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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.

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.

BACKGROUND: Extracellular vesicles (EVs) play an important role in cell–cell communication, and tumor-derived EVs circulating in patient blood can serve as biomarkers. Here, we investigated the potential role of plasma EVs in meningioma patients for tumor detection and determined whether EVs secreted by meningioma cells reflect epigenetic, genomic, and proteomic alterations of original tumors. METHODS: EV concentrations were quantified in patient plasma (n = 46). Short-term meningioma cultures were established (n = 26) and secreted EVs were isolated. Methylation and copy number profiling was performed using 850k arrays, and mutations were identified by targeted gene panel sequencing. Differential quantitative mass spectrometry was employed for proteomic analysis. RESULTS: Levels of circulating EVs were elevated in meningioma patients compared to healthy individuals, and the plasma EV concentration correlated with malignancy grade and extent of peritumoral edema. Postoperatively, EV counts dropped to normal levels, and the magnitude of the postoperative decrease was associated with extent of tumor resection. Methylation profiling of EV-DNA allowed correct tumor classification as meningioma in all investigated cases, and accurate methylation subclass assignment in almost all cases. Copy number variations present in tumors, as well as tumor-specific mutations were faithfully reflected in meningioma EV-DNA. Proteomic EV profiling did not permit original tumor identification but revealed tumor-associated proteins that could potentially be utilized to enrich meningioma EVs from biofluids. CONCLUSIONS: Elevated EV levels in meningioma patient plasma could aid in tumor diagnosis and assessment of treatment response. Meningioma EV-DNA mirrors genetic and epigenetic tumor alterations and facilitates molecular tumor classification.

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.

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.

Glioblastoma (GBM) brain tumours lackingIDH1mutations (IDHwt) have the worst prognosis of all brain neoplasms. Patients receive surgery and chemoradiotherapy but tumours almost always fatally recur. Using RNAseq data from 107 pairs of pre- and post-standard treatment locally recurrent IDHwt GBM tumours, we identified two responder subtypes based on therapy-driven changes in gene expression. In two thirds of patients a specific subset of genes is up-regulated from primary to recurrence (Up responders) and in one third the same genes are down-regulated (Down responders). Characterisation of the responder subtypes indicates subtype-specific adaptive treatment resistance mechanisms. In Up responders treatment enriches for quiescent proneural GBM stem cells and differentiated neoplastic cells with increased neurotransmitter signalling, whereas Down responders commonly undergo therapy-driven mesenchymal transition. Stratifying GBM tumours by response subtype may lead to more effective treatment. In support of this, modulators of gamma aminobutyric acid (GABA) neurotransmitter signalling differentially sensitise Up and Down responder GBM models to standard treatmentin vitro.

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.

The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.

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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 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 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.

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.

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.

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.

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.

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.

Background Women represent an increasing proportion of the overall workforce in medicine but are underrepresented in leadership roles. Methods To explore gender inequalities and challenges in career opportunities, a web-based survey was conducted among the membership of the European Association of Neuro-Oncology and the Brain Tumor Group of the European Organisation for Research and Treatment of Cancer. Results A total of 228 colleagues responded to the survey: 129 women (median age 45 years; range, 25-66 years) and 99 men (median age 48 years; range, 24-81 years); 153 participants (67%) were married and 157 participants (69%) had at least 1 child. Women less often declared being married (60% vs 77%, P = .007) or having a child (63% vs 77%, P = .024). Men more frequently had a full-time position (88% vs 75%, P = .036). Women and men both perceived an underrepresentation of women in leadership positions. Half of participants agreed that the most important challenges for women are leading a team and obtaining a faculty position. Fewer women than men would accept such a position (42% vs 56%). The main reasons were limited time for career and an inappropriate work and life balance. Women specifically cited negative discrimination, limited opportunities, and lack of self-confidence. Discrimination of women at work was perceived by 64% of women vs 47% of men (P = .003). Conclusion Women are perceived as experiencing more difficulties in acquiring a leadership position. Personal preferences may account for an underrepresentation of women in leadership positions, but perceived gender inequalities extend beyond disparities of access to leadership.

