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Background The impact of extent of resection (EOR), residual tumor volume (RTV), and gross-total resection (GTR) in glioblastoma subgroups is currently unknown. This study aimed to analyze their impact on patient subgroups in relation to neurological and functional outcomes. Methods Patients with tumor resection for eloquent glioblastoma between 2010 and 2020 at 4 tertiary centers were recruited from a cohort of 3919 patients. Results One thousand and forty-seven (1047) patients were included. Higher EOR and lower RTV were significantly associated with improved overall survival (OS) and progression-free survival (PFS) across all subgroups, but RTV was a stronger prognostic factor. GTR based on RTV improved median OS in the overall cohort (19.0 months, P Conclusions Maximum resection was especially beneficial in the subgroups aged

Background: Awake mapping has been associated with decreased neurological deficits and increased extent of resection in eloquent glioma resections. However, its effect within clinically relevant glioblastoma subgroups remains poorly understood. We aimed to assess the benefit of this technique in subgroups of patients with glioblastomas based on age, preoperative neurological morbidity, and Karnofsky Performance Score (KPS). Methods: In this propensity score-matched analysis of an international, multicentre, cohort study (GLIOMAP), patients were recruited at four tertiary centres in Europe (Erasmus MC, Rotterdam and Haaglanden MC, The Hague, Netherlands, and UZ Leuven, Leuven, Belgium) and the USA (Brigham and Women's Hospital, Boston, MA). Patients were eligible if they were aged 18–90 years, undergoing resection, had a histopathological diagnosis of primary glioblastoma, their tumour was in an eloquent or near-eloquent location, and they had a unifocal enhancing lesion. Patients either underwent awake mapping during craniotomy, or asleep resection, as per treating physician or multidisciplinary tumour board decision. We used propensity-score matching (1:3) to match patients in the awake group with those in the asleep group to create a matched cohort, and to match patients from subgroups stratified by age (

Purpose: There is no evidence-based systemic therapy for patients with progressive meningiomas for whom surgery or external radiotherapy is no longer an option. In this study, the efficacy and safety of peptide receptor radionuclide therapy (PRRT) in patients with progressive, treatment-refractory meningiomas were evaluated. Methods: Retrospective analysis of all meningioma patients treated with [177Lu]Lu-DOTA-TATE from 2000 to 2020 in our centre. Primary outcomes were response according to RANO bidimensional and volumetric criteria and progression-free survival (PFS). Overall survival (OS) and tumour growth rate (TGR) were secondary endpoints. TGR was calculated as the percentage change in surface or volume per month. Results: Fifteen meningioma patients received [177Lu]Lu-DOTA-TATE (7.5–29.6 GBq). Prior to PRRT, all patients had received external radiotherapy, and 14 patients had undergone surgery. All WHO grades were included WHO 1 (n=3), WHO 2 (n=5), and WHO 3 (n=6). After PRRT, stable disease was observed in six (40%) patients. The median PFS was 7.8 months with a 6-month PFS rate of 60%. The median OS was 13.6 months with a 12-month OS rate of 60%. All patients had progressive disease prior to PRRT, with an average TGR of 4.6% increase in surface and 14.8% increase in volume per month. After PRRT, TGR declined to 3.1% in surface (p=0.016) and 5.0% in volume (p=0.013) per month. Conclusion: In this cohort of meningioma patients with exhaustion of surgical and radiotherapeutic options and progressive disease, it was shown that PRRT plays a role in controlling tumour growth.

Background External ventricular drainage (EVD) is frequently used in neurosurgical procedures for cerebrospinal fluid (CSF) drainage. It is, however, associated with high infection rates, namely secondary meningitis and ventriculitis. Based on a previous high prevalence of these infections among patients with EVDs, we have proposed and implemented a protocol in an effort to decrease the infection rate. The aim of this study was to measure the effect of hospital-wide implementation of the EVD handling protocol on secondary EVD infections. Patients and methods We included 409 consecutive patients who received a new EVD for other indications than infectious pathologies from January 2000 until June 2012. Patients above 18 years of age were divided into pre- (n = 228) and post-protocol (n = 181) groups. Patient and disease demographics, as well as EVD data together with confounders for secondary meningitis were recorded in a database. Propensity score matching was then performed to create groups matched for sex, age, reason for drainage, type of shunt, time in situ and duration of surgery to place the EVD. Binomial logistic regression for confounder adjustment and regression discontinuity analyses were then performed on the matched cohort. Results Infections occurred more frequently in the pre-protocol group (23% vs 9%, p n = 103 in the pre- and n = 178 in the post-protocol groups) showed that the pre-protocol period was independently associated with more infections (OR 2.69; 95%-CI 1.22–5.95, p = 0.01). Conclusions The incidence of secondary EVD infections can be reduced significantly by the implementation of a strict hospital-wide EVD handling protocol.

IntroductionAwake craniotomy is increasingly used to resect intrinsic brain tumors while preserving language. The level of musical training might affect the speed and extend of postoperative language recovery, as increased white matter connectivity in the corpus callosum is described in musicians compared to non-musicians.MethodsIn this cohort study, we included adult patients undergoing treatment for glioma with an awake resection procedure at two neurosurgical centers and assessed language preoperatively (T1) and postoperatively at three months (T2) and one year (T3) with the Diagnostic Instrument for Mild Aphasia (DIMA), transferred to z-scores. Moreover, patients’ musicality was divided into three groups based on the Musical Expertise Criterion (MEC) and automated volumetric measures of the corpus callosum were conducted.ResultsWe enrolled forty-six patients, between June 2015 and September 2021, and divided in: group A (non-musicians, n = 19, 41.3%), group B (amateur musicians, n = 17, 36.9%) and group C (trained musicians, n = 10, 21.7%). No significant differences on postoperative language course between the three musicality groups were observed in the main analyses. However, a trend towards less deterioration of language (mean/SD z-scores) was observed within the first three months on the phonological domain (A: −0.425/0.951 vs. B: −0.00100/1.14 vs. C: 0.0289/0.566, p-value = 0.19) with a significant effect between non-musicians vs. instrumentalists (A: −0.425/0.951 vs. B + C: 0.201/0.699, p = 0.04). Moreover, a non-significant trend towards a larger volume (mean/SD cm3) of the corpus callosum was observed between the three musicality groups (A: 6.67/1.35 vs. B: 7.09/1.07 vs. C: 8.30/2.30, p = 0.13), with the largest difference of size in the anterior corpus callosum in non-musicians compared to trained musicians (A: 3.28/0.621 vs. C: 4.90/1.41, p = 0.02).ConclusionWith first study on this topic, we support that musicality contributes to language recovery after awake glioma surgery, possibly attributed to a higher white matter connectivity at the anterior part of the corpus callosum. Our conclusion should be handled with caution and interpreted as hypothesis generating only, as most of our results were not significant. Future studies with larger sample sizes are needed to confirm our hypothesis.

The value of mapping musical function during awake craniotomy is unclear. Hence, this systematic review was conducted to examine the feasibility and added value of music mapping in patients undergoing awake craniotomy. An extensive search, on 26 March 2021, in four electronic databases (Medline, Embase, Web of Science and Cochrane CENTRAL register of trials), using synonyms of the words "Awake Craniotomy" and "Music Performance," was conducted. Patients performing music while undergoing awake craniotomy were independently included by two reviewers. This search resulted in 10 studies and 14 patients. Intra-operative mapping of musical function was successful in 13 out of 14 patients. Isolated music disruption, defined as disruption during music tasks with intact language/speech and/or motor functions, was identified in two patients in the right superior temporal gyrus, one patient in the right and one patient in the left middle frontal gyrus and one patient in the left medial temporal gyrus. Pre-operative functional MRI confirmed these localizations in three patients. Assessment of post-operative musical function, only conducted in seven patients by means of standardized (57%) and non-standardized (43%) tools, report no loss of musical function. With these results, we conclude that mapping music is feasible during awake craniotomy. Moreover, we identified certain brain regions relevant for music production and detected no decline during follow-up, suggesting an added value of mapping musicality during awake craniotomy. A systematic approach to map musicality should be implemented, to improve current knowledge on the added value of mapping musicality during awake craniotomy.

