A prognostic neural epigenetic signature in high-grade glioma.

Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is limited. We present an epigenetically defined neural signature of glioblastoma that independently predicts patients' survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals a high abundance of malignant stemcell-like cells in high-neural glioblastoma, primarily of the neural lineage. These cells are further classified as neural-progenitor-cell-like, astrocyte-like and oligodendrocyte-progenitor-like, alongside oligodendrocytes and excitatory neurons. In line with these findings, high-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature is associated with decreased overall and progression-free survival. High-neural tumors also exhibit increased functional connectivity in magnetencephalography and resting-state magnet resonance imaging and can be detected via DNA analytes and brain-derived neurotrophic factor in patients' plasma. The prognostic importance of the neural signature was further validated in patients diagnosed with diffuse midline glioma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant. High-neural gliomas likely require a maximized surgical resection approach for improved outcomes.

Sex-dependent characteristics and outcomes after clipping of unruptured intracranial aneurysms: a multicenter propensity score-matched study.

OBJECTIVE: Disparities in the epidemiology and growth rates of aneurysms between the sexes are known. However, little is known about sex-dependent outcomes after microsurgical clipping of unruptured intracranial aneurysms (UIAs). The aim of this study was to examine sex differences in characteristics and outcomes after microsurgical clipping of UIAs and to perform a propensity score-matched analysis using an international multicenter cohort. METHODS: This retrospective cohort study involved the participation of 15 centers spanning four continents. It included adult patients who underwent clipping of UIAs between January 2016 and December 2020. Patients were stratified according to their sex and analyzed for differences in morbidities and aneurysm characteristics. Based on this stratification, female patients were matched to male patients in a 1:1 ratio with a caliper width of 0.1 using propensity score matching. Endpoints included postoperative complications, neurological performance, and aneurysm occlusion at discharge and 24 months after clip placement. RESULTS: A total of 2245 patients with a mean age of 57.3 (range 20-87) years were included. Of these patients, 1675 (74.6%) were female. Female patients were significantly older (mean 57.6 vs 56.4 years, p = 0.03) but had fewer comorbidities. Aneurysms of the internal carotid artery (7.1% vs 4.2%), posterior communicating artery (6.9% vs 1.9%), and ophthalmic artery (6.0% vs 2.8%) were more commonly treated surgically in females, while clipping of aneurysms of the anterior communicating artery was more frequent in males (17.0% vs 25.3%; all p < 0.001). After propensity score matching, female patients were found to have had significantly fewer pulmonary complications (1.4% vs 4.2%, p = 0.01). However, general morbidity (24.5% vs 25.2%, p = 0.72) and mortality (0.5% vs 1.1%, p = 0.34), as well as neurological performance (p = 0.58), were comparable at discharge in both sexes. Lastly, rates of aneurysm occlusion at the time of discharge (95.5% vs 94.9%, p = 0.71) and 24 months after surgery (93.8% vs 96.1%, p = 0.22) did not significantly differ between male and female patients. CONCLUSIONS: Despite overall differences between male and female patients in demographics, comorbidities, and treated aneurysm location, sex did not relevantly affect surgical performance or perioperative complication rates.

Circulating extracellular vesicles as biomarker for diagnosis, prognosis and monitoring in glioblastoma patients.

