape can be used for the informed design of immunotherapy strategies against glioblastoma.

The aim of the present study was to assess the safety of microsurgical resection of intracranial tumors performed by supervised neurosurgical residents. We analyzed prospectively collected data from our institutional patient registry and dichotomized between procedures performed by supervised neurosurgery residents (defined as teaching procedures) or board-certified faculty neurosurgeons (defined as non-teaching procedures). The primary endpoint was morbidity at discharge, defined as a postoperative decrease of ≥10 points on the Karnofsky Performance Scale (KPS). Secondary endpoints included 3-month (M3) morbidity, mortality, the in-hospital complication rate, and complication type and severity. Of 1,446 consecutive procedures, 221 (15.3%) were teaching procedures. Patients in the teaching group were as likely as patients in the non-teaching group to experience discharge morbidity in both uni- (OR 0.85, 95%CI 0.60–1.22, p = 0.391) and multivariate analysis (adjusted OR 1.08, 95%CI 0.74–1.58, p = 0.680). The results were consistent at time of the M3 follow-up and in subgroup analyses. In-hospital mortality was equally low (0.24 vs. 0%, p = 0.461) and the likelihood (p = 0.499), type (p = 0.581) and severity of complications (p = 0.373) were similar. These results suggest that microsurgical resection of carefully selected intracranial tumors can be performed safely by supervised neurosurgical residents without increasing the risk of morbidity, mortality or perioperative complications. Appropriate allocation of operations according to case complexity and the resident’s experience level, however, appears essential.

OBJECTIVE The management of brain tumour patients who would like to resume driving is complex, and needs multidisciplinary input and a consensus among treating physicians. The Swiss Neuro-Oncology Society (SwissNOS) and the Swiss Society for Legal Medicine (SGRM) aim to provide guidance on how to assess “fitness-to-drive” of glioblastoma patients and to harmonise the relevant procedures in Switzerland. METHODS At several meetings, Swiss neuro-oncologists discussed common practices on how to advise patients with a stable, i.e., non-progressive, glioblastoma, who wish to resume driving after the initial standard tumour treatment. All participants of the SwissNOS meetings were invited twice to return a questionnaire (modified Delphi process) on specific tools/procedures they commonly use to assess “fitness-to-drive” of their patients. Answers were analysed to formulate a tentative consensus for a structured and reasonable approach. RESULTS Consensus on minimum requirements for a “fitness-to-drive”programme for glioblastoma patients could be reached among Swiss neuro-oncologists. The recommendations were based on existing guidelines and expert opinions regarding patients with seizures, visual disturbances, cognitive impairment or focal deficits for safe driving. At this point in time, the Swiss neuro-oncologists agreed on the following requirements for glioblastoma patients after the initial standard therapy and without a seizure for at least 12 months: (1) stable cranial magnetic resonance imaging (MRI) according to Response Assessment in Neuro-Oncology (RANO) criteria, to be repeated every 3 months; (2) thorough medical history, including current or new medication, a comprehensive neurological examination at baseline (T0) and every 3 months thereafter, optionally an electrocencephalogram (EEG) at baseline; (3) ophthalmological examination including visual acuity and intact visual fields; and (4) optional neuropsychological assessment with a focus on safe driving. Test results have to be compatible with safe driving at any time-point. Patients should be informed about test results and optionally sign a document. CONCLUSIONS We propose regular thorough clinical neurological examination and brain MRI, optional EEG, neuropsychological and visual assessments to confirm “fitness-to-drive” for glioblastoma patients after initial tumour-directed therapy. The proposed “fitness-to-drive” assessments for glioblastoma patients serves as the basis for a prospective Swiss Pilot Project GLIODRIVE (BASEC ProjectID 2020-00365) to test feasibility, adherence and safety in a structured manner for patients who wish to resume driving. Research will focus on confirming the usefulness of the proposed tools in predicting “fitness-to-drive” and match results with events obtained from the road traffic registry (Strassenverkehrsamt).

