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The current study addresses the question of whether the resection of more than one BM by multiple craniotomies within the same operation is associated with more adverse events (AEs) and worse functional outcome compared to cases in which only one BM was resected. All patients who underwent more than one craniotomy for resection of multiple BM at two Swiss tertiary neurosurgical care centers were included. Any AEs, functional outcome, and overall survival (OS) were analyzed after 1:1 propensity score matching with patients who underwent removal of a single BM only. A total of 94 patients were included in the final study cohort (47 of whom underwent multiple craniotomies). There was no significant difference in the incidence of AEs between the single and the multiple craniotomy group (n = 2 (4.3%) vs. n = 4 (8.5%), p = .7). Change in modified Rankin Scale (mRS) and Karnofsky Performance Status (KPS) at discharge demonstrated that slightly more single craniotomy patients improved in mRS, while the proportion of patients who worsened in mRS (16.3 vs. 16.7%) and KPS (13.6 vs. 15.2%) was similar in both groups (p = .42 for mRS and p = .92 for KPS). Survival analysis showed no significant differences in OS between patients with single and multiple craniotomies (p = .18). Resection of multiple BM with more than one craniotomy may be considered a safe option without increased AEs or worse functional outcome., (© 2024. The Author(s).)

Background: Advancements in metastatic breast cancer (BC) treatment have enhanced overall survival (OS), leading to increased rates of brain metastases (BM). This study analyzes the association between microsurgical tumor reduction and OS in patients with BCBM, considering tumor molecular subtypes and perioperative treatment approaches., Methods: Retrospective analysis of surgically treated patients with BCBM from two tertiary brain tumor Swiss centers. The association of extent of resection (EOR), gross-total resection (GTR) achievement, and postoperative residual tumor volume (RV) with OS and intracranial progression-free survival (IC-PFS) was evaluated using Cox proportional hazard model., Results: 101 patients were included in the final analysis, most patients (38%) exhibited HER2-/HR + BC molecular subtype, followed by HER2 + /HR + (25%), HER2-/HR- (21%), and HER2 + /HR- subtypes (13%). The majority received postoperative systemic treatment (75%) and radiotherapy (84%). Median OS and intracranial PFS were 22 and 8 months, respectively. The mean pre-surgery intracranial tumor volume was 26 cm 3 , reduced to 3 cm 3 post-surgery. EOR, GTR achievement and RV were not significantly associated with OS or IC-PFS, but higher EOR and lower RV correlated with extended OS in patients without extracranial metastases. HER2-positive tumor status was associated with longer OS, extracranial metastases at BM diagnosis and symptomatic lesions with shorter OS and IC-PFS., Conclusions: Our study found that BC molecular subtypes, extracranial disease status, and BM-related symptoms were associated with OS in surgically treated patients with BCBM. Additionally, while extensive resection to minimize residual tumor volume did not significantly affect OS across the entire cohort, it appeared beneficial for patients without extracranial metastases., (© 2024. The Author(s).)

Glioma contains malignant cells in diverse states. Here, we combine spatial transcriptomics, spatial proteomics, and computational approaches to define glioma cellular states and uncover their organization. We find three prominent modes of organization. First, gliomas are composed of small local environments, each typically enriched with one major cellular state. Second, specific pairs of states preferentially reside in proximity across multiple scales. This pairing of states is consistent across tumors. Third, these pairwise interactions collectively define a global architecture composed of five layers. Hypoxia appears to drive the layers, as it is associated with a long-range organization that includes all cancer cell states. Accordingly, tumor regions distant from any hypoxic/necrotic foci and tumors that lack hypoxia such as low-grade IDH-mutant glioma are less organized. In summary, we provide a conceptual framework for the organization of cellular states in glioma, highlighting hypoxia as a long-range tissue organizer., Competing Interests: Declaration of interests I.T. is an advisory board member of Immunitas Therapeutics. M.L.S. is an equity holder, scientific co-founder, and advisory board member of Immunitas Therapeutics. Abcam provided carrier-free antibodies for CODEX experiments (to R.H.)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: During intraoperative neurophysiological monitoring in neurosurgery, brain electrodes are placed to record electrocorticography or to inject current for direct cortical stimulation. A low impedance electrode may improve signal quality., Areas Covered: We review here a brain electrode (WISE Cortical Strip, WCS®), where a thin polymer strip embeds platinum nanoparticles to create conductive electrode contacts. The low impedance contacts enable a high signal-to-noise ratio, allowing for better detection of small signals such as high-frequency oscillations (HFO). The softness of the WCS may hinder sliding the electrode under the dura or advancing it to deeper structures as the hippocampus but assures conformability with the cortex even in the resection cavity. We provide an extensive review on WCS including a market overview, an introduction to the device (mechanistics, cost aspects, performance standards, safety and contraindications) and an overview of the available pre- and post-approval data., Expert Opinion: The WCS improves signal detection by lower impedance and better conformability to the cortex. The higher signal-to-noise ratio improves the detection of challenging signals. The softness of the electrode may be a disadvantage in some applications and an advantage in others.

Pituitary apoplexy (PA) may be complicated by development of subarachnoid hemorrhage (SAH). We conducted a literature review to evaluate the rate of PA-associated tumor rupture and SAH. We conducted a systematic literature search (PubMed, Web of Science, Medline) for patients with PA-associated SAH and report a case SAH following PA. Suitable articles, case series, and case reports were selected based on predefined criteria following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). We reviewed included publications for clinical, radiological, surgical, and histopathological parameters.We present the case of a patient with PA developing extensive SAH whilst on the MRI who underwent delayed transsphenoidal resection. According to our literature review, we found 55 patients with a median age of 46 years; 18 (32.7%) were female. Factors associated with PA-related SAH were hypertension, diabetes mellitus, prior trauma, anticoagulant, and/or antiplatelet therapy. The most common presenting symptoms included severe headache, nausea and/or vomiting, impaired consciousness, and meningeal irritation. Acute onset was described in almost all patients. Twenty-two of the included patients underwent resection. In patients with available outcome, 45.1% had a favorable outcome, 10 (19.6%) had persisting focal neurological deficits, 7 developed cerebral vasospasms (12.7%), and 18 (35.3%) died. Mortality greatly differed between surgically (9.1%) and non-surgically (44.8%) treated patients. PA-associated SAH is a rare condition developing predominantly in males with previously unknown macroadenomas. Timely surgery often prevents aggravation or development of severe neuro-ophthalmological defects and improves clinical outcome., (© 2023. Fondazione Società Italiana di Neurologia.)

