The outcomes measured and reported in observational studies of incidental and untreated intracranial meningioma: A systematic review.

Background: The clinical management of patients with incidental intracranial meningioma varies markedly and is often based on clinician choice and observational data. Heterogeneous outcome measurement has likely hampered knowledge progress by preventing comparative analysis of similar cohorts of patients. This systematic review aimed to summarize the outcomes measured and reported in observational studies. Methods: A systematic literature search was performed to identify published full texts describing active monitoring of adult cohorts with incidental and untreated intracranial meningioma (PubMed, EMBASE, MEDLINE, and CINAHL via EBSCO, completed January 24, 2022). Reported outcomes were extracted verbatim, along with an associated definition and method of measurement if provided. Verbatim outcomes were de-duplicated and the resulting unique outcomes were grouped under standardized outcome terms. These were classified using the taxonomy proposed by the "Core Outcome Measures in Effectiveness Trials" (COMET) initiative. Results: Thirty-three published articles and 1 ongoing study were included describing 32 unique studies: study designs were retrospective n = 27 and prospective n = 5. In total, 268 verbatim outcomes were reported, of which 77 were defined. Following de-duplication, 178 unique verbatim outcomes remained and were grouped into 53 standardized outcome terms. These were classified using the COMET taxonomy into 9 outcome domains and 3 core areas. Conclusions: Outcome measurement across observational studies of incidental and untreated intracranial meningioma is heterogeneous. The standardized outcome terms identified will be prioritized through an eDelphi survey and consensus meeting of key stakeholders (including patients), in order to develop a Core Outcome Set for use in future observational studies.

The outcomes measured and reported in intracranial meningioma clinical trials: A systematic review.

Background: Meningioma clinical trials have assessed interventions including surgery, radiotherapy, and pharmacotherapy. However, agreement does not exist on what, how, and when outcomes of interest should be measured. To do so would allow comparative analysis of similar trials. This systematic review aimed to summarize the outcomes measured and reported in meningioma clinical trials. Methods: Systematic literature and trial registry searches were performed to identify published and ongoing intracranial meningioma clinical trials (PubMed, Embase, Medline, CINAHL via EBSCO, and Web of Science, completed January 22, 2022). Reported outcomes were extracted verbatim, along with an associated definition and method of measurement if provided. Verbatim outcomes were deduplicated and the resulting unique outcomes were grouped under standardized outcome terms. These were classified using the taxonomy proposed by the "Core Outcome Measures in Effectiveness Trials" (COMET) initiative. Results: Thirty published articles and 18 ongoing studies were included, describing 47 unique clinical trials: Phase 2 n = 33, phase 3 n = 14. Common interventions included: Surgery n = 13, radiotherapy n = 8, and pharmacotherapy n = 20. In total, 659 verbatim outcomes were reported, of which 84 were defined. Following de-duplication, 415 unique verbatim outcomes remained and were grouped into 115 standardized outcome terms. These were classified using the COMET taxonomy into 29 outcome domains and 5 core areas. Conclusions: Outcome measurement across meningioma clinical trials is heterogeneous. The standardized outcome terms identified will be prioritized through an eDelphi survey and consensus meeting of key stakeholders (including patients), in order to develop a core outcome set for use in future meningioma clinical trials.

Local administration of irinotecan using an implantable drug delivery device stops high-grade glioma tumor recurrence in a glioblastoma tumor model.

The treatment for Glioblastoma is limited due to the presence of the blood brain barrier, which restricts the entry of chemotherapeutic drugs into the brain. Local delivery into the tumor resection margin has the potential to improve efficacy of chemotherapy. We developed a safe and clinically translatable irinotecan implant for local delivery to increase its efficacy while minimizing systemic side effects. Irinotecan-loaded implants were manufactured using hot melt extrusion, gamma sterilized at 25 kGy, and characterized for their irinotecan content, release, and drug diffusion. Their therapeutic efficacy was evaluated in a patient-derived xenograft mouse resection model of glioblastoma. Their safety and translatability were evaluated using histological analysis of brain tissue and serum chemistry analysis. Implants containing 30% and 40% w/w irinotecan were manufactured without plasticizer. The 30% and 40% implants showed moderate local toxicity up to 2- and 6-day post-implantation. Histopathology of the implantation site showed signs of necrosis at days 45 and 14 for the 30% and 40% implants. Hematological analysis and clinical chemistry showed no signs of serious systemic toxicity for either implant. The 30% implants had an 80% survival at day 148, with no sign of tumor recurrence. Gamma sterilization and 12-month storage had no impact on the integrity of the 30% implants. This study demonstrates that the 30% implants are a promising novel treatment for glioblastoma that could be quickly translated into the clinic.