In contrast to most other tumors, the anatomical extent of brain tumors is not objectified and quantified through staging. Staging systems are built on the understanding of the anatomical sequence of tumor progression and its relation to histopathological dedifferentiation and survival. While major advances in the understanding of primary brain tumors at a histological, cellular and molecular level have been achieved in recent decades, our understanding at a macroscopic anatomical level is limited. The aim of this study was to describe the anatomical phenotype of the most frequent brain tumor entities based on topographic probability and growth behavior analysis. The association of anatomical tumor features with survival probability was assessed and a prototypical staging system for WHO grade II-IV glioma was proposed based on the hypothesized anatomical sequence of tumor progression. The analysis is based on data from a consecutive cohort of 1000 patients with first diagnosis of a primary or secondary brain tumor. On preoperative MRI, the relative tumor density (RTD) of different topographic, phylogenetic and ontogenetic parcellation units was derived through normalization of the relative tumor prevalence to the relative volume of the respective structure. While primary central nervous system lymphoma (PCNSL) showed a high RTD along white matter tracts, the RTD in metastases was highest along terminal arterial flow areas. Neuroepithelial tumors (NT) demonstrated a high and homogeneous RTD along all sectors of the ventriculo-cortical axis, avoiding adjacent units, consistent with a transpallial behavior within phylo-ontogenetic radial units. Additionally, the topographic probability in NT correlated with morphogenetic processes of convergence and divergence of radial units during phylo- and ontogenesis. The anatomical tumor growth behavior was analyzed by comparing pre- and postoperative MRI, showing that a ventriculofugal growth dominates in NT. With progressive histopathological dedifferentiation of NT, a gradual deviation from this neuroepithelial anatomical behavior was found. By comparing survival probability, we identified prognostically critical steps in the anatomical behavior of NT. Based on a hypothesized sequence of anatomical tumor progression, we developed a three-level prototypical staging system for WHO grade II-IV glioma. This staging system proved to be accurate across histological, molecular, radiomorphological and clinical strata based on Kaplan Meier curves and multivariable survival analysis. Similar to staging systems for other tumors, a staging system such as this one may have the potential to inform stage-adapted treatment decisions.

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.

Glioblastoma remains to be one of the most lethal solid cancers and novel therapies are urgently needed. There is increasing interest in the role of the HGF/MET pathway in the response of glioblastoma to radiotherapy. c-MET-mediated radioresistance may be partially induced via proinvasive and DNA damageresponse pathways and HGF may be involved in the regulation of immune responses. Here, we explored the role of the c-MET pathway in response to radiotherapy and investigated potential modes of action that mediate synergistic effects of MET pathway inhibition and irradiation in syngeneic murine glioma models in vitro and in vivo. Murine glioma cells express HGF and c-MET and respond with c-MET phosphorylation upon exposure to exogenous HGF. In vitro, glioma cell viability and proliferation are not affected by pharmacological or genetic c-MET pathway interference, and the c-MET inhibitor tepotinib fails to sensitize glioma cells to irradiation. Conversely, in vivo c-MET inhibition combined with focal radiotherapy synergistically prolongs survival in two syngeneic orthotopic glioma models compared with either treatment alone. Complementary studies demonstrated that synergy was lost when gliomas were established and treated in immunodeficient mice, and importantly, also when c-MET gene expression was disrupted in the tumor. Thus, synergistic suppression of experimental syngeneic glioma growth by irradiation and c-MET inhibition requires at least two mechanisms, expression of c-MET in the tumor and a functional immune system. In summary, our data suggest clinical evaluation of c-MET pathway inhibition in combination with radiotherapy in human glioblastoma.