T cell recognition of human leukocyte antigen (HLA)-presented tumor-associated peptides is central for cancer immune surveillance. Mass spectrometry (MS)-based immunopeptidomics represents the only unbiased method for the direct identification and characterization of naturally presented tumor-associated peptides, a key prerequisite for the development of T cell-based immunotherapies. This study reports on the implementation of ion mobility separation-based time-of-flight (TOF IMS ) MS for next-generation immunopeptidomics, enabling high-speed and sensitive detection of HLA-presented peptides. Applying TOF IMS -based immunopeptidomics, a novel extensive benign TOFIMS dataset was generated from 94 primary benign samples of solid tissue and hematological origin, which enabled the expansion of benign reference immunopeptidome databases with > 150,000 HLA-presented peptides, the refinement of previously described tumor antigens, as well as the identification of frequently presented self antigens and not yet described tumor antigens comprising low abundant mutation-derived neoepitopes that might serve as targets for future cancer immunotherapy development., (© 2023. The Author(s).)

Purpose: The selection of patients for further therapy after meningioma surgery remains a challenge. Progress has been made in this setting in selecting patients that are more likely to have an aggressive disease course by using molecular tests such as gene panel sequencing and DNA methylation profiling. The aim of this study was to create a preselection tool warranting further molecular work-up., Methods: All patients undergoing surgery for resection or biopsy of a cranial meningioma from January 2013 until December 2018 at the University Hospital Zurich with available tumor histology were included. Various prospectively collected clinical, radiological, histological and immunohistochemical variables were analyzed and used to train a logistic regression model to predict tumor recurrence or progression. Regression coefficients were used to generate a scoring system grading every patient into low, intermediate, and high-risk group for tumor progression or recurrence., Results: Out of a total of 13 variables preselected for this study, previous meningioma surgery, Simpson grade, progesterone receptor staining as well as presence of necrosis and patternless growth on histopathological analysis of 378 patients were included into the final model. Discrimination showed an AUC of 0.81 (95% CI 0.73 - 0.88), the model was well-calibrated. Recurrence-free survival was significantly decreased in patients in intermediate and high-risk score groups (p-value < 0.001)., Conclusion: The proposed prediction model showed good discrimination and calibration. This prediction model is based on easily obtainable information and can be used as an adjunct for patient selection for further molecular work-up in a tertiary hospital setting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Padevit, Vasella, Friedman, Mutschler, Jenkins, Held, Rushing, Wirsching, Weller, Regli and Neidert.)

Objective: Epileptic fast ripple oscillations (FR, 250-500 Hz) indicate epileptogenic tissue with high specificity. However, their low amplitude makes detection demanding against noise. Since thermal noise is reduced by low impedance electrodes (LoZ), we investigate here whether this noise reduction is relevant in the FR frequency range., Methods: We analyzed intracranial electrocorticography during neurosurgery of 10 patients where a low impedance electrode was compared to a standard electrode (HiZ) with equal surface area during stimulation of the somatosensory evoked potential, which evokes a robust response in the FR frequency range. To estimate the noise level, we computed the difference between sweep 2n and sweep 2n + 1 for all sweeps., Results: The power spectral density of the noise spectrum improved for the LoZ over all frequencies. In the FR range, the median noise level improved from HiZ (0.153 µV) to LoZ (0.089 µV). For evoked FR, the detection rate improved (91% for HiZ vs. 100% for LoZ)., Conclusions: Low impedance electrodes for intracranial EEG reduce noise in the FR frequency range and may thereby improve FR detection., Significance: Improving the measurement chain may enhance the diagnostic value of FR as biomarkers for epileptogenic tissue., Competing Interests: Competing interests JS is member of the inomed scientific advisory board and has received speaker fees for giving presentations at inomed in-house courses on IONM. MCN has received a research grant from Novocure, honoraria for consulting or lectures from Novocure and MSD. MCN has reviewed documentation for WISE and his institution has received research funds from WISE Srl., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Treatment with the alkylating agent temozolomide is known to be prognostically beneficial in a subset of glioblastoma patients. Response to such chemotherapeutic treatment and the prognostic benefit have been linked to the methylation status of O 6 -methylguanine-DNA methyltransferase (MGMT). To date, it has not been entirely resolved which methylation pattern of MGMT is most relevant to predict response to temozolomide treatment and outcome. In this retrospective study, we compared the methylation patterns, analyzed by Sanger sequencing, of 27 isocitrate dehydrogenase (IDH)-wildtype glioblastoma patients that survived more than 3 years (long-term survivors) with those of 24 patients who survived less than a year after initial surgery (short-term survivors). Random Forest-, Correlation-, and ROC-curve analyses were performed. The data showed that MGMT is typically methylated in long-term survivors, whereas no prominent methylation is observed in short-term survivors. The methylation status of CpGs, especially in the promoter and exon1/enhancer region correlated highly with outcome. In addition, age and temozolomide treatment were strongly associated with overall survival. Some CpGs in the enhancer region, in particular CpG 86 (bp + 154), demonstrated high values associated with overall survival in the Random Forest analysis. Our data confirm previously published prognostic factors in IDH-wildtype glioblastoma patients, including age and temozolomide treatment as well as the global MGMT methylation status. The area frequently used for decision making to administer temozolomide at the end of exon1 of MGMT, was associated with outcome. However, our data also suggest that the enhancer region, especially CpG 86 (bp + 154) is of strong prognostic value. Therefore, we propose further investigation of the enhancer region in a large prospective study in order to confirm our findings, which might result in an optimized prediction of survival in glioblastoma patients, likely linked to response to temozolomide treatment., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Meningiomas are the most common primary intracranial tumors. Although most symptomatic cases can be managed by surgery and/or radiotherapy, a relevant number of patients experience an unfavorable clinical course and additional treatment options are needed. As meningiomas are often perfused by dural branches of the external carotid artery, which is located outside the blood-brain barrier, they might be an accessible target for immunotherapy. However, the landscape of naturally presented tumor antigens in meningioma is unknown. We here provide a T-cell antigen atlas for meningioma by in-depth profiling of the naturally presented immunopeptidome using LC-MS/MS. Candidate target antigens were selected based on a comparative approach using an extensive immunopeptidome data set of normal tissues. Meningioma-exclusive antigens for HLA class I and II are described here for the first time. Top-ranking targets were further functionally characterized by showing their immunogenicity through in vitro T-cell priming assays. Thus, we provide an atlas of meningioma T-cell antigens which will be publicly available for further research. In addition, we have identified novel actionable targets that warrant further investigation as an immunotherapy option for meningioma., (© 2023. The Author(s).)

