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Purpose: Prophylactic insertion of an external ventricular drainage (EVD) prior to the resection of posterior fossa metastases (PFMs) is a common approach to address postoperative transient and permanent hydrocephalus. However, predicting surgery-related hydrocephalus in the preoperative phase continues to be a challenge. This study aims to analyze the incidence, preoperatively collectable risk factors and necessity of perioperative external ventricular drainage placement after posterior fossa metastasis surgery., Methods: All patients undergoing surgery for PFMs at the authors' neuro-oncological center between 2015 and 2021 were identified and assessed for postoperative hydrocephalus occurrence. Tumour volume, edema volume, and 4th ventricle volume were assessed on preoperative magnetic resonance imaging scans using the IntelliSpace Portal 5.0. A multivariable logistic regression analysis was performed to identify possible predictors for postoperative hydrocephalus occurrence., Results: Postoperative hydrocephalus occurred in 14 of the 130 identified PFM patients (11%). Multivariable analysis and receiver operating characteristic (ROC) analysis revealed a 4th -ventricle-to-tumor-volume ratio ≤ 0.02 (OR 33.1, 95% CI 3.8-284.3, p = 0.001), an edema-to- tumor-volume ratio ≤ 0.85 (OR 10.6, 95% CI 2.4-47.4, p = 0.002), an imaging-morphological contact to the 4th ventricle (OR 5, 95% CI 1.4-18, p = 0.013), and multiple intracranial metastases (OR 2.4, 95% CI 1-5.9, p = 0.045) as independent predictors for surgery-related postoperative hydrocephalus occurrence., Conclusion: The present study identifies preoperatively detectable risk factors for the occurrence of postoperative hydrocephalus following surgery for PFMs. These findings may provide guidance in clinical decision-making regarding prophylactic EVD placement., Competing Interests: Declarations. Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the University Hospital Bonn (No. 250/19). Consent to participate: Informed consent was not sought as a retrospective study design was used. Consent to publish: All authors agreed to the publication of the manuscript. Previous publication: None. Previous presentations: Data included in this manuscript have been presented in part at the 75h national day of Deutsche Gesellschaft für Neurochirurgie/German Society of Neurosurgery (DGNC) in Göttingen 06/2024 and sections day of Sektionstagung Deutsche Gesellschaft für Neurochirurgie/German Society of Neurosurgery (DGNC) 09/2024. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Glioblastoma cells rely on connexin 43 (Cx43)-based gap junctions (GJs) for intercellular communication, enabling them to integrate into a widely branched malignant network. Although there are promising prospects for new targeted therapies, the lack of clinically feasible GJ inhibitors has impeded their adoption in clinical practice. In the present study, we investigated tonabersat (TO), a blood-brain-barrier-penetrating drug with GJ-inhibitory properties, in regard to its potential to disassemble intercellular connectivity in glioblastoma networks. Fluorescence-guided measurements of calcein cell-to-cell transfer were used to study functional intercellular connectivity. Specific DNA fragmentation rates of propidium iodide-stained nuclei were measured as a surrogate readout for cell death using flow cytometry. CRISPR/Cas9-mediated gene editing of Cx43 served as a validation tool of cellular effects related to Cx43 GJ inhibition. 3' mRNA sequencing was performed for molecular downstream analysis. We found that TO reduced intercellular GJ-mediated cytosolic traffic and yielded a significant reduction of tumor microtube (TM) length. TO-mediated inhibition of cellular tumor networks was accompanied by a synergistic effect for temozolomide-induced cell death. CRISPR/Cas9 Cx43-knockout revealed similar results, indicating that TO-mediated inhibitory effects rely on the inhibition of Cx43-based GJs. Gene set enrichment analyses found that GJ-mediated synergistic cytotoxic effects were linked to a significant upregulation of cell death signaling pathways. In conclusion, TO disrupts TM-based network connectivity via GJ inhibition and renders glioblastoma cells more susceptible to cytotoxic therapy. Given its previous use in clinical trials for migraine therapy, TO might harbor the potential of bridging the idea of a GJ-targeted therapeutic approach from bench to bedside., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Objective: High-field magnetic resonance imaging (MRI) is a standard in the diagnosis of epilepsy. However, high costs and technical barriers have limited adoption in low- and middle-income countries. Even in high-income nations, many individuals with epilepsy face delays in undergoing MRI. Recent advancements in ultra-low-field (ULF) MRI technology, particularly the development of portable scanners, offer a promising solution to the limited accessibility of MRI. In this study, we present and evaluate the imaging capability of ULF MRI in detecting structural abnormalities typically associated with epilepsy and compare it to high-field MRI at 3 T., Methods: Data collection was conducted within 3 consecutive weeks at the University Hospital Bonn. Inclusion criteria were a minimum age of 18 years, diagnosed epilepsy, and clinical high-field MRI with abnormalities. We used a .064 T Swoop portable MR Imaging System. Both high-field MRI and ULF MRI scans were evaluated independently by two experienced neuroradiologists as part of their clinical routine, comparing pathology detection and diagnosis completeness., Results: Twenty-three individuals with epilepsy were recruited. One subject presented with a dual pathology. Across the entire cohort, in 17 of 24 (71%) pathologies, an anomaly colocalizing with the actual lesion was observed on ULF MRI. For 11 of 24 (46%) pathologies, the full diagnosis could be made based on ULF MRI. Tumors and posttraumatic lesions could be diagnosed best on ULF MRI, whereas cortical dysplasia and other focal pathologies were the least well diagnosed., Significance: This single-center series of individuals with epilepsy demonstrates the feasibility and utility of ULF MRI for the field of epileptology. Its integration into epilepsy care offers transformative potential, particularly in resource-limited settings. Further research is needed to position ULF MRI within imaging modalities in the diagnosis of epilepsy., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The concept of precision oncology, the application of targeted drugs based on comprehensive molecular profiling, has revolutionized treatment strategies in oncology. This review summarizes the current status of precision oncology in glioblastoma (GBM), the most common and aggressive primary brain tumor in adults with a median survival below 2 years. Targeted treatments without prior target verification have consistently failed. Patients with BRAF V600E-mutated GBM benefit from BRAF/MEK-inhibition, whereas targeting EGFR alterations was unsuccessful due to poor tumor penetration, tumor cell heterogeneity, and pathway redundancies. Systematic screening for actionable molecular alterations resulted in low rates (< 10%) of targeted treatments. Efficacy was observed in one-third and currently appears to be limited to BRAF-, VEGFR-, and mTOR-directed treatments. Advancing precision oncology for GBM requires consideration of pathways instead of single alterations, new trial concepts enabling rapid and adaptive drug evaluation, a focus on drugs with sufficient bioavailability in the CNS, and the extension of target discovery and validation to the tumor microenvironment, tumor cell networks, and their interaction with immune cells and neurons., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

In recent years, the discovery of functional and communicative cellular tumour networks has led to a new understanding of malignant primary brain tumours. In this review, the authors shed light on the diverse nature of cell-to-cell connections in brain tumours and propose an innovative treatment approach to address the detrimental connectivity of these networks. The proposed therapeutic outlook revolves around three main strategies: (a) supramarginal resection removing a substantial portion of the communicating tumour cell front far beyond the gadolinium-enhancing tumour mass, (b) morphological isolation at the single cell level disrupting structural cell-to-cell contacts facilitated by elongated cellular membrane protrusions known as tumour microtubes (TMs), and (c) functional isolation at the single cell level blocking TM-mediated intercellular cytosolic exchange and inhibiting neuronal excitatory input into the malignant network. We draw an analogy between the proposed therapeutic outlook and the Alcatraz Federal Penitentiary, where inmates faced an impassable sea barrier and experienced both spatial and functional isolation within individual cells. Based on current translational efforts and ongoing clinical trials, we propose the Alcatraz-Strategy as a promising framework to tackle the harmful effects of cellular brain tumour networks., (© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Objective: Visual acuity (VA) constitutes an important outcome measure in surgery for medial sphenoid wing meningioma (SWM). This study aimed to assess the recovery of tumor-associated impairment of VA and its impact on patient-reported outcome measures (PROMs) as an indication of vision-related quality of life in patients who had undergone surgery for medial SWM., Methods: From 2009 to 2018, 153 consecutive patients with medial SWM underwent surgical treatment at the authors' institutions. Tumor-associated VA was evaluated both on admission and during postoperative follow-up examinations, using Snellen charts. Multivariable analysis was performed to identify independent predictors for postoperative improvement of VA. PROMs were collected based on the National Eye Institute 25-Item Visual Function Questionnaire., Results: Of patients with medial SWM, 53 of 153 (35%) experienced preoperative impairment of VA. The median preoperative duration of visual symptoms was 12 (IQR 3-17) months for the entire study cohort. Multivariable analysis revealed a preoperative duration of visual symptoms ≤ 4 months to be independently associated with postoperative improvement of VA (p = 0.009). Evaluation of PROMs indicated a superior postoperative qualitative extent in the overall health (p = 0.027) and activities of daily living (p = 0.031) categories if preoperative duration of visual impairment was ≤ 4 months., Conclusions: The overall preoperative duration of tumor-related visual impairment significantly correlates to the extent of postoperative visual improvement as well as vision-related PROMs in medial SWM surgery. These results might aid in preoperative patient counseling and help optimize decision-making and preoperative estimation of long-term visual outcome.