Utility of a prognostic assessment tool to predict survival following surgery for brain metastases.

Background: Brain metastases account for more than 50% of all intracranial tumors and are associated with poor outcomes. Treatment decisions in this highly heterogenous cohort remain controversial due to the myriad of treatment options available, and there is no clearly defined standard of care. The prognosis in brain metastasis patients varies widely with tumor type, extracranial disease burden and patient performance status. Decision-making regarding treatment is, therefore, tailored to each patient and their disease. Methods: This is a retrospective cohort study assessing survival outcomes following surgery for brain metastases over a 50-month period (April 1, 2014-June 30, 2018). We compared predicted survival using the diagnosis-specific Graded Prognostic Assessment (ds-GPA) with actual survival. Results: A total of 186 patients were included in our cohort. Regression analysis demonstrated no significant correlation between actual and predicted outcome. The most common reason for exclusion was insufficient information being available to the neuro-oncology multidisciplinary team (MDT) meeting to allow GPA calculation. Conclusions: In this study, we demonstrate that "predicted survival" using the ds-GPA does not correlate with "actual survival" in our operated patient cohort. We also identify a shortcoming in the amount of information available at MDT in order to implement the GPA appropriately. Patient selection for aggressive therapies is crucial, and this study emphasizes the need for treatment decisions to be individualized based on patient and cancer clinical characteristics.

Development of a core outcome set for use in adult primary glioma phase III interventional trials: A mixed methods study.

Background: Glioma interventional studies should collect data aligned with patient priorities, enabling treatment benefit assessment and informed decision-making. This requires effective data synthesis and meta-analyses, underpinned by consistent trial outcome measurement, analysis, and reporting. Development of a core outcome set (COS) may contribute to a solution. Methods: A 5-stage process was used to develop a COS for glioma trials from the UK perspective. Outcome lists were generated in stages 1: a trial registry review and systematic review of qualitative studies and 2: interviews with glioma patients and caregivers. In stage 3, the outcome lists were de-duplicated with accessible terminology, in stage 4 outcomes were rated via a 2-round Delphi process, and stage 5 comprised a consensus meeting to finalize the COS. Patient-reportable COS outcomes were identified. Results: In Delphi round 1, 96 participants rated 35 outcomes identified in stages 1 and 2, to which a further 10 were added. Participants (77/96) rated the resulting 45 outcomes in round 2. Of these, 22 outcomes met a priori threshold for inclusion in the COS. After further review, a COS consisting of 19 outcomes grouped into 7 outcome domains (survival, adverse events, activities of daily living, health-related quality of life, seizure activity, cognitive function, and physical function) was finalized by 13 participants at the consensus meeting. Conclusions: A COS for glioma trials was developed, comprising 7 outcome domains. Additional research will identify appropriate measurement tools and further validate this COS.

European Cancer Organisation Essential Requirements for Quality Cancer Care: Adult glioma.

European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCCs) are explanations of the organisation and actions necessary to provide high-quality care to patients with a specific cancer type. They are compiled by a working group of European experts representing disciplines involved in cancer care, and provide oncology teams, patients, policymakers and managers with an overview of the essential requirements in any healthcare system. The focus here is on adult glioma. Gliomas make up approximately 80% of all primary malignant brain tumours. They are highly diverse and patients can face a unique cognitive, physical and psychosocial burden, so personalised treatments and support are essential. However, management of gliomas is currently very heterogeneous across Europe and there are only few formally-designated comprehensive cancer centres with brain tumour programmes. To address this, the ERQCC glioma expert group proposes frameworks and recommendations for high quality care, from diagnosis to treatment and survivorship. Wherever possible, glioma patients should be treated from diagnosis onwards in high volume neurosurgical or neuro-oncology centres. Multidisciplinary team working and collaboration is essential if patients' length and quality of life are to be optimised.

