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Background: Medulloblastoma (MB) is the most common malignant pediatric brain tumor, with 5-year survival rates > 70%. Cranial radiotherapy (CRT) to the whole brain, with posterior fossa boost (PFB), underpins treatment for non-infants; however, radiotherapeutic insult to the normal brain has deleterious consequences to neurocognitive and physical functioning, and causes accelerated aging/frailty. Approaches to ameliorate radiotherapy-induced late-effects are lacking and a paucity of appropriate model systems hinders their development., Methods: We have developed a clinically relevant in vivo model system that recapitulates the radiotherapy dose, targeting, and developmental stage of childhood medulloblastoma. Consistent with human regimens, age-equivalent (postnatal days 35-37) male C57Bl/6J mice received computerized tomography image-guided CRT (human-equivalent 37.5 Gy EQD2, n  = 12) ± PFB (human-equivalent 48.7 Gy EQD2, n  = 12), via the small animal radiation research platform and were longitudinally assessed for > 12 months., Results: CRT was well tolerated, independent of PFB receipt. Compared to a sham-irradiated group ( n  = 12), irradiated mice were significantly frailer following irradiation (frailty index; P  = .0002) and had reduced physical functioning; time to fall from a rotating rod (rotarod; P  = .026) and grip strength ( P  = .006) were significantly lower. Neurocognitive deficits were consistent with childhood MB survivors; irradiated mice displayed significantly worse working memory (Y-maze; P  = .009) and exhibited spatial memory deficits (Barnes maze; P  = .029). Receipt of PFB did not induce a more severe late-effect profile., Conclusions: Our in vivo model mirrored childhood MB radiotherapy and recapitulated features observed in the late-effect profile of MB survivors. Our clinically relevant model will facilitate both the elucidation of novel/target mechanisms underpinning MB late effects and the development of novel interventions for their amelioration., Competing Interests: The authors have no conflicts of interest to declare., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Purpose: Patients with glioblastoma who are older or have poor performance status (PS) experience particularly poor clinical outcomes. At the time of study initiation, these patients were treated with short-course radiation therapy (40 Gy in 15 fractions). Olaparib is an oral inhibitor of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP) that is well tolerated as a single agent but exacerbates acute radiation toxicity in extracranial sites. Preclinical data predicted that PARP inhibitors would enhance radiosensitivity in glioblastoma without exacerbating adverse effects on the normal brain., Methods and Materials: Phase 1 of the PARADIGM trial was a 3+3 dose-escalation study testing olaparib in combination with radiation therapy (40 Gy 15 fractions) in patients with newly diagnosed glioblastoma who were unsuitable for radical treatment either because they were aged 70 years or older (World Health Organization PS 0-1) or aged 18 to 69 years with PS 2. The primary outcome was the recommended phase 2 dose of olaparib. Secondary endpoints included safety and tolerability, overall survival, and progression-free survival. Effects on cognitive function were assessed via the Mini Mental State Examination., Results: Of 16 eligible patients (56.25% male; median age, 71.5 years [range, 44-78]; 75% PS 0-1), 1 dose-limiting toxicity was reported (grade 3 agitation). Maximum tolerated dose was not reached and the recommended phase 2 dose was determined as 200 mg twice daily. Median overall survival and progression-free survival were 10.8 months (80% CI, 7.3-11.4) and 5.5 months (80% CI, 3.9-5.9), respectively. Mini Mental State Examination plots indicated that cognitive function was not adversely affected by the olaparib-radiation therapy combination., Conclusions: Olaparib can be safely combined with hypofractionated brain radiation therapy and is well tolerated in patients unsuitable for radical chemoradiation. These results enabled initiation of a randomized phase 2 study and support future trials of PARP inhibitors in combination with radiation therapy for patients with brain tumors., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published models inconsistently associate glioblastoma size with overall survival (OS). This study aimed to investigate the prognostic effect of tumour size in a large cohort of patients diagnosed with GBM and interrogate how sample size and non-linear transformations may impact on the likelihood of finding a prognostic effect. In total, 279 patients with a IDH-wildtype unifocal WHO grade 4 GBM between 2014 and 2020 from a retrospective cohort were included. Uni-/multivariable association between core volume, whole volume (CV and WV), and diameter with OS was assessed with (1) Cox proportional hazard models +/- log transformation and (2) resampling with 1,000,000 repetitions and varying sample size to identify the percentage of models, which showed a significant effect of tumour size. Models adjusted for operation type and a diameter model adjusted for all clinical variables remained significant ( p = 0.03). Multivariable resampling increased the significant effects ( p < 0.05) of all size variables as sample size increased. Log transformation also had a large effect on the chances of a prognostic effect of WV. For models adjusted for operation type, 19.5% of WV vs. 26.3% log-WV ( n = 50) and 69.9% WV and 89.9% log-WV ( n = 279) were significant. In this large well-curated cohort, multivariable modelling and resampling suggest tumour volume is prognostic at larger sample sizes and with log transformation for WV.

Background: Neuro-oncology patients and caregivers should have equitable access to rehabilitation, supportive-, and palliative care. To investigate existing issues and potential solutions, we surveyed neuro-oncology professionals to explore current barriers and facilitators to screening patients' needs and referral to services., Methods: Members of the European Association of Neuro-Oncology and the European Organisation for Research and Treatment of Cancer Brain Tumor Group (EORTC-BTG) were invited to complete a 39-item online questionnaire covering the availability of services, screening, and referral practice. Responses were analyzed descriptively; associations between sociodemographic/clinical variables and screening/referral practice were explored., Results: In total, 103 participants completed the survey (67% women and 57% medical doctors). Fifteen professions from 23 countries were represented. Various rehabilitation, supportive-, and palliative care services were available yet rated "inadequate" by 21-37% of participants. Most respondents with a clinical role ( n  = 94) declare to screen (78%) and to refer (83%) their patients routinely for physical/cognitive/emotional issues. Survey completers ( n  = 103) indicated the main reasons for not screening/referring were (1) lack of suitable referral options (50%); (2) shortage of healthcare professionals (48%); and (3) long waiting lists (42%). To improve service provision, respondents suggested there is a need for education about neuro-oncology-specific issues (75%), improving the availability of services (65%) and staff (64%), developing international guidelines (64%), and strengthening the existing evidence-base for rehabilitation (60%)., Conclusions: Detecting and managing neuro-oncology patients' and caregivers' rehabilitation, supportive,- and palliative care needs can be improved. Better international collaboration can help address healthcare disparities., Competing Interests: B.F.: No COI. D.L.: No COI. D.K.M.: No COI. F.J.: honoraria for lectures and consultations from the following for-profit companies: Novartis, Seagen. G.N.: received honoraria for lectures from Blue Earth Diagnostics and for advisory board participation from Telix Pharmaceuticals. K.B.: No COI. L.R.E.: has received a grant from Bristol Meyer Squibb and honoraria for lectures or advisory board from Bayer, Janssen, Leo Pharma, Pierre Fabre, Roche, Seattle Genetics and Servier. M.S.: No COI. M.G.: reports personal financial interests as an invited speaker for BrainLab and treasurer for the EORTC. N.E.: No COI. N.S.: No COI. P.M.: received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Janssen, Servier, Miltenyi, Böhringer-Ingelheim, Telix, Medscape. R.L.: No COI. R.R.: has received honoraria for lectures or consultation or advisory board from the following companies: UCB, Novocure, Bayer, Servier, Cure-Vac. R.I.: No COI. T.M.: No COI. W.A.: No COI. C.A. Research funding and honoraria from AstraZeneca, Benevolent AI, Duke Street Bio. S.C.S.: Honoraria from Bayer, Chimerix; laboratory project support from Apollomics, Blue Earth Diagnostics; consultancy fees from CeCaVa, Miltenyi, Tocagen, Servier; travel support from Blue Earth Diagnostics. K.P.: No COI., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

