Glutamate dehydrogenase (GLUD1) links glutamine metabolism and redox regulation, yet its prognostic and functional relevance across different glioma subtypes warrants further study. Here, we show that GLUD1 expression was inversely associated with tumor grade and positively associated with survival across glioma subtypes, a relationship not fully recapitulated by broader glutaminolysis-related gene signatures. To investigate the consequences of GLUD1 inhibition, we treated endogenous IDH-mutant and IDH-wildtype glioma cell lines with the reported GLUD1 inhibitor R162. GLUD1 inhibition reduced viability in all cell lines tested. This effect was not rescued by α-ketoglutarate (α-KG) supplementation, indicating that impaired tricarboxylic acid (TCA) cycle anaplerosis was not the primary mechanism underlying GLUD1 dependency. Instead, GLUD1 inhibition caused intracellular glutamate accumulation, increased reactive oxygen species (ROS), γ-H2AX induction, and elevated intracellular calcium, while complementary in silico analyses predicted disruption of mitochondrial membrane potential following R162 exposure. Together, these findings indicate that GLUD1 inhibition induces metabolic and redox stress associated with disrupted glutamate and calcium homeostasis and DNA damage. Our findings distinguish the favorable prognostic value of GLUD1 expression from the cellular vulnerability revealed by its inhibition, supporting further investigations of GLUD1 as both a prognostic biomarker and potential therapeutic target in glioma.

Background:This study is part of the Swedish national research project BRAVE ( B rain Tumor  R elated  A ggression and  V iolence  E xposure), which has highlighted extensive suffering among family members exposed to violence by brain tumor patients with behavioral and personality changes (BPC). The aim was to explore the needs, support received, and perceived gaps in support among family members exposed to violence by individuals suffering from brain tumor-related BPC. Methods:Individual interviews were conducted with 25 family members who had experienced violence from a brain tumor patient. The data were analyzed using qualitative content analysis. Results:Participants stressed the need for a holistic care approach, including private consultations with family members to enable the disclosure of violence by brain tumor patients. An integrated care approach and continuity of care were seen as essential for building trust, identifying violence, and supporting both patients and families. Participants expressed frustration with the healthcare system's rigid focus on patient autonomy, even in cases where patients lacked cognitive capacity, leaving families without adequate information and support. They expressed that family members exposed to violence by brain tumor patients had complex needs for support. Conclusions:The support needs of family members exposed to violence by individuals with brain tumors are multifaceted, and interventions must be tailored to specific circumstances. Addressing these needs requires coordinated efforts from multiple stakeholders. An intervention that provides appropriate support for patients, family members, and staff who encounter them is urgently needed.

MGMT promoter methylation is a key predictive biomarker for response to alkylating agents in glioblastoma. However, there is no consensus regarding optimal analytical method or cut-off. This study aimed to define a clinically relevant survival-based cut-off value for MGMT using a standardized pyrosequencing assay. Patients from five Swedish university hospitals with MGMT promoter methylation status analyzed using the Therascreen MGMT Pyro Kit, investigating CpGs 76–79, were identified. Glioblastoma patients treated with radiotherapy and concomitant temozolomide were selected from the Swedish CNS Tumor Registry. Quantitative MGMT status, both mean value and percentage of methylation for each individual CpG, was analyzed using an unsupervised bimodal normal mixture model and a survival-informed approach adjusted for established prognostic factors. A total of 451 patients were included. The unsupervised model identified a cut-off at ≥ 11

BACKGROUND:Knowledge is lacking regarding how the experience of being exposed to violence is affected when the perpetrator suffers from behavioral and personality changes (BPC) due to a brain tumor. This study is part of the Swedish national research project BRAVE - Brain Tumor Related Aggression and Violence Exposure. The aim was to explore experiences of family members exposed to violence by a person suffering from BPC associated with a brain tumor. METHODS:Individual interviews were conducted with 25 family members who have been exposed to violence by patients with primary brain tumor. The interviews were analyzed using qualitative content analysis. RESULTS:The participants reported various forms of violence and expressed intense suffering, loneliness and social isolation. The homes sometimes shifted from being a safe place to being a place marked by fear and unpredictability. In adapting to violence, what initially seemed unreasonable, gradually became "the new normal". Different strategies to minimize risks and damage were described. Self-blame and shame were often associated with an inability to love the patient "in sickness and in health", despite the violent actions by the patient. When the death of the perpetrator was viewed as the only means of escape, participants also expressed feelings of guilt and shame. CONCLUSIONS:Our study highlights extensive suffering, vulnerability, loneliness and isolation among family members exposed to violence by brain tumor patients. An intervention that provides appropriate support for brain tumor patients, family members and staff who encounter them is urgently needed.

