Treatment of glioblastoma (GBM) remains a challenging task, with limited treatment options, none offering a cure. Immune therapy has proven effective across different cancers with remarkable response rates. Tumor mutational burden (TMB) is a marker of response, but technical and methodological differences in TMB estimates have made a proper assessment and comparison challenging. Here, we analyzed a prospective collection of paired samples from 35 patients with newly diagnosed GBM, all of whom were wild-type (WT) for isocitrate dehydrogenase, before and after treatment with radiotherapy and temozolomide. Seven patients (20%) had O6-methylguanine-DNA methyltransferase-methylated tumors. Six patients (17%) had two relapse surgeries, and tissue from all three surgeries was collected. We found that accurate evaluation of TMB was confounded by high variability in the cancer cell fraction of relapse samples. To ameliorate this, we developed a model to adjust for tumor purity based on the relative density distribution of variant allele frequencies in each primary-relapse pair. Additionally, we examined the mutation spectra of shared and private mutations. After tumor purity adjustment, we found TMB comparison reliable in tumors with tumor purity between 15% and 40%, resulting in 27/35 patients (77.1%). TMB remained unchanged from 0.65 mutations per megabase (Mb) to 0.67/Mb before and after treatment, respectively. Examination of the mutation spectra revealed a dominance of C > T transitions at CpG sites in both shared and relapse-private mutations, consistent with cytosine deamination and the clock-like mutational signature 1. We present and apply a cellularity correction approach that enables more accurate assessment of TMB in paired tumor samples. We did not find a significant increase in TMB after correcting for cancer cell fraction. Our study raises significant concerns when determining TMB. Although a small sample size, corrected TMB can have a clinical significance when stratifying patients to experimental treatment, for example, immune checkpoint therapy.

Aim: This is a long-term open follow-up of a prospective double-blind crossover study, where electrodes were bilaterally implanted in both the Subthalamic nucleus (STN) and internal pallidum (GPi) in patients with isolated dystonia. Methods: Patients with isolated dystonia were included to undergo surgery with Deep Brain stimulation (DBS) and after randomization, in a double-blind cross-over study, receiving bilateral stimulation of either STN or GPi for 6 months in each target. Preoperative and postoperative assessments with the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the 36-item Short Form Health Survey (SF-36) were performed. In this long-term follow-up (LFU), these ratings were repeated, and patients were evaluated with cognitive tests. Results: 21 patients were included in the protocol, 9 patients with generalized dystonia, 12 with a diagnosis of cervical dystonia. The mean duration of disease was 19.3 years, age at time of surgery 50.1 years. Fourteen patients participated in the LFU. At a mean follow-up of 10.2 years (range 4.8-15.4), BFMDRS movement score was improved with a mean of 36% (p < 0.05) compared with baseline. At LFU both a statistically significant improvement of stimulation in STN on BFMDRS movement score (p = 0.029) and Gpi (p = 0.008) was demonstrated, no significant difference was found between the two targets (p = 0.076). SF-36 improved for both targets. Conclusion: In this study we performed a long-term follow-up in 14 patients with cervical or generalized dystonia, who received stimulation in GPi, STN or both. The mean follow-up time was more than 10 years. Our data support a long-term effect of both STN-DBS and GPi-DBS in dystonia with equal effect and safety for up to 15 years. STN has been proven a viable safe and effective target and may be used as an alternative to GPi in both adult-onset cervical dystonia and generalized dystonia.

We describe an ethical framework for the surgical treatment of brain tumour patients, specifically for the treating surgeon, the researcher, and with a special emphasis on end-of-life decision making. Different ethical axes are systematically described, integrated and illustrated with case discussions.

Glioblastoma cancer-stem like cells (GSCs) display marked resistance to ionizing radiation (IR), a standard of care for glioblastoma patients. Mechanisms underpinning radio-resistance of GSCs remain largely unknown. Chromatin state and the accessibility of DNA lesions to DNA repair machineries are crucial for the maintenance of genomic stability. Understanding the functional impact of chromatin remodeling on DNA repair in GSCs may lay the foundation for advancing the efficacy of radio-sensitizing therapies. Here, we present the results of a high-content siRNA microscopy screen, revealing the transcriptional elongation factor SPT6 to be critical for the genomic stability and self-renewal of GSCs. Mechanistically, SPT6 transcriptionally up-regulates BRCA1 and thereby drives an error-free DNA repair in GSCs. SPT6 loss impairs the self-renewal, genomic stability and tumor initiating capacity of GSCs. Collectively, our results provide mechanistic insights into how SPT6 regulates DNA repair and identify SPT6 as a putative therapeutic target in glioblastoma.