OBJECTIVE Given the high-risk nature of arteriovenous malformation (AVM) resections, accurate pre- and intraoperative imaging of the vascular morphology is a crucial component that may contribute to successful surgical results. Surprisingly, current gold standard imaging techniques for surgical guidance of AVM resections are mostly preoperative, lacking the necessary flexibility to cater to intraoperative changes. Micro-Doppler imaging is a unique high-resolution technique relying on high frame rate ultrasound and subsequent Doppler processing of microvascular hemodynamics. In this paper the authors report the first application of intraoperative, coregistered magnetic resonance/computed tomograpy, micro-Doppler imaging during the neurosurgical resection of an AVM in the parietal lobe. OBSERVATIONS The authors applied intraoperative two-dimensional and three-dimensional (3D) micro-Doppler imaging during resection and were able to identify key anatomical features including draining veins, supplying arteries and microvasculature in the nidus itself. Compared to the corresponding preoperative 3D-digital subtraction angiography (DSA) image, the micro-Doppler images could delineate vascular structures and visualize hemodynamics with higher, submillimeter scale detail, even at significant depths (>5 cm). Additionally, micro-Doppler imaging revealed unique microvascular morphology of surrounding healthy vasculature. LESSONS The authors conclude that micro-Doppler imaging in its current form has clear potential as an intraoperative counterpart to preoperative contrast-dependent DSA, and the microvascular details it provides could build new ground to further study cerebrovascular pathophysiology.

Three-dimensional (3D) stereophotogrammetry is a novel imaging technique that has gained popularity in the medical field as a reliable, non-invasive, and radiation-free imaging modality. It uses optical sensors to acquire multiple 2D images from different angles which are reconstructed into a 3D digital model of the subject's surface. The technique proved to be especially useful in craniofacial applications, where it serves as a tool to overcome the limitations imposed by conventional imaging modalities and subjective evaluation methods. The capability to acquire high-dimensional data in a quick and safe manner and archive them for retrospective longitudinal analyses, provides the field with a methodology to increase the understanding of the morphological development of the cranium, its growth patterns and the effect of different treatments over time.This review describes the role of 3D stereophotogrammetry in the evaluation of craniosynostosis, including reliability studies, current and potential clinical use cases, and practical challenges. Finally, developments within the research field are analyzed by means of bibliometric networks, depicting prominent research topics, authors, and institutions, to stimulate new ideas and collaborations in the field of craniofacial 3D stereophotogrammetry.We anticipate that utilization of this modality's full potential requires a global effort in terms of collaborations, data sharing, standardization, and harmonization. Such developments can facilitate larger studies and novel deep learning methods that can aid in reaching an objective consensus regarding the most effective treatments for patients with craniosynostosis and other craniofacial anomalies, and to increase our understanding of these complex dysmorphologies and associated phenotypes.

BACKGROUND Major obstacles that have impeded the development of effective new therapies for GBM include inter- and intratumoral heterogeneity, the blood-brain-barrier and use of sub-optimal cell line-based preclinical models. Taking these hurdles into account, we have set up a patient-derived GBM drug-screening platform. We optimized protocols to improve cell culture success rate and retrospectively assessed the predictive power of our assay for patient response to TMZ. A large panel of GBM cells was screened for sensitivity to available oncological agents. Drugs of interest were selected based on favorable physicochemical properties for BBB crossing and potent activity in (a subset of) GBM cultures. Finally, we determined the success rate of performing a small-scale screen with 20 selected agents within 4 weeks of receiving tumor tissue. RESULTS By combining both CUSA and tissue piece-derived dissociation protocols, culture success increased to 95%, ensuring representation of the near-complete spectrum of GBM subtypes. Single-cell sequencing studies confirmed heterogeneity in our low-passage cell cultures. In vitro screening of TMZ on a large cohort (n = 55) identified 3 response categories (responders/intermediates/non-responders) for which Cox regression analysis revealed significantly different overall survival curves of corresponding patients. Screening of 107 FDA-approved anticancer agents on 45 GBM cultures underscored the tremendous intertumoral heterogeneity in drug sensitivities. We identified 20 potent agents each effective at clinically-achievable concentrations in (a subset of) GBM cultures and having favorable BBB penetration properties (CNS-MPO score). Screening of these agents on a per patient basis within 4 weeks of receiving tissue was successful in 18 out of 24 (75%) tested tumors. In the remaining cases the tumor cells grew very slowly and longer culture times were required. CONCLUSION Our drug screening platform offers a tool to predict TMZ response and assess sensitivity to candidate treatments, either for GBM subsets or on a per patient basis.

There is no evidence-based systemic therapy for patients with progressive meningiomas for whom surgery or external radiotherapy is no longer an option. In this study, the efficacy and safety of peptide receptor radionuclide therapy (PRRT) in patients with progressive, treatment-refractory meningiomas were evaluated.Retrospective analysis of all meningioma patients treated with [Fifteen meningioma patients received [In this cohort of meningioma patients with exhaustion of surgical and radiotherapeutic options and progressive disease, it was shown that PRRT plays a role in controlling tumour growth.

Introduction Traumatic axonal injury (TAI) is a condition defined as multiple, scattered, small hemorrhagic, and/or non-hemorrhagic lesions, alongside brain swelling, in a more confined white matter distribution on imaging studies, together with impaired axoplasmic transport, axonal swelling, and disconnection after traumatic brain injury (TBI). Ever since its description in the 1980s and the grading system by Adams et al., our understanding of the processes behind this entity has increased. Methods We performed a scoping systematic, narrative review by interrogating Ovid MEDLINE, Embase, and Google Scholar on the pathophysiology, biomarkers, and diagnostic tools of TAI patients until July 2020. Results We underline the misuse of the Adams classification on MRI without proper validation studies, and highlight the hiatus in the scientific literature and areas needing more research. In the past, the theory behind the pathophysiology relied on the inertial force exerted on the brain matter after severe TBI inducing a primary axotomy. This theory has now been partially abandoned in favor of a more refined theory involving biochemical processes such as protein cleavage and DNA breakdown, ultimately leading to an inflammation cascade and cell apoptosis, a process now described as secondary axotomy. Conclusion The difference in TAI definitions makes the comparison of studies that report outcomes, treatments, and prognostic factors a daunting task. An even more difficult task is isolating the outcomes of isolated TAI from the outcomes of severe TBI in general. Targeted bench-to-bedside studies are required in order to uncover further pathways involved in the pathophysiology of TAI and, ideally, new treatments.

BackgroundThe tumor-selective human adenovirus Delta24-RGD is currently under investigation in phase II clinical trials for patients with recurrent glioblastoma (GBM). To improve treatments for patients with GBM, we explored the potential of combining Delta24-RGD with antibodies targeting immune checkpoints.MethodsC57BL/6 mice were intracranially injected with GL261 cells and treated with a low dose of Delta24-RGD virus. The expression dynamics of 10 co-signaling molecules known to affect immune activity was assessed in tumor-infiltrating immune cells by flow cytometry after viral injection. The antitumor activity was measured by tumor cell killing and IFNγ production in co-cultures. Efficacy of the combination viro-immunotherapy was tested in vitro and in the GL261 and CT2A orthotopic mouse GBM models. Patient-derived GBM cell cultures were treated with Delta24-RGD to assess changes in PD-L1 expression induced by virus infection.ResultsDelta24-RGD therapy increased intratumoral CD8+ T cells expressing Inducible T-cell co-stimulator (ICOS) and PD-1. Functionality assays confirmed a significant positive correlation between tumor cell lysis and IFNγ production in ex vivo cultures (Spearman r = 0.9524; P < .01). Co-cultures significantly increased IFNγ production upon treatment with PD-1 blocking antibodies. In vivo, combination therapy with low-dose Delta24-RGD and anti-PD-1 antibodies significantly improved outcome compared to single-agent therapy in both syngeneic mouse glioma models and increased PD-1+ tumor-infiltrating CD8+ T cells. Delta24-RGD infection induced tumor-specific changes in PD-L1 expression in primary GBM cell cultures.ConclusionsThis study demonstrates the potential of using low-dose Delta24-RGD therapy to sensitize glioma for combination with anti-PD-1 antibody therapy.