Summary 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., Our manuscript challenges the current paradigm that Glioblastoma (GBM) is a poor candidate for immunotherapy, therefore impacting on clinical approaches. We identify NK cells as a target for immunosuppression in GBM, with multiple suppressive pathways within GBM human tumours. We also identify a group of GBM patients with higher immunological activity, who will benefit from immunotherapies that target these immunosuppressive pathways.

The authors wish to make the following corrections to this paper [1] [...]

BACKGROUND Glioma diagnosis can be devastating, and results in a wide range of symptoms. Relatively little is known about the long-term challenges these symptoms pose on HRQOL. The aim of this review is to identify the long-term HRQOL issues reported at least two years following diagnosis of glioma. METHOD Systematic literature searches were carried out using Medline, EMBASE, CINAHL, PsycINFO, and Web of Science Core Collection. Searches were designed to identify a range of reported HRQOL aspects defined as physical, mental or social issues, in adult WHO grade II or III patients. To capture the full extent of patients’ experience, studies of any design reporting on primary data where patients had at least two years follow-up from diagnosis were included. WHO grade I and grade IV tumours were excluded due to their different prognoses and the expected nature of their disease trajectories. Narrative synthesis was used to collate findings. RESULTS The search returned 8438 articles. 477 titles remained after title and abstract screening, with seventeen full text articles included in the final analysis. The majority of studies used quantitative methods, with only two articles reporting qualitative or mixed methodology. Articles were predominantly cross-sectional studies (n = 9), along with cohort studies (n = 3), clinical trials (n = 3) and pilot studies (n = 2). Results indicated that patients reported a variety of issues influencing their HRQOL, with emotional/psychological/cognitive changes the most frequently reported. Physical complaints included problems with fatigue, seizures and maintaining daily activity. Social challenges included strained social relationships and issues managing finances. Patient coping strategies were found to significantly influence wellbeing and subsequent HRQOL. CONCLUSION Glioma patients’ long-term HRQOL and daily functioning can be impacted by their physical, mental and social wellbeing. Findings from this review lay the groundwork for efforts to improve patient long-term HRQOL.

In response to major changes in diagnostic algorithms and the publication of mature results from various large clinical trials, the European Association of Neuro-Oncology (EANO) recognized the need to provide updated guidelines for the diagnosis and management of adult patients with diffuse gliomas. Through these evidence-based guidelines, a task force of EANO provides recommendations for the diagnosis, treatment and follow-up of adult patients with diffuse gliomas. The diagnostic component is based on the 2016 update of the WHO Classification of Tumors of the Central Nervous System and the subsequent recommendations of the Consortium to Inform Molecular and Practical Approaches to CNS Tumour Taxonomy — Not Officially WHO (cIMPACT-NOW). With regard to therapy, we formulated recommendations based on the results from the latest practice-changing clinical trials and also provide guidance for neuropathological and neuroradiological assessment. In these guidelines, we define the role of the major treatment modalities of surgery, radiotherapy and systemic pharmacotherapy, covering current advances and cognizant that unnecessary interventions and expenses should be avoided. This document is intended to be a source of reference for professionals involved in the management of adult patients with diffuse gliomas, for patients and caregivers, and for health-care providers., Herein, the European Association of Neuro-Oncology (EANO) provides recommendations for the diagnosis, treatment and follow-up of adult patients with diffuse gliomas. These evidence-based guidelines incorporate major changes in diagnostic algorithms based on the 2016 update of the WHO Classification of Tumors of the Central Nervous System as well as on evidence from recent large clinical trials.

BackgroundEffective 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.MethodsWe 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.ResultsFifty-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.ConclusionsHydroxychloroquine with short-course radiotherapy did not improve survival compared to radiotherapy alone in elderly patients with glioblastoma.