Background: It is well established that patients with glioma may experience adverse general (eg, headache) or focal symptoms (eg, personality changes) and neurocognitive deficits (eg, planning), but they may also experience severe emotional distress. We investigated the prevalence of depressive symptoms in patients with newly diagnosed glioma and in matched cancer-free persons. Methods: For this study, we recruited patients with glioma diagnosed within 12 months at all 4 neurosurgical clinics in Denmark. The cancer-free comparison group was identified through the Danish Central Person Register and matched on sex and age. Participants’ depressive symptoms were evaluated using the Center for Epidemiologic Studies Depression Scale (CES-D; score range, 0–60), with a cutoff score ≥16 indicating moderate-to-severe depressive symptoms. Results: In this study, 363 of 554 patients with glioma and 481 of 1,304 cancer-free persons participated. Mean age of all patients was 55 years and 60% of the population was male. Mean scores for depressive symptoms were statistically significantly higher among patients with glioma, with a mean CES-D score of 10.9 (95% CI, 10.1–11.8) compared with 5.3 (95% CI, 4.7–5.8) among cancer-free persons ( P <.0001). Overall, 92 patients with glioma (25%) and 30 cancer-free persons (6%) had moderate-to-severe depressive symptoms. After adjustment for marital status, education level, and comorbidity, the prevalence of depressive symptoms was 5 times higher among patients with glioma compared with cancer-free persons. Conclusions: A substantially higher prevalence of moderate-to-severe depressive symptoms was identified in patients with glioma compared with cancer-free persons. This indicates the importance of programs to systematically identify and manage depressive symptoms in patients with glioma.

Background The COVID-19 pandemic confronts healthcare workers, including neurosurgeons, with difficult choices regarding which patients to treat. Methods In order to assist ethical triage, this article gives an overview of the main considerations and ethical principles relevant when allocating resources in times of scarcity. Results We discuss a framework employing four principles: prioritizing the worst off, maximizing benefits, treating patients equally, and promoting instrumental value. We furthermore discuss the role of age and comorbidity in triage and highlight some principles that may seem intuitive but should not form a basis for triage. Conclusions This overview is presented on behalf of the European Association of Neurosurgical Societies and can be used as a toolkit for neurosurgeons faced with ethical dilemmas when triaging patients in times of scarcity.

Glioblastoma (GBM) is an incurable brain tumor for which new treatment strategies are urgently needed. Next‐generation sequencing of GBM has most often been performed retrospectively and on archival tissue from both diagnostic and relapse surgeries with limited knowledge of clinical information, including treatment given. We sought to investigate the genomic composition prospectively in treatment‐naïve patients, searched for possible targetable aberrations, and investigated for prognostic and/or predictive factors. A total of 108 newly diagnosed GBM patients were included. Clinical information, progression‐free survival, and overall survival (OS) were noted. Tissues were analyzed by whole‐exome sequencing, single nucleotide polymorphism (SNP) and transcriptome arrays, and RNA sequencing; assessed for mutations, fusions, tumor mutational burden (TMB), and chromosomal instability (CI); and classified into GBM subgroups. Each genomic report was discussed at a multidisciplinary tumor board meeting to evaluate for matching trials. From 111 consecutive patients, 97.3% accepted inclusion in this study. Eighty‐six (77%) were treated with radiation therapy/temozolomide (TMZ) and adjuvant TMZ. One NTRK2 and three FGFR3‐TACC3 fusions were identified. Copy number alterations in GRB2 and SMYD4 were significantly correlated with worse median OS together with known clinical variables like age, performance status, steroid dose, and O6‐methyl‐guanine‐DNA‐methyl‐transferase status. Patients with CI‐median or TMB‐high had significantly worse median OS compared to CI‐low/high or TMB‐low/median. In conclusion, performing genomic profiling at diagnosis enables evaluation of genomic‐driven therapy at the first progression. Furthermore, TMB‐high or CI‐median patients had worse median OS, which can support the possibility of offering experimental treatment already at the first line for this group.