BackgroundPatients with glioblastoma experience a substantial symptom burden that negatively affects functioning in daily life. Symptoms frequently co-occur and may form symptom clusters, yet the robustness, generalizability, and temporal stability of these clusters remain insufficiently studied. This is particularly relevant given the dynamic disease course and treatment-related effects in glioblastoma.MethodsWe used data from the CODAGLIO 2.0 database, comprising adult patients with newly diagnosed or recurrent glioblastoma from seven randomized controlled trials not included in previous clustering studies. Symptoms were assessed using 18 symptom scales from EORTC QLQ-C30 and QLQ-BN20 questionnaires at baseline and 3-month follow-up. Symptom prevalence and multi-symptom co-occurrence were described. Symptom clusters were identified using Spearman correlations, partial correlations, and hierarchical cluster analysis and compared with previously reported clusters. Cluster stability over time was evaluated using cophenetic correlation, tanglegrams, entanglement, and adjusted Rand index scores.ResultsAmong 1,795 patients with baseline HRQoL data, 1678 patients (94%) reported multi-symptom co-occurrence at baseline and 1045 patients (96%) at follow-up. Fatigue, communication deficits, motor dysfunction, drowsiness, insomnia, and visual disorder were most prevalent. Four clinically meaningful symptom clusters were identified: pain–headache, motor dysfunction–weakness of the legs, fatigue–drowsiness, and a seizure-related cluster. These clusters largely aligned with previously reported findings and showed moderate stability over time (cophenetic correlation 0.84; adjusted Rand index 0.41), with greatest variability observed in seizure-related symptoms.ConclusionSymptom clusters in glioblastoma are robust yet dynamic. Incorporating cluster-based and longitudinal symptom assessment may enhance symptom monitoring and support more personalized supportive care strategies.

BACKGROUND:We assessed the clinical relevance of age and sex as risk factors for health-related quality of life (HRQoL) in patients with adult-type diffuse glioma. MATERIALS AND METHODS:The CODAGLIO 2.0 database contains 16 randomized trials from 5369 patients with glioma. Patients' HRQoL was assessed using EORTC QLQ-C30 and QLQ-BN20 questionnaires. In 8 HRQoL scales, we compared mean HRQoL at baseline with the general population and evaluated factors associated with HRQoL over time using linear mixed models (LMMs). We used the anchor-based minimally important difference to interpret clinically relevant changes. RESULTS:We included 4301 patients with baseline HRQoL followed up to 3 months. Compared to the general population, patients with glioma at baseline had statistically and clinically relevant worse HRQoL, which was still evident after stratifying by age and sex groups. In LMMs, compared to patients aged ≤60 years, those >60 years had statistically significant associations with worse physical functioning: -2.40 (95% confidence interval [CI] -4.14 to -0.71), better social: 4.88 (2.68-7.30) and role: 3.79 (1.39-6.16) functioning, and less fatigue: -3.43 (-5.44 to -1.33) and pain: -4.56 (-6.18 to -2.93). Compared to men, women had statistically significant associations with worse physical and social functioning and more fatigue and pain. Associations between age, sex, and HRQoL were not clinically relevant. Performance status had clinically relevant associations in 5/8 scales. CONCLUSION:Patients with glioma have clinically relevant worse HRQoL compared to the general population. There are statistically but not clinically significant associations between age, sex, and certain HRQoL scales.

