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Objectives: Symptoms of raised intracranial pressure (ICP) in recurrent high-grade glioma (HGG) generally require corticosteroid treatment, often causing toxicity with variable effects on ICP symptoms. Acetazolamide reduces ICP when used in other clinical non-cancer settings. The aim of the study was to explore whether the addition of oral acetazolamide enables safe dexamethasone dose reduction in management of raised ICP in recurrent HGG., Methods: Participants had recurrent HGG with any of dexamethasone recommencement, dose increase or dependency; prior/current bevacizumab was an exclusion. Eligible participants were randomised 1:1 to acetazolamide or placebo for 8 weeks. Standardised protocols were used for dexamethasone dosing, with planned dose decrease from day 5 once ICP symptoms were stable. The primary endpoint was a composite of dexamethasone dose reduction and stable Karnofsky Performance Status Secondary endpoints included toxicity and feasibility., Results: Thirty participants (15 per group) were enrolled (mean age 58 years) from seven Australian sites. The mean baseline dexamethasone dose was 6.2 mg. Mean duration on study treatment was 38 days (placebo group) and 31 days (acetazolamide group) with nine participants (30%) completing all study treatments (six placebo, three acetazolamide). Study withdrawal was due to adverse events (n=6; one placebo, five acetazolamide) and disease progression (n=6 (three per arm)). Four participants (13%) (two per arm) were stable responders. Ten participants experienced a total of 13 serious adverse events (acetazolamide arm: five participants (33%), six events, two related)., Conclusions: The study closed early due to poor accrual and increasing availability of bevacizumab. The addition of acetazolamide did not facilitate dexamethasone reduction., Trial Registration Number: ACTRN12615001072505., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Glioma accounts for approximately 80% of malignant adult brain cancer and its most common subtype, glioblastoma, has one of the lowest 5-year cancer survivals. Fifty risk-associated variants within 34 glioma genetic risk regions have been found by genome-wide association studies (GWAS) with a sex difference reported for 8q24.21 region. We conducted an Australian GWAS by glioma subtype and sex., Methods: We analyzed genome-wide data from the Australian Genomics and Clinical Outcomes of Glioma (AGOG) consortium for 7 573 692 single nucleotide polymorphisms (SNPs) for 560 glioma cases and 2237 controls of European ancestry. Cases were classified as glioblastoma, non-glioblastoma, astrocytoma or oligodendroglioma. Logistic regression analysis was used to assess the associations of SNPs with glioma risk by subtype and by sex., Results: We replicated the previously reported glioma risk associations in the regions of 2q33.3 C2orf80, 2q37.3 D2HGDH, 5p15.33 TERT, 7p11.2 EGFR, 8q24.21 CCDC26, 9p21.3 CDKN2BAS, 11q21 MAML2, 11q23.3 PHLDB1, 15q24.2 ETFA, 16p13.3 RHBDF1, 16p13.3 LMF1, 17p13.1 TP53, 20q13.33 RTEL, and 20q13.33 GMEB2 (P < .05). We also replicated the previously reported sex difference at 8q24.21 CCDC26 (P = .0024) with the association being nominally significant for both sexes (P < .05)., Conclusions: Our study supports a stronger female risk association for the region 8q24.21 CCDC26 and highlights the importance of analyzing glioma GWAS by sex. A better understanding of sex differences could provide biological insight into the cause of glioma with implications for prevention, risk prediction and treatment., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Purpose: This study aimed to: determine the supportive care available for Australian patients with High Grade Glioma (HGG) and their carers; identify service gaps; and inform changes needed to implement guidelines and Optimal Care Pathways., Methods: This cross-sectional online survey recruited multidisciplinary health professionals (HPs) who were members of the Cooperative Trials Group for Neuro-Oncology involved in management of patients diagnosed with HGG in Australian hospitals. Descriptive statistics were calculated. Fisher's exact test was used to explore differences between groups., Results: 42 complete responses were received. A majority of MDT meetings were attended by a: neurosurgeon, radiation oncologist, medical oncologist, radiologist, and care coordinator. Less than 10% reported attendance by a palliative care nurse; physiotherapist; neuropsychologist; or speech therapist. Most could access referral pathways to a cancer care coordinator (76%), neuropsychologist (78%), radiation oncology nurse (77%), or psycho-oncologist (73%), palliative care (93-100%) and mental health professionals (60-85%). However, few routinely referred to an exercise physiologist (10%), rehabilitation physician (22%), dietitian (22%) or speech therapist (28%). Similarly, routine referrals to specialist mental health services were not standard practice. Nearly all HPs (94%) reported HGG patients were advised to present to their GP for pre-existing conditions/comorbidities; however, most HPs took responsibility (≤ 36% referred to GP) for social issues, mental health, symptoms, cancer complications, and treatment side-effects., Conclusions: While certain services are accessible to HGG patients nationally, improvements are needed. Psychosocial support, specialist allied health, and primary care providers are not yet routinely integrated into the care of HGG patients and their carers despite these services being considered essential in clinical practice guidelines and optimal care pathways., (© 2022. The Author(s).)