BACKGROUND: Extracellular vesicles (EVs) obtained by noninvasive liquid biopsy from patient blood can serve as biomarkers. Here, we investigated the potential of circulating plasma EVs to serve as an indicator in the diagnosis, prognosis and treatment response of glioblastoma patients. METHODS: Plasma samples were collected from glioblastoma patients at multiple timepoints before and after surgery. EV concentrations were measured by nanoparticle tracking analysis and imaging flow cytometry. Tumor burden and edema were quantified by 3D reconstruction. EVs and tumors were further monitored in glioma-bearing mice. RESULTS: Glioblastoma patients displayed a 5.5-fold increase in circulating EVs compared to healthy donors (p < 0.0001). Patients with higher EV levels had a significantly shorter overall survival and progression-free survival than patients with lower levels, and the plasma EV concentration was an independent prognostic parameter for overall survival. EV levels correlated with the extent of peritumoral FLAIR hyperintensity but not with the size of the contrast-enhancing tumor, and similar findings were obtained in mice. Postoperatively, EV concentrations decreased rapidly back to normal levels, and the magnitude of the decline was associated with the extent of tumor resection. EV levels remained low during stable disease, but increased again upon tumor recurrence. In some patients, EV resurgence preceded the magnetic resonance imaging (MRI) detectability of tumor relapse. CONCLUSIONS: Our findings suggest that leakiness of the blood-brain barrier may primarily be responsible for the high circulating EV concentrations in glioblastoma patients. Elevated EVs reflect tumor presence, and their quantification may thus be valuable in assessing disease activity.

Temporal change of DNA methylation subclasses between matched newly diagnosed and recurrent glioblastoma.

The longitudinal transition of phenotypes is pivotal in glioblastoma treatment resistance and DNA methylation emerged as an important tool for classifying glioblastoma phenotypes. We aimed to characterize DNA methylation subclass heterogeneity during progression and assess its clinical impact. Matched tissues from 47 glioblastoma patients were subjected to DNA methylation profiling, including CpG-site alterations, tissue and serum deconvolution, mass spectrometry, and immunoassay. Effects of clinical characteristics on temporal changes and outcomes were studied. Among 47 patients, 8 (17.0%) had non-matching classifications at recurrence. In the remaining 39 cases, 28.2% showed dominant DNA methylation subclass transitions, with 72.7% being a mesenchymal subclass. In general, glioblastomas with a subclass transition showed upregulated metabolic processes. Newly diagnosed glioblastomas with mesenchymal transition displayed increased stem cell-like states and decreased immune components at diagnosis and exhibited elevated immune signatures and cytokine levels in serum. In contrast, tissue of recurrent glioblastomas with mesenchymal transition showed increased immune components but decreased stem cell-like states. Survival analyses revealed comparable outcomes for patients with and without subclass transitions. This study demonstrates a temporal heterogeneity of DNA methylation subclasses in 28.2% of glioblastomas, not impacting patient survival. Changes in cell state composition associated with subclass transition may be crucial for recurrent glioblastoma targeted therapies.

Microsurgical Clipping of Unruptured Anterior Circulation Aneurysms-A Global Multicenter Investigation of Perioperative Outcomes.

BACKGROUND AND OBJECTIVES: Microsurgical aneurysm repair by clipping continues to be highly important despite increasing endovascular treatment options, especially because of inferior occlusion rates. This study aimed to present current global microsurgical treatment practices and to identify risk factors for complications and neurological deterioration after clipping of unruptured anterior circulation aneurysms. METHODS: Fifteen centers from 4 continents participated in this retrospective cohort study. Consecutive patients who underwent elective microsurgical clipping of untreated unruptured intracranial aneurysm between January 2016 and December 2020 were included. Posterior circulation aneurysms were excluded. Outcome parameters were postsurgical complications and neurological deterioration (defined as decline on the modified Rankin Scale) at discharge and during follow-up. Multivariate regression analyses were performed adjusting for all described patient characteristics. RESULTS: Among a total of 2192 patients with anterior circulation aneurysm, complete occlusion of the treated aneurysm was achieved in 2089 (95.3%) patients at discharge. The occlusion rate remained stable (94.7%) during follow-up. Regression analysis identified hypertension (P < .02), aneurysm diameter (P < .001), neck diameter (P < .05), calcification (P < .01), and morphology (P = .002) as preexisting risk factors for postsurgical complications and neurological deterioration at discharge. Furthermore, intraoperative aneurysm rupture (odds ratio 2.863 [CI 1.606-5.104]; P < .01) and simultaneous clipping of more than 1 aneurysm (odds ratio 1.738 [CI 1.186-2.545]; P < .01) were shown to be associated with an increased risk of postsurgical complications. Yet, none of the surgical-related parameters had an impact on neurological deterioration. Analyzing volume-outcome relationship revealed comparable complication rates (P = .61) among all 15 participating centers. CONCLUSION: Our international, multicenter analysis presents current microsurgical treatment practices in patients with anterior circulation aneurysms and identifies preexisting and surgery-related risk factors for postoperative complications and neurological deterioration. These findings may assist in decision-making for the optimal therapeutic regimen of unruptured anterior circulation aneurysms.