Background: Maximum tumor resection improves overall survival (OS) in patients with glioblastoma. The extent of resection (EOR) is historically dichotomized. The RANO resect group recently proposed criteria for volumetry-based EOR assessment in patients that were treated according to Stupp´s protocol. The purpose of this study was (1) to investigate the prognostic value of EOR in patients receiving combined chemotherapy with lomustine (CCNU)/temozolomide (TMZ), and (2) to analyse the prognostic performance of binary EOR assessment compared to volumetric assessment., Methods: 78 patients with newly diagnosed MGMT-methylated GBM undergoing tumor resection followed by radiochemotherapy with CCNU/TMZ were included in this study. Residual contrast-enhancing (CE) tumor volume after the first resection was measured and its influence on OS and PFS was analysed using uni- and multivariable Cox regression analysis as well as two-sided log rank test. Patients were divided into RTV ≤1 cm³, >1 cm³ - ≤5 cm³ and >5 cm³ following the proposed criteria of the RANO resect group., Results: Prolonged OS was associated with age <60 years, low RTV, and gross total resection (GTR). Residual tumor volume (RTV) had a superior prognostic value compared to binary EOR assessment. Patients with total or near total resection of CE tumor (≤1 cm³ RTV) showed prolonged OS (median 54.4 months, 95% CI 46.94-not reached), with a 5-year survival rate of 49%., Conclusion: Low RTV is associated with increased survival in glioblastoma patients undergoing radiochemotherapy with CCNU/TMZ. This study demonstrates the applicability of the recently proposed RANO resect criteria in this subgroup of patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: The rarity of cerebellar glioblastoma presents a significant challenge in clinical practice due to the lack of extensive prognostic data on long-term survival rates, rendering it an underrepresented entity compared to its supratentorial counterpart. This study aims to analyze potential differences in survival outcome between patients with cerebellar and supratentorial glioblastomas., Methods: From 2009 to 2020, 8 patients underwent surgical treatment for cerebellar glioblastoma at the authors' institution. These patients were individually matched with a cohort of 205 consecutive patients from our institutional database with supratentorial glioblastoma, taking into account key prognostic parameters. Progression-free survival (PFS) and overall survival (OS) rates were compared. Additionally, we performed a systematic literature review to compile further survival data on cerebellar glioblastoma patients., Results: The median OS for cerebellar glioblastoma patients was 18 months (95% CI 11-25). The balanced matched-pair analysis showed no significant difference in survival when compared to patients with supratentorial glioblastoma, exhibiting a median OS of 23 months (95% CI 0-62) (p = 0.63). Respective values for PFS were 8 months (95% CI 4-12) for cerebellar and 7 months (95% CI 0-16) for supratentorial glioblastoma (p = 0.2). The systematic review revealed that median OS for cerebellar glioblastoma in current literature ranges from 7 to 21 months., Conclusions: The present findings indicate that patients with supra- and infratentorial glioblastoma do not significantly differ in regard to survival outcome parameters. This similarity in prognosis might encourage clinicians to consider surgical interventions for both supra- and infratentorial glioblastoma in a similar manner., (© 2024. The Author(s).)

Purpose: Little is known about the effect of SARS-CoV-2 infection on glioblastoma (GBM) growth, metabolism, and prognosis. Immunological changes within GBM tissue are potentially symptomatic, underlining the urgent need for a better understanding of this phenomenon. To date, the complex underlying biology has not been fully elucidated. A decisive role of the tumor microenvironment (TME) and the components of the immune system acting within it is assumed., Methods: Immunohistochemical staining of SARS-CoV-2 spike protein and immune cell infiltration of TME was performed on the tumor tissue of one patient. This patient developed hemiparesis 14 days after symptomatic SARS-CoV-2 infection, leading to tumor diagnosis. Subsequently and after biopsy, there was an unexpectedly good response to chemotherapy only. In looking for further evidence of the potential of SARS-CoV-2 to influence the course of GBM, two additional adult patients that had transient MRI changes and neurological deterioration following SARS-CoV-2 infection were evaluated., Results: In the patient for whom neurological deterioration in the course of SARS-CoV-2 led to GBM diagnosis, immunohistochemistry revealed virus-specific protein accumulation in the tumor cells, microglial activation, and the formation of T-cell nodules. In the other two patients, the findings were compatible with symptomatic pseudoprogression that occurred in a temporal relationship with SARS-CoV-2 infection., Conclusion: The results indicate a possible association between clinically relevant changes in GBM biology and SARS-CoV-2 infection, with histological confirmation of SARS-CoV-2-associated changes within the tumor tissue. The exact pathomechanism and underlying inflammatory pathways require further investigation., (© 2024. The Author(s).)

Background: The term gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features could not be established., Methods: We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization., Results: Median overall survival (OS) was 15.5 months (interquartile range, 10.9-27.7) with a 2-year survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2-55.7); grade III: 15.9 months (11.4-26.3); grade IV: 10.4 months (8.8-14.4). By DNA methylation profiling (n = 49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wild-type (n = 31/49, 63.3%) with enriched subclasses pedHGG&#95;RTK2 (n = 19), pedHGG&#95;A/B (n = 6), and pedHGG&#95;MYCN (n = 5), but only one pedHGG&#95;RTK1 case. Within the pedHGG, H3-/IDH-wild-type subgroup, recurrent alterations in EGFR (n = 10) and BCOR (n = 9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wild-type subgroup TP53 alterations had a significant negative effect on OS., Conclusions: Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG&#95;RTK2, pedHGG&#95;A/B, EGFR and BCOR mutations, chromosome 6 rearrangements)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

The chemokine CXCL12 promotes glioblastoma (GBM) recurrence after radiotherapy (RT) by facilitating vasculogenesis. Here we report outcomes of the dose-escalation part of GLORIA (NCT04121455), a phase I/II trial combining RT and the CXCL12-neutralizing aptamer olaptesed pegol (NOX-A12; 200/400/600 mg per week) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose (MTD), recommended phase II dose (RP2D), NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life (QOL), median progression-free survival (PFS), 6-months PFS and overall survival (OS). Treatment was safe with no dose-limiting toxicities or treatment-related deaths. The MTD has not been reached and, thus, 600 mg per week of NOX-A12 was established as RP2D for the ongoing expansion part of the trial. With increasing NOX-A12 dose levels, a corresponding increase of NOX-A12 plasma levels was observed. Of ten patients enrolled, nine showed radiographic responses, four reached partial remission. All but one patient (90%) showed at best response reduced perfusion values in terms of relative cerebral blood volume (rCBV). The median PFS was 174 (range 58-260) days, 6-month PFS was 40.0% and the median OS 389 (144-562) days. In a post-hoc exploratory analysis of tumor tissue, higher frequency of CXCL12 + endothelial and glioma cells was significantly associated with longer PFS under NOX-A12. Our data imply safety of NOX-A12 and its efficacy signal warrants further investigation., (© 2024. The Author(s).)

Therapeutic management of patients with leptomeningeal carcinomatosis (LC) may require treatment of concomitant hydrocephalus (HC) in addition to intrathecal chemotherapy (ITC). Ventriculoperitoneal shunts (VPS) equipped with a valve for manual deactivation of shunt function and a concomitant reservoir for application of ITC pose an elegant solution to both problems. The present study evaluates indication, feasibility, and safety of such a modified shunt/reservoir design (mS/R). All patients with LC aged ≥ 18 years who had undergone mS/R implantation between 2013 and 2020 at the authors' institution were further analyzed. ITC was indicated following the recommendation of the neuro-oncological tumor board and performed according to a standardized protocol. Sixteen patients with LC underwent mS/R implantation for subsequent ITC and concomitant treatment of HC. Regarding HC-related clinical symptoms, 69% of patients preoperatively exhibited lethargy, 38% cognitive impairment, and 38% (additional) visual disturbances. Postoperatively, 86% of patients achieved subjective improvement of HC-related symptoms. Overall, postoperative complications occurred in three patients (19%). No patient encountered cancer treatment-related complications. The present study describes a combination procedure consisting of a standard VPS-system and a standard reservoir for patients suffering from LC and HC. No cancer treatment-related complications occurred, indicating straightforward handling and thus safety.