Background The majority of patients diagnosed with glioblastoma are >60 years. Three randomized trials addressed the roles of radiotherapy (RT) and temozolomide (TMZ) for elderly patients. NORDIC and NOA-08 compared RT versus TMZ, while CE.6 randomized between hypofractionated RT and RT + TMZ. All showed significant benefits for the TMZ arms, especially for those patients with O6-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumors. This pooled analysis aimed at identifying additional factors that could improve individualized treatment recommendations. Methods Analyses were performed separately in the RT and TMZ arms of the pooled NORDIC and NOA-08 data, and in the RT and TMZ/RT arms of CE.6. The prognostic value of baseline clinical factors, comorbidities, and quality of life (QoL) scores were assessed. Results NORDIC + NOA-08 (NN) included 715 patients and CE.6 included 562 patients. Median age for NN was 71 and 73 years for CE.6. In NN and CE.6 respectively, 66.2% versus 70.5% underwent resection and 50.9% and 75.3% were on steroids. In NN, 401 patients received RT alone and 281 in CE.6, while 314 were randomized to TMZ alone in NN and 281 to concomitant RT + TMZ in CE.6. Known clinical prognostic factors, such as extent of resection and WHO performance status were confirmed, as was MGMT promoter methylation status for TMZ-treated patients. TMZ-treated patients with 2 or 3 comorbidities; hypertension, diabetes, and/or stroke had worse survival, both in NN (P = .022) and CE.6 (P = .022). Baseline QoL had a minor association with outcome. Conclusion Consideration of comorbidities allows improved personalized treatment decisions for elderly glioblastoma patients.

BACKGROUND:Patients with oligodendroglioma have a relatively favorable prognosis. The long-term impacts of the tumor itself and its treatment on health-related quality of life (HRQOL) and cognition remain largely unclear. We investigated associations between treatment and functioning of survivors of oligodendroglioma. METHODS:In this cross-sectional observational study, patients with oligodendroglioma, isocitrate dehydrogenase-mutant and 1p/19q-codeleted, diagnosed ≥ 5 years ago, were recruited. Patients completed patient-reported outcome measures (EORTC QLQ-C30; BN20; MOS Cognitive Complaints Scale) and cognitive tests (HVLT-R, TMT, COWAT). Associations between HRQOL and cognition outcomes, and clinical variables (time since diagnosis; age at diagnosis; progression; tumor location; treatments delivered; time since treatment; current medication) were explored with regression analyses. RESULTS:In total, 237 patients M = 9.9 years postdiagnosis (SD = 4.2, range 5.0-25.8) took part from 33 sites across 9 countries. Clinically relevant levels of impairment were noted in >40% of patients on EORTC QLQ-C30 scales for cognitive functioning (56.1%), emotional functioning (49.8%), fatigue (45.1%), and physical functioning (40.5%). In individuals, cognitive impairment ranged from 17.7% for processing speed to 46.0% for episodic verbal memory (delayed recall). Among other clinical factors such as current use of antiseizure medication or antidepressants, age, disease progression, time since diagnosis and time since treatment, and radiotherapy treatment (ever received) was linked to HRQOL and cognitive functioning outcomes (posthoc analyses for cumulative radiotherapy dose: not significant). CONCLUSIONS:In oligodendroglioma survivors, HRQOL and cognitive impairment are prevalent even years into follow-up. Supportive care and rehabilitation should be prioritized to mitigate these challenges and improve daily functioning. TRIAL REGISTRATION:NCT04708548.

Patients with traditional high-grade glioma (grade 3-4) generally report worse health-related quality of life (HRQoL) compared to patients with low-grade glioma (grade 1-2). However, HRQoL changes over time across different molecularly defined tumor types, and associations between HRQoL and tumor types are unclear. We examined HRQoL data from the CODAGLIO 2.0 database, comprising patients with glioma from 16 randomized controlled trials. HRQoL was measured using the EORTC QLQ-C30 and QLQ-BN20 questionnaires. We analyzed differences in mean HRQoL at baseline and 3-month follow-up across tumor types (glioblastoma IDH-wildtype, astrocytoma IDH-mutant, and oligodendroglioma IDH-mutant/1p19q codeleted) and used linear mixed models (LMMs) to assess factors independently associated with HRQoL outcomes. We included 4,301 patients with baseline HRQoL data, of which 3,215 (75%) had 3-month follow-up assessments. In stratified analyses, at 3 months, physical, role, and cognitive functioning were statistically and clinically significantly worse in glioblastoma compared to astrocytoma and oligodendroglioma. In LMMs, patients with astrocytoma showed worse physical functioning (-2.78, 95% CI: -4.68 to -1.01), cognitive functioning (-3.63, -6.18 to -1.05), pain (2.74, 0.41-4.95), communication deficits (5.03, 2.44-7.66), and seizures (4.49, 2.55-6.72), and oligodendroglioma patients showed worse social functioning (-5.39, -10.57 to -0.11), communication deficits (7.40, 1.63-12.81), and seizures (8.61, 4.17-14.26), compared to glioblastoma. None of these associations reached the threshold for clinical relevance. WHO performance status (PS) was the only variable in multivariable analysis with both statistically and clinically significant associations in 5/8 HRQoL scales. Patients with glioblastoma show statistically clinically significantly worse physical and role functioning compared to IDH-mutant glioma. However, after adjusting for other variables in LMMs, patients with glioblastoma show statistically but not clinically significantly better HRQoL on several scales than patients with IDH-mutant glioma. WHO PS should be considered a critical factor in clinical decision-making, given its clinically meaningful association with most HRQoL scales.