Since its description in 1985, the transapical petrosal transtentorial or Kawase approach has become a viable option of approaching lesions located in and around the apex of the petrous bone, Meckel's cave, and the anterolateral surface of the brain stem while preserving cranial nerve function. At the Brain Tumor Center, Erasmus MC, 25 patients were treated using the Kawase approach between 2004 and 2018 for various indications, including petroclival meningiomas, chondrosarcomas, pontine cavernomas, trigeminal schwannomas, and posterior circulation aneurysms. Hearing preservation was achieved in all patients; new abducens nerve and trochlear nerve palsies were present in three and six patients, respectively, of which a total of eight required ophthalmological correction. Seven patients experienced a cerebrospinal fluid fistula postoperatively, but this complication appeared self-limiting in all cases, with one patient experiencing secondary meningitis. After modifying our closure technique, the rate of fistulas dropped to zero. The observed direct postoperative mortality was 4% (one patient), although not related to the approach itself. In conclusion, the Kawase approach is a highly complex, but essential middle fossa approach, extremely robust, and able to serve a wide array of pathologies together with its extensions. It is very accurate for performing hearing preservation surgery, but not without caveats and inherent risk of complications.

Little is known about the results of young vascular neurosurgeons who perform only microsurgical clip reconstruction in the era since the International Subarachnoid Aneurysm Trial (ISAT) or about the training and caseload required to equivocate the results of senior, more experienced colleagues. The aim of this study was to compare clinical outcomes of patients treated by young and senior vascular neurosurgeons at Erasmus MC University Medical Center Rotterdam, adjusting for case mix.A partially prospective and partially retrospective database was used. Hierarchical mixed models with a random intercept for surgeon were used for confounder adjustment, and propensity score matching for complexity was used to create comparable groups.The study included 609 patients harboring 767 aneurysms. Most (86%) of the aneurysms had at least 1 complexity characteristic, with the majority having 3 characteristics. The most often encountered complexity characteristics were the presence of a broad neck and the presence of branches emerging from the aneurysm. Use of temporary clipping and skull base approaches was significantly higher in the young vascular neurosurgeons group (P0.0001). The complexity score differed significantly between senior and young vascular neurosurgeons (P0.001). After propensity score matching for complexity, multivariable logistic regression showed young vascular neurosurgeons to be significantly associated with better outcomes for ruptured aneurysms (propensity score weighted odds ratio 0.55 [95% confidence interval 0.35-0.88], P = 0.01).In a high-volume neurovascular center where both endovascular and microsurgical treatment options are available, young vascular neurosurgeons can be trained to achieve at least the same results as their senior colleagues despite increased complexity.

BACKGROUND Evidence suggests that smaller residual tumor volumes after initial surgery are associated with longer survival in patients with astrocytoma, IDH-mutant, grade II. For IDH-mutant glioma of higher grade but also for oligodendroglioma, IDH-mutant, and 1p/19q codeleted, the impact of residual tumor volume on survival is unclear. This could be related to the limited follow-up of patients with oligodendroglioma that typically have long overall survival. We expanded a previously published series of patients increase the duration of follow-up and the spectrum of tumor grades. METHODS Single center observational cohort study of patients with adult-type diffuse glioma, IDH-mutant, all WHO-2021 grades, from 2003 to 2021 . Molecular characteristics were assessed by next-generation targeted sequencing. Tumor volumes were calculated by semi-automatic 3D segmentation on pre- and postoperative MRI-scans. Associations between prognostic factors and survival were assessed using univariate and multivariate Cox proportional hazards models. RESULTS 384 patients with IDH-mutant glioma (174 oligodendroglioma, 212 astrocytoma) were followed for a median of 7 years. Median age at diagnosis was 41 years (IQR 33 – 55). Significant prognostic factors for survival were Karnofsky performance status, 1p19q-status and post-operative tumor volume. Smaller post-operative tumor volume was associated with better survival, both in astrocytoma and oligodendroglioma. Age, tumor grade and MRI-contrast enhancement were not associated with survival. CONCLUSION Lower residual tumor volume after first surgery is a strong prognostic factor in all IDH-mutant glioma subgroups, even in patients with very small residual tumor. Importantly, age and histological tumor grade were not significantly associated with survival. The data serves as further support for optimal initial resections of tumors suspected for IDH-mutant glioma, also in oligodendroglioma.

BACKGROUND The dismal prognosis of glioblastoma (GBM) patients, with a median survival of less than 15 months despite maximal therapy urgently warrants new therapeutic approaches. Clinical trials employing oncolytic viruses (OVs) have shown encouraging results, however, in each OV clinical trial only a small subset of patients responded to treatment. As inter-tumoral heterogeneity has been the key challenge in treating GBM, we hypothesized that development of an in vitro co-culture model for assessment of viral replication and subsequent immune response might ultimately predict in vivo OV efficacy for individual GBM patients. METHODS 20 patient-derived GBM cell cultures were tested with dose-ranges of two clinically relevant OVs (DNX2401 and rQnestin34.5 V1) to determine the EC50 values (half-maximal effective concentration). To discriminate between responders and non-responders six of these cultures were infected using MOI 10 for DNX2401 and 0.25 for rQnestin34.5V1, and co-cultured with autologous PBMCs. OV-induced changes in gene and protein expression of immune associated genes were assessed using targeted gene expression (NanoString Technology) and ELISA. RESULTS DNX2401 EC50 values ranged from 0.35 to > 600 and from 0.04 to 1.77 for rQnestin34.5V1. Induction of pro-inflammatory cytokines and chemokines differed per virus and per patient. Enhanced OV infection or oncolysis efficiency did not lead to increased levels of IFNγ production. Importantly, longer exposure to dexamethasone prior to PBMC isolation correlated with suppressed IFNγ production. CONCLUSION We established an autologous GBM cells/PBMCs co-culture model which reflects inter-tumoral heterogeneity in terms of cytokine induction and virus-specific changes in gene and protein expression upon OV infection. Immune activation is not directly related to degree of infection or oncolysis and can be hampered by prolonged prior dexamethasone use. These first results support our hypothesis that improved prediction of response rates in oncolytic virotherapy for GBM may require a personalized approach with an in vitro test system.

INTRODUCTION Little progress has been made in the development of effective new therapies for glioblastoma (GBM) the past decades. Fresh patient-derived GBM cell culture models have become the gold standard for GBM drug discovery and development. One of the major obstacles in identifying novel candidate drugs against GBM remains the blood-brain barrier (BBB). Therefore, it is crucial to select drugs with favourable physicochemical properties to cross BBB and reach the tumour tissue in therapeutically effective concentrations. In current drug repurposing approach, we evaluated available anti-cancer agents in our patient-derived drug screening platform against GBM. METHODS The FDA-approved Oncology Drug Set II library was tested on 45 primary GBM cell cultures. We developed a drug shortlisting pipeline combining efficacy data with pharmacodynamic and pharmacokinetic characteristics of each compound. The therapeutic efficacy of the selected agent was assessed in an orthotopic mouse PDX model, while penetration into the CNS by LC/MS/MS. RESULTS Omacetaxine mepesuccinate (OMA) was ranked as one of the most promising candidates applying our drug selection approach. In vitro, OMA revealed anti-tumour activity at IC50 values well-below reported Cmax plasma values in approximately 80% of GBM cultures. NanoString nCounter analysis, revealed DNA damage repair as the main pathway involved in OMA’s anti-tumour effect. Activation of caspase 3/7 activity and decrease of glioma cell invasiveness were also linked to its anti-tumour effect. In vivo, 1mg/kg dose of OMA was found to reach the brain tumour tissue in concentrations similar to the reported IC50 values in vitro. No adverse reactions were noted and a survival benefit was observed in a proportion of the treated mice. CONCLUSIONS At 1 mg/kg, OMA reaches the tumour brain tissue in therapeutically effective concentrations in mice while a moderate therapeutic benefit was observed. Additional in vivo experiments are ongoing investigating higher dosages of OMA and longer exposure.

Background Evidence-based cognitive rehabilitation programs for brain tumor patients are not widely available, despite the high need. We aimed to evaluate the effects of a tablet-based cognitive rehabilitation program on cognitive performance, cognitive complaints, fatigue, and psychological distress in primary brain tumor patients following neurosurgery. Also, attrition, adherence and patient satisfaction with the program were evaluated. Methods Adults with presumed low-grade glioma and meningioma were recruited before surgery. Three months thereafter, participants were allocated to the intervention group or waiting-list control group using minimization. The 10-week eHealth app ReMind, based on the effective face-to-face intervention, consisted of psychoeducation, strategy-training and attention retraining. Performance-based cognitive outcomes and patient-reported outcomes were assessed before surgery and 3, 6 and 12 months thereafter. Mean scores, percentages of cognitively impaired individuals and reliable change indices (RCIs) were compared between groups. Results Sixty-two out of 183 eligible patients were randomized. Of the people who declined, 56% reported that participation would to be too burdensome. All participants found a tablet-app suitable for delivery of cognitive rehabilitation and 90% rated the program as “good” or “excellent”. Performance-based cognitive outcomes and patient-reported outcomes did not significantly differ in group means over time nor RCIs between the intervention (final n = 20) and control group (final n = 25). Conclusions Recruitment at this early stage was difficult, resulting in limited statistical power. No significant effects were demonstrated, while adherence and satisfaction with the eHealth program were good. In clinical practice, ReMind may be helpful, if timing would be adapted to patients’ needs.