Purpose: High-grade disease accounts for ~ 70% of all glioma, and has a high mortality rate. Few modifiable exposures are known to be related to glioma risk or mortality., Methods: We examined associations between lifetime physical activity and physical activity at different ages (15-18 years, 19-29 years, 30-39 years, last 10 years) with the risk of glioma diagnosis, using data from a hospital-based family case-control study (495 cases; 371 controls). We followed up cases over a median of 25 months to examine whether physical activity was associated with all-cause mortality. Physical activity and potential confounders were assessed by self-administered questionnaire. We examined associations between physical activity (metabolic equivalent [MET]-h/wk) and glioma risk using unconditional logistic regression and with all-cause mortality in cases using Cox regression., Results: We noted a reduced risk of glioma for the highest (≥ 47 MET-h/wk) versus lowest (< 24 METh/wk) category of physical activity for lifetime activity (OR = 0.58, 95% CI: 0.38-0.89) and at 15-18 years (OR = 0.57, 95% CI: 0.39-0.83). We did not observe any association between physical activity and all-cause mortality (HR for lifetime physical activity = 0.91, 95% CI: 0.64-1.29)., Conclusion: Our findings are consistent with previous research that suggested physical activity during adolescence might be protective against glioma. Engaging in physical activity during adolescence has many health benefits; this health behavior may also offer protection against glioma., (© 2022. The Author(s).)

Introduction: Grades 2 and 3 gliomas (G2/3 gliomas), when combined, are the second largest group of malignant brain tumours in adults. The outcomes for G2/3 gliomas at progression approach the dismal outcomes for glioblastoma (GBM), yet there is a paucity of trials for Australian patients with relapsed G2/3 gliomas compared with patients with GBM. LUMOS will be a pilot umbrella study for patients with relapsed G2/3 gliomas that aims to match patients to targeted therapies based on molecular screening with contemporaneous tumour tissue. Participants in whom no actionable or no druggable mutation is found, or in whom the matching drug is not available, will form a comparator arm and receive standard of care chemotherapy. The objective of the LUMOS trial is to assess the feasibility of this approach in a multicentre study across five sites in Australia, with a view to establishing a national molecular screening platform for patient treatment guided by the mutational analysis of contemporaneous tissue biopsies METHODS AND ANALYSIS: This study will be a multicentre pilot study enrolling patients with recurrent grade 2/3 gliomas that have previously been treated with radiotherapy and chemotherapy at diagnosis or at first relapse. Contemporaneous tumour tissue at the time of first relapse, defined as tissue obtained within 6 months of relapse and without subsequent intervening therapy, will be obtained from patients. Molecular screening will be performed by targeted next-generation sequencing at the reference laboratory (PathWest, Perth, Australia). RNA and DNA will be extracted from representative formalin-fixed paraffin embedded tissue scrolls or microdissected from sections on glass slides tissue sections following a review of the histology by pathologists. Extracted nucleic acid will be quantified by Qubit Fluorometric Quantitation (Thermo Fisher Scientific). Library preparation and targeted capture will be performed using the TruSight Tumor 170 (TST170) kit and samples sequenced on NextSeq 550 (Illumina) using NextSeq V.2.5 hi output reagents, according to the manufacturer's instructions. Data analysis will be performed using the Illumina BaseSpace TST170 app v1.02 and a custom tertiary pipeline, implemented within the Clinical Genomics Workspace software platform from PierianDx (also refer to section 3.2). Primary outcomes for the study will be the number of patients enrolled and the number of patients who complete molecular screening. Secondary outcomes will include the proportion of screened patients enrolled; proportion of patients who complete molecular screening; the turn-around time of molecular screening; and the value of a brain tumour specific multi-disciplinary tumour board, called the molecular tumour advisory panel as measured by the proportion of patients in whom the treatment recommendation was refined compared with the recommendations from the automated bioinformatics platform of the reference laboratory testing., Ethics and Dissemination: The study was approved by the lead Human Research Ethics Committee of the Sydney Local Health District: Protocol No. X19-0383. The study will be conducted in accordance with the principles of the Declaration of Helsinki 2013, guidelines for Good Clinical Practice and the National Health and Medical Research Council National Statement on Ethical Conduct in Human Research (2007, updated 2018 and as amended periodically). Results will be disseminated using a range of media channels including newsletters, social media, scientific conferences and peer-reviewed publications., Trial Registration Number: ACTRN12620000087954; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: This study aimed to determine how carer distress and psychological morbidity change over time following a patient's diagnosis of high-grade glioma (HGG) and identify factors associated with changes in carers' psychological status., Methods: Carers of patients with HGG planned for chemoradiotherapy were recruited to this longitudinal cohort study. Carers completed questionnaires during patients' chemoradiotherapy and 3 and 6 months later including the following: the Distress Thermometer (DT); General Health Questionnaire-12 (GHQ-12); and three single-item questions about understanding of information presented by health professionals, confidence to care and preparedness to care for their relative/friend. Linear latent growth models were applied., Results: The time 1 questionnaire was completed by 118 carers, of these 70 carers provided responses to the third time point. Carer distress and psychological morbidity were most prominent proximal to diagnosis, but remained high over time. Sixty-two percent of participants had moderate or high distress on the DT at time 1, 61% at time 2 and 58% at time 3. Scores on the DT and the GHQ-12 correlated significantly at all time points as did changes in scores over time (p < .001). However, for individual carers, the DT or GHQ-12 scores at one time point did not strongly predict scores at subsequent time points., Conclusion: In carers of patients with HGG, distress levels are consistently high and cannot be predicted at any time point. Carers should be monitored over time to identify evolving psychological morbidity. The single-item DT correlates highly with GHQ-12 scores and is a suitable tool for rapid repeated screening.