Screening of predicted synergistic multi-target therapies in glioblastoma identifies new treatment strategies.

Background: IDH-wildtype glioblastoma (GBM) is a highly malignant primary brain tumor with a median survival of 15 months after standard of care, which highlights the need for improved therapy. Personalized combination therapy has shown to be successful in many other tumor types and could be beneficial for GBM patients. Methods: We performed the largest drug combination screen to date in GBM, using a high-throughput effort where we selected 90 drug combinations for their activity onto 25 patient-derived GBM cultures. 43 drug combinations were selected for interaction analysis based on their monotherapy efficacy and were tested in a short-term (3 days) as well as long-term (18 days) assay. Synergy was assessed using dose-equivalence and multiplicative survival metrics. Results: We observed a consistent synergistic interaction for 15 out of 43 drug combinations on patient-derived GBM cultures. From these combinations, 11 out of 15 drug combinations showed a longitudinal synergistic effect on GBM cultures. The highest synergies were observed in the drug combinations Lapatinib with Thapsigargin and Lapatinib with Obatoclax Mesylate, both targeting epidermal growth factor receptor and affecting the apoptosis pathway. To further elaborate on the apoptosis cascade, we investigated other, more clinically relevant, apoptosis inducers and observed a strong synergistic effect while combining Venetoclax (BCL targeting) and AZD5991 (MCL1 targeting). Conclusions: Overall, we have identified via a high-throughput drug screening several new treatment strategies for GBM. Moreover, an exceptionally strong synergistic interaction was discovered between kinase targeting and apoptosis induction which is suitable for further clinical evaluation as multi-targeted combination therapy.

Refining the Intraoperative Identification of Suspected High-Grade Glioma Using a Surgical Fluorescence Biomarker: GALA BIDD Study Report.

BACKGROUND: Improving intraoperative accuracy with a validated surgical biomarker is important because identifying high-grade areas within a glioma will aid neurosurgical decision-making and sampling. METHODS: We designed a multicentre, prospective surgical cohort study (GALA-BIDD) to validate the presence of visible fluorescence as a pragmatic intraoperative surgical biomarker of suspected high-grade disease within a tumour mass in patients undergoing 5-aminolevulinic acid (5-ALA) fluorescence-guided cytoreductive surgery. RESULTS: A total of 106 patients with a suspected high-grade glioma or malignant transformation of a low-grade glioma were enrolled. Among the 99 patients who received 5-ALA, 89 patients were eligible to assess the correlation of fluorescence with diagnosis as per protocol. Of these 89, 81 patients had visible fluorescence at surgery, and 8 patients had no fluorescence. A total of 80 out of 81 fluorescent patients were diagnosed as high-grade gliomas on postoperative central review with 1 low-grade glioma case. Among the eight patients given 5-ALA who did not show any visible fluorescence, none were high-grade gliomas, and all were low-grade gliomas. Of the seven patients suspected radiologically of malignant transformation of low-grade gliomas and with visible fluorescence at surgery, six were diagnosed with high-grade gliomas, and one had no tissue collected. CONCLUSION: In patients where there is clinical suspicion, visible 5-ALA fluorescence has clinical utility as an intraoperative surgical biomarker of high-grade gliomas and can aid surgical decision-making and sampling. Further studies assessing the use of 5-ALA to assess malignant transformation in all diffuse gliomas may be valuable.

Transcriptome analysis reveals tumor microenvironment changes in glioblastoma.