Purpose: After surgical resection of brain metastases (BMs), intraoperative radiation therapy (IORT) provides a promising alternative to adjuvant external beam radiation therapy by enabling superior organ-at-risk preservation, reduction of in-hospital times, and timely admission to subsequent systemic treatments, which increasingly comprise novel targeted immunotherapeutic approaches. We sought to assess the safety and efficacy of IORT in combination with immune checkpoint inhibitors (ICIs) and other targeted therapies (TTs)., Methods and Materials: In a multicentric approach incorporating individual patient data from 6 international IORT centers, all patients with BMs undergoing IORT were retrospectively assessed for combinatorial treatment with ICIs/TTs and evaluated for toxicity and cumulative rates, including wound dehiscence, radiation necrosis, leptomeningeal spread, local control, distant brain progression (DBP), and estimated overall survival., Results: In total, 103 lesions with a median diameter of 34 mm receiving IORT combined with immunomodulatory systemic treatment or other TTs were included. The median follow-up was 13.2 (range, 1.2-102.4) months, and the median IORT dose was 25 (range, 18-30) Gy prescribed to the applicator surface. There was 1 grade 3 adverse event related to IORT recorded (2.2%). A 4.9% cumulative radiation necrosis rate was observed. The 1-year local control rate was 98.0%, and the 1-year DBP-free survival rate was 60.0%. Median time to DBP was 5.5 (range, 1.0-18.5) months in the subgroup of patients experiencing DBP, and the cumulative leptomeningeal spread rate was 4.9%. The median estimated overall survival was 26 (range, 1.2 to not reached) months with a 1-year survival rate of 74.0%. Early initiation of immunotherapy/TTs was associated with a nonsignificant trend toward improved DBP rate and overall survival., Conclusions: The combination of ICIs/TTs with IORT for resected BMs does not seem to increase toxicity and yields encouraging local control outcomes in the difficult-to-treat subgroup of larger BMs. Time gaps between surgery and systemic treatment could be shortened or avoided. The definitive role of IORT in local control after BM resection will be defined in a prospective trial., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Patients with spinal metastases (SM) from solid neoplasms typically exhibit progression to an advanced cancer stage. Such metastases can either develop concurrently with an existing cancer diagnosis (termed metachronous SM) or emerge as the initial indication of an undiagnosed malignancy (referred to as synchronous SM). The present study investigates the prognostic implications of synchronous compared to metachronous SM following surgical resection., Methods: From 2015 to 2020, a total of 211 individuals underwent surgical intervention for SM at our neuro-oncology facility. We conducted a survival analysis starting from the date of the neurosurgical procedure, comparing those diagnosed with synchronous SM against those with metachronous SM., Results: The predominant primary tumor types included lung cancer (23%), prostate cancer (21%), and breast cancer (11.3%). Of the participants, 97 (46%) had synchronous SM, while 114 (54%) had metachronous SM. The median overall survival post-surgery for those with synchronous SM was 13.5 months (95% confidence interval (CI) 6.1-15.8) compared to 13 months (95% CI 7.7-14.2) for those with metachronous SM (p = 0.74)., Conclusions: Our findings suggest that the timing of SM diagnosis (synchronous versus metachronous) does not significantly affect survival outcomes following neurosurgical treatment for SM. These results support the consideration of neurosurgical procedures regardless of the temporal pattern of SM manifestation., (© 2024. The Author(s).)

Background: Glioblastoma is the most frequent and a particularly malignant primary brain tumor with no efficacy-proven standard therapy for recurrence. It has recently been discovered that excitatory synapses of the AMPA-receptor subtype form between non-malignant brain neurons and tumor cells. This neuron-tumor network connectivity contributed to glioma progression and could be efficiently targeted with the EMA/FDA approved antiepileptic AMPA receptor inhibitor perampanel in preclinical studies. The PerSurge trial was designed to test the clinical potential of perampanel to reduce tumor cell network connectivity and tumor growth with an extended window-of-opportunity concept., Methods: PerSurge is a phase IIa clinical and translational treatment study around surgical resection of progressive or recurrent glioblastoma. In this multicenter, 2-arm parallel-group, double-blind superiority trial, patients are 1:1 randomized to either receive placebo or perampanel (n = 66 in total). It consists of a treatment and observation period of 60 days per patient, starting 30 days before a planned surgical resection, which itself is not part of the study interventions. Only patients with an expected safe waiting interval are included, and a safety MRI is performed. Tumor cell network connectivity from resected tumor tissue on single cell transcriptome level as well as AI-based assessment of tumor growth dynamics in T2/FLAIR MRI scans before resection will be analyzed as the co-primary endpoints. Secondary endpoints will include further imaging parameters such as pre- and postsurgical contrast enhanced MRI scans, postsurgical T2/FLAIR MRI scans, quality of life, cognitive testing, overall and progression-free survival as well as frequency of epileptic seizures. Further translational research will focus on additional biological aspects of neuron-tumor connectivity., Discussion: This trial is set up to assess first indications of clinical efficacy and tolerability of perampanel in recurrent glioblastoma, a repurposed drug which inhibits neuron-glioma synapses and thereby glioblastoma growth in preclinical models. If perampanel proved to be successful in the clinical setting, it would provide the first evidence that interference with neuron-cancer interactions may indeed lead to a benefit for patients, which would lay the foundation for a larger confirmatory trial in the future., Trial Registration: EU-CT number: 2023-503938-52-00 30.11.2023., (© 2024. The Author(s).)

Prognostic factors and standards of care for astrocytoma, isocitrate dehydrogenase (IDH)-mutant, CNS WHO grade 4, remain poorly defined. Here we sought to explore disease characteristics, prognostic markers, and outcome in patients with this newly defined tumor type. We determined molecular biomarkers and assembled clinical and outcome data in patients with IDH-mutant astrocytomas confirmed by central pathology review. Patients were identified in the German Glioma Network cohort study; additional cohorts of patients with CNS WHO grade 4 tumors were identified retrospectively at two sites. In total, 258 patients with IDH-mutant astrocytomas (114 CNS WHO grade 2, 73 CNS WHO grade 3, 71 CNS WHO grade 4) were studied. The median age at diagnosis was similar for all grades. Karnofsky performance status at diagnosis inversely correlated with CNS WHO grade (p < 0.001). Despite more intensive treatment upfront with higher grade, CNS WHO grade was strongly prognostic: median overall survival was not reached for grade 2 (median follow-up 10.4 years), 8.1 years (95% CI 5.4-10.8) for grade 3, and 4.7 years (95% CI 3.4-6.0) for grade 4. Among patients with CNS WHO grade 4 astrocytoma, median overall survival was 5.5 years (95% CI 4.3-6.7) without (n = 58) versus 1.8 years (95% CI 0-4.1) with (n = 12) homozygous CDKN2A deletion. Lower levels of global DNA methylation as detected by LINE-1 methylation analysis were strongly associated with CNS WHO grade 4 (p < 0.001) and poor outcome. MGMT promoter methylation status was not prognostic for overall survival. Histomolecular stratification based on CNS WHO grade, LINE-1 methylation level, and CDKN2A status revealed four subgroups of patients with significantly different outcomes. In conclusion, CNS WHO grade, global DNA methylation status, and CDKN2A homozygous deletion are prognostic in patients with IDH-mutant astrocytoma. Combination of these parameters allows for improved prediction of outcome. These data aid in designing upcoming trials using IDH inhibitors., (© 2024. The Author(s).)

Introduction: Diffuse midline gliomas (DMG) are universally lethal central nervous system tumors that carry almost unanimously the clonal driver mutation histone-3 K27M (H3K27M). The single amino acid substitution of lysine to methionine harbors a neoantigen that is presented in tumor tissue. The long peptide vaccine H3K27M-vac targeting this major histocompatibility complex class II (MHC class II)-restricted neoantigen induces mutation-specific immune responses that suppress the growth of H3K27M + flank tumors in an MHC-humanized rodent model., Methods: INTERCEPT H3 is a non-controlled open label, single arm, multicenter national phase 1 trial to assess safety, tolerability and immunogenicity of H3K27M-vac in combination with standard radiotherapy and the immune checkpoint inhibitor atezolizumab (ATE). 15 adult patients with newly diagnosed K27M-mutant histone-3.1 (H3.1K27M) or histone-3.3 (H3.3K27M) DMG will be enrolled in this trial. The 27mer peptide vaccine H3K27M-vac will be administered concomitantly to standard radiotherapy (RT) followed by combinatorial treatment with the programmed death-ligand 1 (PD-L1) targeting antibody ATE. The first three vaccines will be administered bi-weekly (q2w) followed by a dose at the beginning of recovery after RT and six-weekly administrations of doses 5 to 11 thereafter. In a safety lead-in, the first three patients (pts. 1-3) will be enrolled sequentially., Perspective: H3K27M-vac is a neoepitope targeting long peptide vaccine derived from the clonal driver mutation H3K27M in DMG. The INTERCEPT H3 trial aims at demonstrating (1) safety and (2) immunogenicity of repeated fixed dose vaccinations of H3K27M-vac administered with RT and ATE in adult patients with newly diagnosed H3K27M-mutant DMG., Trial Registration: NCT04808245., (© 2023. Deutsche Gesellschaft für Neurologie e.V.)