Microbial organisms have key roles in numerous physiological processes in the human body and have recently been shown to modify the response to immune checkpoint inhibitors 1,2 . Here we aim to address the role of microbial organisms and their potential role in immune reactivity against glioblastoma. We demonstrate that HLA molecules of both glioblastoma tissues and tumour cell lines present bacteria-specific peptides. This finding prompted us to examine whether tumour-infiltrating lymphocytes (TILs) recognize tumour-derived bacterial peptides. Bacterial peptides eluted from HLA class II molecules are recognized by TILs, albeit very weakly. Using an unbiased antigen discovery approach to probe the specificity of a TIL CD4 + T cell clone, we show that it recognizes a broad spectrum of peptides from pathogenic bacteria, commensal gut microbiota and also glioblastoma-related tumour antigens. These peptides were also strongly stimulatory for bulk TILs and peripheral blood memory cells, which then respond to tumour-derived target peptides. Our data hint at how bacterial pathogens and bacterial gut microbiota can be involved in specific immune recognition of tumour antigens. The unbiased identification of microbial target antigens for TILs holds promise for future personalized tumour vaccination approaches., (© 2023. The Author(s).)

Background: Poor-grade aneurysmal subarachnoid hemorrhage (aSAH) is associated with high mortality and poor disability outcome. Data on quality of life (QoL) among survivors are scarce because patients with poor-grade aSAH are underrepresented in clinical studies reporting on QoL after aSAH., Objective: To provide prospective QoL data on survivors of poor-grade aSAH to aid clinical decision making and counseling of relatives., Methods: The herniation World Federation of Neurosurgical Societies scale study was a prospective observational multicenter study in patients with poor-grade (World Federation of Neurosurgical Societies grades 4 & 5) aSAH. We collected data during a structured telephone interview 6 and 12 months after ictus. QoL was measured using the EuroQoL - 5 Dimensions - 3 Levels (EQ-5D-3L) questionnaire, with 0 representing a health state equivalent to death and 1 to perfect health. Disability outcome for favorable and unfavorable outcomes was measured with the modified Rankin Scale., Results: Two hundred-fifty patients were enrolled, of whom 237 were included in the analysis after 6 months and 223 after 12 months. After 6 months, 118 (49.8%) patients were alive, and after 12 months, 104 (46.6%) patients were alive. Of those, 95 (80.5%) and 89 (85.6%) reached a favorable outcome with mean EQ-5D-3L index values of 0.85 (±0.18) and 0.86 (±0.18). After 6 and 12 months, 23 (19.5%) and 15 (14.4%) of those alive had an unfavorable outcome with mean EQ-5D-3L index values of 0.27 (±0.25) and 0.19 (±0.14)., Conclusion: Despite high initial mortality, the proportion of poor-grade aSAH survivors with good QoL is reasonably large. Only a minority of survivors reports poor QoL and requires permanent care., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Radiotherapy is widely used for brain tumors but can cause radiation necrosis (RN). Laser interstitial thermal therapy (LITT) is a relatively new therapeutic modality for RN and its impact on patient outcome is still not well understood. Based on a systematic literature search (n=33), the authors discuss the available evidence. Most studies found a positive safety/efficacy profile, as LITT may help to lengthen survival, prevent progression, taper steroids, and improve neurological symptoms while remaining safe. Prospective studies on this subject are needed and may result in LITT becoming an essential therapeutic option for the treatment of RN., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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

Purpose: The low mutational load of some cancers is considered one reason for the difficulty to develop effective tumor vaccines. To overcome this problem, we developed a strategy to design neopeptides through single amino acid mutations to enhance their immunogenicity., Experimental Design: Exome and RNA sequencing as well as in silico HLA-binding predictions to autologous HLA molecules were used to identify candidate neopeptides. Subsequently, in silico HLA-anchor placements were used to deduce putative T-cell receptor (TCR) contacts of peptides. Single amino acids of TCR contacting residues were then mutated by amino acid replacements. Overall, 175 peptides were synthesized and sets of 25 each containing both peptides designed to bind to HLA class I and II molecules applied in the vaccination. Upon development of a tumor recurrence, the tumor-infiltrating lymphocytes (TIL) were characterized in detail both at the bulk and clonal level., Results: The immune response of peripheral blood T cells to vaccine peptides, including natural peptides and designed neopeptides, gradually increased with repetitive vaccination, but remained low. In contrast, at the time of tumor recurrence, CD8+ TILs and CD4+ TILs responded to 45% and 100%, respectively, of the vaccine peptides. Furthermore, TIL-derived CD4+ T-cell clones showed strong responses and tumor cell lysis not only against the designed neopeptide but also against the unmutated natural peptides of the tumor., Conclusions: Turning tumor self-peptides into foreign antigens by introduction of designed mutations is a promising strategy to induce strong intratumoral CD4+ T-cell responses in a cold tumor like glioblastoma., (©2022 The Authors; Published by the American Association for Cancer Research.)