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. 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.

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 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 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.

Background and purpose: Magnetic Resonance (MR)-only radiotherapy requires geometrically accurate MR images over the full scanner Field of View (FoV). This study aimed to investigate the repeatability of distortion measurements made using a commercial large FoV phantom and analysis software and the sensitivity of these measurements to small set-up errors. Materials and methods: Geometric distortion was measured using a commercial phantom and software with 2D and 3D acquisition sequences on three different MR scanners. Two sets of repeatability measurements were made: three scans acquired without moving the phantom between scans (single set-up) and five scans acquired with the phantom re-set up in between each scan (repeated set-up). The set-up sensitivity was assessed by scanning the phantom with an intentional 1 mm lateral offset and independently an intentional 1° rotation. Results: The mean standard deviation of distortion for all phantom markers for the repeated set-up scans was

Magnetic resonance imaging (MRI) offers superior soft-tissue contrast as compared with computed tomography (CT), which is conventionally used for radiation therapy treatment planning (RTP) and patient positioning verification, resulting in improved target definition. The 2 modalities are co-registered for RTP; however, this introduces a systematic error. Implementing an MRI-only radiation therapy workflow would be advantageous because this error would be eliminated, the patient pathway simplified, and patient dose reduced. Unlike CT, in MRI there is no direct relationship between signal intensity and electron density; however, various methodologies for MRI-only RTP have been reported. A systematic review of these methods was undertaken. The PRISMA guidelines were followed. Embase and Medline databases were searched (1996 to March, 2017) for studies that generated synthetic CT scans (sCT)s for MRI-only radiation therapy. Sixty-one articles met the inclusion criteria. This review showed that MRI-only RTP techniques could be grouped into 3 categories: (1) bulk density override; (2) atlas-based; and (3) voxel-based techniques, which all produce an sCT scan from MR images. Bulk density override techniques either used a single homogeneous or multiple tissue override. The former produced large dosimetric errors (>2%) in some cases and the latter frequently required manual bone contouring. Atlas-based techniques used both single and multiple atlases and included methods incorporating pattern recognition techniques. Clinically acceptable sCTs were reported, but atypical anatomy led to erroneous results in some cases. Voxel-based techniques included methods using routine and specialized MRI sequences, namely ultra-short echo time imaging. High-quality sCTs were produced; however, use of multiple sequences led to long scanning times increasing the chances of patient movement. Using nonroutine sequences would currently be problematic in most radiation therapy centers. Atlas-based and voxel-based techniques were found to be the most clinically useful methods, with some studies reporting dosimetric differences of

BACKGROUND A primary brain tumour (PrBT) diagnosis can be devastating, and results in a wide range of symptoms. Relatively little is known about the long-term challenges these symptoms pose on HRQOL. The aim of this review is to identify the long-term HRQOL issues reported at least two years following diagnosis of a PrBT. MATERIAL AND METHODS Systematic literature searches were carried out using Medline, EMBASE, CINAHL, PsycINFO and Web of Science Core Collection. Searches were designed to identify a range of reported HRQOL aspects defined as physical, mental or social issues, in adult WHO grade II or III patients. To capture the full extent of patients’ experience, studies of any design reporting on primary data where patients had at least two years follow-up from diagnosis were included. WHO grade I and grade IV tumours were excluded due to their different prognoses and the expected nature of their disease trajectories. Quality assessment was conducted using the Mixed Methods Appraisal Tool (MMAT). Narrative synthesis was used to collate findings. RESULTS The search returned 8438 articles. 477 titles remained after title and abstract screening, with eighteen full text articles included in the final analysis. The majority of studies used quantitative methods, with only two articles reporting qualitative or mixed methodology. Articles were predominantly cross-sectional studies (n = 10), along with cohort studies (n = 3), clinical trials (n = 3) and pilot studies (n = 2). Results indicated that patients reported a variety of issues influencing their HRQOL, with emotional/psychological/cognitive changes being the most commonly reported. Physical complaints included problems with fatigue, seizures and maintaining daily activity. Social challenges included strained social relationships and issues managing finances. Patient coping strategies were found to significantly influence wellbeing and subsequent HRQOL. CONCLUSION PrBT patients’ long-term HRQOL and daily functioning can be impacted by their physical, mental and social wellbeing. Findings from this review lay the groundwork for efforts to improve patient HRQOL in long-term survivorship.