High grade gliomas are the most common primary aggressive brain tumours with a very poor prognosis and a median survival of less than 2 years. The standard management protocol of newly diagnosed glioblastoma patients involves surgery followed by radiotherapy, chemotherapy in the form of temozolomide and further adjuvant temozolomide. The recent advances in molecular profiling of high-grade gliomas have further enhanced our understanding of the disease. Although the management of glioblastoma is standardised in newly diagnosed adult patients there is a lot of debate regarding the best treatment approach for the newly diagnosed elderly glioblastoma patients. In this review article we attempt to summarise the findings regarding surgery, radiotherapy, chemotherapy, and their combination in order to offer the best possible management modality for this group of patients. Elderly patients 65-70 with an excellent functional level could be considered as candidates for the standards treatment consisting of surgery, standard radiotherapy with concomitant and adjuvant temozolomide. Similarly, elderly patients above 70 with good functional status could receive the above with the exception of receiving a shorter course of radiotherapy instead of standard. In elderly GBM patients with poorer functional status and MGMT promoter methylation temozolomide chemotherapy can be considered. For elderly patients who cannot tolerate chemotherapy, hypofractionated radiotherapy is an option. In contrast to the younger adult patients, it seems that a careful individualised approach is a key element in deciding the best treatment options for this group of patients., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Background: Glioblastoma (GBM) brain tumors lacking IDH1 mutations (IDHwt) have the worst prognosis of all brain neoplasms. Patients receive surgery and chemoradiotherapy but tumors almost always fatally recur., Results: Using RNA sequencing data from 107 pairs of pre- and post-standard treatment locally recurrent IDHwt GBM tumors, we identify two responder subtypes based on longitudinal changes in gene expression. In two thirds of patients, a specific subset of genes is upregulated from primary to recurrence (Up responders), and in one third, the same genes are downregulated (Down responders), specifically in neoplastic cells. Characterization of the responder subtypes indicates subtype-specific adaptive treatment resistance mechanisms that are associated with distinct changes in the tumor microenvironment. In Up responders, recurrent tumors are enriched in quiescent proneural GBM stem cells and differentiated neoplastic cells, with increased interaction with the surrounding normal brain and neurotransmitter signaling, whereas Down responders commonly undergo mesenchymal transition. ChIP-sequencing data from longitudinal GBM tumors suggests that the observed transcriptional reprogramming could be driven by Polycomb-based chromatin remodeling rather than DNA methylation., Conclusions: We show that the responder subtype is cancer-cell intrinsic, recapitulated in in vitro GBM cell models, and influenced by the presence of the tumor microenvironment. Stratifying GBM tumors by responder subtype may lead to more effective treatment., (© 2024. The Author(s).)

Background: Glioblastoma (GBM) is the most common adult malignant brain tumour, with an incidence of 5 per 100,000 per year in England. Patients with tumours showing O 6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation represent around 40% of newly diagnosed GBM. Relapse/tumour recurrence is inevitable. There is no agreed standard treatment for patients with GBM, therefore, it is aimed at delaying further tumour progression and maintaining health-related quality of life (HRQoL). Limited clinical trial data exist using cannabinoids in combination with temozolomide (TMZ) in this setting, but early phase data demonstrate prolonged overall survival compared to TMZ alone, with few additional side effects. Jazz Pharmaceuticals (previously GW Pharma Ltd.) have developed nabiximols (trade name Sativex®), an oromucosal spray containing a blend of cannabis plant extracts, that we aim to assess for preliminary efficacy in patients with recurrent GBM., Methods: ARISTOCRAT is a phase II, multi-centre, double-blind, placebo-controlled, randomised trial to assess cannabinoids in patients with recurrent MGMT methylated GBM who are suitable for treatment with TMZ. Patients who have relapsed ≥ 3 months after completion of initial first-line treatment will be randomised 2:1 to receive either nabiximols or placebo in combination with TMZ. The primary outcome is overall survival time defined as the time in whole days from the date of randomisation to the date of death from any cause. Secondary outcomes include overall survival at 12 months, progression-free survival time, HRQoL (using patient reported outcomes from QLQ-C30, QLQ-BN20 and EQ-5D-5L questionnaires), and adverse events., Discussion: Patients with recurrent MGMT promoter methylated GBM represent a relatively good prognosis sub-group of patients with GBM. However, their median survival remains poor and, therefore, more effective treatments are needed. The phase II design of this trial was chosen, rather than phase III, due to the lack of data currently available on cannabinoid efficacy in this setting. A randomised, double-blind, placebo-controlled trial will ensure an unbiased robust evaluation of the treatment and will allow potential expansion of recruitment into a phase III trial should the emerging phase II results warrant this development., Trial Registration: ISRCTN: 11460478., Clinicaltrials: Gov: NCT05629702., (© 2024. The Author(s).)