Cerebrospinal fluid (CSF) leakage is a well-known complication of craniotomies and there are several dural closure techniques. One commonly used commercial product as adjunct for dural closure is the collagen-bound fibrin sealant TachoSil®. We analysed whether the addition of TachoSil has beneficial effects on postoperative complications and outcomes. Our prospective, institutional database was retrospectively queried, and 662 patients undergoing craniotomy were included. Three hundred fifty-two were treated with dural suture alone, and in 310, TachoSil was added after primary suture. Our primary endpoint was the rate of postoperative complications associated with CSF leakage. Secondary endpoints included functional, disability and neurological outcome. Systematic review according to PRISMA guidelines was performed to identify studies comparing primary dural closure with and without additional sealants. Postoperative complications associated with CSF leakage occurred in 24 (7.74%) and 28 (7.95%) procedures with or without TachoSil, respectively (p = 0.960). Multivariate analysis confirmed no significant differences in complication rate between the two groups (aOR 0.97, 95% CI 0.53-1.80, p = 0.930). There were no significant disparities in postoperative functional, disability or neurological scores. The systematic review identified 661 and included 8 studies in the qualitative synthesis. None showed a significant superiority of additional sealants over standard technique regarding complications, rates of revision surgery or outcome. According to our findings, we summarize that routinary use of TachoSil and similar products as adjuncts to primary dural sutures after intracranial surgical procedures is safe but without clear advantage in complication avoidance or outcome. Future studies should investigate whether their use is beneficial in high-risk settings., (© 2022. The Author(s).)

Background: Recent therapeutic advances in metastatic melanoma have led to improved overall survival (OS) rates, with consequently an increased incidence of brain metastases (BM). The role of BM resection in the era of targeted and immunotherapy should be reassessed. In the current study we analysed the role of residual intracranial tumour load in a cohort of melanoma BM patients., Methods: Retrospective single-centre analysis of a prospective registry of resected melanoma BM from 2013 to 2021. Correlations of residual tumour volume and outcome were determined with respect to patient, tumour and treatment regimens characteristics., Results: 121 individual patients (66% male, mean age 59.9 years) were identified and included in the study. Pre- and postoperative systemic treatments included BRAF/MEK inhibitors, as well as combination or monotherapy of immune-checkpoint inhibitors (ICIs). Median OS of the entire cohort was 20 months. Cox proportional-hazard analysis revealed postoperative anti-CTLA4+anti-PD-1 therapy (HR 0.07, p = .01) and postoperative residual intracranial tumour burden (HR 1.4, p = .027) as significant predictors for OS. Further analysis revealed that ICI-naïve patients with residual tumour volume ≤3.5 cm 3 and postoperative ICI showed significantly prolonged OS compared to patients with residual volume >3.5 cm 3 (p < .0001). Subgroup analysis of ICI-naïve patients showed steroid intake postoperatively to be negatively associated with OS, however residual tumour volume ≤3.5 cm 3 remained independently correlated with superior OS (HR 0.14, p < .001)., Conclusion: Besides known predictive factors like postoperative ICI, a maximal intracranial tumour burden reduction seems to be beneficial, especially in ICI-naïve patients. This highlights the importance of local CNS control and the need to further investigating the role of initial surgical tumour load reduction in randomised clinical trials., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RD has intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer and touchIME outside the submitted work. MW has received research grants from Apogenix, Merck, Sharp & Dohme, Merck (EMD), Philogen and Quercis, and honoraria for lectures or advisory board participation or consulting from Adastra, Bayer, Bristol Meyer Squibb, Medac, Merck, Sharp & Dohme, Merck (EMD), Nerviano Medical Sciences, Novartis, Orbus, Philogen and yMabs outside the submitted work. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: During neurosurgical procedures, strip electrodes should have low impedance and sufficient adherence on the brain surface. We evaluated the signal quality, safety, and performance of a novel strip electrode (WISE Cortical Strip, WCS®), with conductive electrode contacts created with platinum nanoparticles embedded in a polymer base., Methods: In a multicenter interventional, non-inferiority study, we compared WCS to a conventional strip electrode (Ad-Tech). We recorded impedance and somatosensory evoked potentials (SEP) and determined the signal-to-noise ratio (SNR). We performed direct stimulation of the motor cortex. An external clinical event committee rated safety and adverse events and users rated usability., Results: During 32 brain surgeries in the paracentral region, WCS was rated safe and effective in signal transmission. Two seizure events were classified as probably related to the stimulation with WCS. The users rated WCS adhesion to the brain as satisfactory but reported difficulties sliding the WCS under the dura. The median (IQR) impedance of WCS was lower than for Ad-Tech: 2.7 (2.3-3.7) vs 5.30 (4.3-6.6) kΩ (p < 0.005). The SNR of SEP was non-inferior for WCS compared to Ad-Tech., Conclusions: The impedance of WCS was lower than Ad-Tech without safety limitations. In small craniotomies not exposing the motor cortex its use may be limited., Significance: Low impedance electrodes facilitate recordings with high SNR., Competing Interests: Conflict of interest None of the authors have potential conflicts of interest to be disclosed. All authors declare that they participated in the study without receiving personal compensation. AS, KS, JS are members of the IOM board of inomed Medizintechnik GmbH and have received speaker honoraria. MCN has reviewed documentation for WISE and his institution has received research funds from WISE Srl., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Maximum safe resection followed by chemoradiotherapy as current standard of care for WHO grade III and IV gliomas can be influenced by the occurrence of perioperative adverse events (AE). The aim of this study was to determine the association of AE with the timing and choice of subsequent treatments as well as with overall survival (OS)., Methods: Prospectively collected data of 283 adult patients undergoing surgery for WHO grade III and IV gliomas at the University Hospital Zurich between January 2013 and June 2017 were analyzed. We assessed basic patient characteristics, KPS, extent of resection, and WHO grade, and we classified AE as well as modality, timing of subsequent treatment (delay, interruption, or non-initiation), and OS., Results: In 117 patients (41%), an AE was documented between surgery and the 3-month follow-up. There was a significant association of AE with an increased time to initiation of subsequent therapy (p = 0.005) and a higher rate of interruption (p < 0.001) or non-initiation (p < 0.001). AE grades correlated with time to initiation of subsequent therapy (p = 0.038). AEs were associated with shorter OS in univariate analysis (p < 0.001)., Conclusion: AEs are associated with delayed and/or altered subsequent therapy and can therefore limit OS. These data emphasize the importance of safety within the maximum-safe-resection concept., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Weber, Padevit, Müller, Velz, Vasella, Voglis, Gramatzki, Weller, Regli, Sarnthein and Neidert.)