Classification of Brain Tumors by Nanopore Sequencing of Cell-Free DNA from Cerebrospinal Fluid.

BACKGROUND: Molecular brain tumor diagnosis is usually dependent on tissue biopsies or resections. This can pose several risks associated with anesthesia or neurosurgery, especially for lesions in the brain stem or other difficult-to-reach anatomical sites. Apart from initial diagnosis, tumor progression, recurrence, or the acquisition of novel genetic alterations can only be proven by re-biopsies. METHODS: We employed Nanopore sequencing on cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) and analyzed copy number variations (CNV) and global DNA methylation using a random forest classifier. We sequenced 129 samples with sufficient DNA. These samples came from 99 patients and encompassed 22 entities. Results were compared to clinical diagnosis and molecular analysis of tumor tissue, if available. RESULTS: 110/129 samples were technically successful, and 50 of these contained detectable circulating tumor DNA (ctDNA) by CNV or methylation profiling. ctDNA was detected in samples from patients with progressive disease but also from patients without known residual disease. CNV plots showed diagnostic and prognostic alterations, such as C19MC amplifications in embryonal tumors with multilayered rosettes or Chr.1q gains and Chr.6q losses in posterior fossa group A ependymoma, respectively. Most CNV profiles mirrored the profiles of the respective tumor tissue. DNA methylation allowed exact classification of the tumor in 22/110 cases and led to incorrect classification in 2/110 cases. Only 5/50 samples with detected ctDNA contained tumor cells detectable through microscopy. CONCLUSIONS: Our results suggest that Nanopore sequencing data of cfDNA from CSF samples may be a promising approach for initial brain tumor diagnostics and an important tool for disease monitoring.

Global Outcomes for Microsurgical Clipping of Unruptured Intracranial Aneurysms: A Benchmark Analysis of 2245 Cases.

BACKGROUND AND OBJECTIVES: Benchmarks represent the best possible outcome and help to improve outcomes for surgical procedures. However, global thresholds mirroring an optimal and reachable outcome for microsurgical clipping of unruptured intracranial aneurysms (UIA) are not available. This study aimed to define standardized outcome benchmarks in patients who underwent clipping of UIA. METHODS: A total of 2245 microsurgically treated UIA from 15 centers were analyzed. Patients were categorized into low- ("benchmark") and high-risk ("nonbenchmark") patients based on known factors affecting outcome. The benchmark was defined as the 75th percentile of all centers' median scores for a given outcome. Benchmark outcomes included intraoperative (eg, duration of surgery, blood transfusion), postoperative (eg, reoperation, neurological status), and aneurysm-related factors (eg, aneurysm occlusion). Benchmark cutoffs for aneurysms of the anterior communicating/anterior cerebral artery, middle cerebral artery, and posterior communicating artery were determined separately. RESULTS: Of the 2245 cases, 852 (37.9%) patients formed the benchmark cohort. Most operations were performed for middle cerebral artery aneurysms (53.6%), followed by anterior communicating and anterior cerebral artery aneurysms (25.2%). Based on the results of the benchmark cohort, the following benchmark cutoffs were established: favorable neurological outcome (modified Rankin scale ≤2) ≥95.9%, postoperative complication rate ≤20.7%, length of postoperative stay ≤7.7 days, asymptomatic stroke ≤3.6%, surgical site infection ≤2.7%, cerebral vasospasm ≤2.5%, new motor deficit ≤5.9%, aneurysm closure rate ≥97.1%, and at 1-year follow-up: aneurysm closure rate ≥98.0%. At 24 months, benchmark patients had a better score on the modified Rankin scale than nonbenchmark patients. CONCLUSION: This study presents internationally applicable benchmarks for clinically relevant outcomes after microsurgical clipping of UIA. These benchmark cutoffs can serve as reference values for other centers, patient registries, and for comparing the benefit of other interventions or novel surgical techniques.