Response Assessment in Neuro-Oncology (RANO) response criteria have been established and were updated in 2023 for MRI-based response evaluation of diffuse gliomas in clinical trials. In addition, PET-based imaging with amino acid tracers is increasingly considered for disease monitoring in both clinical practice and clinical trials. So far, a standardised framework defining timepoints for baseline and follow-up investigations and response evaluation criteria for PET imaging of diffuse gliomas has not been established. Therefore, in this Policy Review, we propose a set of criteria for response assessment based on amino acid PET imaging in clinical trials enrolling participants with diffuse gliomas as defined in the 2021 WHO classification of tumours of the central nervous system. These proposed PET RANO criteria provide a conceptual framework that facilitates the structured implementation of PET imaging into clinical research and, ultimately, clinical routine. To this end, the PET RANO 1.0 criteria are intended to encourage specific investigations of amino acid PET imaging of gliomas., Competing Interests: Declaration of interests NLA has received honoraria for consultation or advisory board participation from Novartis (Advanced Accelerator Applications), Telix Pharmaceuticals, and Servier; and research funding from Novocure. NG received honoraria for lectures from Blue Earth Diagnostics and honoraria for advisory board participation from Telix Pharmaceuticals. BME is on the advisory board and is a paid consultant for Medicenna, MedQIA, Servier Pharmaceuticals, Siemens, Janssen Pharmaceuticals, Imaging Endpoints, Kazia, Chimerix, Sumitomo Dainippon Pharma Oncology, ImmunoGenesis, Ellipses Pharma, Monteris, Neosoma, Alpheus Medical, Sagimet Biosciences, Sapience Therapeutics, Orbus Therapeutics, and the Global Coalition for Adaptive Research. MJvdB has received honoraria from Roche, AstraZeneca, Servier, Boehringer, Genenta, Fore Biotherapeutics, Incyte, and Nerviano. ELR reports personal financial interests as an advisory board member for Bayer, Janssen, Leo Pharma, Pierre Fabre, Roche, Seattle Genetics, and Servier; and institutional funding from Bristol Myers Squibb. MJM has received research support from Bristol Myers Squibb and travel support from Pierre Fabre. GM has received honoraria for lectures from BrainLab. RR has received research grants from Bayer, and honoraria for lectures or consulting from UCB, Novocure, Genenta, Curevac, and Servier. AMS has received research support to his institution from Medimmune, AVID, Telix Pharmaceuticals, ITM, Fusion, Cyclotek, Adalta, TheraMyc, Curis, Humanigen, and Antengene; funding support from the Medical Research Future Fund, Australian Brain Cancer Mission, Cure Brain Cancer Foundation, National Breast Cancer Foundation, Australian Cancer Research Foundation, National Imaging Facility, and Victorian Cancer Agency; and is a National Health and Medical Research Council Investigator. MS has received honoraria for consultancy from Bracco and honoraria for lectures from GE Healthcare, AuntMinnie, and Fondazione Internazionale Menarini (all paid to their institution). BS has received honoraria for lectures and consultation from Novocure. J-CT has received honoraria for lectures, consultation, or advisory board participation from SeagGen, AAA-Novartis, Novocure, and Munich Surgical Imaging. AV has received honoraria for lectures and advisory board participation from Curium, Eisai, and General Electrics. MW has received research grants from Quercis and Versameb; and honoraria for lectures or advisory board participation or consulting from Bayer, Curevac, Medac, Novartis, Novocure, Orbus, Philogen, Roche, and Servier. PYW has received research support from AstraZeneca, Black Diamond, Bristol Myers Squibb, Celgene, Chimerix, Eli Lilly, Erasca, Genentech/Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Servier, Vascular Biogenics, and VBI Vaccines; and honoraria for serving as a consultant or on advisory boards for AstraZeneca, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, GSK, Merck, Mundipharma, Novartis, Novocure, Nuvation Bio, Prelude Therapeutics, Sapience, Servier, Sagimet, Vascular Biogenics, and VBI Vaccines. MP has received honoraria for lectures, consultation, or advisory board participation from Bayer, Bristol Myers Squibb, Novartis, Gerson Lehrman Group, CMC Contrast, GSK, Mundipharma, Roche, BMJ Journals, MedMedia, AstraZeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dohme, Tocagen, Adastra, Gan & Lee Pharmaceuticals, and Servier; and travel support from Servier, Roche, and Medsir., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

High-grade gliomas are primary brain tumors that are incredibly refractory long-term to surgery and chemoradiation, with no proven durable salvage therapies for patients that have failed conventional treatments. Post-treatment, the latent glioma and its microenvironment are characterized by a senescent-like state of mitotic arrest and a senescence-associated secretory phenotype (SASP) induced by prior chemoradiation. Although senescence was once thought to be irreversible, recent evidence has demonstrated that cells may escape this state and re-enter the cell cycle, contributing to tumor recurrence. Moreover, senescent tumor cells could spur the growth of their non-senescent counterparts, thereby accelerating recurrence. In this review, we highlight emerging evidence supporting the use of senolytic agents to ablate latent, senescent-like cells that could contribute to tumor recurrence. We also discuss how senescent cell clearance can decrease the SASP within the tumor microenvironment thereby reducing tumor aggressiveness at recurrence. Finally, senolytics could improve the long-term sequelae of prior therapy on cognition and bone marrow function. We critically review the senolytic drugs currently under preclinical and clinical investigation and the potential challenges that may be associated with deploying senolytics against latent glioma. In conclusion, senescence in glioma and the microenvironment are critical and potential targets for delaying or preventing tumor recurrence and improving patient functional outcomes through senotherapeutics., (© 2023. The Author(s).)