Background: Direct stimulation and diffusion tensor imaging/tractography are established techniques that assist in complex surgery for lesions in the eloquent area of the central nervous system., Objective: To continuously map the corticospinal tract (CST) by direct stimulation during brainstem surgery and to explore the association between direct brainstem stimulation and the shortest distance from the stimulation point to the CST (DS-to-T)., Methods: We prospectively enrolled 30 consecutive patients for microsurgical resection of lesions within or in proximity to the brainstem between January 2019 and August 2021. Direct stimulation with initially 2 mA was performed for mapping and monitoring the motor fiber tracts. To evaluate CST status and measure DS-to-T, postoperative diffusion tensor imaging/tractography was used. Preoperative and postoperative modified Ranking Scale and motor function were evaluated to assess the clinical outcome., Results: Intraoperative direct brainstem stimulation was successfully performed in all patients with a total of 909 stimulation points. One patient experienced a temporary neurological deficit postoperatively. Mapping of the CST was achieved in 5 patients. DS-to-T was ≤4 mm when motor-evoked potential responses were positive under 2 mA stimulation and ≤2 mm under 1 mA. Overall sensitivity and specificity for this association were 84.7% and 100%, respectively., Conclusion: This study further supports the paradigm for continuous CST monitoring and mapping through direct brainstem stimulation. The relationship between stimulation intensity and DS-to-T in brainstem surgery could help surgeon's better estimate the safe edge intraoperatively., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Soluble αKlotho (sKl) is a disease-specific biomarker that is elevated in patients with acromegaly and declines after surgery for pituitary adenoma. Approximately 25% of patients do not achieve remission after surgery, therefore a risk stratification for patients early in the course of their disease may allow for the identification of patients requiring adjuvant treatment. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) have been assessed as biomarker for disease activity, however the value of sKl as a predictive biomarker of surgical success has not been evaluated yet. In this study, we measured serum biomarkers before and after transsphenoidal pituitary surgery in 55 treatment-naïve patients. Based on biochemical findings at follow-up (7-16 years), we divided patients into three groups: (A) long-term cure (defined by normal IGF-1 and random low GH (< 1 μg/l) or a suppressed GH nadir (< 0.4/μg/l) on oral glucose testing); (B) initial remission with later disease activity; (C) persistent clinical and/or biochemical disease activity. sKl levels positively related to GH, IGF-1 levels and tumor volume. Interestingly, there was a statistically significant difference in pre- and postoperative levels of sKl between the long-term cure group and the group with persistent disease activity. This study provides first evidence that sKl may serve as an additional marker for surgical success, decreasing substantially in all patients with initial clinical remission while remaining high after surgery in patients with persistent disease activity., (© 2022. The Author(s).)

Background: Glioblastoma is the most common malignant primary brain tumour in adults and driven by various genomic alterations. Next generation sequencing (NGS) provides timely information about the genetic landscape of tumours and might detect targetable mutations. To date, differences exist in the application and NGS assays used as it remains unclear to what extent these variants may affect clinical decision making. In this survey-based study, we investigated the use of NGS in adult patients with glioblastoma in Switzerland., Methods: All eight primary care centres for Neuro-Oncology in Switzerland participated in this survey. The NGS assays used as well as the criteria for the application of NGS in newly diagnosed glioblastoma were investigated. Decision trees were analysed for consensus and discrepancies using the objective consensus methodology., Results: Seven out of eight centres perform NGS in patients with newly diagnosed glioblastoma using custom made or commercially available assays. The criteria most relevant to decision making were age, suitability of standard treatment and fitness. NGS is most often used in fitter patients under the age of 60 years who are not suitable for standard therapy, while it is rarely performed in patients in poor general health., Conclusion: NGS is frequently applied in glioblastomas in adults in Neuro-Oncology centres in Switzerland despite seldom changing the course of treatment to date., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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