To date, source imaging (SI) has been performed using epileptiform discharges (ED) detected by magnetoencephalography (MEG) or electroencephalography (EEG). A few case studies has combined MEG and EEG recordings and performed electromagnetic source imaging (cEMSI). This study tries to elucidate the role of cEMSI in presurgical evaluation. A MEG whole-head 306-channel Elekta Neuromag® system, and simultaneous high density EEG (70 electrodes, range 58–80) using a non-magnetic cap (EASYCAP) were recorded in 141 consecutive patients. Fifty patients were operated and had one year follow up. MEG-EEG was inspected for EDs. Signals were analyzed using CURRY 7 Neuroimaging Suite. For each cluster, using the visually detected EDs as templates, automated algorithms scanned the recordings, and detected EDs were visually checked. To improve the signal-to-noise ratio, EDs with similar topography were averaged. Two different inverse solutions were applied: equivalent current dipole (ECD) and a distributed source model (DSM): sLORETA. We performed electric SI, magnetic SI, and cEMSI. All analyses were performed using individual head models from the patients’ MRIs. We calculated the odds ratio (OR) of becoming seizure-free when operation was concordant vs discordant with the localization of the SI. Combining both EEG and MEG signals (cEMSI) gave an OR of 5.8 for ECD and 19.2 for DSM. OR of cEMSI using DSM was significantly higher than both ESI (p = 0.02) and MSI (p = 0.03). Combined EMSI achieved significantly higher odds ratio for becoming seizure-free compared to electric SI and magnetic SI.

Introduction There is a lack of high-quality prospective, systematic studies using independent assessors of outcome of microvascular decompression as treatment for trigeminal neuralgia. Methods Clinical characteristics and outcome data were recorded prospectively from consecutive classical trigeminal neuralgia patients, using standardized interviews. Degree of neurovascular contact was evaluated by a 3.0 Tesla MRI blinded to symptomatic side. Patients were assessed before and 12 months after surgery by a neurologist. Results Twenty-six men and 33 women completed 12 months follow-up. Forty-one patients (69%) had an excellent outcome (no pain, no medication). Ten (18%) patients had a good outcome. Eight (12%) patients had no improvement or had worsening of pain. MRI showed neurovascular contact with morphological changes in 34 patients (58%). Odds ratio between neurovascular contact with morphological changes and excellent outcome was 4.4 (Cl 1.16-16.26), p=0.029. Odds ratio between male sex and excellent outcome was 11.38 (Cl 2.12-59.52), p=0.004. No significant association was found between excellent outcome and concomitant persistent pain, current age or disease duration. Conclusion Neurovascular contact with morphological changes and male sex are positive predictive factors for outcome of microvascular decompression. The findings enable clinicians to better inform patients before surgery.

Background: Glioblastoma (GB) is an incurable brain cancer with limited treatment options. The aim was to test the feasibility of using cell-free DNA (cfDNA) to support evaluation of treatment response, pseudo-progression and whether progression could be found before clinical and/or radiologic progression. Results: CfDNA fluctuated during treatment with the highest levels before diagnostic surgery and at progression. An increase was seen in 3 out of 4 patients at the time of progression while no increase was seen in 3 out of 4 patients without progression. CfDNA levels could aid in 3 out of 3 questionable cases of pseudo-progression. Methods: Eight newly diagnosed GB patients were included. Blood samples were collected prior to diagnosis, before start and during oncologic treatment until progression. Seven patients received concurrent radiotherapy/Temozolomide with adjuvant Temozolomide with one of the patients included in a clinical trial with either immunotherapy or placebo as add-on. One patient received radiation alone. CfDNA concentration was determined for each blood sample. Conclusions: It was feasible to measure cfDNA concentration. Despite the limited cohort size, there was a good tendency between cfDNA and treatment course and -response, respectively with the highest levels at progression.

BackgroundPrognosis of medically treated trigeminal neuralgia patients is assumed to be poor, but the evidence is lacking. Thus, prospective real-life studies of medical management of trigeminal neuralgia are warranted.MethodsThis was an observational study. Patients were consecutively enrolled in a structured management program at a specialist centre for facial pain. Optimisation of medical treatment, physiotherapy, psychotherapy, and advice from trained nurses, were parts of the program. Medically intractable patients were referred for neurosurgery. Data-collection was prospective using standardised schemes and patient surveys. The aim was to describe the two-year outcome of medical treatment at the specialist centre. The primary outcome was a 50% reduction in the overall burden of pain according to a Numerical Rating Scale (NRS) after two years.ResultsA total of 186 primary TN patients were enrolled in the program of which 103 patients remained medically managed and completed the two-year follow-up. Fifty patients were treated surgically within the first two years of follow-up. Half of the medically managed patients (53 (51%)), had more than a 50% reduction in the overall burden of pain over the two-year period. The overall burden of pain on NRS decreased from mean 5.34 to 3.00, p<0.01. There was no significant association between primary outcome and sex, depression and/or anxiety, concomitant persistent pain, or neurovascular contact with morphological changes of the trigeminal nerve.ConclusionsPatients with trigeminal neuralgia improve over a two-year period when enrolled in a structured medical management program. Optimisation of drug treatment, continuous advice and education and support by the multidisciplinary team, referral of the medically intractable patients for surgery or the natural history of the disease, can be some of the reasons for the improvement. The favourable prognosis provides hope and optimism for medically managed TN patients.Trial registrationCurrent study was observational, and patients were offered standard clinical care and laboratory workups according to current American Academy of Neurology and European Federation of Neurological Societies treatment guidelines. The study has been registered at ClincalTrials.gov. ID: NCT03838393.