Background Several studies reported a correlation between anatomic location and genetic background of low-grade gliomas (LGGs). As such, tumor location may contribute to presurgical clinical decision-making. Our purpose was to visualize and compare the spatial distribution of different WHO 2016 gliomas, frequently aberrated single genes and DNA copy number alterations within subgroups, and groups of postoperative tumor volume. Methods Adult grade II glioma patients (WHO 2016 classified) diagnosed between 2003 and 2016 were included. Tumor volume and location were assessed with semi-automatic software. All volumes of interest were mapped to a standard reference brain. Location heatmaps were created for each WHO 2016 glioma subgroup, frequently aberrated single genes and copy numbers (CNVs), as well as heatmaps according to groups of postoperative tumor volume. Differences between subgroups were determined using voxelwise permutation testing. Results A total of 110 IDH mutated astrocytoma patients, 92 IDH mutated and 1p19q co-deleted oligodendroglioma patients, and 22 IDH wild-type astrocytoma patients were included. We identified small regions in which specific molecular subtypes occurred more frequently. IDH-mutated LGGs were more frequently located in the frontal lobes and IDH wild-type tumors more frequently in the basal ganglia of the right hemisphere. We found no localizations of significant difference for single genes/CNVs in subgroups, except for loss of 9p in oligodendrogliomas with a predilection for the left parietal lobes. More extensive resections in LGG were associated with frontal locations. Conclusions WHO low-grade glioma subgroups show differences in spatial distribution. Our data may contribute to presurgical clinical decision-making in LGG patients.

BackgroundMutations of the isocitrate dehydrogenase (IDH) gene occur in over 80% of low-grade gliomas and secondary glioblastomas. Despite considerable efforts, endogenous in vitro IDH-mutated glioma models remain scarce. Availability of these models is key for the development of new therapeutic interventions.MethodsCell cultures were established from fresh tumor material and expanded in serum-free culture media. D-2-Hydroxyglutarate levels were determined by mass-spectrometry. Genomic and transcriptomic profiling were carried out on the Illumina Novaseq platform, methylation profiling was performed with the Infinium MethylationEpic BeadChip array. Mitochondrial respiration was measured with the Seahorse XF24 Analyzer. Drug screens were performed with an NIH FDA-approved anti-cancer drug set and two IDH-mutant specific inhibitors.ResultsA set of twelve patient-derived IDHmt cell cultures was established. We confirmed high concordance in driver mutations, copy number and methylation profiles between the tumors and derived cultures. Homozygous deletion of CDKN2A/B was observed in all cultures. IDH-mutant cultures had lower mitochondrial reserve capacity. IDH-mutant specific inhibitors did not affect cell viability or global gene expression. Screening of 107 FDA-approved anti-cancer drugs identified nine compounds with potent activity against IDHmt gliomas, including three compounds with favorable pharmacokinetic characteristics for CNS penetration: teniposide, omacetaxine mepesuccinate, and marizomib.ConclusionsOur twelve IDH-mutant cell cultures show high similarity to the parental tissues and offer a unique tool to study the biology and drug sensitivities of high-grade IDHmt gliomas in vitro. Our drug screening studies reveal lack of sensitivity to IDHmt inhibitors, but sensitivity to a set of nine available anti-cancer agents.Key pointsIDHmt glioma cultures closely resemble their parental tumorsMicroscopic monitoring of early passages and colony isolation increases IDH1mt culture successDrug screening identified nine candidate repurposed drugs for IDHmt gliomaImportance of the studyIDH-mutations are highly prevalent in low grade and secondary high-grade gliomas. Despite this high frequency however, very few in vitro models have been reported for IDH-mutated gliomas. In this manuscript we describe and characterize in detail twelve primary cultures from IDH-mutant astrocytomas. We show that these cultures retain most of the genetic, epigenetic and metabolic features of their respective parental tumors. Because of these similarities, these independent model systems will not only help understand the molecular defects driven by the mutation, but are also vital to identify means to target these tumors. Screening of 107 FDA-approved anti-cancer agents on these cultures identified a set of highly effective agents that may offer candidates for either systemic or assisted delivery treatment of this tumor subtype.

Background The current understanding of mechanisms behind migraine pain has been greatly enhanced with the recent therapies targeting calcitonin gene-related peptide and its receptor. The clinical efficacy of calcitonin gene-related peptide-blocking drugs indicates that, at least in a considerable proportion of patients, calcitonin gene-related peptide is a key molecule in migraine pain. There are several receptors and molecular pathways that can affect the release of and response to calcitonin gene-related peptide. One of these could be purinergic receptors that are involved in nociception, but these are greatly understudied with respect to migraine. Objective We aimed to explore purinergic receptors as potential anti-migraine targets. Methods We used the human middle meningeal artery as a proxy for the trigeminal system to screen for possible anti-migraine candidates. The human findings were followed by intravital microscopy and calcitonin gene-related peptide release measurements in rodents. Results We show that the purinergic P2Y13 receptor fulfills all the features of a potential anti-migraine target. The P2Y13 receptor is expressed in both the human trigeminal ganglion and middle meningeal artery and activation of this receptor causes: a) middle meningeal artery contraction in vitro; b) reduced dural artery dilation following periarterial electrical stimulation in vivo and c) a reduction of CGRP release from both the dura and the trigeminal ganglion in situ. Furthermore, we show that P2X3 receptor activation of the trigeminal ganglion causes calcitonin gene-related peptide release and middle meningeal artery dilation. Conclusion Both an agonist directed at the P2Y13 receptor and an antagonist of the P2X3 receptor seem to be viable potential anti-migraine therapies.

Intracranial pressure (ICP) monitoring is one of the mainstays in the treatment of severe traumatic brain injury (TBI), but different approaches to monitoring exist. The aim of this systematic review and meta-analysis is to compare the effectiveness and complication rate of ventricular drainage (VD) versus intracranial parenchymal (IP) catheters to monitor and treat raised ICP in patients with TBI. Pubmed, Embase, Web of Science, Google Scholar, and the Cochrane Database were searched for articles comparing ICP monitoring-based management with VDs and monitoring with IP monitors through March 2018. Study selection, data extraction, and quality assessment were performed independently by two authors. Outcomes assessed were mortality, functional outcome, need for decompressive craniectomy, length of stay, overall complications, such as infections, and hemorrhage. Pooled effect estimates were calculated with random effects models and expressed as relative risk (RR) for dichotomous outcomes and mean difference (MD) for ordinal outcomes, with corresponding 95% confidence intervals (CI). Six studies were included: one randomized controlled trial and five observational cohort studies. Three studies reported mortality, functional outcome, and the need for a surgical decompression, and three only reported complications. The quality of the studies was rated as poor, with critical or serious risk of bias. The pooled analysis did not show a statistically significant difference in mortality (RR = 0.90, 95% CI = 0.60-1.36, p = 0.41) or functional outcome (MD = 0.23, 95% CI = 0.67-1.13, p = 0.61). The complication rate of VDs was higher (RR = 2.56, 95% CI = 1.17-5.61, p = 0.02), and consisted mainly of infectious complications; that is, meningitis. VDs caused more complications, particularly more infections, but there was no difference in mortality or functional outcome between the two monitoring modalities. However, the studies had a high risk of bias. A need exists for high quality comparisons of VDs versus IP monitor-based management strategies on patient outcomes.