Background Brain tumors, whether primary or secondary, have limited therapeutic options despite advances in understanding driver gene mutations and heterogeneity within tumor cells. The cellular and molecular composition of brain tumor stroma, an important modifier of tumor growth, has been less investigated to date. Only few studies have focused on the vasculature of human brain tumors despite the fact that the blood-brain barrier (BBB) represents the major obstacle for efficient drug delivery. Methods In this study, we employed RNA sequencing to characterize transcriptional alterations of endothelial cells (EC) isolated from primary and secondary human brain tumors. We used an immunoprecipitation approach to enrich for EC from normal brain, glioblastoma (GBM), and lung cancer brain metastasis (BM). Results Analysis of the endothelial transcriptome showed deregulation of genes implicated in cell proliferation, angiogenesis, and deposition of extracellular matrix (ECM) in the vasculature of GBM and BM. Deregulation of genes defining the BBB dysfunction module was found in both tumor types. We identified deregulated expression of genes in vessel-associated fibroblasts in GBM. Conclusion We characterize alterations in BBB genes in GBM and BM vasculature and identify proteins that might be exploited for developing drug delivery platforms. In addition, our analysis on vessel-associated fibroblasts in GBM shows that the cellular composition of brain tumor stroma merits further investigation.

Introduction The postoperative functional status of patients with intracranial tumors is influenced by patient-specific factors, including age. Research question This study aimed to elucidate the association between age and postoperative morbidity or mortality following the resection of brain tumors. Material and methods A multicenter database was retrospectively reviewed. Functional status was assessed before and 3–6 months after tumor resection by the Karnofsky Performance Scale (KPS). Uni- and multivariable linear regression were used to estimate the association of age with postoperative change in KPS. Logistic regression models for a ≥10-point decline in KPS or mortality were built for patients ≥75 years. Results The total sample of 4864 patients had a mean age of 56.4 ​± ​14.4 years. The mean change in pre-to postoperative KPS was −1.43. For each 1-year increase in patient age, the adjusted change in postoperative KPS was −0.11 (95% CI -0.14 - - 0.07). In multivariable analysis, patients ≥75 years had an odds ratio of 1.51 to experience postoperative functional decline (95%CI 1.21–1.88) and an odds ratio of 2.04 to die (95%CI 1.33–3.13), compared to younger patients. Discussion Patients with intracranial tumors treated surgically showed a minor decline in their postoperative functional status. Age was associated with this decline in function, but only to a small extent. Conclusion Patients ≥75 years were more likely to experience a clinically meaningful decline in function and about two times as likely to die within the first 6 months after surgery, compared to younger patients.

BACKGROUND The most widely used classifications of adverse events (AEs) in neurosurgery define their severity according to the therapy used to treat them. This concept has substantial shortcomings because it does not reflect the severity of AEs that are not treated, such as new neurological deficits. OBJECTIVE To present a novel multidimensional and patient-centered classification of the severity of AE in neurosurgery and evaluate its applicability. METHODS The Therapy-Disability-Neurology (TDN) grading system classifies AEs depending on the associated therapy, disability, and neurological deficits. We conducted a 2-center retrospective observational study on 6071 interventions covering the whole neurosurgical spectrum with data prospectively recorded between 2013 and 2019 at 2 institutions from 2 countries. RESULTS Using the first patient cohort (4680 interventions), a positive correlation was found between severity of AE and LOS as well as treatment cost. Each grade was associated with a greater deterioration of the Karnofsky Performance Status Scale (KPS) at discharge and at follow-up. When using the same methods on the external validation cohort (1391 interventions), correlations between the grades of AE, LOS, and KPS at discharge were even more pronounced. CONCLUSION Our results suggest that the TDN grade is consistent with clinical and economic repercussions of AE and thus reflects AE severity. It is easily interpreted and enables comparison between different medical centers. The standardized report of the severity of AE in the scientific literature could constitute an important step forward toward a more critical, patient-centered, and evidence-based decision-making in neurosurgery.