Machine learning based outcome prediction of microsurgically treated unruptured intracranial aneurysms.

Machine learning (ML) has revolutionized data processing in recent years. This study presents the results of the first prediction models based on a long-term monocentric data registry of patients with microsurgically treated unruptured intracranial aneurysms (UIAs) using a temporal train-test split. Temporal train-test splits allow to simulate prospective validation, and therefore provide more accurate estimations of a model's predictive quality when applied to future patients. ML models for the prediction of the Glasgow outcome scale, modified Rankin Scale (mRS), and new transient or permanent neurological deficits (output variables) were created from all UIA patients that underwent microsurgery at the Kepler University Hospital Linz (Austria) between 2002 and 2020 (n = 466), based on 18 patient- and 10 aneurysm-specific preoperative parameters (input variables). Train-test splitting was performed with a temporal split for outcome prediction in microsurgical therapy of UIA. Moreover, an external validation was conducted on an independent external data set (n = 256) of the Department of Neurosurgery, University Medical Centre Hamburg-Eppendorf. In total, 722 aneurysms were included in this study. A postoperative mRS > 2 was best predicted by a quadratic discriminant analysis (QDA) estimator in the internal test set, with an area under the receiver operating characteristic curve (ROC-AUC) of 0.87 ± 0.03 and a sensitivity and specificity of 0.83 ± 0.08 and 0.71 ± 0.07, respectively. A Multilayer Perceptron predicted the post- to preoperative mRS difference > 1 with a ROC-AUC of 0.70 ± 0.02 and a sensitivity and specificity of 0.74 ± 0.07 and 0.50 ± 0.04, respectively. The QDA was the best model for predicting a permanent new neurological deficit with a ROC-AUC of 0.71 ± 0.04 and a sensitivity and specificity of 0.65 ± 0.24 and 0.60 ± 0.12, respectively. Furthermore, these models performed significantly better than the classic logistic regression models (p < 0.0001). The present results showed good performance in predicting functional and clinical outcomes after microsurgical therapy of UIAs in the internal data set, especially for the main outcome parameters, mRS and permanent neurological deficit. The external validation showed poor discrimination with ROC-AUC values of 0.61, 0.53 and 0.58 respectively for predicting a postoperative mRS > 2, a pre- and postoperative difference in mRS > 1 point and a GOS < 5. Therefore, generalizability of the models could not be demonstrated in the external validation. A SHapley Additive exPlanations (SHAP) analysis revealed that this is due to the most important features being distributed quite differently in the internal and external data sets. The implementation of newly available data and the merging of larger databases to form more broad-based predictive models is imperative in the future.

Epigenetic profiling reveals a strong association between lack of 5-ALA fluorescence and EGFR amplification in IDH-wildtype glioblastoma.