Objective: While prior retrospective studies have suggested that delayed cerebral ischemia (DCI) is a predictor of neuropsychological deficits after aneurysmal subarachnoid hemorrhage (aSAH), all studies to date have shown a high risk of bias. This study was designed to determine the impact of DCI on the longitudinal neuropsychological outcome after aSAH, and importantly, it includes a baseline examination after aSAH but before DCI onset to reduce the risk of bias., Methods: In a prospective, multicenter study (8 Swiss centers), 112 consecutive alert patients underwent serial neuropsychological assessments (Montreal Cognitive Assessment [MoCA]) before and after the DCI period (first assessment, < 72 hours after aSAH; second, 14 days after aSAH; third, 3 months after aSAH). The authors compared standardized MoCA scores and determined the likelihood for a clinically meaningful decline of ≥ 2 points from baseline in patients with DCI versus those without., Results: The authors screened 519 patients, enrolled 128, and obtained complete data in 112 (87.5%; mean [± SD] age 53.9 ± 13.9 years; 66.1% female; 73% World Federation of Neurosurgical Societies [WFNS] grade I, 17% WFNS grade II, 10% WFNS grades III-V), of whom 30 (26.8%) developed DCI. MoCA z-scores were worse in the DCI group at baseline (-2.6 vs -1.4, p = 0.013) and 14 days (-3.4 vs -0.9, p < 0.001), and 3 months (-0.8 vs 0.0, p = 0.037) after aSAH. Patients with DCI were more likely to experience a decline of ≥ 2 points in MoCA score at 14 days after aSAH (adjusted OR [aOR] 3.02, 95% CI 1.07-8.54; p = 0.037), but the likelihood was similar to that in patients without DCI at 3 months after aSAH (aOR 1.58, 95% CI 0.28-8.89; p = 0.606)., Conclusions: Aneurysmal SAH patients experiencing DCI have worse neuropsychological function before and until 3 months after the DCI period. DCI itself is responsible for a temporary and clinically meaningful decline in neuropsychological function, but its effect on the MoCA score could not be measured at the time of the 3-month follow-up in patients with low-grade aSAH with little or no impairment of consciousness. Whether these findings can be extrapolated to patients with high-grade aSAH remains unclear. Clinical trial registration no.: NCT03032471 (ClinicalTrials.gov).

Unlike other tumours, the anatomical extent of brain tumours is not objectified and quantified through staging. Staging systems are based on understanding the anatomical sequence of tumour progression and its relationship to histopathological dedifferentiation and survival. The aim of this study was to describe the spatiotemporal phenotype of the most frequent brain tumour entities, to assess the association of anatomical tumour features with survival probability and to develop a staging system for WHO grade 2 and 3 gliomas and glioblastoma. Anatomical phenotyping was performed on a consecutive cohort of 1000 patients with first diagnosis of a primary or secondary brain tumour. Tumour probability in different topographic, phylogenetic and ontogenetic parcellation units was assessed on preoperative MRI through normalization of the relative tumour prevalence to the relative volume of the respective structure. We analysed the spatiotemporal tumour dynamics by cross-referencing preoperative against preceding and subsequent MRIs of the respective patient. The association between anatomical phenotype and outcome defined prognostically critical anatomical tumour features at diagnosis. Based on a hypothesized sequence of anatomical tumour progression, we developed a three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma. This staging system was validated internally in the original cohort and externally in an independent cohort of 300 consecutive patients. While primary CNS lymphoma showed highest probability along white matter tracts, metastases enriched along terminal arterial flow areas. Neuroepithelial tumours mapped along all sectors of the ventriculocortical axis, while adjacent units were spared, consistent with a transpallial behaviour within phylo-ontogenetic radial units. Their topographic pattern correlated with morphogenetic processes of convergence and divergence of radial units during phylo- and ontogenesis. While a ventriculofugal growth dominated in neuroepithelial tumours, a gradual deviation from this neuroepithelial spatiotemporal behaviour was found with progressive histopathological dedifferentiation. The proposed three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma correlated with the degree of histological dedifferentiation and proved accurate in terms of survival upon both internal and external validation. In conclusion, this study identified specific spatiotemporal phenotypes in brain tumours through topographic probability and growth pattern assessment. The association of anatomical tumour features with survival defined critical steps in the anatomical sequence of neuroepithelial tumour progression, based on which a staging system for WHO grade 2 and 3 gliomas and glioblastoma was developed and validated., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Microsurgical resection of brainstem cavernous malformations (BSCMs) can be performed today with acceptable morbidity and mortality. However, in this highly eloquent location, the indication for surgery remains challenging. We aimed to elaborate a score system that may help clinicians with their choice of treatment in patients with BSCMs in this study. A single-center series of 88 consecutive BSCMs patients with 272 follow-up visits were included in this study. Univariable and multivariable generalized estimating equations (GEE) were constructed to identify the association of variables with treatment decisions. A score scale assigned points for variables that significantly contributed to surgical decision-making. Surgical treatment was recommended in 37 instances, while conservative treatment was proposed in 235 instances. The mean follow-up duration was 50.4 months, and the mean age at decision-making was 45.9 years. The mean BSCMs size was 14.3 ml. In the multivariable GEE model, patient age, lesion size, hemorrhagic event(s), mRS, and axial location were identified as significant factors for determining treatment options. With this proposed score scale (grades 0-XII), non-surgery was the first option at grades 0-III. The crossover point between surgery and non-surgery recommendations lay between grades V and VI while surgical treatment was found in favor at grades VII-X. In conclusion, the proposed BSCM operating score is a clinician-friendly tool, which may help neurosurgeons decide on the treatment for patients with BSCMs., (© 2021. The Author(s).)

Understanding the molecular principles that govern the composition of the MHC-I immunopeptidome across different primary tissues is fundamentally important to predict how T cells respond in different contexts in vivo . Here, we performed a global analysis of the MHC-I immunopeptidome from 29 to 19 primary human and mouse tissues, respectively. First, we observed that different HLA-A, HLA-B, and HLA-C allotypes do not contribute evenly to the global composition of the MHC-I immunopeptidome across multiple human tissues. Second, we found that tissue-specific and housekeeping MHC-I peptides share very distinct properties. Third, we discovered that proteins that are evolutionarily hyperconserved represent the primary source of the MHC-I immunopeptidome at the organism-wide scale. Fourth, we uncovered new components of the antigen processing and presentation network, including the carboxypeptidases CPE, CNDP1/2, and CPVL. Together, this study opens up new avenues toward a system-wide understanding of antigen presentation in vivo across mammalian species., Competing Interests: Heiko Schuster is an employee of Immatics Biotechnologies GmbH. Hans-Georg Rammensee is a shareholder of Immatics Biotechnologies GmbH and Curevac AG., (© 2022 The Author(s).)