Background: Brain metastases derived from non-small cell lung cancer (NSCLC) represent a significant clinical problem. We aim to characterize the genomic landscape of brain metastases derived from NSCLC and assess clinical actionability., Methods: We searched Embase, MEDLINE, Web of Science, and BIOSIS from inception to 18/19 May 2022. We extracted information on patient demographics, smoking status, genomic data, matched primary NSCLC, and programmed cell death ligand 1 expression., Results: We found 72 included papers and data on 2346 patients. The most frequently mutated genes from our data were EGFR ( n  = 559), TP53 ( n  = 331), KRAS ( n  = 328), CDKN2A ( n  = 97), and STK11 ( n  = 72). Common missense mutations included EGFR L858R ( n  = 80) and KRAS G12C ( n  = 17). Brain metastases of ever versus never smokers had differing missense mutations in TP53 and EGFR , except for L858R and T790M in EGFR , which were seen in both subgroups. Of the top 10 frequently mutated genes that had primary NSCLC data, we found 37% of the specific mutations assessed to be discordant between the primary NSCLC and brain metastases., Conclusions: To our knowledge, this is the first systematic review to describe the genomic landscape of brain metastases derived from NSCLC. These results provide a comprehensive outline of frequently mutated genes and missense mutations that could be clinically actionable. These data also provide evidence of differing genomic landscapes between ever versus never smokers and primary NSCLC compared to the BM. This information could have important consequences for the selection and development of targeted drugs for these patients., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: The proportion of women among healthcare and biomedical research professionals in neuro-oncology is growing. With changes in cultural expectations and work-life balance considerations, more men aspire to nonfull-time jobs, yet, leadership positions remain dominated by men., Methods: The European Association of Neuro-Oncology (EANO) disparity committee carried out a digital survey to explore gender balance and actions suitable to promote gender equality. The survey was distributed among EANO members in 2021, with responses analyzed descriptively., Results: In total, 262 participants completed the survey (141 women, 53.8%; median age 43). Respondents were neurosurgeons (68, 26.0%); neurologists (67, 25.6%), medical oncologists (43, 16.4%), or other healthcare or research professionals; 208 participants (79.4%) worked full-time. Positive action to enforce the role of women in neuro-oncology was deemed necessary by 180 participants (68.7%), but only 28 participants (10.7%) agreed that women only should be promoted until gender balance is reached. A majority of respondents (162, 61.8%) felt that women with an equivalent CV should be prioritized over men to reach gender balance. If in the future the balance favored women at higher positions, 112 respondents (42.7%) agreed to apply positive action for men. The top indicators considered relevant to measure gender balance were: salary for similar positions (183/228, 80.3%), paid overtime (176/228, 77.2%), number of permanent positions (164/228, 71.9%), protected time for research (161/227, 70.9%), and training opportunities (157/227, 69.2%)., Conclusions: Specific indicators may help to measure and promote gender balance and should be considered for implementation among healthcare professionals in neuro-oncology., Competing Interests: E.L.R. reports personal financial interests as an advisory board member for Bayer, Janssen, Leo Pharma, Pierre Fabre, and Seattle Genetics; institutional funding from BMS. F.B. has no conflict of interest to declare. G.M. reports personal financial interests as an invited speaker for BrainLab and treasurer for the European Organisation for Research and Treatment of Cancer; institutional funding from AstraZeneca. N.G. has received honoraria for lectures from Blue Earth Diagnostics and for advisory board participation from Telix Pharmaceuticals. M.T. has no conflict of interest to declare. K.P. has no conflict of interest to declare. R.R. reports personal financial interests for advisory board membership for GENENTA, expert testimony for Novocure, and as an invited speaker for Bayer and UCB. Personal financial interests as an independent data monitoring committee member for Novocure, Servier, and CureVac. S.N. has no conflict of interest to declare. M.G. has no conflict of interest to declare. M.P. reports personal financial interests for advisory board membership for Abbvie, Adastra, AstraZeneca, Bayer, BMJ Journals, Bristol-Myers Squibb (BMS), CMC Contrast, Daiichi Sankyo, Gan & Lee Pharmaceuticals, Gerson Lehrman, GlaxoSmithKline (GSK), Lilly, Medahead, MedMedia, Merck Sharp & Dohme (MSD), Mundipharma, Novartis, Roche, Sanofi and Tocagen; institutional funding as coordinating principal investigator for PharmaMar and institutional research grants from Abbvie, Boehringer-Ingelheim, BMS, Daiichi Sankyo, GSK, MSD, Novocure and Roche. He reports non-financial interests as Past President of the European Association of Neuro-Oncology, Brain Tumor Group Chair for the European Organisation for Research and Treatment of Cancer, and as a member of the Multi-Site Guideline Advisory Group for the American Society of Clinical Oncology. M.W. reports personal financial interests as an advisory board member from Bayer, Curevac, Merck (EMD), Novartis, Novocure, and Philogen; personal financial interests as an independent data monitoring committee member for Orbus; institutional research grants from Quercis and Versameb. He also reports non-financial interests from a leadership role for the European Organisation for Research and Treatment of Cancer. S.C.S. received honoraria for lectures, advisory boards, or consultation from Bayer, Blue Earth, Tocagen, CeCaVa, and research grant funding from Apollomics. L.D. has no conflict of interest to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Studies focusing on the return to work (RTW) experiences of patients with a brain tumor (BT) are scarce. We aimed to explore, in-depth, the occupational expectations, experiences, and satisfaction of patients who RTW after a BT diagnosis and treatment, those not able to, and their family caregivers., Methods: This multicenter, cross-sectional study utilized semi-structured interviews and reflexive thematic analysis. Interviews were conducted with adults diagnosed with primary BT, in employment/self-employed before diagnosis, currently in follow-up care, and also with their caregivers., Results: In total, 23 interviews (17 patients/6 caregivers) took place. Five themes were developed: (1) Early (adjustments and) expectations: "Thought I would be back at work the following Monday"; pre-treatment patients wanted to be better informed about potential recovery time and side-effects. (2) Drivers to RTW: "Getting my life back on track"; RTW was seen as a symbol of normality and also dictated by financial pressures. (3) Experiences returning to work: "It's had its ups and downs": patients who had successfully returned were supported by employers financially, emotionally, and practically. (4) Required support: "He had surgery and that was it": suggested support included a back-to-work scheme and comprehensive financial support. (5) Caring and paid work: The "juggling act": carer's work was significantly impacted; often reducing/increasing their working hours while managing increasing caring demands., Conclusions: Future research focusing on RTW in neuro-oncology populations is needed. Interventions should be developed to improve employer/employee communication, and increase knowledge about BT care and possibilities for RTW, to support patients and caregivers towards sustained employment., Competing Interests: No conflict of interest exists for any author., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Central nervous system (CNS) tumor patients commonly undergo multimodality treatment in the course of their disease. Adverse effects and complications from these interventions have not been systematically studied, but pose significant challenges in clinical practice and impact function and quality of life, especially in the management of long-term brain tumor survivors. Here, the European Association of Neuro-Oncology (EANO) has developed recommendations to prevent, diagnose, and manage adverse effects and complications in the adult primary brain CNS tumor (except lymphomas) patient population with a specific focus on surgery, radiotherapy, and pharmacotherapy. Specifically, we also provide recommendations for dose adaptations, interruptions, and reexposure for pharmacotherapy that may serve as a reference for the management of standard of care in clinical trials. We also summarize which interventions are unnecessary, inactive or contraindicated. This consensus paper should serve as a reference for the conduct of standard therapy within and outside of clinical trials., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Patients with glioblastoma have a poor prognosis and treatment is palliative in nature from diagnosis. It is therefore critical that the benefits and burdens of treatments are clearly discussed with patients and caregivers., Aim: To explore experiences and preferences around glioblastoma treatment communication in patients, family caregivers and healthcare professionals., Design: Qualitative design. A thematic analysis of semi-structured interviews., Setting/participants: A total of 15 adult patients with glioblastoma, 13 caregivers and 5 healthcare professionals were recruited from Leeds Teaching Hospitals NHS Trust., Results: Four themes were identified: (1) Communication practice and preferences . Risks and side-effects of anti-tumour treatments were explained clearly, with information layered and repeated. Treatment was often understood to be 'the only option'. Understanding the impact of side-effects could be enhanced, alongside information about support services. (2) What matters most . Patients/caregivers valued being well-supported by a trusted treatment team, feeling involved, having control and quality of life. Healthcare professionals similarly highlighted trust, maintaining independence and emotional support as key. (3) Decision-making . With limited treatment options, trust and control are crucial in decision-making. Patients ultimately prefer to follow healthcare professional advice but want to be involved, consider alternatives and voice what matters to them. (4) Impact of COVID-19 . During the pandemic, greater efforts to maintain good communication were necessary. Negative impacts of COVID-19 were limited, caregivers appeared most disadvantaged by pandemic-related restrictions., Conclusions: In glioblastoma treatment communication, where prognosis is poor and treatmentwill not result in cure, building trusting relationships, maintaining a sense of control and being well-informed are identified as critical.

Purpose: People with primary malignant brain tumors (PMBT) undergo anti-tumor treatment and are followed up with MRI interval scans. There are potential burdens and benefits to interval scanning, yet high-quality evidence to suggest whether scans are beneficial or alter outcomes of importance for patients is lacking. We aimed to gain an in-depth understanding of how adults living with PMBTs experience and cope with interval scanning., Methods: Twelve patients diagnosed with WHO grade III or IV PMBT from two sites in the UK took part. Using a semi-structured interview guide, they were asked about their experiences of interval scans. A constructivist grounded theory approach was used to analyze data., Results: Although most participants found interval scans uncomfortable, they accepted that scans were something that they had to do and were using various coping methods to get through the MRI scan. All participants said that the wait between their scan and results was the most difficult part. Despite the difficulties they experienced, all participants said that they would rather have interval scans than wait for a change in their symptoms. Most of the time, scans provided relief, gave participants some certainty in an uncertain situation, and a short-term sense of control over their lives., Conclusion: The present study shows that interval scanning is important and highly valued by patients living with PMBT. Although interval scans are anxiety provoking, they appear to help people living with PMBT cope with the uncertainty of their condition., (© 2023. The Author(s).)

Introduction: Brain tumors cause morbidity and mortality in part through peritumoral brain edema. The current main treatment for peritumoral brain edema are corticosteroids. Due to the increased recognition of their side-effect profile, there is growing interest in finding alternatives to steroids but there is little formal study of animal models of peritumoral brain edema. This study aims to summarize the available literature., Methods: A systematic search was undertaken of 5 literature databases (Medline, Embase, CINAHL, PubMed and the Cochrane Library). The generic strategy was to search for various terms associated with "brain tumors", "brain edema" and "animal models"., Results: We identified 603 reports, of which 112 were identified as relevant for full text analysis that studied 114 peritumoral brain edema animal models. We found significant heterogeneity in the species and strain of tumor-bearing animals, tumor implantation method and edema assessment. Most models did not produce appreciable brain edema and did not test for observable manifestations thereof., Conclusion: No animal model currently exists that enable the investigation of novel candidates for the treatment of peritumoral brain edema. With current interest in alternative treatments for peritumoral brain edema, there is an unmet need for clinically relevant animal models., (© 2023. The Author(s).)