Clinical observations suggest dynamic alterations in behavior after brain surgery. While some alterations reportedly occur within days others gradually develop over several months. These alterations can be attributed to the pre-surgical impact of the diseased tissue, neuronal damage caused by the surgery, and subsequent plasticity. A key step towards a systems-level understanding of the brain-behavior relationships is to capture the dynamics of the cognitive alterations. Here, we first established in 38 healthy individuals that the day-to-day smartphone interactions can be used to inform on cognitive processing speed. Next, we analyzed the smartphone interactions in 12 patients undergoing intracranial tumor surgery, with postsurgical follow-up of up to a year. In healthy individuals, the speed of the touchscreen interactions was highly correlated to choice reaction times (R2 = 0.71) but less so to simple reaction times (R2 = 0.15) on Deary-Liewald tests. Touchscreen interactions slowed immediately after surgery but the post-surgical changes varied between patients. Data-driven models revealed the time-constant of the short-term postsurgical changes and the time taken to stabilize after the surgery. Furthermore, by using conceptually distinct types of touchscreen interaction speeds – i.e. unlocking time and app locating speed – we established that the post-surgical changes are domain-specific. Interestingly, in this small sample, the pre-surgical smartphone speeds were highly related to the speeds post-stabilization (R2 = 0.75 to 0.95). The proxy measures of cognition seamlessly captured on the smartphone can reveal postsurgical dynamics inaccessible to conventional testing. We propose that the transient cognitive alterations indicate the time-constrained influence of distinct neuronal mechanisms triggered by the surgery.

BackgroundThe most widely used classifications of adverse events (AE) in surgical neurology assign a grade to AE that depends on the therapy used to treat them or on new neurologic deficits. Both concepts have substantial shortcomings in grading AE severity. We present a novel multidimensional approach to this challenge and aim at validating the new grading system.MethodsThe new Therapy-Disability-Neurology (TDN) grading system classifies AE into five grades, depending on the associated therapy, disability, and neurologic deficits. We conducted a two-center study on 6071 interventions covering the whole neurosurgical spectrum with data prospectively recorded between January 2013 and September 2019 at the University Hospital Zurich (USZ) and at the Fondazione IRCCS Istituto Neurologico Carlo Besta (FINCB).FindingsUsing data from USZ, a positive correlation was found between the severity of AE and the length of hospital stay (LOS) as well as treatment cost. Each grade was associated with a greater deterioration of the Karnofsky Performance Status Scale (KPS) at discharge and at follow-up. Additionally, there was a correlation between the severity of AE and absolute KPS values. When using the same methods on an external validation cohort from FINCB, correlations between the grade of AE, LOS, and KPS at discharge were even more pronounced.InterpretationOur results suggest that the TDN grade is consistent with clinical and economic repercussions of AE and thus reflects AE severity. It is objective, practical, easily interpreted, and enables comparison between different medical centers. The TDN grade will constitute an important step forward towards a more precise and standardized documentation of AE and ultimately lead to a more critical and patient-centered appraisal of process and outcome measures in surgical neurology.FundingNone.

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.

Purpose Deciding whether to re-operate patients with intracranial tumor recurrence or remnant is challenging, as the data on safety of repeated procedures is limited. This study set out to evaluate the risks for morbidity, mortality, and complications after repeated operations, and to compare those to primary operations. Methods Retrospective observational two-center study on consecutive patients undergoing microsurgical tumor resection. The data derived from independent, prospective institutional registries. The primary endpoint was morbidity at 3 months (M3), defined as significant decrease on the Karnofsky Performance Scale (KPS). Secondary endpoints were mortality, rate and severity of complications according to the Clavien–Dindo Grade (CDG). Results 463/2403 (19.3%) were repeated procedures. Morbidity at M3 occurred in n = 290 patients (12.1%). In univariable analysis, patients undergoing repeated surgery were 98% as likely as patients undergoing primary surgery to experience morbidity (OR 0.98, 95% CI 0.72–1.34, p = 0.889). In multivariable analysis adjusted for age, sex, tumor size, histology and posterior fossa location, the relationship remained stable (aOR 1.25, 95% CI 0.90–1.73, p = 0.186). Mortality was n = 10 (0.4%) at discharge and n = 95 (4.0%) at M3, without group differences. At least one complication occurred in n = 855, and the rate (35.5% vs. 35.9%, p = 0.892) and severity (CDG; p = 0.520) was similar after primary and repeated procedures. Results were reproduced in subgroup analyses for meningiomas, gliomas and cerebral metastases. Conclusions Repeated surgery for intracranial tumors does not increase the risk of morbidity. Mortality, and both the rate and severity of complications are comparable to primary operations. This information is of value for patient counseling and the informed consent process. Electronic supplementary material The online version of this article (10.1007/s11060-018-03058-y) contains supplementary material, which is available to authorized users.