Background: 5-aminolevulinic acid (5-ALA) fluorescence-guided resection increases the percentage of complete CNS tumor resections and improves the progression-free survival of IDH-wildtype glioblastoma patients. A small subset of IDH-wildtype glioblastoma shows no 5-ALA fluorescence. An explanation for these cases is missing. In this study, we used DNA methylation profiling to further characterize non-fluorescent glioblastomas. Methods: Patients with newly diagnosed and recurrent IDH-wildtype glioblastoma that underwent surgery were analyzed. The intensity of intraoperative 5-ALA fluorescence was categorized as non-visible or visible. DNA was extracted from tumors and genome-wide DNA methylation patterns were analyzed using Illumina EPIC (850k) arrays. Furthermore, 5-ALA intensity was measured by flow cytometry on human gliomasphere lines (BT112 and BT145). Results: Of 74 included patients, 12 (16.2%) patients had a non-fluorescent glioblastoma, which were compared to 62 glioblastomas with 5-ALA fluorescence. Clinical characteristics were equally distributed between both groups. We did not find significant differences between DNA methylation subclasses and 5-ALA fluorescence (P = .24). The distribution of cells of the tumor microenvironment was not significantly different between the non-fluorescent and fluorescent tumors. Copy number variations in EGFR and simultaneous EGFRvIII expression were strongly associated with 5-ALA fluorescence since all non-fluorescent glioblastomas were EGFR-amplified (P < .01). This finding was also demonstrated in recurrent tumors. Similarly, EGFR-amplified glioblastoma cell lines showed no 5-ALA fluorescence after 24 h of incubation. Conclusions: Our study demonstrates an association between non-fluorescent IDH-wildtype glioblastomas and EGFR gene amplification which should be taken into consideration for recurrent surgery and future studies investigating EGFR-amplified gliomas.

Epigenetic neural glioblastoma enhances synaptic integration and predicts therapeutic vulnerability.

Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is nascent. We present an epigenetically defined neural signature of glioblastoma that independently affects patients' survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals high abundance of stem cell-like malignant cells classified as oligodendrocyte precursor and neural precursor cell-like in high-neural glioblastoma. High-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature associates with decreased survival as well as increased functional connectivity and can be detected via DNA analytes and brain-derived neurotrophic factor in plasma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant.

Association of the classification of intraoperative adverse events (ClassIntra) with complications and neurological outcome after neurosurgical procedures: a prospective cohort study.

PURPOSE: To analyze the reliability of the classification of intraoperative adverse events (ClassIntra) to reflect intraoperative complications of neurosurgical procedures and the potential to predict the postoperative outcome including the neurological performance. The ClassIntra classification was recently introduced and found to be reliable for assessing intraoperative adverse events and predicting postoperative complications across different surgical disciplines. Nevertheless, its potential role for neurosurgical procedures remains elusive. METHODS: This is a prospective, monocentric cohort study assessing the ClassIntra in 422 adult patients who underwent a neurosurgical procedure and were hospitalized between July 1, 2021, to December 31, 2021. The primary outcome was the occurrence of intraoperative complications graded according to ClassIntra and the association with postoperative outcome reflected by the Clavien-Dindo classification and comprehensive complication index (CCI). The ClassIntra is defined as intraoperative adverse events as any deviation from the ideal course on a grading scale from grade 0 (no deviation) to grade V (intraoperative death) and was set at sign-out in agreement between neurosurgeon and anesthesiologist. Secondary outcomes were the neurological outcome after surgery as defined by Glasgow Coma Scale (GCS), modified Rankin scale (mRS), Neurologic Assessment in Neuro-Oncology (NANO) scale, National Institute Health of Strokes Scale (NIHSS), and Karnofsky Performance Score (KPS), and need for unscheduled brain scan. RESULTS: Of 442 patients (mean [SD] age, 56.1 [16.2]; 235 [55.7%] women and 187 [44.3%] men) who underwent a neurosurgical procedure, 169 (40.0%) patients had an intraoperative adverse event (iAE) classified as ClassIntra I or higher. The NIHSS score at admission (OR, 1.29; 95% CI, 1.03-1.63, female gender (OR, 0.44; 95% CI, 0.23-0.84), extracranial procedures (OR, 0.17; 95% CI, 0.08-0.61), and emergency cases (OR, 2.84; 95% CI, 1.53-3.78) were independent risk factors for a more severe iAE. A ClassIntra ≥ II was associated with increased odds of postoperative complications classified as Clavien-Dindo (p < 0.01), neurological deterioration at discharge (p < 0.01), prolonged hospital (p < 0.01), and ICU stay (p < 0.01). For elective craniotomies, severity of ClassIntra was associated with the CCI (p < 0.01) and need for unscheduled CT or MRI scan (p < 0.01). The proportion of a ClassIntra ≥ II was significantly higher for emergent craniotomies (56.2%) and associated with in-hospital mortality, and an unfavorable neurological outcome (p < 0.01). CONCLUSION: Findings of this study suggest that the ClassIntra is sensitive for assessing intraoperative adverse events and sufficient to identify patients with a higher risk for developing postoperative complications after a neurosurgical procedure.