Background:The care of patients with brain tumors is a complex task that requires quality standards and quality assurance indicators. In the present study, several quality indicators were evaluated in routine clinical care. Methods:The EORTC Brain Tumor Group (BTG) developed quality indicators from published guidelines and tested them in 19 BTG sites across Europe. Each site extracted data from the files of 20 randomly selected glioblastoma patients diagnosed in 2018. Associations between quality indicators, site characteristics and median overall survival (mOS) were examined. Results:A total of 364 patient files were evaluated at 19 sites. Excellent compliance was observed in the documentation of neuropathology report with isocitrate dehydrogenase (IDH) status (92.0%), O6 -methylguanine DNA methyltransferase promoter methylation (MGMT) status (78.0%), multidisciplinary case discussion (95.3 %), extent of resection (87.1%), and radiotherapy details (96.9%) as well as consent to chemotherapy (75.5%). Performance was not as good for early postoperative MRI (67.2%), psycho-oncological care (40.5%), avoiding antineoplastic therapy in the last weeks of life (63.1%) and early referral to palliative services (23.5%). Timely start of radiotherapy (P = .0153), the presence of a radiotherapy report in the medical record (P = .0077), and patient education on oral chemotherapy (P = .0002) were positively associated with mOS, while early referral to palliative care was associated with shorter mOS (P < .0001). Conclusions:The quality indicators tested in this research project performed with some variability between sites. Significant associations between individual quality indicators and mOS were observed. The proposed quality indicators should be validated prospectively.

Background The treatment of elderly/ frail patients with glioblastoma is a balance between avoiding undue toxicity, while not withholding effective treatment. It remains debated, whether these patients should receive combined chemo-radiotherapy with temozolomide (RT/TMZ -> TMZ) regardless of the O6-methylguanine DNA methyltransferase gene promoter (MGMTp) methylation status. MGMT is a well-known resistance factor blunting the treatment effect of TMZ, by repairing the most genotoxic lesion. Epigenetic silencing of the MGMTp sensitizes glioblastoma to TMZ. For risk-adapted treatment, it is of utmost importance to accurately identify patients, who will not benefit from TMZ treatment.Methods Here, we present a reanalysis of the clinical trials CE.6 and the pooled NOA-08 and Nordic trials in elderly glioblastoma patients that compared RT to RT/TMZ -> TMZ, or RT to TMZ, respectively. For 687 patients with available MGMTp methylation data, we applied a cutoff discerning truly unmethylated glioblastoma, established in a pooled analysis of 4 clinical trials for glioblastoma, with RT/TMZ -> TMZ treatment, using the same quantitative methylation-specific MGMTp PCR assay.Results When applying this restricted cutoff to the elderly patient population, we confirmed that glioblastoma with truly unmethylated MGMTp derived no benefit from TMZ treatment. In the Nordic/NOA-08 trials, RT was better than TMZ, suggesting little or no benefit from TMZ.Conclusions For evidence-based treatment of glioblastoma patients validated MGMTp methylation assays should be used that accurately identify truly unmethylated patients. Respective stratified management of patients will reduce toxicity without compromising outcomes and allow testing of more promising treatment options. For the podcast associated with this article, please visit 'https://soc-neuro-onc.libsyn.com/tmz-and-mgmt-in-elderly-gbm-patients'