A better understanding of transcriptional evolution of IDH-wild-type glioblastoma may be crucial for treatment optimization. Here, we perform RNA sequencing (RNA-seq) (n = 322 test, n = 245 validation) on paired primary-recurrent glioblastoma resections of patients treated with the current standard of care. Transcriptional subtypes form an interconnected continuum in a two-dimensional space. Recurrent tumors show preferential mesenchymal progression. Over time, hallmark glioblastoma genes are not significantly altered. Instead, tumor purity decreases over time and is accompanied by co-increases in neuron and oligodendrocyte marker genes and, independently, tumor-associated macrophages. A decrease is observed in endothelial marker genes. These composition changes are confirmed by single-cell RNA-seq and immunohistochemistry. An extracellular matrix-associated gene set increases at recurrence and bulk, single-cell RNA, and immunohistochemistry indicate it is expressed mainly by pericytes. This signature is associated with significantly worse survival at recurrence. Our data demonstrate that glioblastomas evolve mainly by microenvironment (re-)organization rather than molecular evolution of tumor cells.

Protocol for the Tessa Jowell BRAIN MATRIX Platform Study.

INTRODUCTION: Gliomas are the most common primary tumour of the central nervous system (CNS), with an estimated annual incidence of 6.6 per 100 000 individuals in the USA and around 14 deaths per day from brain tumours in the UK. The genomic and biological landscape of brain tumours has been increasingly defined and, since 2016, the WHO classification of tumours of the CNS incorporates molecular data, along with morphology, to define tumour subtypes more accurately. The Tessa Jowell BRAIN MATRIX Platform (TJBM) study aims to create a transformative clinical research infrastructure that leverages UK National Health Service resources to support research that is patient centric and attractive to both academic and commercial investors. METHODS AND ANALYSIS: The TJBM study is a programme of work with the principal purpose to improve the knowledge of glioma and treatment for patients with glioma. The programme includes a platform study and subsequent interventional clinical trials (as separate protocols). The platform study described here is the backbone data-repository of disease, treatment and outcome data from clinical, imaging and pathology data being collected in patients with glioma from secondary care hospitals. The primary outcome measure of the platform is time from biopsy to integrated histological-molecular diagnosis using whole-genome sequencing and epigenomic classification. Secondary outcome measures include those that are process centred, patient centred and framework based. Target recruitment for the study is 1000 patients with interim analyses at 100 and 500 patients. ETHICS AND DISSEMINATION: The study will be performed in accordance with the recommendations guiding physicians in biomedical research involving human subjects, adopted by the 18th World Medical Association General Assembly, Helsinki, Finland and stated in the respective participating countries' laws governing human research, and Good Clinical Practice. The protocol was initially approved on 18 February 2020 by West Midlands - Edgbaston Research Ethics Committee; the current protocol (v3.0) was approved on 15 June 2022. Participants will be required to provide written informed consent. A meeting will be held after the end of the study to allow discussion of the main results among the collaborators prior to publication. The results of this study will be disseminated through national and international presentations and peer-reviewed publications. Manuscripts will be prepared by the Study Management Group and authorship will be determined by mutual agreement. TRIAL REGISTRATION NUMBER: NCT04274283, 18-Feb-2020; ISRCTN14218060, 03-Feb-2020.

FUTURE-GB: functional and ultrasound-guided resection of glioblastoma - a two-stage randomised control trial.

INTRODUCTION: Surgery remains the mainstay for treatment of primary glioblastoma, followed by radiotherapy and chemotherapy. Current standard of care during surgery involves the intraoperative use of image-guidance and 5-aminolevulinic acid (5-ALA). There are multiple other surgical adjuncts available to the neuro-oncology surgeon. However, access to, and usage of these varies widely in UK practice, with limited evidence of their use. The aim of this trial is to investigate whether the addition of diffusion tensor imaging (DTI) and intraoperative ultrasound (iUS) to the standard of care surgery (intraoperative neuronavigation and 5-ALA) impacts on deterioration free survival (DFS). METHODS AND ANALYSIS: This is a two-stage, randomised control trial (RCT) consisting of an initial non-randomised cohort study based on the principles of the IDEAL (Idea, Development, Exploration, Assessment and Long-term follow-up) stage-IIb format, followed by a statistically powered randomised trial comparing the addition of DTI and iUS to the standard of care surgery. A total of 357 patients will be recruited for the RCT. The primary outcome is DFS, defined as the time to either 10-point deterioration in health-related quality of life scores from baseline, without subsequent reversal, progressive disease or death. ETHICS AND DISSEMINATION: The trial was registered in the Integrated Research Application System (Ref: 264482) and approved by a UK research and ethics committee (Ref: 20/LO/0840). Results will be published in a peer-reviewed journal. Further dissemination to participants, patient groups and the wider medical community will use a range of approaches to maximise impact. TRIAL REGISTRATION NUMBER: ISRCTN38834571.