Many traits of cancer progression (e.g., development of metastases or resistance to therapy) are facilitated by tumour evolution: Darwinian selection of subclones with distinct genotypes or phenotypes that enable such progression. Characterising these subclones provide an opportunity to develop drugs to better target their specific properties but requires the accurate identification of somatic mutations shared across multiple spatiotemporal tumours from the same patient. Current best practices for calling somatic mutations are optimised for single samples, and risk being too conservative to identify shared mutations with low prevalence in some samples. We reasoned that datasets from multiple matched tumours can be used for mutual validation and thus propose an adapted two-stage approach: (1) low-stringency mutation calling to identify mutations shared across samples irrespective of the weight of evidence in a single sample; (2) high-stringency mutation calling to further characterise mutations present in a single sample. We applied our approach to three-independent cohorts of paired primary and recurrent glioblastoma tumours, two of which have previously been analysed using existing approaches, and found that it significantly increased the amount of biologically relevant shared somatic mutations identified. We also found that duplicate removal was detrimental when identifying shared somatic mutations. Our approach is also applicable when multiple datasets e.g. DNA and RNA are available for the same tumour.

Background CNS tumors, including medulloblastoma and pediatric glioblastoma (pGBM) account for the majority of solid pediatric malignancies. There remains an unmet need to identify novel treatment approaches in poor prognosis and relapsed pediatric brain tumors, where therapeutic options are limited. Small-molecule B-cell lymphoma 2 (BCL-2) family inhibitors may enhance tumor cell killing when combined with conventional and targeted chemotherapeutic agents. We investigated the effect of disrupting BCL-2 and B cell lymphoma-extra large (BCL-XL) protein function using ABT-263, ABT-199 and WEHI-539 in medulloblastoma and pGBM cells following treatment with MLN8237, an Aurora kinase inhibitor under investigation as a novel agent for the treatment of malignant brain tumors. Methods Tumor cell growth and viability were determined by MTT/WST-1 assays and flow cytometry. Effects on cell phenotype, cell cycle progression, and ploidy were determined by live cell imaging and DNA content analysis. Apoptosis was determined by annexin V/propidium iodide staining and time-lapse microscopy and confirmed by measuring caspase-3/7 activity and western blotting and by short interfering RNA (siRNA) knockdown of BCL-2 associated X protein/BCL-2 antagonist killer (BAX/BAK). Results ABT-263, in combination with MLN8237, reduced mitotic slippage and polyploidy and promoted the elimination of mitotically defective cells via a BAX/BAK-dependent, caspase-mediated apoptotic pathway. The BCL-XL antagonist, WEHI-539, significantly augmented tumor cell killing when used in combination with MLN8237, as well as sensitized resistant brain tumor cells to a novel BAX activator, SMBA1. In addition, siRNA-mediated knockdown of BCL-XL sensitized pGBM and medulloblastoma cells to MLN8237 and mimicked the effect of combination drug treatment. Conclusion Selective small-molecule inhibitors of BCL-XL may enhance the efficacy of MLN8237 and other targeted chemotherapeutic agents.