Objective To determine the diagnostic accuracy and clinical utility of electromagnetic source imaging (EMSI) in presurgical evaluation of patients with epilepsy. Methods We prospectively recorded magnetoencephalography (MEG) simultaneously with EEG and performed EMSI, comprising electric source imaging, magnetic source imaging, and analysis of combined MEG-EEG datasets, using 2 different software packages. As reference standard for irritative zone (IZ) and seizure onset zone (SOZ), we used intracranial recordings and for localization accuracy, outcome 1 year after operation. Results We included 141 consecutive patients. EMSI showed localized epileptiform discharges in 94 patients (67%). Most of the epileptiform discharge clusters (72%) were identified by both modalities, 15% only by EEG, and 14% only by MEG. Agreement was substantial between inverse solutions and moderate between software packages. EMSI provided new information that changed the management plan in 34% of the patients, and these changes were useful in 80%. Depending on the method, EMSI had a concordance of 53% to 89% with IZ and 35% to 73% with SOZ. Localization accuracy of EMSI was between 44% and 57%, which was not significantly different from MRI (49%-76%) and PET (54%-85%). Combined EMSI achieved significantly higher odds ratio compared to electric source imaging and magnetic source imaging. Conclusion EMSI has accuracy similar to established imaging methods and provides clinically useful, new information in 34% of the patients. Classification of evidence This study provides Class IV evidence that EMSI had a concordance of 53%-89% and 35%-73% (depending on analysis) for the localization of epileptic focus as compared with intracranial recordings-IZ and SOZ, respectively.

Background and purposeAccurate localization of the epileptic focus is essential for surgical treatment of patients with drug‐resistant epilepsy. Electric source imaging (ESI) is increasingly used in pre‐surgical evaluation. However, most previous studies have analysed interictal (II) discharges. Prospective studies comparing the feasibility and accuracy of II and ictal (IC) ESI are lacking.MethodsWe prospectively analysed long‐term video‐electroencephalography recordings (LTM) of patients admitted for pre‐surgical evaluation. We performed ESI of II and IC signals using two methods, i.e. equivalent current dipole (ECD) and a distributed source model (DSM). LTM recordings employed the standard 25‐electrode array (including inferior temporal electrodes). An age‐matched template head model was used for source analysis. Results were compared with intracranial recordings, conventional neuroimaging methods [magnetic resonance imaging (MRI), positron emission tomography (PET), single‐photon emission computed tomography (SPECT)] and outcome at 1 year after surgery.ResultsA total of 87 consecutive patients were analysed. ECD gave a significantly higher proportion of patients with localized focal abnormalities (94%) compared with MRI (70%), PET (66%) and SPECT (64%). Agreement between the ESI methods and intracranial recording was moderate to substantial (k = 0.56–0.79). A total of 54 patients were operated (47 patients more than 1 year ago) and 62% of them became seizure‐free. The localization accuracy of II‐ESI was 51% for DSM and 57% for ECD, and that for IC‐ESI was 51% for DSM and 62% for ECD. The differences between the ESI methods were not significant. Differences in localization accuracy between ESI and MRI (55%), PET (33%) and SPECT (40%) were not significant.ConclusionsThe II‐ESI and IC‐ESI of LTM data have high feasibility and their localization accuracy is similar to that of conventional neuroimaging methods.

Tumor mutational load (TML) is the number of nonsynonymous mutations in a tumor sample. TML has proved predictive of response to immune therapy (IT) in other TML-high tumors. Research in TML in glioblastoma (GBM) is limited and has to our knowledge not been done prospectively in paired samples before and after treatment. Over a 2-year period from February 2016 to March 2018, 27 patients with newly diagnosed GBM were included. All patients had one biopsy at diagnosis and another when having secondary surgery due to progression. Three patients had three surgeries. We noted clinical and pathological data. Blood samples were extracted and whole exome sequencing has been performed. We are now investigating TML including clonal and subclonal mutations, mutations in mismatch repair genes and the aberrant cell fraction. TML will be reported as per Megabase exome and will be adjusted for coverage in each sample. All the included patients had primary GBM with isocitrate dehydrogenase (IDH) wild type. O-6-methylguanine-DNA methyltransferase (MGMT) was methylated in 6 patients (22%) and the majority of patients have been treated with chemo/radiation with Temozolomide. Since the patients were included from our daily clinical oncological department, the clinical characteristics resembled the average GBM patient according to age, performance status, treatment, progression-free survival and overall survival. Analyses are forthgoing and will be ready at the time of the SNO-meeting. An agreement of how to report TML is strongly needed and TML should be included in future trials in GBM.