Practical guidance for running late-phase platform protocols for clinical trials: lessons from experienced UK clinical trials units.

BACKGROUND: Late-phase platform protocols (including basket, umbrella, multi-arm multi-stage (MAMS), and master protocols) are generally agreed to be more efficient than traditional two-arm clinical trial designs but are not extensively used. We have gathered the experience of running a number of successful platform protocols together to present some operational recommendations. METHODS: Representatives of six UK clinical trials units with experience in running late-phase platform protocols attended a 1-day meeting structured to discuss various practical aspects of running these trials. We report and give guidance on operational aspects which are either harder to implement compared to a traditional late-phase trial or are specific to platform protocols. RESULTS: We present a list of practical recommendations for trialists intending to design and conduct late-phase platform protocols. Our recommendations cover the entire life cycle of a platform trial: from protocol development, obtaining funding, and trial set-up, to a wide range of operational and regulatory aspects such as staffing, oversight, data handling, and data management, to the reporting of results, with a particular focus on communication with trial participants and stakeholders as well as public and patient involvement. DISCUSSION: Platform protocols enable many questions to be answered efficiently to the benefit of patients. Our practical lessons from running platform trials will support trial teams in learning how to run these trials more effectively and efficiently.

Reconfiguration from emergency to urgent elective neurosurgery for glioblastoma patients improves length of stay, surgical adjunct use, and extent of resective surgery.

Background: Glioblastoma (GB) is the most common intrinsic brain cancer and is notorious for its aggressive nature. Despite widespread research and optimization of clinical management, the improvement in overall survival has been limited. The aim of this study was to characterize the impact of service reconfiguration on GB outcomes in a single centre. Methods: Patients with a histopathological confirmation of a diagnosis of GB between 01/01/2014 and 31/12/2019 were retrospectively identified. Demographic and tumour characteristics, survival, treatment (surgical and oncological), admission status, use of surgical adjunct (5-aminolevulinic acid, intra-operative neuro-monitoring), the length of stay, extent of resection, and surgical complications were recorded from the hospital databases. Results: From August 2018 the neurosurgical oncology service was reconfigured to manage high-grade tumours on an urgent outpatient basis by surgeons specializing in oncology. We demonstrate that these changes resulted in an increase in elective admissions, greater use of intra-operative adjuncts resulting in the improved extent of tumour resection, and a reduction in median length of stay and associated cost-savings. Conclusions: Optimizing neuro-oncology patient management through service reconfiguration resulted in increased use of intra-operative adjuncts, improved surgical outcomes, and reduced hospital costs. These changes also have the potential to improve survival and disease-free progression for patients with GB.

Development of a core outcome set and identification of patient-reportable outcomes for primary brain tumour trials: protocol for the COBra study.

INTRODUCTION: Primary brain tumours, specifically gliomas, are a rare disease group. The disease and treatment negatively impacts on patients and those close to them. The high rates of physical and cognitive morbidity differ from other cancers causing reduced health-related quality of life. Glioma trials using outcomes that allow holistic analysis of treatment benefits and risks enable informed care decisions. Currently, outcome assessment in glioma trials is inconsistent, hindering evidence synthesis. A core outcome set (COS) - an agreed minimum set of outcomes to be measured and reported - may address this. International initiatives focus on defining core outcomes assessments across brain tumour types. This protocol describes the development of a COS involving UK stakeholders for use in glioma trials, applicable across glioma types, with provision to identify subsets as required. Due to stakeholder interest in data reported from the patient perspective, outcomes from the COS that can be patient-reported will be identified. METHODS AND ANALYSIS: Stage I: (1) trial registry review to identify outcomes collected in glioma trials and (2) systematic review of qualitative literature exploring glioma patient and key stakeholder research priorities. Stage II: semi-structured interviews with glioma patients and caregivers. Outcome lists will be generated from stages I and II. Stage III: study team will remove duplicate items from the outcome lists and ensure accessible terminology for inclusion in the Delphi survey. Stage IV: a two-round Delphi process whereby the outcomes will be rated by key stakeholders. Stage V: a consensus meeting where participants will finalise the COS. The study team will identify the COS outcomes that can be patient-reported. Further research is needed to match patient-reported outcomes to available measures. ETHICS AND DISSEMINATION: Ethical approval was obtained (REF SMREC 21/59, Cardiff University School of Medicine Research Ethics Committee). Study findings will be disseminated widely through conferences and journal publication. The final COS will be adopted and promoted by patient and carer groups and its use by funders encouraged. PROSPERO REGISTRATION NUMBER: CRD42021236979.