Aims The increasing use of highly conformal radiation techniques to treat meningioma confers a greater need for accurate targeting. Several groups have shown that positron emission tomography/computed tomography (PET/CT) information alters meningioma targets contoured by single observers, but whether this translates into improved accuracy has not been defined. As magnetic resonance imaging (MRI) is the cornerstone of meningioma target contouring, simultaneous PET/MRI may be superior to PET/CT. We assessed whether 68 Ga DOTATATE PET imaging (from PET/CT and PET/MRI) reduced interobserver variability (IOV) in meningioma target volume contouring. Materials and methods Ten patients with meningioma underwent simultaneous 68 Ga DOTATATE PET/MRI followed by PET/CT. They were selected as it was anticipated that target volume definition in their cases would be particularly challenging. Three radiation oncologists contoured target volumes according to an agreed protocol: gross tumour volume (GTV) and clinical target volume (CTV) on CT/MRI alone, CT/MRI+PET(CT) and CT/MRI+PET(MRI). GTV/CTV Kouwenhoven conformity levels (KCL), regions of contour variation and qualitative differences between PET(CT) and PET(MRI) were evaluated. Results There was substantial IOV in contouring. GTV mean KCL: CT/MRI 0.34, CT/MRI+PET(CT) 0.38, CT/MRI+PET(MRI) 0.39 ( P = 0.06). CTV mean KCL: CT/MRI 0.31, CT/MRI+PET(CT) 0.35, CT/MRI+PET(MRI) 0.35 ( P = 0.04 for all groups; P > 0.05 for individual pairs). One observer consistently contoured largest and one smallest. Observers rarely decreased volumes in relation to PET. Most IOV occurred in bone followed by dural tail, postoperative bed and venous sinuses. Tumour edges were qualitatively clearer on PET(MRI) versus PET(CT), but this did not affect contouring. Conclusion IOV in contouring challenging meningioma cases was large and only slightly improved with the addition of 68 Ga DOTATATE PET. Simultaneous PET/MRI for meningioma contouring is feasible, but did not improve IOV versus PET/CT. Whether volumes can be safely reduced according to PET requires evaluation.

BACKGROUND Oncolytic viruses represent a novel treatment approach in GBM through oncolytic targeting as well as local immune activation. We designed a phase Ib, open-label study of intravenous reovirus (pelareorep) with GM-CSF alongside standard chemoradiotherapy to assess safety and tolerability. METHODS 15 patients with newly diagnosed GBM were treated with GM-CSF 50mg subcutaneously (days 1–3) and pelareorep (days 4–5) in weeks 1 and 4 of chemoradiotherapy, and week 1 of adjuvant temozolomide course: 7 patients received 1x1010TCID50 (dose level 1); 8 received 3x1010TCID50 (dose level 2). The primary objective was to determine the maximum tolerated dose of pelareorep and GM-CSF with standard chemoradiotherapy. Secondary objectives were to gain preliminary assessment of the activity of the combination and assess treatment compliance. RESULTS 1 dose limiting toxicity (DLT) and 20 SAEs were experienced overall; median number of SAEs per patient was 2. Commonest SAEs were nervous system disorders, predominantly seizures. SARs included fever/flu-like episodes (n=5), fall (n=1) and headache (n=1). Two SUSARs occurred in dose level 2, classed as vascular disorders manifesting as hypotension episodes – one was a DLT. Suspected relationship of SARs: pelareorep (n=6); temozolomide (n=1); radiotherapy (n=1); all study drugs (n=1). 87% of patients (n=13) completed chemoradiotherapy without unplanned delays. Adjuvant treatment was delayed in 21% of cycles overall, with the majority due to inadequate haematology/biochemistry values (44% of delays). Pelareorep was omitted in 4 instances in 4 patients during chemoradiotherapy and omitted in 4 instances in 3 patients during adjuvant treatment. CONCLUSION We present the first clinical data using intravenous pelareorep with GM-CSF alongside standard chemoradiotherapy in patients with GBM, suggesting that the combination is tolerable. Further analysis is underway and efficacy results will be ready for presentation at the conference. This work was supported by CRUK, The Brain Tumour Charity, Yorkshire Cancer Research and Oncolytics Biotech Inc.