Abstract BACKGROUND Patients with IDH-mutant, 1p/19-codeleted oligodendroglioma have a relatively favourable prognosis and can experience long periods of stable disease. Treatment modalities used vary, and the long-term impacts of both the tumour itself and its treatment on patient health-related quality of life (HRQOL) and cognition remain largely unclear. We aimed to investigate associations between treatment and functioning of oligodendroglioma patients ≥5 years after diagnosis. MATERIAL AND METHODS In this international cross-sectional observational study, patients with histologically and molecularly confirmed oligodendroglioma (IDH mutant, 1p/19q codeleted) diagnosed ≥5 years ago, were recruited through the European Organisation for Research and Treatment of Cancer (EORTC) networks. Diagnosis and treatment data were collected from medical records; patients completed outcomes for HRQOL (EORTC QLQ-C30; BN20), self-reported cognitive functioning (MOS Cognitive Functioning Scale) and cognitive tests (HVLT-R, TMT, COWAT) once. Associations between HRQOL and cognition outcomes, and clinical variables (time since diagnosis; progression; tumour location; treatments delivered; current medication; Karnofsky Performance Status (KPS)) were explored with regression analyses. RESULTS 242 oligodendroglioma patients on average 9.9 years post-diagnosis (sd=4.3, range=5.0-26.3) took part from 33 sites across 9 countries. Patients were M=52 years old (sd=12, range=23-78), the majority were men (N=145; 60%). Higher KPS, no radiotherapy (ever), no current medication (anxiolytics/sedatives, antidepressants, dexamethasone) were associated with better generic HRQOL outcomes (QLQ-C30 functioning scale models; R2 range 0.068-0.371, all p<.001). Higher KPS, fewer recurrences, no radiotherapy treatment (ever), and no current antidepressant use were of predictive value for better disease-specific HRQOL (BN20 multi-item scale models; R2 range 0.067-0.246, p<0.001). Fewer subjective cognitive complaints were associated with higher KPS and no current antipsychotic medication use (R2=0.153, p<0.001). Better KPS, right hemispheric tumours, longer time since diagnosis, no chemotherapy (ever), no radiotherapy (ever), and no current medication use (dexamethasone, antipsychotics) were predictive of better cognitive functioning (multivariable models R2 range 0.056-0.248, p<0.001). CONCLUSION In oligodendroglioma survivors ≥5 years after diagnosis, better HRQOL and cognitive outcomes appear consistently linked with higher KPS, no current medication use and no radiotherapy (ever); with cognitive outcomes additionally associated with chemotherapy treatment. This information can support treatment decision-making. Targeted evaluation and support for patients should be implemented to optimise clinical outcomes.

Background. TTFields is recommended internationally for the treatment of glioblastoma. In Sweden, TTFields requires a possibly challenging collaboration between the patient, next-of-kin, healthcare, and the private company providing the device, both from an ethical and practical perspective. Little is known about glioblastoma patients' own experiences of TTFields treatment. Methods. Semi-structured individual interviews were conducted with 31 patients with glioblastoma who had been offered TTFields by the healthcare. These were analyzed by qualitative content analysis. Results. Participants described there being multiple actors around them as TTFields users; (1) device prescription from physicians, sometimes providing insufficient information, (2) practical assistance from next-of-kin, necessary to access treatment, (3) home visits from the private company staff for device control, where close bonds between patients and TTFields staff occurred. TTFields treatment created hope and a feeling of control in an otherwise hopeless situation, sometimes evoking worries at the time of planned treatment stop. Some refrained from TTFields or discontinued early due to fear or experience of negative effects on quality of life. Others described finding practical and mental solutions for coping with the treatment in everyday life. Conclusions. Our study identified a need for better support and information from healthcare providers for TTFields. A solution is necessary for assistance with TTFields for those without support from next-of-kin. The study raises the question of possible advantages of healthcare handling the technical support of the device instead of a private company, thereby avoiding a true or perceived influence on the patient's decision to continue or stop treatment.