Multiple craniotomies in a single surgery - the resection of scattered brain metastases.

Patients with brain metastases (BM), who can benefit from resection of multiple scattered lesions, often will not be offered a procedure involving multiple craniotomies in one session due to the overall poor prognosis. However, carefully selected candidates may well benefit from the resection of multiple lesions using multiple craniotomies through a significantly shortened hospital stay, aggressive decompression, and rapid eligibility for adjuvant therapies. In this retrospective analysis, the records of patients, who were treated for multiple BM using one surgical session involving multiple craniotomies, were reviewed. A group of patients with multiple BM, whose surgery only involved one craniotomy, were assigned to a control group. Clinical and surgical characteristics, preoperative and postoperative Karnofsky Performance Scale (KPS), complication rate, preoperative tumor size, number of lesions, number of craniotomies, skin incisions, and intraoperative repositioning of patients were recorded. Thirty-three patients were included in the multiple-craniotomy group. Thirty patients underwent two craniotomies, while three cases involved three craniotomies. Seven patients (21%) were intraoperatively repositioned from a prone to a supine position, which required an average of 23.3 ± 9.3 min from wound closure to the following skin incision. Thirty-six patients with multiple BM and matching characteristics, who received only one craniotomy for the dominant lesion, served as the control group. No difference was detected in postoperative KPS (p = 0.269), complication rate (p = 0.612), rate of new postoperative neurological deficits (p = 0.278), length of intensive care unit (ICU) (p = 0.991), and hospital stay (p = 0.913). There was a significant difference in average preoperative tumor size (p = 0.002), duration of surgery (p < 0.001), and extent of resection (p = 0.002). In the age of personalized medicine, selected patient may benefit from a single surgery for BM using multiple craniotomies. This study shows no significant increase of the perioperative complication rate for surgeries with multiple craniotomies.

Adult intracranial ependymoma-relevance of DNA methylation profiling for diagnosis, prognosis, and treatment.

BACKGROUND: A methylation-based classification of ependymoma has recently found broad application. However, the diagnostic advantage and implications for treatment decisions remain unclear. Here, we retrospectively evaluate the impact of surgery and radiotherapy on outcome after molecular reclassification of adult intracranial ependymomas. METHODS: Tumors diagnosed as intracranial ependymomas from 170 adult patients collected from 8 diagnostic institutions were subjected to DNA methylation profiling. Molecular classes, patient characteristics, and treatment were correlated with progression-free survival (PFS). RESULTS: The classifier indicated an ependymal tumor in 73.5%, a different tumor entity in 10.6%, and non-classifiable tumors in 15.9% of cases, respectively. The most prevalent molecular classes were posterior fossa ependymoma group B (EPN-PFB, 32.9%), posterior fossa subependymoma (PF-SE, 25.9%), and supratentorial ZFTA fusion-positive ependymoma (EPN-ZFTA, 11.2%). With a median follow-up of 60.0 months, the 5- and 10-year-PFS rates were 64.5% and 41.8% for EPN-PFB, 67.4% and 45.2% for PF-SE, and 60.3% and 60.3% for EPN-ZFTA. In EPN-PFB, but not in other molecular classes, gross total resection (GTR) (P = .009) and postoperative radiotherapy (P = .007) were significantly associated with improved PFS in multivariable analysis. Histological tumor grading (WHO 2 vs. 3) was not a predictor of the prognosis within molecularly defined ependymoma classes. CONCLUSIONS: DNA methylation profiling improves diagnostic accuracy and risk stratification in adult intracranial ependymoma. The molecular class of PF-SE is unexpectedly prevalent among adult tumors with ependymoma histology and relapsed as frequently as EPN-PFB, despite the supposed benign nature. GTR and radiotherapy may represent key factors in determining the outcome of EPN-PFB patients.