Myeloid cell interferon secretion restricts Zika flavivirus infection of developing and malignant human neural progenitor cells.

Zika virus (ZIKV) can infect human developing brain (HDB) progenitors resulting in epidemic microcephaly, whereas analogous cellular tropism offers treatment potential for the adult brain cancer, glioblastoma (GBM). We compared productive ZIKV infection in HDB and GBM primary tissue explants that both contain SOX2+ neural progenitors. Strikingly, although the HDB proved uniformly vulnerable to ZIKV infection, GBM was more refractory, and this correlated with an innate immune expression signature. Indeed, GBM-derived CD11b+ microglia/macrophages were necessary and sufficient to protect progenitors against ZIKV infection in a non-cell autonomous manner. Using SOX2+ GBM cell lines, we found that CD11b+-conditioned medium containing type 1 interferon beta (IFNß) promoted progenitor resistance to ZIKV, whereas inhibition of JAK1/2 signaling restored productive infection. Additionally, CD11b+ conditioned medium, and IFNß treatment rendered HDB progenitor lines and explants refractory to ZIKV. These findings provide insight into neuroprotection for HDB progenitors as well as enhanced GBM oncolytic therapies.

Imaging Glioblastoma Metabolism by Using Hyperpolarized [1-13C]Pyruvate Demonstrates Heterogeneity in Lactate Labeling: A Proof of Principle Study.

Purpose To evaluate glioblastoma (GBM) metabolism by using hyperpolarized carbon 13 (13C) MRI to monitor the exchange of the hyperpolarized 13C label between injected [1-13C]pyruvate and tumor lactate and bicarbonate. Materials and Methods In this prospective study, seven treatment-naive patients (age [mean ± SD], 60 years ± 11; five men) with GBM were imaged at 3 T by using a dual-tuned 13C-hydrogen 1 head coil. Hyperpolarized [1-13C]pyruvate was injected, and signal was acquired by using a dynamic MRI spiral sequence. Metabolism was assessed within the tumor, in the normal-appearing brain parenchyma (NABP), and in healthy volunteers by using paired or unpaired t tests and a Wilcoxon signed rank test. The Spearman ρ correlation coefficient was used to correlate metabolite labeling with lactate dehydrogenase A (LDH-A) expression and some immunohistochemical markers. The Benjamini-Hochberg procedure was used to correct for multiple comparisons. Results The bicarbonate-to-pyruvate (BP) ratio was lower in the tumor than in the contralateral NABP (P < .01). The tumor lactate-to-pyruvate (LP) ratio was not different from that in the NABP (P = .38). The LP and BP ratios in the NABP were higher than those observed previously in healthy volunteers (P < .05). Tumor lactate and bicarbonate signal intensities were strongly correlated with the pyruvate signal intensity (ρ = 0.92, P < .001, and ρ = 0.66, P < .001, respectively), and the LP ratio was weakly correlated with LDH-A expression in biopsy samples (ρ = 0.43, P = .04). Conclusion Hyperpolarized 13C MRI demonstrated variation in lactate labeling in GBM, both within and between tumors. In contrast, bicarbonate labeling was consistently lower in tumors than in the surrounding NABP. Keywords: Hyperpolarized 13C MRI, Glioblastoma, Metabolism, Cancer, MRI, Neuro-oncology Supplemental material is available for this article. Published under a CC BY 4.0 license.