Surgery is the only treatment option with the potential to cure epilepsy. This review is a description of the multidisciplinary and multimodal presurgical evaluation process and the outcome of the Danish epilepsy surgery programme. The outcome aligns with international results and serious complications to surgery are very rare. The annual number of operations per capita compares to neighbouring countries and is equally distributed across Denmark. In accordance with international recommendations, Danish drug-resistant patients should be referred to epilepsy surgery evaluation at an early stage of the disease.

Glioblastoma (GBM) ranks among the most lethal cancers, with current therapies offering only palliation. Inter‐ and intrapatient heterogeneity is a hallmark of GBM, with epigenetically distinct cancer stem‐like cells (CSCs) at the apex. Targeting GSCs remains a challenging task because of their unique biology, resemblance to normal neural stem/progenitor cells, and resistance to standard cytotoxic therapy. Here, we find that the chromatin regulator, JmjC domain histone H3K36me2/me1 demethylase KDM2B, is highly expressed in glioblastoma surgical specimens compared to normal brain. Targeting KDM2B function genetically or pharmacologically impaired the survival of patient‐derived primary glioblastoma cells through the induction of DNA damage and apoptosis, sensitizing them to chemotherapy. KDM2B loss decreased the GSC pool, which was potentiated by coadministration of chemotherapy. Collectively, our results demonstrate KDM2B is crucial for glioblastoma maintenance, with inhibition causing loss of GSC survival, genomic stability, and chemoresistance.

The greatest challenge in epilepsy surgery lies in the presurgical evaluation. On their own, none of the diagnostic methods can identify the epileptogenic zone. Therefore, a multimodal approach is used. Over the last decades, advances in recording techniques and in signal analysis made it possible to estimate the source of the epileptiform discharges recorded by electroencephalography (EEG source imaging: ESI) and magnetoencephalography (MEG source imaging: MSI). This prospective study investigates the role of electromagnetic source imaging (EMSI) as a non-invasive tool to guide the multidisciplinary epilepsy surgery team. MEG (306 channels) and simultaneous high-density EEG was recorded in 85 consecutive patients with refractory focal epilepsy, referred for conventional non-invasive presurgical evaluation. EMSI, comprising of electric, magnetic source imaging and analysis of combined MEG-EEG datasets, using commercially available software (BESA and CURRY) was used. The Danish epilepsy surgery team evaluated the patients first blinded to EMSI and then including the data from EMSI. At both sessions the multidisciplinary team (MDT) determined the presumed localisation of the epileptogenic zone and decided on location of surgery, intracranial registration (ICR) placement, or not offering epilepsy surgery. The clinical utility of EMSI was defined as the proportion of patients in whom EMSI changed the decision of the MDT. A change was defined useful as follows: (a) change from stop to ICR: the ICR localized the source; (b) change in implantation strategy: the electrode(s) implanted based on the EMSI identified the source; and (c) change from implantation to operation: the patient became seizure-free. The impact of EMSI on patient management-plan was assessed in 85 patients (50 men) in whom EMSI was part of the decision-making process. The age of these patients was between 10 and 70 years (median: 32 years). Thirty-eight patients were MRI negative; in the remaining patients, there were discordance between MRI and data from long-term video-EEG monitoring (semiology and EEG). EMSI changed the management plan in 28/85 patients (33%). For 16.5% (14/85) of the patients the ICR plan changed (additional structures were implanted). For 7% (6/85) of the patients, in whom neither operation nor ICR was suggested, after discussing the EMSI results, ICR was offered. For 9.4% (8/85) of the patients ICR was suggested prior to EMSI; after EMSI these patients skipped ICR and went directly to operation. Finally, for one patient it was decided not to offer operation, after discussing the EMSI. At one-year follow-up 80% (16/20) of these changes proved to be useful, meaning that the EMSI changes located the seizure onset zone, irritative zone or the patient became seizure free. Electromagnetic source imagening provides clinically relevant information that supplements the decision-making process in presurgery evaluation for epilepsy surgery.