Background: The biological understanding of glioblastoma (GB) with gliomatosis cerebri (GC) pattern is poor due to the absence of GC-specific studies. Here, we aimed to identify molecular or clinical parameters that drive GC growth., Methods: From our methylome database of IDH (isocitrate dehydrogenase)-wildtype GB, we identified 158 non-GC and 65 GC cases. GC cases were subdivided into diffuse-infiltrative (subtype 1), multifocal (subtype 2), or tumors with 1 solid mass (subtype 3). We compared clinical, histological, and molecular parameters and conducted a reference-free tumor deconvolution of DNA methylation data based on latent methylation components (LMC)., Results: GC subtype 1 less frequently showed contrast-enhancing tumors, and more frequently lacked morphological GB criteria despite displaying GB DNA methylation profile. However, the tumor deconvolution did not deliver a specific LMC cluster for either of the GC subtypes. Employing the reference-based analysis MethylCIBERSORT, we did not identify significant differences in tumor cell composition. The majority of both GC and non-GC patients received radiochemotherapy as first-line treatment, but there was a major imbalance for resection. The entire GC cohort had significantly shorter overall survival (OS) and time to treatment failure (TTF) than the non-GC cohort. However, when filtering for cases in which only stereotactic biopsy was performed, the comparison of OS and TTF lost statistical significance., Conclusions: Our study offers clinically relevant information by demonstrating a similar outcome for GB with GC growth pattern in the surgically matched analysis. The limited number of cases in the GC subgroups encourages the validation of our DNA methylation analysis in larger cohorts., Competing Interests: J.P.S. has received honoraria for lectures or advisory board participation from Boehringer, Medac, Roche, Seagen, Med-Update, and Novocure. U.H. has received lecture and/or advisory board honoraria from Medac and Bayer. E. Fokas has received honoraria from Celgene, and trial funding support from AstraZeneca that are unrelated to the present study. All other authors declare that they have no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Substitution of lysine 27 to methionine in histone H3 (H3K27M) defines an aggressive subtype of diffuse glioma. Previous studies have shown that a H3K27M-specific long peptide vaccine (H3K27M-vac) induces mutation-specific immune responses that control H3K27M + tumors in major histocompatibility complex-humanized mice. Here we describe a first-in-human treatment with H3K27M-vac of eight adult patients with progressive H3K27M + diffuse midline glioma on a compassionate use basis. Five patients received H3K27M-vac combined with anti-PD-1 treatment based on physician's discretion. Repeat vaccinations with H3K27M-vac were safe and induced CD4 + T cell-dominated, mutation-specific immune responses in five of eight patients across multiple human leukocyte antigen types. Median progression-free survival after vaccination was 6.2 months and median overall survival was 12.8 months. One patient with a strong mutation-specific T cell response after H3K27M-vac showed pseudoprogression followed by sustained complete remission for >31 months. Our data demonstrate safety and immunogenicity of H3K27M-vac in patients with progressive H3K27M + diffuse midline glioma., (© 2023. The Author(s).)

Purpose: The AVAglio trial reported a significant survival benefit for first line bevacizumab treatment in patients with IDH wildtype glioblastoma of the proneural gene expression subtype. We here aim to replicate these findings in an independent trial cohort., Methods: We evaluate the treatment benefit of bevacizumab according to gene expression subtypes of pretreatment tumor samples (n = 123) in the GLARIUS trial (NCT00967330) for MGMT unmethylated glioblastoma patients with Kaplan-Meier analyses, log-rank tests and Cox regression models., Results: Employing the Phillips classifier, bevacizumab conferred a significant PFS advantage in patients with proneural IDH wild-type tumors (10.4 vs. 6.0 months, p = 0.002), but no OS advantage (16.4 vs. 17.4 months, p = 0.6). Multivariable analysis adjusting for prognostic covariates confirmed the absence of a significant OS advantage from bevacizumab (hazard ratio, 1.05, 95% CI, 0.42 to 2.64; p = 0.14). Further, there was no interaction between the proneural subtype and treatment arm (p = 0.15). These results were confirmed in analyses of tumor subgroups according to the Verhaak classifier., Conclusion: In contrast to AVAglio, glioblastoma gene expression subgroups were not associated with a differential OS benefit from first-line bevacizumab in the GLARIUS trial., (© 2023. The Author(s).)

Purpose: Intraoperative radiotherapy (IORT) has become a viable treatment option for resectable brain metastases (BMs). As data on local control and radiation necrosis rates are maturing, we focus on meaningful secondary endpoints such as time to next treatment (TTNT), duration of postoperative corticosteroid treatment, and in-hospital time., Methods: Patients prospectively recruited within an IORT study registry between November 2020 and June 2023 were compared with consecutive patients receiving adjuvant stereotactic radiotherapy (SRT) of the resection cavity within the same time frame. TTNT was defined as the number of days between BM resection and start of the next extracranial oncological therapy (systemic treatment, surgery, or radiotherapy) for each of the groups., Results: Of 95 BM patients screened, IORT was feasible in 84 cases (88%) and ultimately performed in 64 (67%). The control collective consisted of 53 SRT patients. There were no relevant differences in clinical baseline features. Mean TTNT (range) was 36 (9 - 94) days for IORT patients versus 52 (11 - 126) days for SRT patients (p = 0.01). Mean duration of postoperative corticosteroid treatment was similar (8 days; p = 0.83), as was mean postoperative in-hospital time (11 versus 12 days; p = 0.97). Mean total in-hospital time for BM treatment (in- and out-patient days) was 11 days for IORT versus 19 days for SRT patients (p < 0.001)., Conclusion: IORT for BMs results in faster completion of interdisciplinary treatment when compared to adjuvant SRT, without increasing corticosteroid intake or prolonging in-hospital times. A randomised phase III trial will determine the clinical effects of shorter TTNT., (© 2023. The Author(s).)

Purpose: In the randomized CeTeG/NOA-09 trial, lomustine/temozolomide (CCNU/TMZ) was superior to TMZ therapy regarding overall survival (OS) in MGMT promotor-methylated glioblastoma. Progression-free survival (PFS) and pseudoprogression rates (about 10%) were similar in both arms. Further evaluating this discrepancy, we analyzed patterns of postprogression survival (PPS) and MRI features at first progression according to modified RANO criteria (mRANO)., Methods: We classified the patients of the CeTeG/NOA-09 trial according to long vs. short PPS employing a cut-off of 18 months and compared baseline characteristics and survival times. In patients with available MRIs and confirmed progression, the increase in T 1 -enhancing, FLAIR hyperintense lesion volume and the change in ADC mean value of contrast-enhancing tumor upon progression were determined., Results: Patients with long PPS in the CCNU/TMZ arm had a particularly short PFS (5.6 months). PFS in this subgroup was shorter than in the long PPS subgroup of the TMZ arm (11.1 months, p = 0.01). At mRANO-defined progression, patients of the CCNU/TMZ long PPS subgroup had a significantly higher increase of mean ADC values (p = 0.015) and a tendency to a stronger volumetric increase in T 1 -enhancement (p = 0.22) as compared to long PPS patients of the TMZ arm., Conclusion: The combination of survival and MRI analyses identified a subgroup of CCNU/TMZ-treated patients with features that sets them apart from other patients in the trial: short first PFS despite long PPS and significant increase in mean ADC values upon mRANO-defined progression. The observed pattern is compatible with the features commonly observed in pseudoprogression suggesting mRANO-undetected pseudoprogressions in the CCNU/TMZ arm of CeTeG/NOA-09., (© 2023. The Author(s).)