Simple Summary Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor. Despite multimodal treatment, the prognosis of GBM patients remains very poor. Oncolytic virotherapy is being evaluated as novel treatment for this patient group and clinical trials testing oncolytic viruses have shown impressive responses, albeit in a small subset of GBM patients. Obtaining insight into specific tumor- or patient-related characteristics of the responding patients, may in the future improve response rates. In this review we discuss factors related to oncolytic activity of the most widely applied oncolytic virus strains as well as potential biomarkers and future assays that may allow us to predict response to these agents. Such biomarkers and tools may in the future enable personalizing oncolytic virotherapy for GBM patients. Abstract Oncolytic virus (OV) treatment may offer a new treatment option for the aggressive brain tumor glioblastoma. Clinical trials testing oncolytic viruses in this patient group have shown promising results, with patients achieving impressive long-term clinical responses. However, the number of responders to each OV remains low. This is thought to arise from the large heterogeneity of these tumors, both in terms of molecular make-up and their immune-suppressive microenvironment, leading to variability in responses. An approach that may improve response rates is the personalized utilization of oncolytic viruses against Glioblastoma (GBM), based on specific tumor- or patient-related characteristics. In this review, we discuss potential biomarkers for response to different OVs as well as emerging ex vivo assays that in the future may enable selection of optimal OV for a specific patient and design of stratified clinical OV trials for GBM.

Diagnosis and monitoring of primary brain tumours, brain metastasis and acute ischaemic stroke all require invasive, burdensome and costly diagnostics, frequently lacking adequate sensitivity, particularly during disease monitoring. Monocytes are known to migrate to damaged tissues, where they act as tissue macrophages, continuously scavenging, phagocytizing and digesting apoptotic cells and other tissue debris. We hypothesize that upon completion of their tissue-cleaning task, these tissue macrophages might migrate via the lymph system to the bloodstream, where they can be detected and evaluated for their phagolysosomal contents. We discovered a blood monocyte subpopulation carrying the brain-specific glial fibrillary acidic protein in glioma patients and in patients with brain metastasis and evaluated the diagnostic potential of this finding. Blood samples were collected in a cross-sectional study before or during surgery from adult patients with brain lesions suspected of glioma. Together with blood samples from healthy controls, these samples were flowing cytometrically evaluated for intracellular glial fibrillary acidic protein in monocyte subsets. Acute ischaemic stroke patients were tested at multiple time points after onset to evaluate the presence of glial fibrillary acidic protein-carrying monocytes in other forms of brain tissue damage. Clinical data were collected retrospectively. High-grade gliomas (N = 145), brain metastasis (N = 21) and large stroke patients (>100 cm3) (N = 3 versus 6; multiple time points) had significantly increased frequencies of glial fibrillary acidic protein+CD16+ monocytes compared to healthy controls. Based on both a training and validation set, a cut-off value of 0.6% glial fibrillary acidic protein+CD16+ monocytes was established, with 81% sensitivity (95% CI 75–87%) and 85% specificity (95% CI 80–90%) for brain lesion detection. Acute ischaemic strokes of >100 cm3 reached >0.6% of glial fibrillary acidic protein+CD16+ monocytes within the first 2–8 h after hospitalization and subsided within 48 h. Glioblastoma patients with >20% glial fibrillary acidic protein+CD16+ non-classical monocytes had a significantly shorter median overall survival (8.1 versus 12.1 months). Our results and the available literature, support the hypothesis of a tissue-origin of these glial fibrillary acidic protein-carrying monocytes. Blood monocytes carrying glial fibrillary acidic protein have a high sensitivity and specificity for the detection of brain lesions and for glioblastoma patients with a decreased overall survival. Furthermore, their very rapid response to acute tissue damage identifies large areas of ischaemic tissue damage within 8 h after an ischaemic event. These studies are the first to report the clinical applicability for brain tissue damage detection through a minimally invasive diagnostic method, based on blood monocytes and not serum markers, with direct consequences for disease monitoring in future (therapeutic) studies and clinical decision making in glioma and acute ischaemic stroke patients., Van den Bossche et al. report a blood monocyte subset carrying brain-specific proteins and that relatively increases in case of brain tissue damage such as in glioma, brain metastases and stroke, which can be used to detect and monitor disease. Moreover, these monocytes predict survival in glioblastoma patients at presentation., Graphical Abstract Graphical Abstract

Background Mutations of the isocitrate dehydrogenase (IDH) gene occur in over 80% of low-grade gliomas and secondary glioblastomas. Despite considerable efforts, endogenous in vitro IDH-mutated glioma models remain scarce. Availability of these models is key for the development of new therapeutic interventions. Methods Cell cultures were established from fresh tumor material and expanded in serum-free culture media. D-2-Hydroxyglutarate levels were determined by mass spectrometry. Genomic and transcriptomic profiling were carried out on the Illumina Novaseq platform, methylation profiling was performed with the Infinium MethylationEpic BeadChip array. Mitochondrial respiration was measured with the Seahorse XF24 Analyzer. Drug screens were performed with an NIH FDA-approved anti-cancer drug set and two IDH-mutant specific inhibitors. Results A set of twelve patient-derived IDHmt cell cultures was established. We confirmed high concordance in driver mutations, copy numbers and methylation profiles between the tumors and derived cultures. Homozygous deletion of CDKN2A/B was observed in all cultures. IDH-mutant cultures had lower mitochondrial reserve capacity. IDH-mutant specific inhibitors did not affect cell viability or global gene expression. Screening of 107 FDA-approved anti-cancer drugs identified nine compounds with potent activity against IDHmt gliomas, including three compounds with favorable pharmacokinetic characteristics for CNS penetration: teniposide, omacetaxine mepesuccinate, and marizomib. Conclusions Our twelve IDH-mutant cell cultures show high similarity to the parental tissues and offer a unique tool to study the biology and drug sensitivities of high-grade IDHmt gliomas in vitro. Our drug screening studies reveal lack of sensitivity to IDHmt inhibitors, but sensitivity to a set of nine available anti-cancer agents.

Background The membrane of Liliequist is one of the best-known inner arachnoid membranes and an essential intraoperative landmark when approaching the interpeduncular cistern but also an obstacle in the growth of lesions in the sellar and parasellar regions. The limits and exact anatomical description of this membrane are still unclear, as it blends into surrounding structures and joins other arachnoid membranes. Methods We performed a systematic narrative review by searching for articles describing the anatomy and the relationship of the membrane of Liliequist with surrounding structures in MEDLINE, Embase and Google Scholar. Included articles were cross-checked for missing references. Both preclinical and clinical studies were included, if they detailed the clinical relevance of the membrane of Liliequist. Results Despite a common definition of the localisation of the membrane of Liliequist, important differences exist with respect to its anatomical borders. The membrane appears to be continuous with the pontomesencephalic and pontomedullary membranes, leading to an arachnoid membrane complex around the brainstem. Furthermore, Liliequist’s membrane most likely continues along the oculomotor nerve sheath in the cavernous sinus, blending into and giving rise to the carotid-oculomotor membrane. Conclusion Further standardized anatomical studies are needed to clarify the relation of the membrane of Liliequist with surrounding structures but also the anatomy of the arachnoid membranes in general. Our study supports this endeavour by identifying the knowledge hiatuses and reviewing the current knowledge base.

Background: Surgery of GBM nowadays is usually performed under general anesthesia (GA) and resections are often not as aggressive as possible, due to the chance of seriously damaging the patient with a rather low life expectancy. A surgical technique optimizing resection of the tumor in eloquent areas but preventing neurological deficits is necessary to improve survival and quality of life in these patients. Awake craniotomy (AC) with the use of cortical and subcortical stimulation has been widely implemented for low-grade glioma resections (LGG), but not yet for GBM. AC has shown to increase resection percentage and preserve quality of life in LGG and could thus be of important value in GBM surgery. Methods/design: This study is a prospective, multicenter, randomized controlled trial (RCT). Consecutive patients with a glioblastoma in or near eloquent areas (Sawaya grading II/III) will be 1:1 randomized to awake craniotomy or craniotomy under general anesthesia. 246 patients will be included in neurosurgical centers in the Netherlands and Belgium. Primary end-points are: 1) Postoperative neurological morbidity and 2) Proportion of patients with gross-total resections. Secondary end-points are: 1) Health-related quality of life; 2) Progression-free survival (PFS); 3) Overall survival (OS) and 4) Frequency and severity of Serious Adverse Effects in each group. Also, a cost-benefit analysis will be performed. All patients will receive standard adjuvant treatment with concomitant chemoradiotherapy. Discussion: This RCT should demonstrate whether AC is superior to craniotomy under GA on neurological morbidity, extent of resection and survival for glioblastoma resections in or near eloquent areas. Trial registration: Clinicaltrials.gov: NCT03861299 Netherlands Trial Register (NTR): NL7589