Corticosteroid-Dependent Leukocytosis Masks the Predictive Potential of White Blood Cells for Delayed Cerebral Ischemia and Ventriculoperitoneal Shunt Dependency in Aneurysmatic Subarachnoid Hemorrhage.

A multitude of pathological and inflammatory processes determine the clinical course after aneurysmal subarachnoid hemorrhage (aSAH). However, our understanding of predictive factors and therapeutic consequences is limited. We evaluated the predictive value of clinically relevant factors readily available in the ICU setting, such as white blood cell (WBC) count and CRP, for two of the leading comorbidities, delayed cerebral ischemia (DCI) and ventriculoperitoneal (VP) shunt dependency in aSAH patients with and without corticosteroid treatment. We conducted a retrospective analysis of 484 aSAH patients admitted to our institution over an eight-year period. Relevant clinical factors affecting the risk of DCI and VP shunt dependency were identified and included in a multivariate logistic regression model. Overall, 233/484 (48.1%) patients were treated with corticosteroids. Intriguingly, predictive factors associated with the occurrence of DCI differed significantly depending on the corticosteroid treatment status (dexamethasone group: Hunt and Hess grade (p = 0.002), endovascular treatment (p = 0.016); no-dexamethasone group: acute hydrocephalus (p = 0.018), peripheral leukocyte count 7 days post SAH (WBC at day 7) (p = 0.009)). Similar disparities were found for VP shunt dependency (dexamethasone group: acute hydrocephalus (p = 0.002); no-dexamethasone group: WBC d7 (p = 0.036), CRP peak within 72 h (p = 0.015)). Our study shows that corticosteroid-induced leukocytosis negates the predictive prognostic potential of systemic inflammatory markers for DCI and VP shunt dependency, which has previously been neglected and should be accounted for in future studies.

Impact of the SARS-CoV-2 pandemic on the survival of patients with high-grade glioma and best practice recommendations.

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.

DNA methylation subclasses predict the benefit from gross total tumor resection in IDH-wildtype glioblastoma patients.

BACKGROUND: DNA methylation-based tumor classification allows an enhanced distinction into subgroups of glioblastoma. However, the clinical benefit of DNA methylation-based stratification of glioblastomas remains inconclusive. METHODS: Multicentric cohort study including 430 patients with newly diagnosed glioblastoma subjected to global DNA methylation profiling. Outcome measures included overall survival (OS), progression-free survival (PFS), prognostic relevance of EOR and MGMT promoter methylation status as well as a surgical benefit for recurrent glioblastoma. RESULTS: 345 patients (80.2%) fulfilled the inclusion criteria and 305 patients received combined adjuvant therapy. DNA methylation subclasses RTK I, RTK II, and mesenchymal (MES) revealed no significant survival differences (RTK I: Ref.; RTK II: HR 0.9 [95% CI, 0.64-1.28]; p = 0.56; MES: 0.69 [0.47-1.02]; p = 0.06). Patients with RTK I (GTR/near GTR: Ref.; PR: HR 2.87 [95% CI, 1.36-6.08]; p < 0.01) or RTK II (GTR/near GTR: Ref.; PR: HR 5.09 [95% CI, 2.80-9.26]; p < 0.01) tumors who underwent gross-total resection (GTR) or near GTR had a longer OS and PFS than partially resected patients. The MES subclass showed no survival benefit for a maximized EOR (GTR/near GTR: Ref.; PR: HR 1.45 [95% CI, 0.68-3.09]; p = 0.33). Therapy response predictive value of MGMT promoter methylation was evident for RTK I (HR 0.37 [95% CI, 0.19-0.71]; p < 0.01) and RTK II (HR 0.56 [95% CI, 0.34-0.91]; p = 0.02) but not the MES subclass (HR 0.52 [95% CI, 0.27-1.02]; p = 0.06). For local recurrence (n = 112), re-resection conveyed a progression-to-overall survival (POS) benefit (p < 0.01), which was evident in RTK I (p = 0.03) and RTK II (p < 0.01) tumors, but not in MES tumors (p = 0.33). CONCLUSION: We demonstrate a survival benefit from maximized EOR for newly diagnosed and recurrent glioblastomas of the RTK I and RTK II but not the MES subclass. Hence, it needs to be debated whether the MES subclass should be treated with maximal surgical resection, especially when located in eloquent areas and at time of recurrence.