Objectives: Radiomics is a promising avenue in non-invasive characterisation of diffuse glioma. Clinical translation is hampered by lack of reproducibility across centres and difficulty in standardising image intensity in MRI datasets. The study aim was to perform a systematic review of different methods of MRI intensity standardisation prior to radiomic feature extraction., Methods: MEDLINE, EMBASE, and SCOPUS were searched for articles meeting the following eligibility criteria: MRI radiomic studies where one method of intensity normalisation was compared with another or no normalisation, and original research concerning patients diagnosed with diffuse gliomas. Using PRISMA criteria, data were extracted from short-listed studies including number of patients, MRI sequences, validation status, radiomics software, method of segmentation, and intensity standardisation. QUADAS-2 was used for quality appraisal., Results: After duplicate removal, 741 results were returned from database and reference searches and, from these, 12 papers were eligible. Due to a lack of common pre-processing and different analyses, a narrative synthesis was sought. Three different intensity standardisation techniques have been studied: histogram matching (5/12), limiting or rescaling signal intensity (8/12), and deep learning (1/12)-only two papers compared different methods. From these studies, histogram matching produced the more reliable features compared to other methods of altering MRI signal intensity., Conclusion: Multiple methods of intensity standardisation have been described in the literature without clear consensus. Further research that directly compares different methods of intensity standardisation on glioma MRI datasets is required., Key Points: • Intensity standardisation is a key pre-processing step in the development of robust radiomic signatures to evaluate diffuse glioma. • A minority of studies compared the impact of two or more methods. • Further research is required to directly compare multiple methods of MRI intensity standardisation on glioma datasets., (© 2022. The Author(s).)

Anti-1-amino-3- 18 fluorine-fluorocyclobutane-1-carboxylic acid ( 18 F-fluciclovine) positron emission tomography (PET) shows preferential glioma uptake but there is little data on how uptake correlates with post-contrast T1-weighted (Gd-T1) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) activity during adjuvant treatment. This pilot study aimed to compare 18 F-fluciclovine PET, DCE-MRI and Gd-T1 in patients undergoing chemoradiotherapy for glioblastoma (GBM), and in a parallel pre-clinical GBM model, to investigate correlation between 18 F-fluciclovine uptake, MRI findings, and tumour biology. 18 F-fluciclovine-PET-computed tomography (PET-CT) and MRI including DCE-MRI were acquired before, during and after adjuvant chemoradiotherapy (60 Gy in 30 fractions with temozolomide) in GBM patients. MRI volumes were manually contoured; PET volumes were defined using semi-automatic thresholding. The similarity of the PET and DCE-MRI volumes outside the Gd-T1 volume boundary was measured using the Dice similarity coefficient (DSC). CT-2A tumour-bearing mice underwent MRI and 18 F-fluciclovine PET-CT. Post-mortem mice brains underwent immunohistochemistry staining for ASCT2 (amino acid transporter), nestin (stemness) and Ki-67 (proliferation) to assess for biologically active tumour. 6 patients were recruited (GBM 1-6) and grouped according to overall survival (OS)-short survival (GBM-SS, median OS 249 days) and long survival (GBM-LS, median 903 days). For GBM-SS, PET tumour volumes were greater than DCE-MRI, in turn greater than Gd-T1. For GBM-LS, Gd-T1 and DCE-MRI were greater than PET. Tumour-specific 18 F-fluciclovine uptake on pre-clinical PET-CT corresponded to immunostaining for Ki-67, nestin and ASCT2. Results suggest volumes of 18 F-fluciclovine-PET activity beyond that depicted by DCE-MRI and Gd-T1 are associated with poorer prognosis in patients undergoing chemoradiotherapy for GBM. The pre-clinical model confirmed 18 F-fluciclovine uptake reflected biologically active tumour.

Background: Glioblastoma multiforme (GBM) is the most common high-grade malignant brain tumour in adults and arises from the glial cells in the brain. The prognosis of treated GBM remains very poor with 5-year survival rates of 5%, a figure which has not improved over the last few decades. Currently, there is a modest 14-month overall median survival in patients undergoing maximum safe resection plus adjuvant chemoradiotherapy. HOX gene dysregulation is now a widely recognised feature of many malignancies., Methods: In this study we have focused on HOX gene dysregulation in GBM as a potential therapeutic target in a disease with high unmet need., Results: We show significant dysregulation of these developmentally crucial genes and specifically that HOX genes A9, A10, C4 and D9 are strong candidates for biomarkers and treatment targets for GBM and GBM cancer stem cells. We evaluated a next generation therapeutic peptide, HTL-001, capable of targeting HOX gene over-expression in GBM by disrupting the interaction between HOX proteins and their co-factor, PBX. HTL-001 induced both caspase-dependent and -independent apoptosis in GBM cell lines., Conclusion: In vivo biodistribution studies confirmed that the peptide was able to cross the blood brain barrier. Systemic delivery of HTL-001 resulted in improved control of subcutaneous murine and human xenograft tumours and improved survival in a murine orthotopic model., (© 2022. The Author(s).)

Background: Detailed prevalence estimates of BRAFV600 mutations and BRAF inhibitor (BRAFi) treatment responses in V600-mutant glioma will inform trial development., Methods: Our systematic review analyzed overall prevalence of BRAFV600 mutations in glioma and BRAFi treatment response., Results: Based on 13 682 patients in 182 publications, the prevalence of BRAFV600 in epithelioid glioblastoma (eGBM) was 69% [95% CI: 45-89%]; pleomorphic xanthoastrocytoma (PXA): 56% [48-64%] anaplastic pleomorphic xanthoastrocytoma (aPXA): 38% [23-54%], ganglioglioma (GG): 40% [33-46%], and anaplastic ganglioglioma (aGG): 46% [18-76%]. Prevalence in astroblastoma was 24% [8-43%], desmoplastic infantile astrocytoma (DIA): 16% [0-57%], subependymal giant cell astrocytoma (SEGA): 8% [0-37%], dysembryoplastic neuroepithelial tumor (DNET): 3% [0-11%], diffuse astrocytoma (DA): 3% [0-9%], and pilocytic astrocytoma (PA): 3% [2-5%]. We reviewed 394 V600-mutant gliomas treated with BRAFi from 130 publications. One hundred and twenty-nine pediatric low-grade gliomas showed 4 (3.1%) complete response (CR); 53 (41.1%) partial response (PR); 64 (49.6%) stable disease (SD) and 8 (6.2%) progressive disease (PD). 25 pediatric high-grade gliomas showed CR; PR; SD; PD in 4 (16.0%); 10 (40.0%), 4 (16.0%); and 7 (28.0%) respectively. Thirty-nine adult low-grade gliomas showed CR; PR; SD; PD of 4 (10.3%); 17 (43.6%); 16 (41.0%) and 2 (5.1%) respectively. Ninety-seven adult high-grade gliomas showed CR; PR; SD; PD of 6 (6.2%); 31 (32.0%); 27 (27.8%); and 33 (34.0%) respectively., Conclusions: BRAFV600 prevalence is highest in eGBM, PXA, aPXA, GG, aGG, and lower in astroblastoma, DIA, SEGA, DNET, DA, and PA. Our data provide the rationale for adjuvant clinical trials of BRAFi in V600-mutant glioma., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Cancer cell invasion is a precondition for tumour metastasis and represents one of the most devastating characteristics of cancer. The development of drugs targeting cell migration, known as migrastatics, may improve the treatment of highly invasive tumours such as glioblastoma (GBM). In this study, investigations into the role of the cell adhesion protein Cellular communication network factor 1 (CCN1, also known as CYR61) in GBM cell migration uncovered a drug resistance mechanism adopted by cells when treated with the small molecule inhibitor CCG-1423. This inhibitor binds to importin α/β inhibiting the nuclear translocation of the transcriptional co-activator MKL1, thus preventing downstream effects including migration. Despite this reported role as an inhibitor of cell migration, we found that CCG-1423 treatment did not inhibit GBM cell migration. However, we could observe cells now migrating by mesenchymal-amoeboid transition (MAT). Furthermore, we present evidence that CCN1 plays a critical role in the progression of GBM with increased expression in higher-grade tumours and matched blood samples. These findings support a potential role for CCN1 as a biomarker for the monitoring and potentially early prediction of GBM recurrence, therefore as such could help to improve treatment of and increase survival rates of this devastating disease.