Background: Complications after neurosurgical operations can have severe impact on patient well-being, which is poorly reflected by current grading systems. The objective of this work was to develop and conduct a feasibility study of a new smartphone application that allows for the longitudinal assessment of postoperative well-being and complications., Methods: We developed a smartphone application "Post OP Tracker" according to requirements from clinical experience and tested it on simulated patients. Participants received regular notifications through the app, inquiring them about their well-being and complications that had to be answered according to their assigned scenarios. After a 12-week period, subjects answered a questionnaire about the app's functionality, user-friendliness, and acceptability., Results: A total of 13 participants (mean age 34.8, range 24-68 years, 4 (30.8%) female) volunteered in this feasibility study. Most of them had a professional background in either health care or software development. All participants downloaded, installed, and applied the app for an average of 12.9 weeks. On a scale of 1 (worst) to 4 (best), the app was rated on average 3.6 in overall satisfaction and 3.8 in acceptance. The design achieved a somewhat favorable score of 3.1. One participant (7.7%) reported major technical issues. The gathered patient data can be used to graphically display the simulated outcome and assess the impact of postoperative complications., Conclusions: This study suggests the feasibility to longitudinally gather postoperative data on subjective well-being through a smartphone application. Among potential patients, our application indicated to be functional, user-friendly, and well accepted. Using this app-based approach, further studies will enable us to classify postoperative complications according to their impact on the patient's well-being., (© 2021. The Author(s).)

Background: Hemorrhage rates of conservatively managed brainstem cavernous malformations (BSCMs) vary widely in the literature. We aimed to elucidate the reason for the variation and to add the results of our experience of BSCMs management over the past decade., Methods: We performed a review of consecutive patients with BSCMs referred to our department in the period 2006-2018. A hemorrhagic event was defined as a radiographically verified intralesional and extralesional hemorrhage. Both retrospective and prospective hemorrhage rates were calculated based on the patient age in years, counted either from birth or from the time of initial presentation until the last contact (or until surgical resection). In addition, we retrieved and reviewed publications with a clear definition of hemorrhagic event and a detailed description of BSCM hemorrhage rate., Results: In total, 118 patients with BSCMs were reviewed, and 78 patients (mean age on admission 45.9 years) were included in the final analysis. The retrospective and prospective hemorrhage rates were 1.9% (95% confidence interval 1.6%-2.3%) per year and 11.9% (95% confidence interval 7.5%-17.8%), respectively. The retrospective hemorrhage rate in the literature review ranged from 1.9% to 6.8% per year with a median value of 3.8%, whereas the prospective hemorrhage rate ranged between 4.1% and 21.5%, with a median value of 10.2%., Conclusions: The reported hemorrhage rates are calculated in 2 different ways. In our patient cohort, both the retrospective and prospective hemorrhage rates were in accordance with those in the literature. The long-term hemorrhage rate lies between the prospective and retrospective rate., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Brain tumors, whether primary or secondary, have limited therapeutic options despite advances in understanding driver gene mutations and heterogeneity within tumor cells. The cellular and molecular composition of brain tumor stroma, an important modifier of tumor growth, has been less investigated to date. Only few studies have focused on the vasculature of human brain tumors despite the fact that the blood-brain barrier (BBB) represents the major obstacle for efficient drug delivery., Methods: In this study, we employed RNA sequencing to characterize transcriptional alterations of endothelial cells (EC) isolated from primary and secondary human brain tumors. We used an immunoprecipitation approach to enrich for EC from normal brain, glioblastoma (GBM), and lung cancer brain metastasis (BM)., Results: Analysis of the endothelial transcriptome showed deregulation of genes implicated in cell proliferation, angiogenesis, and deposition of extracellular matrix (ECM) in the vasculature of GBM and BM. Deregulation of genes defining the BBB dysfunction module was found in both tumor types. We identified deregulated expression of genes in vessel-associated fibroblasts in GBM., Conclusion: We characterize alterations in BBB genes in GBM and BM vasculature and identify proteins that might be exploited for developing drug delivery platforms. In addition, our analysis on vessel-associated fibroblasts in GBM shows that the cellular composition of brain tumor stroma merits further investigation., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The postoperative functional status of patients with intracranial tumors is influenced by patient-specific factors, including age., Research Question: This study aimed to elucidate the association between age and postoperative morbidity or mortality following the resection of brain tumors., Material and Methods: A multicenter database was retrospectively reviewed. Functional status was assessed before and 3-6 months after tumor resection by the Karnofsky Performance Scale (KPS). Uni- and multivariable linear regression were used to estimate the association of age with postoperative change in KPS. Logistic regression models for a ≥10-point decline in KPS or mortality were built for patients ≥75 years., Results: The total sample of 4864 patients had a mean age of 56.4 ​± ​14.4 years. The mean change in pre-to postoperative KPS was -1.43. For each 1-year increase in patient age, the adjusted change in postoperative KPS was -0.11 (95% CI -0.14 - - 0.07). In multivariable analysis, patients ≥75 years had an odds ratio of 1.51 to experience postoperative functional decline (95%CI 1.21-1.88) and an odds ratio of 2.04 to die (95%CI 1.33-3.13), compared to younger patients., Discussion: Patients with intracranial tumors treated surgically showed a minor decline in their postoperative functional status. Age was associated with this decline in function, but only to a small extent., Conclusion: Patients ≥75 years were more likely to experience a clinically meaningful decline in function and about two times as likely to die within the first 6 months after surgery, compared to younger patients., (© 2021 The Authors.)