Role of interhemispheric connectivity in recovery from postoperative supplementary motor area syndrome in glioma patients.

OBJECTIVE: Surgical resection of gliomas involving the supplementary motor area (SMA) frequently results in SMA syndrome, a symptom complex characterized by transient akinesia and mutism. Because the factors influencing patient functional outcomes after surgery remain elusive, the authors investigated network-based predictors in a multicentric cohort of glioma patients. METHODS: The participants were 50 patients treated for glioma located in the SMA at one of the three centers participating in the study. Postoperative functional outcomes (motor deficits, mutism) and duration of symptoms were assessed during hospitalization. Long-term outcome was assessed 3 months after surgery. MRI-based lesion-symptom mapping was performed to estimate the severity of gray matter damage and white matter disconnection. RESULTS: The median duration of acute symptoms was 3 days (range 1-42 days). Long-term deficits involving fine motor movements and speech were found at follow-up in 27 patients (54%). Disconnection of the central callosal fibers was associated with prolonged acute symptoms (p < 0.05). Postoperative mutism was significantly related to disconnection severity of the left frontopontine tract, frontal aslant tract, cingulum, and corticostriatal tract (p < 0.05). Disconnection of midposterior callosal fibers and lesion loads within the left medial Brodmann area 4 were associated with long-term motor deficits (p < 0.05). CONCLUSIONS: This study provides evidence for the pathophysiology and predictive factors of postoperative SMA syndrome by demonstrating the relation of the disconnection of callosal fibers with prolonged symptom duration (central segment) and long-term motor deficits (midposterior segment). These data may be useful for presurgical risk assessment and adequate consultation for patients prior to undergoing resection of glioma located within the SMA region.

Clinical determinants impacting overall survival of patients with operable brain metastases from non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is currently the leading cause of cancer-related death worldwide, and the incidence of brain metastases (BM) in NSCLC patients is continuously increasing. The recent improvements of systemic treatment in NSCLC necessitate continuous updates on prognostic subgroups and factors determining overall survival (OS). In order to improve clinical decision-making in tumor boards, we investigated the clinical determinants affecting survival in patients with resectable NSCLC BM. A retrospective analysis was conducted of NSCLC patients with surgically resectable BM treated in our institution between 01/2015 and 12/2020. The relevant clinical factors affecting survival identified by univariate analysis were included in a multivariate logistic regression model. Overall, 264 patients were identified, with a mean age of 62.39 ± 9.98 years at the initial diagnosis of NSCLC BM and OS of 23.22 ± 1.71 months. The factors that significantly affected OS from the time of primary tumor diagnosis included the systemic metastatic load (median: 28.40 ± 4.82 vs. 40.93 ± 11.18 months, p = 0.021) as well as a number of BM <2 (median: 17.20 ± 2.52 vs. 32.53 ± 3.35 months, p = 0.014). When adjusted for survival time after neurosurgical intervention, a significant survival benefit was found in patients <60 years (median 16.13 ± 3.85 vs. 9.20 ± 1.39 months, p = 0.011) and, among others, patients without any concurrent systemic metastases at time of NSCLC BM diagnosis. Our data shows that the number of BM (singular/solitary), the Karnofsky Performance Status, gender, and age but not localization (infra-/supratentorial), mass-edema index or time to BM occurrence impact OS, and postsurgical survival in NSCLC BM patients. Additionally, our study shows that patients in prognostically favorable clinical subgroups an OS, which differs significantly from current statements in literature. The described clinically relevant factors may improve the understanding of the risks and the course of this disease and Faid future clinical decision making in tumor boards.