Background: The oncogene epidermal growth factor receptor variant III (EGFRvIII) is expressed in approximately one-third of all glioblastomas (GBMs). So far it is not clear if EGFRvIII expression induces replication stress in GBM cells, which might serve as a therapeutical target., Methods: Isogenetic EGFRvIII- and EGFRvIII+ cell lines with endogenous EGFRvIII expression were used. Markers of oncogenic and replication stress such as γH2AX, RPA, 53BP1, ATR, and CHK1 were analyzed using western blot, immunofluorescence, and flow cytometry. The DNA fiber assay was performed to analyze replication, transcription was measured by incorporation of EU, and genomic instability was investigated by micronuclei and CGH-Array analysis. Immunohistochemistry staining was used to detect replication stress markers and R-loops in human GBM samples., Results: EGFRvIII+ cells exhibit an activated replication stress response, increased spontaneous DNA damage, elevated levels of single-stranded DNA, and reduced DNA replication velocity, which are all indicative characteristics of replication stress. Furthermore, we show here that EGFRvIII expression is linked to increased genomic instability. EGFRvIII-expressing cells display elevated RNA synthesis and R-loop formation, which could also be confirmed in EGFRvIII-positive GBM patient samples. Targeting replication stress by irinotecan resulted in increased sensitivity of EGFRvIII+ cells., Conclusion: This study demonstrates that EGFRvIII expression is associated with increased replication stress, R-loop accumulation, and genomic instability. This might contribute to intratumoral heterogeneity but may also be exploited for individualized therapy approaches., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Previous data on glycogen synthase kinase 3 (GSK-3) inhibition in cancer models support a cytotoxic effect with selectivity for tumor cells compared to normal tissue but the effect of these inhibitors in glioma has not been widely studied. Here, we investigate their potential as cytotoxics in glioma., Methods: We assessed the effect of pharmacologic GSK-3 inhibition on established (U87, U251) and patient-derived (GBM1, GBM4) glioblastoma (GBM) cell lines using cytotoxicity assays as well as undertaking a detailed investigation of the effect on cell cycle, mitosis, and centrosome biology. We also assessed drug uptake and efficacy of GSK-3 inhibition alone and in combination with radiation in xenograft models., Results: Using the selective GSK-3 inhibitor AZD2858, we demonstrated single agent cytotoxicity in two patient-derived glioma cell lines (GBM1, GBM4) and two established cell lines (U251 and U87) with IC 50 in the low micromolar range promoting centrosome disruption, failed mitosis, and S-phase arrest. Glioma xenografts exposed to AZD2858 also showed growth delay compared to untreated controls. Combined treatment with radiation increased the cytotoxic effect of clinical radiation doses in vitro and in orthotopic glioma xenografts., Conclusions: These data suggest that GSK-3 inhibition promotes cell death in glioma through disrupting centrosome function and promoting mitotic failure and that AZD2858 is an effective adjuvant to radiation at clinical doses.

Background: Glioma diagnosis can be devastating and result in a range of symptoms. Relatively little is known about the long-term health-related quality of life (HRQOL) challenges faced by these patients. Establishing the impact of diagnosis on HRQOL could help positively tailor clinical decision making regarding patient support and treatment. The aim of this review is to identify the long-term HRQOL issues reported at least 2 years following diagnosis of WHO grade II/III glioma., Method: Systematic literature searches were carried out using Medline, EMBASE, CINAHL, PsycINFO, and Web of Science Core Collection. Searches were designed to identify patient self-reports on HRQOL aspects defined as physical, mental, or social issues. Quality assessment was conducted using the Mixed Methods Appraisal Tool (MMAT). Narrative synthesis was used to collate findings., Results: The search returned 8923 articles. Two hundred seventy-eight titles remained after title and abstract screening, with 21 full-text articles included in the final analysis. The majority of studies used quantitative methods, with 3 articles reporting mixed methodology. Negative emotional/psychological/cognitive changes were the most commonly reported. Physical complaints included fatigue, seizures, and restricted daily activity. Social challenges included strained social relationships and financial problems. Patient coping strategies were suggested to influence patient's survival quality., Conclusion: The consequences of a glioma diagnosis and treatment can have substantial implications for patients' long-term HRQOL and daily functioning. Findings from this review lay the groundwork for efforts to improve patient HRQOL in long-term survivorship., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Preclinical data suggest some cannabinoids may exert antitumour effects against glioblastoma (GBM). Safety and preliminary efficacy of nabiximols oromucosal cannabinoid spray plus dose-intense temozolomide (DIT) was evaluated in patients with first recurrence of GBM., Methods: Part 1 was open-label and Part 2 was randomised, double-blind, and placebo-controlled. Both required individualised dose escalation. Patients received nabiximols (Part 1, n = 6; Part 2, n = 12) or placebo (Part 2 only, n = 9); maximum of 12 sprays/day with DIT for up to 12 months. Safety, efficacy, and temozolomide (TMZ) pharmacokinetics (PK) were monitored., Results: The most common treatment-emergent adverse events (TEAEs; both parts) were vomiting, dizziness, fatigue, nausea and headache. Most patients experienced TEAEs that were grade 2 or 3 (CTCAE). In Part 2, 33% of both nabiximols- and placebo-treated patients were progression-free at 6 months. Survival at 1 year was 83% for nabiximols- and 44% for placebo-treated patients (p = 0.042), although two patients died within the first 40 days of enrolment in the placebo arm. There were no apparent effects of nabiximols on TMZ PK., Conclusions: With personalised dosing, nabiximols had acceptable safety and tolerability with no drug-drug interaction identified. The observed survival differences support further exploration in an adequately powered randomised controlled trial., Clinical Trial Registration: ClinicalTrials.gov: Part 1- NCT01812603; Part 2- NCT01812616.