Abstract BACKGROUND Increased uptake of principal nutrients is one of the attributes of cancer cells. A recent study has shown that glutamine, but not glucose, consumption differed markedly between gliomas and adjacent healthy tissue. However, the prognostic role of glutaminolysis or glutaminolysis-related genes (GRGs) in gliomas remains unclear. Here we sought to determine if the GRG signature correlates with glioma patient survival and if it could identify patients with different outcomes. MATERIAL AND METHODS The RNA-seq and clinical data for The Cancer Genome Atlas (TCGA) was obtained from the GlioVis webpage. We compared the expression of the GRGs (GLUD1, GLUL, GLS1, GLS2, GOT1, GOT2, GPT, GPT2, SLC1A5, and SLC7A5) between 4 non-tumor, 220 IDH wild-type (IDHwt) and 389 IDH mutant (IDHmut) gliomas, of which 154 harbored 1p/19q codeletion. We further performed unsupervised hierarchical clustering for all glioma patients and compared survival between clusters. RESULTS Our results revealed that most GRGs were differentially expressed between non-tumor, IDHwt, and IDHmut gliomas. We found that gliomas grouped into 3 clusters based on the varying GRGs expression. Eighty-eight percent of glioblastomas (GBM, IDHwt) and 19% of all IDHmut tumors were characterized by low GRGs expression. These were denoted as cluster 1, and the remaining samples belonged to clusters 2 or 3, corresponding to intermediate and high GRGs expression groups, respectively. We performed survival analysis separately for IDHwt and IDHmut gliomas and found that cluster 1 patients had the worst prognosis, regardless of IDH status. We further separated IDHmut gliomas according to 1p/19q codeletion status. Oligodendroglioma (1p/19q codeleted) patients had a median survival of 33.2 months, 134.3 months, and 169.8 months in clusters 1, 2, and 3, respectively. No cluster-dependent differences in survival were seen for astrocytoma. For IDHwt (GBM) we found that patients from clusters 1 and 2 had survival of 14 months and 25 months, respectively. Due to the small number of deceased GBM patients in cluster 3, we could not estimate the median survival. The univariate analysis confirmed that cluster membership was an independent predictor of survival in oligodendroglioma (cluster 2 and 3 vs. 1, HR 0.14; 95% CI, 0.05-0.4; p=0.0005) and GBM (cluster 1 vs. 2 and 3, HR 3.05; 95% CI, 1.5-5.9; p=0.0012). CONCLUSION The GRG signature could define metabolic groups with distinct survivals in oligodendroglioma and GBM and constitute a new prognostic factor. We are planning further investigations to confirm our findings.

Abstract BACKGROUND Since the pivotal trial, showing a near 5-month survival advantage with the addition of Optune to standard treatment for glioblastoma (GBM), Optune has been introduced into clinical practice in many countries. In Sweden, the device is prescribed by physicians, while the service of equipment and control of its use occur in the patients’ home by staff from the private company providing the device, this potentially creating a conflict of interest. Also, the daily use of the device necessitates the help of a next of kin. These are unique arrangements for Swedish healthcare, leading to the need of a complex and possibly challenging collaboration, and also raising potential ethical dilemmas.This study investigates Optune treatment for patients with GBM, regarding experiences of those involved in the treatment, namely: patients, next of kin, physicians and staff from the private company providing the device. MATERIAL AND METHODS The aim is to include 20 or more participants in each group (patients and next of kin, respectively). They are individually interviewed. The interviews are transcribed and analyzed using quantitative content analysis. Electronic questionnaires were sent during 2021-2022 to all physicians prescribing Optune at Departments of Oncology or Neurology in Sweden. The questionnaires included quantitative as well as open ended questions. Staff working for the company and visiting the patients and next of kin have also received electronic questionnaires focusing on experiences from their work. RESULTS Challenges were identified by the physicians, but they had varying opinions on the magnitude of the ethical problems. To date, 10 patients and 9 next of kin have been interviewed. Possible categories already identified are: “Information from the healthcare” and “Patient - company staff collaboration”. The questionnaires to the staff have been answered. The results of the interviews with patients and next of kin, as well as the results of the questionnaires to staff, will be presented. CONCLUSION The INTRODUCTION of Optune as a treatment of patients with GBM constitutes a new concept and a need for new solutions for tackling medical, practical and ethical issues. SUPPORT The Medical Research Council of Southeast Sweden (FORSS), and an ALF grant from Region Östergötland.