Background: Spinal intradural tumors can be classified as intradural extramedullary or intramedullary tumors. Spinal meningiomas are among the most frequent intradural, extramedullary tumors (IDEMs), representing 12 % of all meningiomas and 25–45 % of all intradural spinal tumors. Objective: To evaluate postoperative outcome, defined by mortality, tumor recurrence and modified Rankin Scale in patients with spinal meningiomas. Furthermore, to identify factors related to these outcome measures and define possible prognosticators. Methods: A large single center retrospective analysis of 166 consecutive spinal meningioma patients during a 29- year period (1989–2018). Results: Female to male ratio was 5.15 to 1. Of all 166 resected tumors, 159 were WHO grade I and seven were WHO grade II. Histopathologically, the psammomatous type was most common (42.8 %). The thoracic region was the most frequent location (71.1 %), followed by cervical and lumbar locations. A complete resection (Simpson I-III) was achieved in 88.7 %. In 12 cases (7.2 %) recurrences of a spinal meningioma occurred after an interval of 0.70–13.78 years. Postoperative complications consisted of CSF leakage and wound healing problems. Three patients died of direct postoperative complications (1.8 %), nine patients died in follow-up due to unrelated causes. Post-operative complications were related to the overall outcome (p = 0.029). Clinical outcome showed improvement in 117 patients out of 148 (79.1 %) according to modified Rankin Scale; 24 patients remained stable and 7 patients deteriorated. Patients with pre-existing bladder/bowel problems and incomplete resections had higher chance of recurrences. Younger patients also had a higher recurrence rate. Follow-up ranged from 0 to 23 years, median of 0.77 years, most were discontinued after 2 years. Conclusions: The primary treatment of spinal meningiomas remains surgery. Complete resection of spinal meningiomas is achieved in most of the cases, however preserving and improving neurological status has priority over complete tumor resection. Morbidity and mortality is relatively low. Longer follow-up periods are recommended, since recurrences can occur after 10–15 years.

Background and purpose Oncological neurosurgery relies heavily on making continuous, intra-operative tumor-brain delineations based on image-guidance. Limitations of currently available imaging techniques call for the development of real-time image-guided resection tools, which allow for reliable functional and anatomical information in an intra-operative setting. Functional ultrasound (fUS), is a new mobile neuro-imaging tool with unprecedented spatiotemporal resolution, which allows for the detection of small changes in blood dynamics that reflect changes in metabolic activity of activated neurons through neurovascular coupling. We have applied fUS during conventional awake brain surgery to determine its clinical potential for both intra-operative functional and vascular brain mapping, with the ultimate aim of achieving maximum safe tumor resection. Methods During awake brain surgery, fUS was used to image tumor vasculature and task-evoked brain activation with electrocortical stimulation mapping (ESM) as a gold standard. For functional imaging, patients were presented with motor, language or visual tasks, while the probe was placed over (ESM-defined) functional brain areas. For tumor vascular imaging, tumor tissue (pre-resection) and tumor resection cavity (post-resection) were imaged by moving the hand-held probe along a continuous trajectory over the regions of interest. Results A total of 10 patients were included, with predominantly intra-parenchymal frontal and temporal lobe tumors of both low and higher histopathological grades. fUS was able to detect (ESM-defined) functional areas deep inside the brain for a range of functional tasks including language processing. Brain tissue could be imaged at a spatial and temporal resolution of 300 μm and 1.5-2.0 ms respectively, revealing real-time tumor-specific, and healthy vascular characteristics. Conclusion The current study presents the potential of applying fUS during awake brain surgery. We illustrate the relevance of fUS for awake brain surgery based on its ability to capture both task-evoked functional cortical responses as well as differences in vascular characteristics between tumor and healthy tissue. As current neurosurgical practice is still pre-dominantly leaning on inherently limited pre-operative imaging techniques for tumor resection-guidance, fUS enters the scene as a promising alternative that is both anatomically and physiologically informative.

Brain Trauma Foundation (BTF) Guidelines for medical management of severe traumatic brain injury (TBI) have become a global standard for the treatment of TBI patients. We aim to explore the evolution of the guidelines for the management of severe TBI. We reviewed the four editions of the BTF guidelines published over the past 20 years. The 1996 and 2000 editions were merged because of minimal differences, and are referred to as the 1996 edition. We described changes in topics and recommendations over time, and analyzed predictors of survival of recommendations with logistical regression. The guidelines contained 27 recommendations on 18 topics in 2016, 35 recommendations on 15 topics in 2007, and 22 recommendations on 10 topics in 1996. Substantial delays were found between the search for evidence and the guideline publication, ranging from 18 to 34 months. The overall body of evidence comprised 189 studies on 18 topics in 2016, compared with 156 studies on 15 topics in 2007 and 180 studies on 10 topics in 1996. Over time, a total of 175 studies were discarded from the evidence base following more rigorous grading of evidence. A total of 15/23 (65%) of the 1996/2000 recommendations were discarded over time. Out of 12 new recommendations introduced in the 2007 edition, 8 (66%) were discarded in 2016. Survival of recommendations varied between 33% and 100% for level I recommendations and between 11% and 31% for level II and III recommendations. No predictors of survival of recommendations were found. Substantial delays exist between literature search and publication, and survival rate of TBI guideline recommendations is poor. These factors may adversely affect currency and adherence to guidelines. The TBI community should take responsibility for improving the quality of the evidence base and ensuring that the translation of the evidence into guidelines supports clinicians in daily clinical practice.

_Background_ Extensive resections in low-grade glioma (LGG) are associated with improved overall survival (OS). However, World Health Organization (WHO) classification of gliomas has been completely revised and is now predominantly based on molecular criteria. This requires reevaluation of the impact of surgery in molecularly defined LGG subtypes. _Methods_ We included 228 adults who underwent surgery since 2003 for a supratentorial LGG. Pre- and postoperative tumor volumes were assessed with semiautomatic software on T2-weighted images. Targeted next-generation sequencing was used to classify samples according to current WHO classification. Impact of postoperative volume on OS, corrected for molecular profile, was assessed using a Cox proportional hazards model. _Results_ Median follow-up was 5.79 years. In 39 (17.1%) histopathologically classified gliomas, the subtype was revised after molecular analysis. Complete resection was achieved in 35 patients (15.4%), and in 54 patients (23.7%) only small residue (0.1-5.0 cm 3) remained. In multivariable analysis, postoperative volume was associated with OS, with a hazard ratio of 1.01 (95% CI: 1.002-1.02; P = 0.016) per cm 3 increase in volume. The impact of postoperative volume was particularly strong in isocitrate dehydrogenase (IDH) mutated astrocytoma patients, where even very small postoperative volumes (0.1-5.0 cm) already negatively affected OS. _Conclusion_ Our data provide the necessary reevaluation of the impact of surgery in molecularly defined LGG and support maximal resection as first-line treatment for molecularly defined LGG. Importantly, in IDH mutated astrocytoma, even small postoperative volumes have negative impact on OS, which argues for a second-look operation in this subtype to remove minor residues if safely possible.

Objective Glioma patients often complain about problems in daily conversation with a negative impact on quality of life. Disorders in standardized language tests (e.g. naming and fluency), are frequently observed. Most studies claim recovery of language functions within 3 months. However, long-term effects of surgery on spontaneous speech remain unknown. Patients and Methods Eighteen glioma patients were compared to healthy controls in spontaneous speech variables: Type Token Ratio (TTR), Mean Length of Utterance words (MLUw), Incomplete Sentences, Self-corrections and Repetitions. Boston Naming Test (BNT) and Category Fluency (CF) were also assessed. We compared: pre- and 3 months postoperatively (T1-T2), 3 months and 1 year postoperatively (T2-T3), pre- and 1 year postoperatively (T1-T3). Correlations were computed between deviating variables and BNT/CF, tumor localization, and tumor grade. Results Patients had deficits in Incomplete sentences (T1, T2, T3), TTR (T2,T3), MLUw (T3) and Self-corrections (T2). Between T1-T2 no decline was present. Between T2-T3 and T1-T3, there was a decrease of MLUw, Self-corrections and Repetitions and an increase of Incomplete Sentences, BNT and CF were impaired (T1, T2, T3) without differences between test-moments. Most spontaneous speech variables did not correlate with standardized tests. Tumor localization and grade had no influence on spontaneous speech. Conclusion Glioma patients showed impaired spontaneous speech combined with naming and fluency deficits. Surgery appeared to have deteriorated the quality of spontaneous speech until long-term but not the performance at test-level. Hence, spontaneous speech has an added value to standardized tests for diagnosis of language impairments.