Patients with glioblastoma (GBM) have a poor prognosis, and inefficient delivery of drugs to tumors represents a major therapeutic hurdle. Hematopoietic stem cell (HSC)-derived myeloid cells efficiently home to GBM and constitute up to 50% of intratumoral cells, making them highly appropriate therapeutic delivery vehicles. Because myeloid cells are ubiquitously present in the body, we recently established a lentiviral vector containing matrix metalloproteinase 14 (MMP14) promoter, which is active specifically in tumor-infiltrating myeloid cells as opposed to myeloid cells in other tissues, and resulted in a specific delivery of transgenes to brain metastases in HSC gene therapy. Here, we used this novel approach to target transforming growth factor beta (TGFβ) as a key tumor-promoting factor in GBM. Transplantation of HSCs transduced with lentiviral vector expressing green fluorescent protein (GFP) into lethally irradiated recipient mice was followed by intracranial implantation of GBM cells. Tumor-infiltrating HSC progeny was characterized by flow cytometry. In therapy studies, mice were transplanted with HSCs transduced with lentiviral vector expressing soluble TGFβ receptor II-Fc fusion protein under MMP14 promoter. This TGFβ-blocking therapy was compared with the targeted tumor irradiation, the combination of the two therapies, and control. Tumor growth and survival were quantified (statistical significance determined by t-test and log-rank test). T cell memory response was probed through a repeated tumor challenge. Myeloid cells were the most abundant HSC-derived population infiltrating GBM. TGFβ-blocking HSC gene therapy in combination with irradiation significantly reduced tumor burden as compared with monotherapies and the control, and significantly prolonged survival as compared with the control and TGFβ-blocking monotherapy. Long-term protection from GBM was achieved only with the combination treatment (25% of the mice) and was accompanied by a significant increase in CD8+ T cells at the tumor implantation site following tumor rechallenge. We demonstrated a preclinical proof-of-principle for tumor myeloid cell-specific HSC gene therapy in GBM. In the clinic, HSC gene therapy is being successfully used in non-cancerous brain disorders and the feasibility of HSC gene therapy in patients with glioma has been demonstrated in the context of bone marrow protection. This indicates an opportunity for clinical translation of our therapeutic approach., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Glioblastomas are the most common form of malignant primary brain tumor and an important cause of morbidity and mortality. In recent years there have been important advances in understanding the molecular pathogenesis and biology of these tumors, but this has not translated into significantly improved outcomes for patients. In this consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of isocitrate dehydrogenase wildtype (IDHwt) glioblastomas will be discussed. In addition, novel therapies such as targeted molecular therapies, agents targeting DNA damage response and metabolism, immunotherapies, and viral therapies will be reviewed, as well as the current challenges and future directions for research., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

MicroRNAs play an important role in the regulation of mRNA translation and have therapeutic potential in cancer and other diseases. To profile the landscape of microRNAs with significant cytotoxicity in the context of glioblastoma (GBM), we performed a high-throughput screen in adult and pediatric GBM cells using a synthetic oligonucleotide library representing all known human microRNAs. Bioinformatics analysis was used to refine this list and the top seven microRNAs were validated in a larger panel of GBM cells using state-of-the-art in vitro assays. The cytotoxic effect of our most relevant candidate was assessed in a preclinical model. Our screen identified ~100 significantly cytotoxic microRNAs with 70% concordance between cell lines. MicroRNA-1300 (miR-1300) was the most potent and robust candidate. We observed a striking binucleated phenotype in miR-1300 transfected cells due to cytokinesis failure followed by apoptosis. This was also observed in two stem-like patient-derived cultures. We identified the physiological role of miR-1300 as a regulator of endomitosis in megakaryocyte differentiation where blockade of cytokinesis is an essential step. In GBM cells, where miR-1300 is normally not expressed, the oncogene Epithelial Cell Transforming 2 (ECT2) was validated as a direct key target. ECT2 siRNA phenocopied the effects of miR-1300, and ECT2 overexpression led to rescue of miR-1300 induced binucleation. We showed that ectopic expression of miR-1300 led to decreased tumor growth in an orthotopic GBM model. Our screen provides a resource for the neuro-oncology community and identified miR-1300 as a novel regulator of endomitosis with translatable potential for therapeutic application.

Background: Effective treatment for patients at least 70 years with newly diagnosed glioblastoma remains challenging and alternatives to conventional cytotoxics are appealing. Autophagy inhibition has shown promising efficacy and safety in small studies of glioblastoma and other cancers., Methods: We conducted a randomized phase II trial to compare radiotherapy with or without hydroxychloroquine (2:1 allocation). Patients aged at least 70 years with newly diagnosed high-grade glioma deemed suitable for short-course radiotherapy with an ECOG performance status of 0-1 were included. Radiotherapy treatment consisted of 30 Gy, delivered as 6 fractions given over 2 weeks (5 Gy per fraction). Hydroxychloroquine was given as 200 mg orally b.d. from 7 days prior to radiotherapy until disease progression. The primary endpoint was 1-year overall survival (OS). Secondary endpoints included progression-free survival (PFS), quality of life, and toxicity., Results: Fifty-four patients with a median age of 75 were randomized between May 2013 and October 2016. The trial was stopped early in 2016. One-year OS was 20.3% (95% confidence interval [CI] 8.2-36.0) hydroxychloroquine group, and 41.2% (95% CI 18.6-62.6) radiotherapy alone, with a median survival of 7.9 and 11.5 months, respectively. The corresponding 6-month PFS was 35.3% (95% CI 19.3-51.7) and 29.4% (95% CI 10.7-51.1). The outcome in the control arm was better than expected and the excess of deaths in the hydroxychloroquine group appeared unrelated to cancer. There were more grade 3-5 events in the hydroxychloroquine group (60.0%) versus radiotherapy alone (38.9%) without any clear common causation., Conclusions: Hydroxychloroquine with short-course radiotherapy did not improve survival compared to radiotherapy alone in elderly patients with glioblastoma., (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

The limitations of two-dimensional analysis in three-dimensional (3D) cellular imaging impair the accuracy of research findings in biological studies. Here, we report a novel 3D approach to acquisition, analysis and interpretation of tumour spheroid images. Our research interest in mesenchymal-amoeboid transition led to the development of a workflow incorporating the generation and analysis of 3D data with instant structured illumination microscopy and a new ImageJ plugin., Competing Interests: We declare we have no competing interests., (© 2020 The Author(s).)

Glioblastoma (GBM) is an aggressive cancer with a very poor prognosis. Generally viewed as weakly immunogenic, GBM responds poorly to current immunotherapies. To understand this problem more clearly we used a combination of natural killer (NK) cell functional assays together with gene and protein expression profiling to define the NK cell response to GBM and explore immunosuppression in the GBM microenvironment. In addition, we used transcriptome data from patient cohorts to classify GBM according to immunological profiles. We show that glioma stem-like cells, a source of post-treatment tumour recurrence, express multiple immunomodulatory cell surface molecules and are targeted in preference to normal neural progenitor cells by natural killer (NK) cells ex vivo. In contrast, GBM-infiltrating NK cells express reduced levels of activation receptors within the tumour microenvironment, with hallmarks of transforming growth factor (TGF)-β-mediated inhibition. This NK cell inhibition is accompanied by expression of multiple immune checkpoint molecules on T cells. Single-cell transcriptomics demonstrated that both tumour and haematopoietic-derived cells in GBM express multiple, diverse mediators of immune evasion. Despite this, immunome analysis across a patient cohort identifies a spectrum of immunological activity in GBM, with active immunity marked by co-expression of immune effector molecules and feedback inhibitory mechanisms. Our data show that GBM is recognized by the immune system but that anti-tumour immunity is restrained by multiple immunosuppressive pathways, some of which operate in the healthy brain. The presence of immune activity in a subset of patients suggests that these patients will more probably benefit from combination immunotherapies directed against multiple immunosuppressive pathways., (© 2019 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.)