Background The aesthetic outcome after burr hole trepanation for the evacuation of chronic subdural hematomas (cSDH) is often unsatisfactory, as the bony skull defects may cause visible skin depressions. The purpose of this study was to evaluate the efficacy of burr hole cover placement to improve the aesthetic outcome. Methods We reviewed consecutive patients treated by burr hole trepanation for cSDH with or without placement of burr hole covers by a single surgeon between October 2016 and May 2018. The clinical data, including complications, were derived from the institution’s prospective patient registry. The primary endpoint was the aesthetic outcome, as perceived by patients on the aesthetic numeric analog (ANA) scale, assessed by means of a standardized telephone interview. Secondary endpoints were skin depression rates and wound pain, as well as complications. Results From n = 33, outcome evaluation was possible in n = 28 patients (n = 24 male; mean age of 70.4 ± 16.1 years) with uni- (n = 20) or bilateral cSDH (n = 8). A total of 14 burr hole covers were placed in 11 patients and compared to 50 burr holes that were not covered. Patient satisfaction with the aesthetic outcome was significantly better for covered burr holes (mean ANA 9.3 ± 0.74 vs. 7.9 ± 1.0; p

Glioblastoma remains one of the deadliest cancers despite aggressive treatment, which is why novel therapeutic approaches are urgently needed. Chimeric antigen receptor (CAR) T cell therapy has demonstrated significant success in the field of hematological malignancies. However, treating glioblastoma with this type of therapy is more difficult for several reasons such as the lack of suitable target antigens. Here, we generated a second-generation CAR construct targeting the transmembrane protein CD317 (BST-2, HM1.24), which is expressed by human glioma cell lines in vitro as well as in vivo. We demonstrate strong anti-glioma activity of CD317-CAR T cells against different glioma target cells with varying CD317 expression levels. Glioma cells harboring a CRISPR/Cas9-mediated CD317 knockout were not susceptible for these CAR T cells, demonstrating their target antigen-specificity. CD317 is also expressed on T cells and transduction with a CD317-directed CAR impaired expansion of T cells due to residual CD317 expression and subsequent fratricide. Therefore, we silenced CD317 in the transduced T cells by co-expressing the CAR construct with a specific shRNA, which significantly increased the viability, proliferation and cytotoxicity of the CAR T cells. Finally, we observed strong anti-glioma activity of CD317-CAR T cells in clinically relevant orthotopic xenograft glioma mouse models resulting in prolonged survival of CAR T cell-treated animals. Taken together, these data reveal a promising role of CD317 as a novel target for CAR T cell therapy in glioblastoma and warrant further evaluation of this strategy in clinical neuro-oncology.