Utility of 5-ALA for resection of CNS tumours other than high-grade gliomas: a protocol for a systematic review.

INTRODUCTION: 5-aminolevulinic acid (5-ALA) is a proagent developed for fluorescent-guided surgery for high-grade glioma patients associated with a significant increase in resection conferring survival. 5-ALA was shown to penetrate the blood-brain barrier accumulating in malignant glioma cells with high selectivity, sensitivity and positive predictive value. However, those have yet to be explored aiding diagnosis for tumours of the central nervous system (CNS) other than high-grade gliomas (HGG). No up-to-date systematic review exists reporting the major surgical outcomes and diagnostic accuracy. We sought to conduct a systematic review of the literature summarising surgical outcomes, evaluate the quality of diagnostic accuracy reported in the literature and qualitatively assess the evidence to inform future studies. METHODS AND ANALYSIS: We will search electronic databases (Medline, Embase) with subsequent interrogation of references lists of articles reporting the use of 5-ALA for brain tumours other than high-grade glioma adult patients, which also report the extent of resection and/or survival. Prospective and retrospective cohort and case-control studies with more than five patients will be included. Two independent reviewers will screen the abstracts and full articles, with a third reviewer resolving any conflicts. The data will be extracted in a standardised template and outcomes will be reported using descriptive statists. The quality of non-randomised studies will be appraised. ETHICS AND DISSEMINATION: The study will summarise the available evidence on the effect of the clinical utility of 5-ALA in achieving resection and improving survival and its diagnostic accuracy for tumours of the CNS other than HGG. The data will be presented nationally and internationally and the manuscript will be published in a peer-reviewed journal. No ethical approvals were needed. The aim is to inform prospective studies minimising reporting bias allowing for more reliable, reproducible and generalisable results. The study has been registered in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.PROSPERO registration numberCRD42021260542.

Glioma progression is shaped by genetic evolution and microenvironment interactions.

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.

A career in neurosurgery: perceptions and the impact of a national SBNS/NANSIG neurosurgery careers day.

OBJECTIVE: Entrance to neurosurgical training is highly competitive. Without proper advice, information and opportunities, talented individuals may be dissuaded from applying. The Neurology and Neurosurgery Interest Group (NANSIG) organises a Careers Day in Neurosurgery every year. Our objective was to assess the overall utility of a neurosurgery careers day and the perceived factors that attract and detract from the specialty, from attendees of the ninth annual neurosurgery careers day. METHODS: Eighteen-item pre-conference and 19-item post-conference questionnaires were disseminated electronically to conference attendees. Questions aimed to capture: (i) baseline demographics; (ii) previous experience and exposure in neurosurgery; (iii) interest in neurosurgery; (iv) understanding training and a career in neurosurgery; (v) perceived factors of attraction and dissuasion of neurosurgery; and (vi) perceived value, quality and educational purpose of the conference. RESULTS: In total, 77 delegates attended the careers day. Most did not have a formal neurosurgical rotation during medical school (24.7%, n = 19), but almost half had gained neurosurgical experience and presented research work. The careers day increased knowledge of the neurosurgical application process (median Likert score 3/5 to 4/5, p < 0.01), duration of training (72.7-88.3%), and desire to pursue a career in neurosurgery (75.3-81.8%). The most commonly reported factors attracting delegates to neurosurgery were interest in neuroanatomy (80.5%, n = 62), practical skills (64.9%, n = 50), and impact on patients (62.3%, n = 48). The most common dissuasive factors were competition to entry (64.9%, n = 50), long working hours (40.3%, n = 31), and other career interests (35.1%, n = 27). Almost all would recommend the event to a colleague (94.9%, n = 73). CONCLUSIONS: Formal undergraduate exposure to neurosurgery is limited. Neurosurgery careers days increase awareness and understanding of the application process and improve interest in a selected cohort. The factors attracting applicants to neurosurgery remain practical links to neuroanatomy, opportunities in neurosurgery for innovation and research, and direct impact on patients.