Background: Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined., Methods: European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study supported by the Brain Tumor Funders Collaborative in the US and the EORTC Brain Tumor Group. Patients with glioblastoma surviving at least 5 years from diagnosis were identified at 24 sites in Europe, US, and Australia. In patients with isocitrate dehydrogenase (IDH) wildtype tumours, prognostic factors were analysed using the Kaplan-Meier method and the Cox proportional hazards model. A population-based reference cohort was obtained from the Cantonal cancer registry Zurich., Results: At the database lock of July 2020, 280 patients with histologically centrally confirmed glioblastoma (189 IDH wildtype, 80 IDH mutant, 11 incompletely characterised) had been registered. In the IDH wildtype population, median age was 56 years (range 24-78 years), 96 patients (50.8%) were female, 139 patients (74.3%) had tumours with O 6 -methylguanine DNA methyltransferase (MGMT) promoter methylation. Median overall survival was 9.9 years (95% confidence interval [95% CI] 7.9-11.9). Patients without recurrence experienced longer median survival (not reached) than patients with one or more recurrences (8.92 years) (p < 0.001) and had a high rate (48.8%) of MGMT promoter-unmethylated tumours., Conclusions: Freedom from progression is a powerful predictor of overall survival in long-term survivors with glioblastoma. Patients without relapse often have MGMT promoter-unmethylated glioblastoma and may represent a distinct subtype of glioblastoma., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C.H. has received a research grant for protected time by the Filling the Gap foundation and honoraria for lecture from Vifor; E.L.R. has received honoraria for lectures or advisory board from Bayer, Janssen, Leo Pharma, Pierre Fabre, Seattle Genetics; J.C. has received research funding from Servier and Merck and consultant for Servier; R.S. reports consultation for Bayer, Astra Zeneca; W.W. reports consultation for Apogenix, Astra Zeneca, Bayer, Enterome, Medac, MSD and Roche/Genentech with honoraria paid to the Medical Faculty at the University of Heidelberg; F.D. has received honoraria for lectures or advisory board participation from Novocure; P.R. has received honoraria for lectures or advisory board participation from Bristol-Myers Squibb, Boehringer Ingelheim, Debiopharm, Merck Sharp and Dohme, Midatech, Novocure, QED, and Roche and research support from Merck Sharp and Dohme and Novocure; P.H. has received honoraria for lectures or advisory board participation or consulting from Bayer, Lilly, medac, Novartis, Novocure and Seagen; A.H. has received honoraria for lectures, consultation or advisory board participation from Novocure and Novartis; G.L. has received funding for a consulting or advisory role from Bayer, AbbVie, Orbus Therapeutics, BrainFarm, Health4U, Novartis, Braun and Janssen, and funding for travel from Roche, Bayer, and Ipsen; D.K. has received honoraria for lectures, consultation or advisory board participation from Novocure and BrainLab; M.G. reports honoraria from Roche, Novartis, UCB, AbbVie, Daiichi Sankyo, Novocure, Seagen, Bayer, Janssen-Cilag, Medac, Merck, Kyowa Kirin, travel support from Novocure and Medac, research grant from Novocure; D.R. reports support from Agenus, Agios; AnHeart Therapeutics, Avita Biomedical, Inc., Blue Rock Therapeutics, Bristol Myers Squibb, Boston Biomedica, CureVac AG, Del Mar Pharma, DNAtrix, Enterome, Hoffman-LaRoche, Ltd, Imvax, Janssen, Kiyatec, Medicenna Therapeutics, Neuvogen, Novartis, Novocure, Pyramid Bio, Sumitomo Dainippon Pharma. Vivacitas Oncology, Inc, Y-mabs Therapeutics; M.v.d.B has received honoraria for consultancy from Genenta, Servier, Astra Zeneca, Boehringer-Ingelheim, Carthera, Nerviano, Chimerix, Roche, Fore Biotherapeutics, Menarini-Stemline, Incyte and Sumitomo Pharma Oncology; F.L. received research funding from the Fonds Erasme; U.H. reports honoraria for lectures and and/or advisory board participation from Medac, Janssen, Bayer; E.R. reports travels grants BMS, Pfizer, MSD, Sanofi, Roche, Karyo labs Honorarium MSD, Servier; AF.C. received honoraria for lectures and/or advisory board participation from Gilead, Novartis; R.Ru. has received honoraria for lectures or consultation or advisory board from UCB, Novocure, Bayer, Genenta; M.P. has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals; P.W. has received research support from Astra Zeneca/Medimmune, Beigene, Celgene, Chimerix, Eli Lily, Genentech/Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Puma, Servier, Vascular Biogenics, VBI Vaccines and honoraria for advisory board participation or serving on data safety monitoring board from Astra Zeneca, Bayer, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, Novartis, Prelude Therapeutics, Sapience, Servier, Sagimet, Vascular Biogenics, VBI Vaccines; MW has received research grants from Quercis and Versameb, and honoraria for lectures or advisory board participation or consulting from Bayer, Medac, Merck (EMD), Novartis, Orbus, and Philogen. All remaining authors declare that they have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Intraoperative radiation therapy (IORT) is an emerging alternative to adjuvant stereotactic external beam radiation therapy (EBRT) following resection of brain metastases (BM). Advantages of IORT include an instant prevention of tumor regrowth, optimized dose-sparing of adjacent healthy brain tissue and immediate completion of BM treatment, allowing an earlier admission to subsequent systemic treatments. However, prospective outcome data are limited. We sought to assess long-term outcome of IORT in comparison to EBRT., Methods: A total of 35 consecutive patients, prospectively recruited within a study registry, who received IORT following BM resection at a single neuro-oncological center were evaluated for radiation necrosis (RN) incidence rates, local control rates (LCR), distant brain progression (DBP) and overall survival (OS) as long-term outcome parameters. The 1 year-estimated OS and survival rates were compared in a balanced comparative matched-pair analysis to those of our institutional database, encompassing 388 consecutive patients who underwent adjuvant EBRT after BM resection., Results: The median IORT dose was 30 Gy prescribed to the applicator surface. A 2.9% RN rate was observed. The estimated 1 year-LCR was 97.1% and the 1 year-DBP-free survival 73.5%. Median time to DBP was 6.4 (range 1.7-24) months in the subgroup of patients experiencing intracerebral progression. The median OS was 17.5 (0.5-not reached) months with a 1 year-survival rate of 61.3%, which did not not significantly differ from the comparative cohort (p = 0.55 and p = 0.82, respectively)., Conclusion: IORT is a safe and effective fast-track approach following BM resection, with comparable long-term outcomes as adjuvant EBRT., (© 2023. The Author(s).)

Object: Postoperative intensive care unit (ICU) monitoring is a common regime after neurosurgical resection of brain metastasis (BM). In comparison, unplanned secondary readmission to the ICU after initial postoperative treatment course occurs in response to adverse events and might significantly impact patient prognosis. In the present study, we analyzed the potential prognostic implications of unplanned readmission to the ICU and aimed at identifying preoperatively collectable risk factors for the development of such adverse events., Methods: Between 2013 and 2018, 353 patients with BM had undergone BM resection at the authors' institution. Secondary ICU admission was defined as any unplanned admission to the ICU during the initial hospital stay. A multivariable logistic regression analysis was performed to identify preoperatively identifiable risk factors for unplanned ICU readmission., Results: A total of 19 patients (5%) were readmitted to the ICU. Median overall survival (mOS) of patients with unplanned ICU readmission was 2 months (mo) compared to 13 mo for patients without secondary ICU admission (p<0.0001). Multivariable analysis identified "multiple BM" (p=0.02) and "preoperative CRP levels > 10 mg/dl" (p=0.01) as significant and independent predictors of secondary ICU admission., Conclusions: Unplanned ICU readmission following surgical therapy for BM is significantly related to poor OS. Furthermore, the present study identifies routinely collectable risk factors indicating patients that are at a high risk for unplanned ICU readmission after BM surgery., (© 2023. The Author(s).)

Psychoemotional distress affects patients with cancer, including patients with a diagnosis of a malignant brain tumor. Empathy, professional expertise, and conversational skills are required to ensure successful communication with patients. The purpose of this study was to assess whether knowing the communication needs of patients would be helpful to neuro-oncologists before meeting with them. Patients in our neuro-oncology center were asked to complete the National Comprehensive Cancer Network Distress Thermometer (DT) and a study-specific questionnaire on patients' expectations for communication with the treating physician. The questions targeted issues such as attention/caring and awareness of their disease and prognosis. Importance ratings were compared between patients, with high vs. low distress scores to analyze the impact of distress on the patient's needs in physician-patient communication. A total of 81 patients completed the DT and questionnaire. One third ( n = 27) had IDH wild-type astrocytoma, and 42 patients (51.9%) were undergoing therapy for primary or recurrent disease. Mean distress was 4.88 (standard deviation ± 2.64) in the whole cohort, and 56.8% of patients had a high distress score (≥ 5 on a 10-point scale). All issues were assessed as important or very important for communication by the majority of patients, and importance ratings increased in patients with high distress levels for most items. Mean importance ratings correlated significantly with distress scores ( p < .001). Distress was increased in neuro-oncology patients. Patients with higher distress levels considered issues of both attention/caring and medical information about the disease as more important than patients with lower distress levels. Using distress assessment may help physicians and advanced practitioners to tailor the contents of their discussion for successful communication with patients., Competing Interests: The authors have no conflicts of interest to disclose., (© 2023 Harborside™.)