Background: Neurosurgical resection is the mainstay of meningioma treatment. Adverse event (AE) rates of meningioma resections are significant, but preoperative risk factors for major AEs in patients undergoing first-time meningioma surgery are largely unknown. The aim of this study was to explore major AEs and identify preoperative risk factors in patients undergoing first-time meningioma surgery., Methods: Data on all meningioma resections performed at the University Hospital Zurich from 1 January 2013 to 31 December 2018 were collected in a prospective registry. All AEs that occurred within 3 months of surgery were documented in detail and classified as "minor" or "major." Statistical analysis included initial individual bivariate analyses of all preoperative factors and the occurrence of major AEs. Statistically significant variables were then included in a logistic regression model to identify predictors., Results: Three hundred forty-five patients were included in the study. Mean age was 58.1 years, and 77.1% of patients were female. The overall major AE rate was 20.6%; the most common of which was a new focal neurological deficit (12.8% of patients). Six preoperative factors showed a significant association with the occurrence of major AEs in bivariate analysis. All variables included in the logistic regression model showed increased odds of occurrence of major AE, but only tumor complexity as measured by the Milan Complexity Scale was a statistically significant predictor, with a score of 4 or more having twice the odds of major AEs (OR: 2.00, 95% CI: 1.15-3.48)., Conclusion: High tumor complexity is an independent predictor of the occurrence of major AEs following meningioma resection. Preoperative assessment of tumor complexity using the Milan Complexity Scale is warranted and can aid communication with patients about AE rates and surgical decision-making., (© 2021. The Author(s).)

Intraoperative MRI (ioMRI) has become a frequently used tool to improve maximum safe resection in brain tumor surgery. The usability of intraoperatively acquired diffusion-weighted imaging sequences to predict the extent and clinical relevance of new infarcts has not yet been studied. Furthermore, the question of whether more aggressive surgery after ioMRI leads to more or larger infarcts is of crucial interest for the surgeons' operative strategy. Retrospective single-center analysis of a prospective registry of procedures from 2013 to 2019 with ioMRI was used. Infarct volumes in ioMRI/poMRI, lesion localization, mRS, and NIHSS were analyzed for each case. A total of 177 individual operations (60% male, mean age 45.5 years old) met the inclusion criteria. In 61% of the procedures, additional resection was performed after ioMRI, which resulted in a significantly higher number of new ischemic lesions postoperatively (p < .001). The development of new or enlarged ischemic areas upon additional resection could also be shown volumetrically (mean volume in ioMRI 0.39 cm 3 vs. poMRI 2.97 cm 3 ; p < .001). Despite the surgically induced new infarcts, mRS and NIHSS did not worsen significantly in cases with additional resection. Additionally, new perilesional ischemia in eloquently located tumors was not associated with an impaired neurological outcome. Additional resection after ioMRI leads to new or enlarged ischemic areas. However, these new infarcts do not necessarily result in an impaired neurological outcome, even when in eloquent brain areas., (© 2020. The Author(s).)

Background: The most widely used classifications of adverse events (AEs) in neurosurgery define their severity according to the therapy used to treat them. This concept has substantial shortcomings because it does not reflect the severity of AEs that are not treated, such as new neurological deficits., Objective: To present a novel multidimensional and patient-centered classification of the severity of AE in neurosurgery and evaluate its applicability., Methods: The Therapy-Disability-Neurology (TDN) grading system classifies AEs depending on the associated therapy, disability, and neurological deficits. We conducted a 2-center retrospective observational study on 6071 interventions covering the whole neurosurgical spectrum with data prospectively recorded between 2013 and 2019 at 2 institutions from 2 countries., Results: Using the first patient cohort (4680 interventions), a positive correlation was found between severity of AE and LOS as well as treatment cost. Each grade was associated with a greater deterioration of the Karnofsky Performance Status Scale (KPS) at discharge and at follow-up. When using the same methods on the external validation cohort (1391 interventions), correlations between the grades of AE, LOS, and KPS at discharge were even more pronounced., Conclusion: Our results suggest that the TDN grade is consistent with clinical and economic repercussions of AE and thus reflects AE severity. It is easily interpreted and enables comparison between different medical centers. The standardized report of the severity of AE in the scientific literature could constitute an important step forward toward a more critical, patient-centered, and evidence-based decision-making in neurosurgery., (© Congress of Neurological Surgeons 2021.)

Antigen-specific immunotherapies, in particular peptide vaccines, depend on the recognition of naturally presented antigens derived from mutated and unmutated gene products on human leukocyte antigens, and represent a promising low-side-effect concept for cancer treatment. So far, the broad application of peptide vaccines in cancer patients is hampered by challenges of time- and cost-intensive personalized vaccine design, and the lack of neoepitopes from tumor-specific mutations, especially in low-mutational burden malignancies. In this study, we developed an immunopeptidome-guided workflow for the design of tumor-associated off-the-shelf peptide warehouses for broadly applicable personalized therapeutics. Comparative mass spectrometry-based immunopeptidome analyses of primary chronic lymphocytic leukemia (CLL) samples, as representative example of low-mutational burden tumor entities, and a dataset of benign tissue samples enabled the identification of high-frequent non-mutated CLL-associated antigens. These antigens were further shown to be recognized by pre-existing and de novo induced T cells in CLL patients and healthy volunteers, and were evaluated as pre-manufactured warehouse for the construction of personalized multi-peptide vaccines in a first clinical trial for CLL (NCT04688385). This workflow for the design of peptide warehouses is easily transferable to other tumor entities and can provide the foundation for the development of broad personalized T cell-based immunotherapy approaches., Competing Interests: H-GR is shareholder of Immatics Biotechnologies GmbH, Synimmune GmbH, and Curevac AG, and holds a patent application on an adjuvant, XS15. AN, H-GR, and JW are listed as inventors on patents related to peptides described in this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nelde, Maringer, Bilich, Salih, Roerden, Heitmann, Marcu, Bauer, Neidert, Denzlinger, Illerhaus, Aulitzky, Rammensee and Walz.)