INTRODUCTION The search for effective therapies for gliomas is progressively moving towards patient-specific medicine. In order to test patient-tailored therapies, it is vital to develop protocols for reliable establishment of patient-derived glioma cultures. We present a method for reliable culture establishment, with a 95% success rate in 114 consecutive high-grade samples. METHODS Cell cultures were established from either traditionally-resected tumor tissue or ultrasonic surgical aspirator (CUSA) derived tissue fragments, and expanded in serum-free culture, with selection of astrocytic populations if required. Cultures were started from single cells or small tumor fragments of 0.5-3mm (3D). Whole exome and RNA sequencing were carried out with the Illumina Novaseq and HiSeq platforms. Methylation profiling was performed with the Infinium MethylationEPIC array. Cultures and tumors were compared through analysis of single nucleotide polymorphisms and copy number profiles with the Infinium Global Screening Array. Intra-tumoral heterogeneity in cultures was investigated with single-cell transcriptomic sequencing (SORT-seq). We studied tumor-initiating potential by orthotopic injection of cultures in NOD-SCID mice. RESULTS Cultures started from single cells were established from CUSA material more efficiently (92%) than from traditional resection material (70%). 3D-derived cultures had a higher overall efficiency (95% for CUSA, 85% for traditional resection material). We confirmed high concordance in driver mutations, copy number and methylation profiles between tumors and derived cultures. Transcriptomics analysis, comparing tumors and derived cultures, revealed high consistency in gene expression distribution as demonstrated by correlation analysis (r=0.88). Singe-cell RNA-seq shows increased heterogeneity in CUSA derived-cultures, and decreased heterogeneity with passaging over time. Cultures faithfully produce tumors after orthotopic injection in NOD-SCID mice. CONCLUSION We present a highly successful method for the establishment of glioma cultures from patient material, with CUSA-derived cultures revealing greater heterogeneity. Cultures faithfully represent important molecular characteristics of parental tumors and can be used to test potential therapies in vitro.

BACKGROUND Neurosurgical practice still relies heavily on pre-operatively acquired images to guide tumor resections, a practice which comes with inherent pitfalls such as registration inaccuracy due to brain shift, and lack of real-time functional or morphological feedback. Here we describe functional Ultrasound (fUS) as a new high-resolution, depth-resolved, MRI/CT-registered imaging technique able to detect functional regions and vascular morphology during awake and anesthesized tumor resections. MATERIALS AND METHODS fUS relies on high-frame-rate (HFR) ultrasound, making the technique sensitive to very small motions caused by vascular dynamics (µDoppler) and allowing measurements of changes in cerebral blood volume (CBV) with micrometer-millisecond precision. This opens up the possibility to 1) detect functional response, as CBV-changes reflect changes in metabolism of activated neurons through neurovascular coupling, and 2) visualize in-vivo vascular morphology of pathological and healthy tissue with high resolution at unprecedented depths. During a range of anesthetized and awake neurosurgical procedures we acquired vascular and functional images of brain and spinal cord using conventional ultrasound probes connected to a research acquisition system. Building on Brainlab’s Intra-Operative Navigation modules, we co-registered our intra-operative Power Doppler Images (PDIs) to patient-registered MRI/CT-data in real-time. RESULTS During meningioma and glioma resections, our co-registered PDIs revealed fUS’ ability to visualize the tumor’s feeding vessels and vascular borders in real-time, with a level of detail unprecedented by conventional MRI-sequences. During awake resections, fUS was able to detect distinct, ESM-confirmed functional areas as activated during conventional motor and language tasks. In all cases, images were acquired with micrometer-millisecond (300 µm, 1.5–2.0 ms) precision at imaging depths exceeding 5 cm. CONCLUSION fUS is a new real-time, high-resolution and depth-resolved imaging technique, combining favorable imaging specifications with characteristics such as mobility and ease of use which are uniquely beneficial for a potential image-guided neurosurgical tool.

BACKGROUND Awake craniotomy with direct electrical stimulation (DES) is the standard treatment for patients with eloquent area gliomas. Language errors (paraphasias) are detected with DES and they indicate functional boundaries that need to be maintained to preserve quality of life. However, it is not fully clear in which brain locations paraphasias at different linguistic modalities and levels (production, comprehension, reading, writing, phonology, semantics, syntax) occur. MATERIALS AND METHODS A systematic review was conducted. We included 102 studies reporting on specific paraphasias and the corresponding brain locations during awake craniotomy with DES in adult glioma patients. RESULTS First, a wide distribution of brain locations for all paraphasias (n=930) was found, but patterns were observed. Cortically, paraphasias occurred most often in the precentral gyrus (22%), while subcortically, they occurred mainly at the inferior fronto-occipital fascicle (IFOF: 10%). Localization patterns for different paraphasia types and the corresponding language functions were also found: production/articulation (n=393)-precentral gyrus (41%), inferior frontal gyrus (9%), frontal aslant/striatal tract (4%), postcentral gyrus (3%); semantics (n=128)-IFOF (57%), superior temporal gyrus (9%); phonology (n=115)-arcuate fascicle (52%), superior longitudinal fascicle (10%), uncinate fascicle (3%); reading (n=25)-temporal lobe (48%), inferior longitudinal fascicle (32%); syntax (n=15)-inferior frontal gyrus (27%); speech initiation (n=9)-supplementary motor area (33%), frontal aslant tract (22%), frontal striatal tract (22%); writing (n=7)-superior parietal gyrus (71%). Second, 59% of all paraphasias occurred cortically, 40% subcortically and 1% at both levels. CONCLUSION The localization of most paraphasias are consistent with the assumed functionality of those brain locations as presented in the Dutch Linguistic Intraoperative Protocol model. However, new locations for production/articulation, phonology, reading and writing were found. This needs to be taken into consideration for future selection of pre, intra and postoperative language tasks at different language modalities and levels. Additionally, DES should always be applied at the subcortical level as a standard addition to the routine cortical mapping during awake craniotomy. In conclusion, this is the first systematic review on the localization of specific paraphasias during awake craniotomy. Based on the identified language localization patterns, language tasks could be selected more accurately. This could guide, and perhaps improve, pre, intra and postoperative language testing and monitoring, which in turn, may pave the way to a better postoperative language outcome. The possible relation between different intraoperative paraphasias and language outcome has yet to be determined.

Recent publications on the molecular characterization of malignant glioma have had profound impact on the appreciation of tumoral heterogeneity within and between patients. Both these phenomena are implicated in the variability in clinical outcome between patients, as well as the inevitable recurrence of these tumors after conventional treatment. The advent of selective cell culture protocols for the propagation of patient-derived glioma stem-like cells (GSCs) provides researchers the ability to selectively study the cells that could be at the root of tumor proliferation and resistance to therapy. As these techniques are widely applied in contemporary studies and becoming the preferred in vitro model, molecular characterization of GSCs is considered pivotal for the identification and advancement of novel therapies for this devastating disease. This review aims to provide an overview of canonical molecular alterations defining subtypes of malignant glioma as derived from genotypic, transcriptomic and epigenetic profiling in relation to their representation in GSC models. The distribution of these hallmark alterations as found in characterization studies of GSCs is compared between publications. Finally, conclusions of these studies with respect to coverage of driving alterations and translational relevance are provided. By doing so, we provide a contemporary overview of scientific results derived from GSC models and hopefully create appreciation of the advantages and caveats of utilizing these models for studying malignant glioma.

Background Surgery for sagittal synostosis aims at correction of skull shape and restoration of growth potential. Small cranial volume is associated with raised intracranial pressure (ICP). Although many techniques have been described, information on postoperative volume related to early and late remodeling is lacking. Methods Between 2004 and 2008, a total of 95 patients were collected who underwent either early extended strip craniectomy or late total cranial remodeling according to age of presentation. Volume was measured on three-dimensional (3D) photogrammetry. Volume measurements were related to cranial index (CI), head circumference (HCsd), and signs of raised ICP. In a small subset of patients, volume measurements on 3D photogrammetry were assessed for inter- and intrarater reliability and compared to 3D computed tomography (CT). Results Volume was increased in all patients before and after surgery compared to normative values. Postoperatively, late total cranial remodeling resulted in a slightly larger volume than early extended strip craniectomy. Volume measurements showed a good correlation with HCsd (0.67) and a poor relationship with CI (0.13). Headache occurred more frequently in patients with a lower cranial volume. Although papilledema and reoperation showed the same trend, the numbers were too small for statistical analysis. Reproducibility of volume measurements on 3D photogrammetry was high, as was the correlation with measurements on CT. Conclusion Late total cranial remodeling results in a larger postoperative volume, as measured on 3D photogrammetry, than extended strip craniectomy. Clinical signs of raised ICP occur more frequently in patients with a smaller volume. To measure volume, 3D photogrammetry is a good alternative to CT.