Gliosarcoma is a rare histopathological subtype of glioblastoma. Metastatic spreading is unusual. In this report, we illustrate a case of gliosarcoma with extensive extracranial metastases with confirmation of histological and molecular concordance between the primary tumor and a metastatic lesion of the lung. Only the autopsy revealed the extent of metastatic spread and the hematogenous pattern of metastatic dissemination. Moreover, the case bared a familial coincidence of malignant glial tumors as the patient's son was diagnosed with a high-grade glioma shortly after the patient's death. By molecular analysis (Sanger and next generation panel sequencing), we could confirm that both patient's tumors carried mutations in the TP53 gene. Interestingly, the detected mutations were located in different exons. Altogether, this case draws attention to the fact that sudden clinical aggravation could be caused by the rare phenomenon of metastatic spread and should therefore be always taken into consideration, even at an early disease stage. Furthermore, the presented case highlights the contemporary value of autoptic pathological examination., Competing Interests: Conflict of Interest Declaration All authors declare that there are no financial or personal potential competing interests., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Surgical resection is a common treatment modality for brain metastasis (BM). Location of the BM might significantly impact patient survival and therefore might be considered in clinical decision making and patient counseling. In the present study, the authors analyzed infra- and supratentorial BM location for a potential prognostic difference. Between 2013 and 2019, 245 patients with solitary BM received BM resection at the authors' neuro-oncological center. In order to produce a covariate balance for commonly-known prognostic variables (tumor entity, age, preoperative Karnofsky Performance Score, and preoperative Charlson Comorbidity Index), a propensity score matching at a ratio of 1:1 between the cohort of patients with infra- and supratentorial BM location was performed using R. Overall survival (OS) rates were assessed for both matched cohorts of patients with BM. Sixty-one of 245 patients (25%) with solitary BM exhibited an infratentorial tumor location; 184 patients (75%) suffered from supratentorial solitary BM. Patients with infratentorial BM revealed a median OS of 11 months (95% confidence interval (CI) 7.4-14.6 months). Compared with this, median OS for the group of 61 individually matched patients with solitary supratentorial solitary BM was 13 months (95% CI 10.9-15.1 months) (p = 0.32). The present study suggests that the prognostic value of infra- and supratentorial BMs does not significantly differ in patients that undergo surgery for solitary BM. These results might encourage physicians to induce surgical therapy of supra- and infratentorial BM in a similar manner., (© 2023. The Author(s).)

The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has changed the clinical day-to-day practice. The aim of this study was to evaluate the impact of the pandemic on patients with high-grade glioma (HGG) as well as to derive best practice recommendations. We compared a multi-institutional cohort with HGG (n = 251) from 03/2020 to 05/2020 (n = 119) to a historical cohort from 03/2019 to 05/2019 (n = 132). The endpoints were outcome (progression-free survival (PFS) and overall survival (OS)) as well as patterns of care and time intervals between treatment steps. The median OS for WHO grade 4 gliomas was 12 months in 2019 (95% Confidence Interval 9.7-14.3 months), and not reached in 2020 (p = .026). There were no other significant differences in the Kaplan-Meier estimates for OS and PFS between cohorts of 2019 and 2020, neither did stratification by WHO grade reveal any significant differences for OS, PFS or for patterns of care. The time interval between cranial magnetic resonance imaging (cMRI) and biopsy was significantly longer in 2020 cohort (11 versus 21 days, p = .031). Median follow-up was 10 months (range 0-30 months). Despite necessary disease containment policies, it is crucial to ensure that patients with HGG are treated in line with the recent guidelines and standard of care (SOC) algorithms. Therefore, we strongly suggest pursuing no changes to SOC treatment, a timely diagnosis and treatment with short time intervals between first symptoms, initial diagnosis, and treatment, as well as a guideline-based cMRI follow-up., (© 2023. The Author(s).)

Purpose: Patients with brain metastasis (BM) from solid tumors are in an advanced stage of cancer. BM may occur during a known oncological disease (metachronous BM) or be the primary manifestation of previously unknown cancer (synchronous BM). The time of diagnosis might decisively impact patient prognosis and further treatment stratification. In the present study, we analyzed the prognostic impact of synchronous versus (vs.) metachronous BM occurrence following resection of BM., Methods: Between 2013 and 2018, 353 patients had undergone surgical therapy for BM at the authors' neuro-oncological center. Survival stratification calculated from the day of neurosurgical resection was performed for synchronous vs. metachronous BM diagnosis., Results: Non-small-cell lung carcinoma (NSCLC) was the most common tumor entity of primary site (43%) followed by gastrointestinal cancer (14%) and breast cancer (13%). Synchronous BM occurrence was present in 116 of 353 patients (33%), metachronous BM occurrence was present in 237 of 353 patients (67%). NSCLC was significantly more often diagnosed via resection of the BM (56% synchronous vs. 44% metachronous situation, p = 0.0001). The median overall survival for patients with synchronous BM diagnosis was 12 months (95% confidence interval (CI) 7.5-16.5) compared to 13 months (95% CI 9.6-16.4) for patients with metachronous BM diagnosis (p = 0.97)., Conclusions: The present study indicates that time of BM diagnosis (synchronous vs. metachronous) does not significantly impact patient survival following surgical therapy of BM. These results suggest that the indication for neurosurgical BM resection should be made regardless of a synchronous or a metachronous time of BM occurrence., (© 2023. The Author(s).)

Purpose: To determine the safety and outcome profile of five-fraction stereotactic radiotherapy (FSRT) for brain metastases (BM), either as a definitive or adjuvant treatment., Methods: We assessed clinical data of patients receiving five fractions of 7 Gy each (cumulative physical dose of 35 Gy) to BM or surgical cavities. The primary endpoints were toxicity and radiation necrosis (RN) rates. Secondary endpoints were 1-year cumulative local control rate (LCR) and estimated overall survival (OS)., Results: A total of 36 eligible patients receiving FSRT to a total of 49 targets were identified and included. The median follow up was 9 (1.1-56.2) months. The median age was 64.5 (34-92) years, the median ECOG score was 1, and the median Diagnostic-Specific Graded Prognostic Assessment (DS-GPA) score was 2. Treatment was well tolerated and there were no grade 3 adverse events or higher. The overall RN rate was 14.3% and the median time to RN was 12.9 (1.8-23.8) months. RN occurrence was associated with immunotherapy, young age (≤45 years), and large PTV. The cumulative 1-year local control rate was 83.1% and the estimated median local progression free-survival was 18.8 months. The estimated median overall survival was 11 (1.1-56.2) months and significantly superior in those patients presenting with RN., Conclusions: FSRT with 5 × 7 Gy represents a feasible, safe, and efficient fast track approach of intensified FSRT with acceptable LC and comparable RN rates for both the adjuvant and definitive RT settings.

Detection of tumor progression in patients with glioblastoma remains a major challenge. Extracellular vesicles (EVs) are potential biomarkers and can be detected in the blood of patients with glioblastoma. In our study, we evaluated the potential of serum-derived EVs from glioblastoma patients to serve as biomarker for tumor progression. EVs from serum of glioblastoma patients and healthy volunteers were separated by size exclusion chromatography and ultracentrifugation. EV markers were defined by using a proximity-extension assay and bead-based flow cytometry. Tumor progression was defined according to modified RANO criteria. EVs from the serum of glioblastoma patients (n = 67) showed an upregulation of CD29, CD44, CD81, CD146, C1QA and histone H3 as compared to serum EVs from healthy volunteers (P value range: <.0001 to .08). For two independent cohorts of glioblastoma patients, we noted upregulation of C1QA, CD44 and histone H3 upon tumor progression, but not in patients with stable disease. In a multivariable logistic regression analysis, a combination of CD29, CD44, CD81, C1QA and histone H3 correlated with RANO-defined tumor progression with an AUC of 0.76. Measurement of CD29, CD44, CD81, C1QA and histone H3 in serum-derived EVs of glioblastoma patients, along with standard MRI assessment, has the potential to improve detection of true tumor progression and thus could be a useful biomarker for clinical decision making., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Postoperative intensive care unit (ICU) monitoring is an established option to ensure patient safety after resection of newly diagnosed glioblastoma. In contrast, secondary unplanned ICU readmission following complicating events during the initial postoperative course might be associated with severe morbidity and impair initially intended surgical benefit. In the present study, we assessed the prognostic impact of secondary ICU readmission and aimed to identify preoperatively ascertainable risk factors for the development of such adverse events in patients treated surgically for newly diagnosed glioblastoma. Between 2013 and 2018, 240 patients were surgically treated for newly diagnosed glioblastoma at the authors' neuro-oncological center. Secondary ICU readmission was defined as any unplanned admission to the ICU during initial hospital stay. A multivariable logistic regression analysis was performed to identify preoperatively measurable risk factors for unplanned ICU readmission. Nineteen of 240 glioblastoma patients (8%) were readmitted to the ICU. Median overall survival of patients with unplanned ICU readmission was 9 months compared to 17 months for patients without secondary ICU readmission (p=0.008). Multivariable analysis identified "preoperative administration of dexamethasone > 7 days" (p=0.002) as a significant and independent predictor of secondary unplanned ICU admission. Secondary ICU readmission following surgery for newly diagnosed glioblastoma is significantly associated with poor survival and thus may negate surgically achieved prerequisites for further treatment. This underlines the indispensability of precise patient selection as well as the importance of further scientific debate on these highly relevant aspects for patient safety., (© 2023. The Author(s).)