MGMT promoter methylation is the only accepted biomarker with prognostic role in GBM but its routine implementation is limited partly response to TMZ is heterogeneous, but also due to lack of effective alternative treatment options. Therefore, additional biomarkers are needed to enable better prediction of survival and to improve individualized treatment of GBM patients. A potential new biomarker is the epidermal growth factor receptor variant III (EGFRvIII). This constitutively activated deletion variant is present in approximately one third of all IDH wildtype GBM, but its relevance to treatment response is poorly understood. The aim of the present study was to analyze the impact of endogenous EGFRvIII expression on chemosensitivity and the mechanisms underlying any differential treatment response. EGFRvIII expression was associated with prolonged median overall survival but only for GBM patients with MGMT promoter methylated tumors. In line with this, we observed increased TMZ sensitivity of EGFRvIII+ and MGMT promoter methylated cells, which translated into improved survival in xenograft experiments. The increased TMZ sensitivity was associated with an elevated DNA damage induction accompanied by an increased expression of DNA mismatch repair (MMR) proteins in EGFRvIII+ cell lines and EGFRvIII+ GBM patient samples. Subsequently, only a moderate reduction in MMR protein expression resulted in a dramatic TMZ resistance, suggesting that EGFRvIII expression specifically sensitized MGMT deficient cells to TMZ treatment by upregulating MMR. Furthermore, EGFRvIII expression in GBM cell lines was accompanied by increased DNA damage, replication fork slowing, stalling and enhanced origin firing, implying replication stress. Targeting of EGFRvIII-dependent replication stress by irinotecan led to hypersensitivity of EGFRvIII+ cells. Taken together this study illustrates that EGFRvIII-induced upregulation of MMR and replication stress increases chemosensitivity thereby highlighting the vulnerability of EGFRvIII+ GBM to available treatments. These important data may also guide the development of new and more effective personalized strategies.

BACKGROUND Glioblastoma has a poor prognosis despite treatment with surgery and chemo-radiotherapy (CRT). Monitoring early response to CRT is challenging and conventional imaging is sub-optimal for stratifying poorly responding patients for novel agents. Also, imaging is not routinely performed during CRT and consequently, personalised treatment through individualised radiation dose adaption is not possible. AIMS: To evalutate the feasibility of Fluorine-18 Fluciclovine PET-CT for early response assessment during and post-treatment in patients with glioblastoma undergoing standard-of-care CRT. METHODS Patients with confirmed glioblastoma and macroscopic residual tumour post-surgery were consented for PET-CT and MRI prior to CRT (scan 1), after completing 2 weeks (10 fractions) of CRT (scan 2) and 6 weeks after completing treatment (scan 3). For each scan, patients were immobilised in a radiotherapy treatment mask. PET-CT and MRI scans were performed at each timepoint within a few days of each other. Patients were treated and followed up according to local guidelines. RESULTS 6 patients were recruited to the study between June 2018 and May 2019. All patients tolerated the additional imaging without problems. 2 patients were unable to attend their post-treatment PET-CT scan due to clinical deterioration. Fluciclovine PET-CT highlighted potentially active disease beyond the surgical cavity pre-radiotherapy (scan 1) in 3 patients. In 4/6, PET signal persisted after 2 weeks of radiotherapy with stable MRI appearances (scan 2). Frank disease progression was seen in 1 patient on both MRI and PET-CT mid-treatment. 3/4 patients with persistent activity at scan 2, showed disease progression post-treatment on both PET-CT and MRI (scan 3). Another had progressive changes on MRI but stable PET-CT appearances possibly representing pseudoprogression. CONCLUSION These preliminary results suggest that Fluciclovine PET-CT could help in monitoring treatment and further work to assess the ability to guide individualised treatment planning in glioblastoma is warranted.