BACKGROUND Due to the limited success of existing therapies for gliomas, innovative therapeutic options are urgently needed. Chimeric antigen receptor (CAR) T cell therapy has been successful in patients with hematological malignancies. However, using this treatment against solid tumors such as glioblastomas is more challenging. Here, we generated CAR T cells targeting the transmembrane protein CD317 (BST-2, HM1.24) which is overexpressed in glioma cells and may therefore serve as a novel target antigen for CAR T cell-based immunotherapy. MATERIAL AND METHODS CAR T cells targeting CD317 were generated by lentiviral transduction of human T cells from healthy donors. The anti-glioma activity of CD317-CAR T cells was determined in lysis assays using different glioma target cell lines with varying CD317 expression levels. The efficiency of CD317-CAR T cells to control tumor growth in vivo was evaluated in clinically relevant orthotopic xenograft glioma mouse models. RESULTS We created a second-generation CAR construct targeting CD317 and observed strong anti-glioma activity of CD317-CAR T cells in vitro. Glioma cells with a CRISPR/Cas9-mediated CD317 knockout were resistant to CD317-specific CAR T cells, demonstrating their target antigen-specificity. Since CD317 is also expressed by T cells, transduction with a CD317-directed CAR resulted in fratricide of the transduced T cells. Silencing of CD317 in CAR T cells by integrating a specific shRNA into the CAR vector significantly increased the viability, proliferation and cytotoxic function of the CAR T cells. Importantly, intratumoral treatment with CD317-CAR T cells prolonged the survival and cured a significant fraction of glioma-bearing nude mice. CONCLUSION We demonstrate strong CD317-specific anti-tumor activity of CD317-CAR T cells against various glioma cell lines in vitro and in xenograft glioma models in vivo. These data lay a scientific basis for the subsequent evaluation of this therapeutic strategy in clinical neuro-oncology.

OBJECTIVESkin depressions may appear as undesired effects after burr-hole trepanation for the evacuation of chronic subdural hematomas (cSDH). Placement of burr-hole covers to reconstruct skull defects can prevent skin depressions, with the potential to improve the aesthetic result and patient satisfaction. The perception of the relevance of this practice, however, appears to vary substantially among neurosurgeons. The authors aimed to identify current practice variations with regard to the application of burr-hole covers after trepanation for cSDH.METHODSAn electronic survey containing 12 questions was sent to resident and faculty neurosurgeons practicing in different parts of the world, as identified by an Internet search. All responses completed between September 2018 and December 2018 were considered. Descriptive statistics and logistic regression were used to analyze the data.RESULTSA total of 604 responses were obtained, of which 576 (95.4%) provided complete data. The respondents’ mean age was 42.4 years (SD 10.5), and 86.5% were male. The sample consisted of residents, fellows, junior/senior consultants, and department chairs from 79 countries (77.4% Europe, 11.8% Asia, 5.4% America, 3.5% Africa, and 1.9% Australasia). Skin depressions were considered a relevant issue by 31.6%, and 76.0% indicated that patients complain about skin depressions more or less frequently. Burr-hole covers are placed by 28.1% in the context of cSDH evacuation more or less frequently. The most frequent reasons for not placing a burr-hole cover were the lack of proven benefit (34.8%), followed by additional costs (21.9%), technical difficulty (19.9%), and fear of increased complications (4.9%). Most respondents (77.5%) stated that they would consider placing burr-hole covers in the future if there was evidence for superiority of the practice. The use of burr-hole covers varied substantially across countries, but a country’s gross domestic product per capita was not associated with their placement.CONCLUSIONSOnly a minority of neurosurgeons place burr-hole covers after trepanation for cSDH on a regular basis, even though the majority of participants reported complaints from patients regarding postoperative skin depressions. There are significant differences in the patterns of care among countries. Class I evidence with regard to patient satisfaction and safety of burr-hole cover placement is likely to have an impact on future cSDH management.

Highlights • Phylogenetic topographic anatomical patterns drive seizure risk in brain tumors. • Seizure risk in brain tumors may be predicted using a generalized additive model. • This may allow to better tailor antiepileptic therapy in brain tumor patients., Objective The aim of this study was to identify relevant risk factors for epileptic seizures upon initial diagnosis of a brain tumor and to develop and validate a machine learning based prediction to allow for a tailored risk-based antiepileptic therapy. Methods Clinical, electrophysiological and high-resolution imaging data was obtained from a consecutive cohort of 1051 patients with newly diagnosed brain tumors. Factor-associated seizure risk difference allowed to determine the relevance of specific topographic, demographic and histopathologic variables available at the time of diagnosis for seizure risk. The data was divided in a 70/30 ratio into a training and test set. Different machine learning based predictive models were evaluated before a generalized additive model (GAM) was selected considering its traceability while maintaining high performance. Based on a clinical stratification of the risk factors, three different GAM were trained and internally validated. Results A total of 923 patients had full data and were included. Specific topographic anatomical patterns that drive seizure risk could be identified. The involvement of allopallial, mesopallial or primary motor/somatosensory neopallial structures by brain tumors results in a significant and clinically relevant increase in seizure risk. While topographic input was most relevant for the GAM, the best prediction was achieved by a combination of topographic, demographic and histopathologic information (Validation: AUC: 0.79, Accuracy: 0.72, Sensitivity: 0.81, Specificity: 0.66). Conclusions This study identifies specific phylogenetic anatomical patterns as epileptic drivers. A GAM allowed the prediction of seizure risk using topographic, demographic and histopathologic data achieving fair performance while maintaining transparency.