Purpose: In the randomized phase III trial CeTeG/NOA-09, temozolomide (TMZ)/lomustine (CCNU) combination therapy was superior to TMZ in newly diagnosed MGMT methylated glioblastoma, albeit reporting more frequent hematotoxicity. Here, we analyze high grade hematotoxicity and its prognostic relevance in the trial population., Methods: Descriptive and comparative analysis of hematotoxicity adverse events ≥ grade 3 (HAE) according to the Common Terminology of Clinical Adverse Events, version 4.0 was performed. The association of HAE with survival was assessed in a landmark analysis. Logistic regression analysis was performed to predict HAE during the concomitant phase of chemotherapy., Results: HAE occurred in 36.4% and 28.6% of patients under CCNU/TMZ and TMZ treatment, respectively. The median onset of the first HAE was during concomitant chemotherapy (i.e. first CCNU/TMZ course or daily TMZ therapy), and 42.9% of patients with HAE receiving further courses experienced repeat HAE. Median HAE duration was similar between treatment arms (CCNU/TMZ 11.5; TMZ 13 days). Chemotherapy was more often discontinued due to HAE in CCNU/TMZ than in TMZ (19.7 vs. 6.3%, p = 0.036). The occurrence of HAE was not associated with survival differences (p = 0.76). Regression analysis confirmed older age (OR 1.08) and female sex (OR 2.47), but not treatment arm, as predictors of HAE., Conclusion: Older age and female sex are associated with higher incidence of HAE. Although occurrence of HAE was not associated with shorter survival, reliable prediction of patients at risk might be beneficial to allow optimal management of therapy and allocation of supportive measures., Trial Registration: NCT01149109., (© 2023. The Author(s).)

The MIB-1 index is an important risk factor for progression-free survival (PFS) in pituitary adenoma (PA). Preoperatively, the MIB-1 index is not available in the decision-making process. A preoperative method regarding MIB-1 index estimation in PA has not been evaluated so far. Between 2011 and 2021, 109 patients with tumor morphology data, MIB-1 index data, and inflammatory and pituitary hormone laboratory values underwent surgery for PA. An MIB-1 index cutoff point (≥4/<4%) determines the probability of PFS in completely resected PA. An elevated MIB-1 index (≥4%) was present in 32 cases (29.4%) and was significantly associated with increased IGF-1, age ≤ 60, increased ACTH, and increased fibrinogen levels in the multivariable analysis. A scoring system (“FATE”) using preoperative IGF-1, age, ACTH, and plasma fibrinogen level enables the estimation of the MIB-1 index (sensitivity 72%, specificity 68%). The FATE score is also significantly associated with the time to PA progression after the complete resection of the PA. We propose the FATE score to preoperatively estimate the risk of an elevated MIB-1 index (≥4%), which might enable tailoring to medical decision-making, and follow-up interval scheduling, as well as inform future studies analyzing proliferative activities.

Background: Maintenance of functioning and well-being during the progression-free survival (PFS) period is important for glioma patients. This study aimed to determine whether health-related quality of life (HRQoL) can be maintained during progression-free time, and factors associated with HRQoL deterioration in this period., Methods: We included longitudinal HRQoL data from previously published clinical trials in glioma. The percentage of patients with stable HRQoL until progression was determined per scale and at the individual patient level (i.e. considering all scales simultaneously). We assessed time to a clinically relevant deterioration in HRQoL, expressed in deterioration-free survival and time-to-deterioration (the first including progression as an event). We also determined the association between sociodemographic and clinical factors and HRQoL deterioration in the progression-free period., Results: Five thousand five hundred and thirty-nine patients with at least baseline HRQoL scores had a median time from randomization to progression of 7.6 months. Between 9-29% of the patients deteriorated before disease progression on the evaluated HRQoL scales. When considering all scales simultaneously, 47% of patients deteriorated on ≥1 scale. Median deterioration-free survival period ranged between 3.8-5.4 months, and median time-to-deterioration between 8.2-11.9 months. For most scales, only poor performance status was independently associated with clinically relevant HRQoL deterioration in the progression-free period., Conclusions: HRQoL was maintained in only 53% of patients in their progression-free period, and treatment was not independently associated with this deterioration in HRQoL. Routine monitoring of the patients' functioning and well-being during the entire disease course is therefore important, so that interventions can be initiated when problems are signaled., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

In light of increasing health-care costs, higher medical expenses should be justified socioeconomically. Therefore, we calculated the effectiveness and cost effectiveness of PET using the radiolabeled amino acid O -(2- 18 F-fluoroethyl)-l-tyrosine ( 18 F-FET) compared with conventional MRI for early identification of responders to adjuvant temozolomide chemotherapy. A recently published study in isocitrate dehydrogenase wild-type glioma patients suggested that 18 F-FET PET parameter changes predicted a significantly longer survival already after 2 cycles whereas MRI changes were not significant. Methods: To determine the effectiveness and cost effectiveness of serial 18 F-FET PET imaging, we analyzed published clinical data and calculated the associated costs from the perspective of the German Statutory Health Insurance system. Based on a decision-tree model, the effectiveness of 18 F-FET PET and MRI was calculated-that is, the probability to correctly identify a responder as defined by an overall survival of at least 15 mo. To determine the cost effectiveness, the incremental cost effectiveness ratio (ICER) was calculated-that is, the cost for each additionally identified responder by 18 F-FET PET who would have remained undetected by MRI. The robustness of the results was tested by deterministic and probabilistic Monte Carlo sensitivity analyses. Results: Compared with MRI, 18 F-FET PET increased the rate of correctly identified responders to chemotherapy by 26%; thus, 4 patients needed to be examined by 18 F-FET PET to identify 1 additional responder. Considering the respective costs for serial 18 F-FET PET and MRI, the ICER resulted in €4,396.83 for each additional correctly identified responder by 18 F-FET PET. Sensitivity analyses confirmed the robustness of the results. Conclusion: In contrast to conventional MRI, the model suggests that 18 F-FET PET is cost-effective in terms of ICER values. Considering the high cost of temozolomide, the integration of 18 F-FET PET has the potential to avoid premature chemotherapy discontinuation at reasonable cost., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective: Patients with spinal metastasis (SM) are at advanced stages of systemic cancer disease. Surgical therapy for SM is a common treatment modality enabling histopathological diagnosis and the prevention of severe neurological deficits. However, surgery for SM in this vulnerable patient cohort may require prolonged postoperative intensive care treatment, which could adversely affect the anticipated benefit of the surgery. We therefore assessed postoperative prolonged mechanical ventilation (PMV) as an indicator for intensive care treatment with regard to potential correlations with early postoperative mortality and overall survival (OS)., Methods: Between 2015 and 2019, 198 patients were surgically treated for SM at the author´s neurosurgical department. PMV was defined as postoperative mechanical ventilation of more than 24 hours. A multivariate analysis was performed to identify pre- and perioperative collectable predictors for 30 days mortality., Results: Twenty out of 198 patients (10%) with SM suffered from postoperative PMV. Patients with PMV exhibited a median OS rate of 1 month compared to 12 months for patients without PMV (p < 0.0001). The 30 days mortality was 70% and after one year 100%. The multivariate analysis identified "PMV > 24 hrs" (p < 0.001, OR 0.3, 95% CI 0.02-0.4) as the only significant and independent predictor for 30 days mortality (Nagelkerke's R2 0.38)., Conclusions: Our data indicate postoperative PMV to significantly correlate to high early postoperative mortality rates as well as to poor OS in patients with surgically treated SM. These findings might encourage the initiation of further multicenter studies to comprehensively investigate PMV as a so far underestimated negative prognostic factor in the course of surgical treatment for SM., 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 Hamed, Brandecker, Rana, Potthoff, Eichhorn, Bode, Schmeel, Radbruch, Schäfer, Herrlinger, Köksal, Giordano, Vatter, Schneider and Banat.)