Background: Gliomas are associated with significant healthcare burden, yet reports of costs are scarce. While many costs are unavoidable there may be treatable symptoms contributing to higher costs. We describe healthcare and societal costs in glioma patients at high risk for depression and their family caregivers, and explore relationships between costs and treatable symptoms., Methods: Data from a multicenter randomized trial on effects of internet-based therapy for depressive symptoms were used (NTR3223). Costs of self-reported healthcare utilization, medication use, and productivity loss were calculated for patients and caregivers separately. We used generalized linear regression models to predict costs with depressive symptoms, fatigue, cognitive complaints, tumor grade (low-/high-grade), disease status (stable or active/progression), and intervention (use/non-use) as predictors., Results: Multiple assessments from baseline through 12 months from 91 glioma patients and 46 caregivers were used. Mean overall costs per year were M = €20,587.53 (sd = €30,910.53) for patients and M = €5,581.49 (sd = €13,102.82) for caregivers. In patients, higher healthcare utilization costs were associated with more depressive symptoms; higher medication costs were associated with active/progressive disease. In caregivers, higher overall costs were linked with increased caregiver fatigue, cognitive complaints, and lower patient tumor grade. Higher healthcare utilization costs were related to more cognitive complaints and lower tumor grade. More productivity loss costs were associated with increased fatigue (all P < 0.05)., Conclusions: There are substantial healthcare and societal costs for glioma patients and caregivers. Associations between costs and treatable psychological symptoms indicate that possibly, adequate support could decrease costs., Trial Registration: Netherlands Trial Register NTR3223.

The oncogene epidermal growth factor receptor variant III (EGFRvIII) is frequently expressed in glioblastomas (GBM) but its impact on therapy response is still under controversial debate. Here we wanted to test if EGFRvIII influences the sensitivity towards the alkylating agent temozolomide (TMZ). Therefore, we retrospectively analyzed the survival of 336 GBM patients, demonstrating that under standard treatment, which includes TMZ, EGFRvIII expression is associated with prolonged survival, but only in patients with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated tumors. Using isogenic GBM cell lines with endogenous EGFRvIII expression we could demonstrate that EGFRvIII increases TMZ sensitivity and results in enhanced numbers of DNA double-strand breaks and a pronounced S/G2-phase arrest after TMZ treatment. We observed a higher expression of DNA mismatch repair (MMR) proteins in EGFRvIII+ cells and patient tumor samples, which was most pronounced for MSH2 and MSH6. EGFRvIII-specific knockdown reduced MMR protein expression thereby increasing TMZ resistance. Subsequent functional kinome profiling revealed an increased activation of p38- and ERK1/2-dependent signaling in EGFRvIII expressing cells, which regulates MMR protein expression downstream of EGFRvIII. In summary, our results demonstrate that the oncoprotein EGFRvIII sensitizes a fraction of GBM to current standard of care treatment through the upregulation of DNA MMR.

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear 1,2 . Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.

Tumor stem cells and malignant multicellular networks have been separately implicated in the therapeutic resistance of glioblastoma multiforme (GBM), the most aggressive type of brain cancer in adults. Here, we show that small-molecule inhibition of RHO-associated serine/threonine kinase proteins (ROCKi) significantly promoted the outgrowth of neurite-like cell projections in cultures of heterogeneous patient-derived GBM stem-like cells. These projections formed de novo -induced cellular network (iNet) 'webs', which regressed after withdrawal of ROCKi. Connected cells within the iNet web exhibited long range Ca 2+ signal transmission, and significant lysosomal and mitochondrial trafficking. In contrast to their less-connected vehicle control counterparts, iNet cells remained viable and proliferative after high-dose radiation. These findings demonstrate a link between ROCKi-regulated cell projection dynamics and the formation of radiation-resistant multicellular networks. Our study identifies means to reversibly induce iNet webs ex vivo , and may thereby accelerate future studies into the biology of GBM cellular networks., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Background: Childhood brain tumour survivors who receive cranial radiotherapy undergo regular surveillance for the development ofhypothalamic-pituitary (HP) axis dysfunction. Much less attention has been given to radiation-induced hypopituitarism in patients with malignant brain tumours of adult onset., Design: Retrospective cohort study., Patients/measurements: We assessed the effects of cranial radiotherapy (cXRT) on pituitary function in 58 adults (32 male) with gliomas distant to the HP axis. The XRT dose exposure at the HP axis was correlated with individual axis dysfunction to establish dose thresholds., Results: Mean age at cXRT was 41.2 ± 10.9 years and duration of endocrine follow-up 8.2 ± 5.2 years. Mean XRT dose to the HP axis was 35.9 ± 15.5 Gy. Overall prevalence of radiation-induced hypopituitarism was 84.5%. GH, LH/FSH, ACTH and TSH deficiency were present in 82.8%, 20.7%, 19% and 6.9% of patients, respectively. Hyperprolactinaemia was noted in 10.3% (n = 6) and was persistent in one case. GH deficiency and "any degree of hypopituitarism" positively correlated with the radiotherapy dose to the hypothalamic-pituitary axis. HP axis XRT dose thresholds for the development of GHD, LH/FSH, ACTH and TSH deficiency were established at 10, 30, 32 and 40.8 Gy, respectively. A gradual increase in the prevalence of all anterior pituitary hormone deficits was observed throughout the follow-up period., Conclusions: Hypopituitarism post-cXRT in adults with gliomas is a frequent, progressive and dose-dependent phenomenon. Dose thresholds suggest long-term endocrine surveillance is important where the HP axis XRT dose is higher than 30 Gy. Identification of deficits to allow early and appropriate hormone replacement therapy is important to improve well-being in these individuals with limited prognosis., (© 2019 John Wiley & Sons Ltd.)

The overall survival for patients with primary glioblastoma is very poor. Glioblastoma contains a subpopulation of glioma stem cells (GSC) that are responsible for tumour initiation, treatment resistance and recurrence. PPARα is a transcription factor involved in the control of lipid, carbohydrate and amino acid metabolism. We have recently shown that PPARα gene and protein expression is increased in glioblastoma and has independent clinical prognostic significance in multivariate analyses. In this work, we report that PPARα is overexpressed in GSC compared to foetal neural stem cells. To investigate the role of PPARα in GSC, we knocked down its expression using lentiviral transduction with short hairpin RNA (shRNA). Transduced GSC were tagged with luciferase and stereotactically xenografted into the striatum of NOD-SCID mice. Bioluminescent and magnetic resonance imaging showed that knockdown (KD) of PPARα reduced the tumourigenicity of GSC in vivo. PPARα-expressing control GSC xenografts formed invasive histological phenocopies of human glioblastoma, whereas PPARα KD GSC xenografts failed to establish viable intracranial tumours. PPARα KD GSC showed significantly reduced proliferative capacity and clonogenic potential in vitro with an increase in cellular senescence. In addition, PPARα KD resulted in significant downregulation of the stem cell factors c-Myc, nestin and SOX2. This was accompanied by downregulation of the PPARα-target genes and key regulators of fatty acid oxygenation ACOX1 and CPT1A, with no compensatory increase in glycolytic flux. These data establish the aberrant overexpression of PPARα in GSC and demonstrate that this expression functions as an important regulator of tumourigenesis, linking self-renewal and the malignant phenotype in this aggressive cancer stem cell subpopulation. We conclude that targeting GSC PPARα expression may be a therapeutically beneficial strategy with translational potential as an adjuvant treatment. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland., (© 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)