Background Few studies have assessed physical functioning in glioma patients with grade II, III, and IV glioma prior to undergoing adjuvant radiation with or without chemotherapy. The aim of this study was to describe the baseline physical functioning capacity of patients with glioma prior to adjuvant therapy compared to validated cutoffs required to maintain independence. Methods This study is a cross-sectional study that recruited patients with grade II, III, and IV glioma (n = 33) undergoing adjuvant radiation with or without chemotherapy. The six-minute walk, thirty-second sit-to-stand, and timed "Up & Go" assessments were used to describe baseline physical functioning. Perceived quality of life from the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ-C30) version 3.0 was used to quantify the quality of life. Results Mean distance walked in the six-minute walk test was 416.2 m (SD 137.6 m) with a mean of 12.2 stands (SD 3.4 stands) achieved during the thirty-second sit-to-stand. Median time to complete the timed "Up & Go" assessment was 7 s (interquartile range: 3 s). One-sample t tests suggest walking distance and chair stands were significantly lower than cutoff criterions to maintain independent living, t (32) = −5.96, P <.001, bias-corrected accelerated 95% CI [370.7-460.4], and t (32) = −4.60, P <.01, bias-corrected accelerated 95% CI [11.0-13.4], respectively. Wilcoxon signed-rank test identified significantly shorter median time taken to complete the timed "Up & Go" test compared to the cutoff criterion (z = −4.43, n = 33, P <.01). Conclusion This study suggests glioma patient's aerobic endurance and lower limb strength are below criterion cutoffs recommended to maintain independent living. Timed "Up & Go" scores did not exceed the criterion cutoff, indicating respectable levels of mobility. [ABSTRACT FROM AUTHOR]

Background Sleep is an important element in health-related quality of life of cancer patients and caregivers. This study aimed to explore the experience of sleep disturbance in people with malignant brain tumors (BT) and their family caregivers. Methods Participants were recruited from ambulatory neuro-oncology clinics. Semi-structured interviews were conducted with 24 patients (67% with high-grade gliomas) and 14 caregivers. Data were analyzed thematically using a framework synthesis. Results We identified six themes relating to perceptions of the nature, impact, causal factors, and interventions for sleep disturbance, beliefs about sleep and impact, and personal coping strategies. Participants described their sleep disturbance in terms of insomnia symptoms; most commonly difficulties initiating and maintaining sleep. Participants had varied views on causal factors including the BT diagnosis and treatment and caregiver burden. However, excessive thinking and BT-related anxiety were evident in both patients and caregivers. The described impact on daytime functioning due to non-restful sleep and fatigue appeared to be significant and many participants needed daytime naps, although they understated the impact on individual functioning. Some participants were reluctant to seek help from clinicians for sleep disturbance due to previous experiences where sleep disturbance was overlooked, or because they held negative views toward pharmacological interventions. Participants reported various coping strategies, ranging from relaxation-promoting techniques to behaviors to distract thinking at night that may instead disturb sleep. Conclusions Psychological factors contribute to sleep disturbance in patients with BT and caregivers. This population may benefit from information about sleep disturbance and interventions targeting anxiety. [ABSTRACT FROM AUTHOR]