INTRODUCTION Postponing adjuvant treatment after resection in IDH-mutated low-grade glioma (LGG) seems appropriate in selected patients. Here we describe the clinical course of these patients during post-resection active monitoring with MRI scans, as literature on this topic is scarce. METHODS We included IDH-mutated LGG patients that underwent surgery between 2003–2016, with clinical follow-up including MR scans available. Samples were classified according to the 2016 WHO classification. We collected baseline clinical information, estimates of seizure control during follow-up, longitudinal evolution of post-resection LGG volumes when adjuvant therapy was postponed, and the clinicians’ reasons to either start immediate adjuvant treatment or postpone treatment, and reasons to initiate adjuvant treatment in later stage. We compared patients that underwent immediate postsurgical adjuvant treatment with patients that underwent active MRI monitoring until further progression. RESULTS AND CONCLUSIONS 197 patients were included, of which 108 were IDH-mutated astrocytomas, and 89 were oligodendrogliomas. Of these, 97 patients were actively followed with MRI scans, and 100 patients underwent immediate adjuvant therapy after initial surgery. Patients that received immediate adjuvant therapy were older and had less extensive resections than patients wherein adjuvant treatment was postponed (median age 45 years vs. 37 years, P< 0.001; median postoperative tumor volume 31cm3 vs 2.68cm3, P< 0.001). The duration of the active surveillance period in the patients wherein adjuvant treatment was postponed correlated with the extent of resection, with shorter time until adjuvant treatment in case of larger postoperative tumor volumes. All LGG lesions showed continuous growth during the active surveillance period, with median growth rates of 3mm/year for oligodendrogliomas and 4mm/year in IDH- mutated astrocytomas (P = 0.0093). Seizures were well controlled, with the majority of patients using only one anti-epileptic drug. The majority of patients stayed asymptomatic during follow-up, and the reason to initiate further adjuvant treatment was always radiological growth.

Within a prospective, observational, multi-center cohort study 68 hospitals (of which 66 responded), mostly academic (n = 60,91%) level I trauma centers (n = 44.67%) in 20 countries were asked to complete questionnaires regarding the "standard of care" for severe neurotrauma patients in their hospitals. From the questionnaire pertaining to ICU management, 12 questions related to admission criteria were selected for this analysis. The questionnaires were completed by 66 centers. The median number of TBI patients admitted to the ICU was 92 [interquartile range (IQR): 52-160] annually. Admission policy varied: in 45 (68%) centers, patients with a Glasgow Come Score (GCS) between 13 and 15 without CT abnormalities but with other risk factors would be admitted to the ICU while the rest indicated that they would not admit these patients routinely to the ICU. We found no association between ICU admission policy and the presence of a dedicated neuro ICU, the discipline in charge of rounds, the presence of step down beds or geographic location (North-Western Europe vs. South-Eastern Europe and Israel). Variation in admission policy, primarily of mild TBI patients to ICU exists, even among high-volume academic centers and seems to be largely independent of other center characteristics. The observed variation suggests a role for comparative effectiveness research to investigate the potential benefit and cost-effectiveness of a liberal versus more restrictive admission policies. (C) 2018 Elsevier Inc. All rights reserved.

There is an ongoing debate on the role of corticosteroids in the treatment of chronic subdural hematoma (CSDH). This study aims to evaluate the effectiveness of corticosteroids for the treatment of CSDH compared to surgery. A systematic search was performed in relevant databases up to January 2019 to identify RCTs or observational studies that compared at least two of three treatment modalities: the use of corticosteroids as a monotherapy (C), corticosteroids as an adjunct to surgery (CS), and surgery alone (S). Outcome measures were good neurological outcome, need for reintervention, mortality, and complications. Effect estimates were pooled and presented as relative risk (RR) with 95% confidence interval (95%CI). Of 796 initially identified studies, 7 were included in the meta-analysis. Risk of bias was generally high. There were no differences in good neurological outcome between treatment modalities. The need for reintervention varied between 4 and 58% in C, 4–12% in CS, and 7–26% in S. The need for reintervention was lower in CS compared with C (RR 3.34 [95% CI 1.53–7.29]; p

INTRODUCTION: Despite hundreds of training models for microsurgery being available in the literature, very few of them are scientifically validated. We chose to validate our low-fidelity training model on flower petals by comparing it head-to-head with a moderate fidelity training model, the anastomosis on chicken leg femoral artery. MATERIALS AND METHODS: A total of 16 participants of different levels of expertise were randomized into 2 groups, 1 training on flower petals and 1 on chicken leg femoral arteries. The groups were evaluated on performing a rat femoral artery anastomosis using the validated Stanford Microsurgical Assessment (SMaRT) Scale. The Mann-Whitney U test was used to check for statistically significant differences between the groups. The flower petal sutures were also evaluated and Pearson correlation was used to check for associations between better petal anastomosis scores and better final SMaRT results. RESULTS: After 6 weeks of flower petal training, microsurgical trainees had significantly better overall SMaRT scores than trainees using chicken leg training, better fine tissue feeling, and better scores in knot tying. The anastomosis times for the rat femoral arteries did not differ between the 2 groups. Good scores for flower petals strongly correlated with a better SMaRT score for the anastomosis. The number of rats used in training reduced after the implementation of this model in continuous training. CONCLUSIONS: The flower petal technique, despite being a low-fidelity model, shows superiority in developing fine tissue feeling and improved knot tying in microsurgery beginners and intermediate level practitioners adding this training model to their program. Further research needs to establish if the improvements also apply to already seasoned microsurgeons and whether the petal score has predictive value for future clinical application.

GABAergic fast-spiking parvalbumin-positive (PV) interneurons are frequently myelinated in the cerebral cortex. However, the factors governing the topography of cortical interneuron myelination remain incompletely understood. Here, we report that segmental myelination along neocortical interneuron axons is strongly predicted by the joint combination of interbranch distance and local axon caliber. Enlargement of PV+ interneurons increased axonal myelination, while reduced cell size led to decreased myelination. Next, we considered regular-spiking SOM+ cells, which normally have relatively shorter interbranch distances and thinner axon diameters than PV+ cells, and are rarely myelinated. Consistent with the importance of axonal morphology for guiding interneuron myelination, enlargement of SOM+ cell size dramatically increased the frequency of myelinated axonal segments. Lastly, we confirm that these findings also extend to human neocortex by quantifying interneuron axonal myelination from ex vivo surgical tissue. Together, these findings establish a predictive model of neocortical GABAergic interneuron myelination determined by local axonal morphology.

Background Migraine is associated with activation of the trigeminovascular system, release of calcitonin gene-related peptide (CGRP) and dilation of dural arteries. Novel treatments target calcitonin gene-related peptide or its receptor, which are present in all vascular beds, raising cardiovascular concerns. Erenumab is a human CGRP-receptor antibody approved for the prophylactic treatment of migraine. Methods We characterised the relaxant responses to CGRP in the absence and presence of erenumab (1 μM) in isolated human middle meningeal, internal mammary and (proximal and distal) coronary arteries. Furthermore, in human internal mammary arteries from cardiovascularly-compromised patients, we assessed the pharmacological specificity of erenumab by investigating whether the vasodilatory responses to acetylcholine, sodium nitroprusside, pituitary adenylate cyclase activating polypeptide-38 (PACAP), vasoactive intestinal peptide and nicardipine, along with the vasoconstrictor responses to dihydroergotamine, were modified by erenumab. Results Calcitonin gene-related peptide induced concentration-dependent vasodilatory responses in all vessels studied that were significantly antagonised by erenumab. In human internal mammary arteries from cardiovascularly-compromised patients, the responses to acetylcholine, sodium nitroprusside, PACAP, vasoactive intestinal peptide, nicardipine and dihydroergotamine were unaffected by erenumab. Conclusion Erenumab inhibits calcitonin gene-related peptide-induced vasodilatory responses in human middle meningeal arteries, human internal mammary arteries and human coronary arteries. Moreover, erenumab shows functional specificity as no interaction was observed with the relaxant responses to several vasodilators, nor the dihydroergotamine-dependent vasoconstrictor responses.