Patients with BM are in advanced stages of systemic cancer, which may translate into significant alterations of body composition biomarkers, such as BMD. The present study investigated the prognostic value of BMD on overall survival (OS) of 95 patients with surgically-treated BM related to NSCLC. All patients were treated in a large tertiary care neuro-oncological center between 2013 and 2018. Preoperative BMD was determined from the first lumbar vertebrae (L1) from routine preoperative staging computed tomography (CT) scans. Results were stratified into pathologic and physiologic values according to recently published normative reference ranges and correlated with survival parameters. Median preoperative L1-BMD was 99 Hounsfield units (HU) (IQR 74-195) compared to 140 HU (IQR 113-159) for patients with pathological and physiologic BMD ( p = 0.03), with a median OS of 6 versus 15 months ( p = 0.002). Multivariable analysis revealed pathologic BMD as an independent prognostic predictor for increased 1-year mortality ( p = 0.03, OR 0.5, 95% CI 0.2-1.0). The present study suggests that decreased preoperative BMD values may represent a previously unrecognized negative prognostic factor in patients of BM requiring surgery for NSCLC. Based on guideline-adherent preoperative staging, BMD may prove to be a highly individualized, readily available biomarker for prognostic assessment and treatment guidance in affected patients.

MIB-1 index is an important predictor of meningioma progression and was found to be correlated with COX-2 expression. However, the impact of low-dose acetylsalicylic acid (ASA) on MIB-1 index and clinical symptoms is unclear. Between 2009 and 2022, 710 patients with clinical data, tumor-imaging data, inflammatory laboratory (plasma fibrinogen, serum C-reactive protein) data, and neuropathological reports underwent surgery for primary cranial WHO grade 1 and 2 meningioma. ASA intake was found to be significantly associated with a low MIB-1 labeling index in female patients ≥ 60 years. Multivariable analysis demonstrated that female patients ≥ 60 years with a non-skull-base meningioma taking ASA had a significantly lower MIB-1 index (OR: 2.6, 95%: 1.0-6.6, p = 0.04). Furthermore, the intake of ASA was independently associated with a reduced burden of symptomatic epilepsy at presentation in non-skull-base meningiomas in both genders (OR: 3.8, 95%CI: 1.3-10.6, p = 0.03). ASA intake might have an anti-proliferative effect in the subgroup of elderly female patients with non-skull-base meningiomas. Furthermore, anti-inflammatory therapy seems to reduce the burden of symptomatic epilepsy in non-skull-base meningiomas. Further research is needed to investigate the role of anti-inflammatory therapy in non-skull-base meningiomas.

Objective: MIB-1 index is an important predictor of meningioma progression. However, MIB-1 index is not available in the preoperative tailored medical decision-making process. A preoperative scoring sheet independently estimating MIB-1 indices in spinal meningioma (SM) patients has not been investigated so far., Methods: Between 2000 and 2020, 128 patients with clinical data, tumor imaging data, inflammatory laboratory (plasma fibrinogen, serum C-reactive protein) data, and neuropathological reports (MIB-1, mitotic count, CD68 staining) underwent surgery for spinal WHO grade 1 and 2 meningioma., Results: An optimal MIB-1 index cut-off value (≥5/<5) predicting recurrence was calculated by ROC curve analysis (AUC: 0.83; 95%CI: 0.71-0.96). An increased MIB-1 index (≥5%) was observed in 55 patients (43.0%) and multivariable analysis revealed significant associations with baseline Modified McCormick Scale ≥2, age ≥65, and absence of calcification. A four-point scoring sheet (MAC-Spinal Meningioma) based on M odified McCormick, A ge, and C alcification facilitates prediction of the MIB-1 index (sensitivity 71.1%, specificity 60.0%). Among those patients with a preoperative MAC-Meningioma Score ≥3, the probability of a MIB-1 index ≥5% was 81.3%., Conclusion: This novel score (MAC-Spinal Meningioma) supports the preoperative estimation of an increased MIB-1 index, which might support preoperative patient-surgeon consultation, surgical decision making and enable a tailored follow-up schedule or an individual watch-and-wait strategy., 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 Wach, Hamed, Lampmann, Güresir, Schmeel, Becker, Herrlinger, Vatter and Güresir.)

Background: The randomized phase 3 CeTeG/NOA-09 trial assessed whether CCNU plus temozolomide was superior to temozolomide alone in newly diagnosed MGMT promoter methylated glioblastoma patients. Survival was significantly improved from 31.4 months (temozolomide) to 48.1 months (CCNU plus temozolomide). In view of this encouraging data, we assessed safety and efficacy of this regimen under real-life conditions., Methods: We retrospectively collected clinical and radiographic data from adult newly diagnosed MGMT promoter methylated IDH wildtype glioblastoma patients from five neuro-oncology centers in Germany. For inclusion in our analysis, treatment with CCNU and temozolomide had to be performed for at least six weeks (one course)., Results: Seventy patients were included. Median progression-free survival was 14.4 months and median overall survival 33.8 months. Patients with TTFields treatment for at least 8 weeks and CCNU plus temozolomide ( n  = 22, 31%) had a prolonged progression-free survival compared to those with TTFields treatment for less than eight weeks ( n  = 48, 69%) (21.5 versus 11.2 months; P  = .0105). In a multivariable Cox regression analysis, TTFields treatment for eight weeks or longer together with CCNU plus temozolomide and a Karnofsky performance score ≥ 90% were independent prognostic factors for progression-free and overall survival. Pseudoprogression occurred in n  = 16 (33%) of investigated n  = 49 (70%) patients. In n  = 31 (44%) patients high-grade hematotoxicity was observed., Conclusions: The results from this multicentric trial indicate that-under real-life conditions-toxicity and survival estimates are comparable to the CeTeG/NOA-09 trial. TTFields therapy for at least eight weeks in combination with this regimen was independently associated with prolonged survival., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Cancer cells can organize and communicate in functional networks. Similarly to other networks in biology and sociology, these can be highly relevant for growth and resilience. In this Perspective, we demonstrate by the example of glioblastomas and other incurable brain tumours how versatile multicellular tumour networks are formed by two classes of long intercellular membrane protrusions: tumour microtubes and tunnelling nanotubes. The resulting networks drive tumour growth and resistance to standard therapies. This raises the question of how to disconnect brain tumour networks to halt tumour growth and whether this can make established therapies more effective. Emerging principles of tumour networks, their potential relevance for tumour types outside the brain and translational implications, including clinical trials that are already based on these discoveries, are discussed., (© 2022. Springer Nature Limited.)

Purpose: The role of obesity in glioblastoma remains unclear, as previous analyses have reported contradicting results. Here, we evaluate the prognostic impact of obesity in two trial populations; CeTeG/NOA-09 (n = 129) for MGMT methylated glioblastoma patients comparing temozolomide (TMZ) to lomustine/TMZ, and GLARIUS (n = 170) for MGMT unmethylated glioblastoma patients comparing TMZ to bevacizumab/irinotecan, both in addition to surgery and radiotherapy., Methods: The impact of obesity (BMI ≥ 30 kg/m 2 ) on overall survival (OS) and progression-free survival (PFS) was investigated with Kaplan-Meier analysis and log-rank tests. A multivariable Cox regression analysis was performed including known prognostic factors as covariables., Results: Overall, 22.6% of patients (67 of 297) were obese. Obesity was associated with shorter survival in patients with MGMT methylated glioblastoma (median OS 22.9 (95% CI 17.7-30.8) vs. 43.2 (32.5-54.4) months for obese and non-obese patients respectively, p = 0.001), but not in MGMT unmethylated glioblastoma (median OS 17.1 (15.8-18.9) vs 17.6 (14.7-20.8) months, p = 0.26). The prognostic impact of obesity in MGMT methylated glioblastoma was confirmed in a multivariable Cox regression (adjusted odds ratio: 2.57 (95% CI 1.53-4.31), p < 0.001) adjusted for age, sex, extent of resection, baseline steroids, Karnofsky performance score, and treatment arm., Conclusion: Obesity was associated with shorter survival in MGMT methylated, but not in MGMT unmethylated glioblastoma patients., (© 2022. The Author(s).)

Abducens nerve palsy is a severe dysfunction after petroclival meningioma (PC MNG) surgery. The objective of this investigation was to analyze abducens nerve outcomes in patients who underwent the retrosigmoid approach in relation to the MIB-1 index. Thirty-two patients with primary sporadic PC MNG were retrospectively analyzed. Mean follow-up was 28.0 months. Analysis of the MIB-1 index was performed to evaluate the abducens nerve outcome. An optimal MIB-1 index cut-off value (<4/≥4) in the association with postoperative CN VI palsy was determined by ROC analysis (AUC: 0.74, 95% CI: 0.57−0.92). A new-onset CN VI palsy was present in 7 cases (21.88%) and was significantly associated with an increased MIB-1 index (≥4%, p = 0.025) and a peritumoral edema in the brachium pontis (p = 0.047) which might be caused by the increased growth rate. Tumor volume, cavernous sinus infiltration, auditory canal invasion, and Simpson grading were not associated with new CN VI deficits. Six (85.7%) of the 7 patients with both an increased MIB-1 index (≥4%) and new abducens nerve palsy still had a CN VI deficit at the 12-month follow-up. A peritumoral edema caused by a highly proliferative PC MNG with an elevated MIB-1 index (≥4%) is associated with postoperative abducens nerve deficits.