IntroductionOutcomes rated on impairment scales are satisfactory after burr hole trepanation for chronic subdural haematoma (cSDH). However, the surgery leads to bony defects in the skull with skin depressions above that are frequently considered aesthetically unsatisfactory by the patients. Those defects could be covered by the approved medical devices (burr hole covers), but this is rarely done today. We wish to assess, whether the application of burr hole covers after trepanation for the evacuation of cSDH leads to higher patient satisfaction with the aesthetical result at 90 days postoperative, without worsening disability outcomes or increasing the complication rate.Methods and analysisThis is a prospective, single-blinded, randomised, controlled, investigator-initiated clinical trial enrolling 80 adult patients with first-time unilateral or bilateral cSDH in Switzerland. The primary outcome is the difference in satisfaction with the aesthetic result of the scar, comparing patients allocated to the intervention (burr hole cover) and control (no burr hole cover) group, measured on the Aesthetic Numeric Analogue scale at 90 days postoperative. Secondary outcomes include differences in the rates of skin depression, complications, as well as neurological, disability and health-related quality of life outcomes until 12 months postoperative.Ethics and disseminationThe institutional review board (Kantonale Ethikkommission Zürich) approved this study on 29 January 2019 under case number BASEC 2018–01180. This study determines, whether a relatively minor modification of a standard surgical procedure can improve patient satisfaction, without worsening functional outcomes or increasing the complication rate. The outcome corresponds to the value-based medicine approach of modern patient-centred medicine. Results will be published in peer-reviewed journals and electronic patient data will be safely stored for 15 years.Trial registration numberNCT03755349.

Objectives To determine the rate of surgical-site infections (SSI) in neurosurgical procedures involving a shared-resource intraoperative magnetic resonance imaging (ioMRI) scanner at a single institution derived from a prospective clinical quality management database. Methods All consecutive neurosurgical procedures that were performed with a high-field, 2-room ioMRI between April 2013 and June 2016 were included ( N = 195; 109 craniotomies and 86 endoscopic transsphenoidal procedures). The incidence of SSIs within 3 months after surgery was assessed for both operative groups (craniotomies vs. transsphenoidal approach). Results Of the 109 craniotomies, 6 patients developed an SSI (5.5%, 95% confidence interval [CI] 1.2–9.8%), including 1 superficial SSI, 2 cases of bone flap osteitis, 1 intracranial abscess, and 2 cases of meningitis/ventriculitis. Wound revision surgery due to infection was necessary in 4 patients (4%). Of the 86 transsphenoidal skull base surgeries, 6 patients (7.0%, 95% CI 1.5–12.4%) developed an infection, including 2 non-central nervous system intranasal SSIs (3%) and 4 cases of meningitis (5%). Logistic regression analysis revealed that the likelihood of infection significantly decreased with the number of operations in the new operational setting (odds ratio 0.982, 95% CI 0.969–0.995, P = 0.008). Conclusions The use of a shared-resource ioMRI in neurosurgery did not demonstrate increased rates of infection compared with the current available literature. The likelihood of infection decreased with the accumulating number of operations, underlining the importance of surgical staff training after the introduction of a shared-resource ioMRI.