Patients with glioblastoma (GBM) have a poor outcome, but even among patients receiving the same therapies and with good prognostic factors, one can find those with exceptionally short and long survival. From the Nordic trial, which randomized GBM patients of 60 years or older between two radiotherapy arms (60 Gy or 34 Gy) or temozolomide (TMZ), we selected 59 with good prognostic factors. These selected GBM patients were equally distributed according to treatment and MGMT promoter methylation status but had long or short survival. Methylation profiling with the Illumina Infinium Methylation EPIC BeadChip arrays was performed and utilized for methylation-based CNS tumor classification, and pathway enrichment analysis of differentially methylated CpG sites (DMCs), as well as calculation of epigenetic age acceleration with three different algorithms, to compare the long and short survival groups. Samples identified by the classifier as non-GBM IDH wildtype were excluded. DMCs between long- and short-term survivors were found in patients with methylated MGMT promoter treated with TMZ (123,510), those with unmethylated MGMT treated with 60Gy radiotherapy (4,086), and with methylated MGMT promoter treated with 34Gy radiotherapy (39,649). Long-term survivors with methylated MGMT promoter treated with TMZ exhibited hypermethylation of the Wnt signaling and the platelet activation, signaling, and aggregation pathways. The joint analysis of radiotherapy arms revealed 319 DMCs between long- and short-term survivors with unmethylated MGMT and none for samples with methylated MGMT promoter. An analysis comparing epigenetic age acceleration between patients with long- and short-term survival across all treatment arms showed a decreased epigenetic age acceleration for the latter. We identified DMCs for both TMZ and RT-treated patients and epigenetic age acceleration as a potential prognostic marker, but further systematic analysis of larger patient cohorts is necessary for confirmation of their prognostic and/or predictive properties.

Sex disparities in glioblastoma (GBM) have received increasing attention. Sex-related differences for several molecular markers have been reported, which could impact on clinical factors and outcomes. We therefore analyzed data on all patients with GBM reported to the Swedish National Quality Registry for Primary Brain Tumors, according to sex, with a focus on prognostic factors and survival. All glioma patients registered during 20 years, from 1 January 1999 until 31 December 2018, with SNOMED codes 94403, 94413, and 94423, were analyzed. Chi2-test, log-rank test, and Kaplan–Meier analyses were performed. We identified 5243 patients, of which 2083 were females and 3160 males, resulting in a ratio of 1:1.5. We found sex related differences, with women having diagnostic surgery at a significantly higher age (p = 0.001). Women were also reported to have a worse preoperative performance status (PPS) (<0.001). There was no gender difference for the type of surgery performed. For women with radical surgery, overall survival was slightly better than for men (p = 0.045). The time period did not influence survival, neither for 1999–2005 nor 2006–2018, after temozolomide treatment was introduced (p = 0.35 and 0.10, respectively). In the multivariate analysis including sex, age, surgery, and PPS, a survival advantage was noted for women, but this was not clinically relevant (HR = 0.92, p = 0.006). For patients with GBM; sex-related differences in clinical factors could be identified in a population-based cohort. In this dataset, for survival, the only advantage noted was for women who had undergone radical surgery, although this was clinically almost negligible.

Patients with glioblastoma (GBM) have a short survival, but even among patients receiving the same therapies and with good prognostic factors, one can find those with exceptionally short and long survival. In the Nordic trial, patients with GBM, 60 years or older, were randomized between 2 radiotherapy arms or TMZ. We selected 59 patients, equally distributed between the 3 treatment arms and MGMT promoter methylation status, with good prognostic factors, but with short or long survival. We performed methylation profiling with the Illumina Infinium Methylation EPIC BeadChip arrays in conjunction with a methylation-based CNS tumor classifier, analysis of differentially methylated CpG sites (DMCs) and pathway enrichment analysis. Samples classified as non-GBM IDH wildtype were excluded and in the analysis of long vs. short survivors with documented progression or tumor-related death, we found DMCs in the TMZ, MGMT promoter methylated group (123,510), as well as in the 60Gy, MGMT promoter unmethylated group (4,086) and 34Gy, MGMT promoter methylated group (39,649). The joint analysis of the RT arms revealed 319 DMCs in the MGMT unmethylated group but no differences for MGMT promoter methylated samples, or in any of the analyses independent of MGMT status. Interestingly, in the long-term survivors with methylated MGMT promoter treated with TMZ we found hypermethylation of the Wnt signaling and the platelet activation, signaling and aggregation pathways. We identified DMCs for both TMZ and RT treated patients. Further systematic analysis of larger patient cohorts is necessary for confirmation of their predictive properties.