Background Emerging evidence supports the clinical impact of sleep disturbance (SD) on cancer patients. This study aimed to determine the prevalence and predictors of SD in people with malignant brain tumors and caregivers, and explore any relationship between the patient-caregiver dyad's sleep. Methods Eighty-one adults with primary malignant (91%) or metastatic (9%) brain tumors and their family caregivers (n = 44) completed a series of self-report questionnaires, including the Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index, and the drowsiness item of The MD Anderson Symptom Inventory-Brain Tumor in an Australian ambulatory neuro-oncology setting. Participants were grouped by the PSQI cutoff (SD > 5), and binary logistic regression analyses were performed to identify risk factors. Results Of patients, 53% reported SD and 15% of those clinically significant insomnia, and 27% reported moderate to severe daytime drowsiness. Whereas anxiety, depression, fatigue, pain, neurocognitive symptoms, and antiemetic use were higher in patients with SD, fatigue and KPS were strong predictors of SD. In caregivers, 55% reported poor sleep and 13% clinical insomnia. Anxiety, caregiver burden, and comorbid illness were significantly associated with caregivers' SD. The individual's SD did not affect the chance of the other member of the patient-caregiver dyad experiencing SD. Conclusions More than half the sample had sleep disturbance, which was linked to many concomitant symptoms, such as fatigue in patients and anxiety in caregivers, potentially contributing to distress and functional impairment. Understanding underlying mechanisms of SD, the potential use of these clinical predictors in care settings, and options for management is warranted. [ABSTRACT FROM AUTHOR]

Background Glioma O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status informs clinical decision making. Worldwide different methods and cutoff levels are used, which can lead to discordant methylation results. Methods We conducted an international survey to clarify which methods are regularly used and why. We also explored opinions regarding international consensus on methods and cutoff. Results The survey had 152 respondents from 25 countries. MGMT methylation status is determined for all glioblastomas in 37% of laboratories. The most common methods are methylation-specific polymerase chain reaction (msPCR) (37%) and pyrosequencing (34%). A method is selected for simplicity (56%), cost-effectiveness (50%), and reproducibility of results (52%). For sequencing, the number of CpG sites analyzed varies from 1–3 up to more than 16. For 50% of laboratories, the company producing the kit determines which CpG sites are examined, whereas 33% select the sites themselves. Selection of cutoff is equally distributed among a cutoff defined in the literature, by the local laboratory, or by the outside laboratory performing the analysis. This cutoff varies, reported from 1% to 30%, and in 1 laboratory tumor is determined as methylated in case of 1 methylated CpG site of 17 analyzed. Some report tumors as unmethylated or weakly vs highly methylated. An international consensus on MGMT methylation method and cutoff is warranted by 66% and 76% of respondents, respectively. The method preferred would be msPCR (45%) or pyrosequencing (42%), whereas 18% suggest next-generation sequencing. Conclusion Although analysis of MGMT methylation status is routine, there is controversy regarding laboratory methods and cutoff level. Most respondents favor development of international consensus guidelines. [ABSTRACT FROM AUTHOR]

Marginal communities, such as culturally and linguistically diverse (CALD) patients, have significantly lower rates of recruitment, accrual, and retention in cancer clinical trials. A combination of language and cultural barriers means that trial participation from CALD communities remains at suboptimal levels, which in turn favors research findings that are biased towards therapeutic effects or toxicities within the context of non-CALD populations. Here we outline some key challenges and implications for CALD patient participation in glioma research in countries such as Australia, where English is the language of governance and health services implementation. We highlight multistakeholder interventions to improve both investigator recruitment and participation of CALD communities in future glioma research, particularly in this era when global migration has come of age. Enhancing research participation of CALD communities ensures not only wider understanding of genetic heterogeneity to improve glioma outcomes but also equity in access to care. [ABSTRACT FROM PUBLISHER]

High-grade gliomas continue to have dismal prognosis despite advances made in understanding the molecular genetics, signaling pathways, cytoskeletal dynamics, and the role of stem cells in gliomagenesis. Conventional treatment approaches, including surgery, radiotherapy, and cytotoxic chemotherapy, have been used with limited success. Therapeutic advances using molecular targeted therapy, immunotherapy, and others such as dietary treatments have not been able to halt tumor progression and disease-related death. High-grade gliomas (World Health Organization grades III/IV) are histologically characterized by cellular and nuclear atypia, neoangiogenesis, and necrosis. The expression of vascular endothelial growth factor, a molecular mediator, plays a key role in vascular proliferation and tumor survival. Targeting vascular endothelial growth factor has demonstrated promising results, with improved quality of life and progression-free survival. Bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor, is approved by the Food and Drug Administration as a single agent in recurrent glioblastoma and is associated with manageable toxicity. This review discusses the efficacy, practical aspects, and response assessment challenges with the use of bevacizumab in the treatment of high-grade gliomas. [ABSTRACT FROM AUTHOR]