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.

Multiple surgical resections for progressive IDH wildtype glioblastoma-is it beneficial?

PURPOSE: The role of repeat resection for recurrent glioblastoma (rGB) remains equivocal. This study aims to assess the overall survival and complications rates of single or repeat resection for rGB. METHODS: A single-centre retrospective review of all patients with IDH-wildtype glioblastoma managed surgically, between January 2014 and January 2022, was carried out. Patient survival and factors influencing prognosis were analysed, using Kaplan-Meier and Cox regression methods. RESULTS: Four hundred thirty-two patients were included, of whom 329 underwent single resection, 83 had two resections and 20 patients underwent three resections. Median OS (mOS) in the cohort who underwent a single operation was 13.7 months (95% CI: 12.7-14.7 months). The mOS was observed to be extended in patients who underwent second or third-time resection, at 22.9 months and 44.7 months respectively (p < 0.001). On second operation achieving > 95% resection or residual tumour volume of < 2.25 cc was significantly associated with prolonged survival. There was no significant difference in overall complication rates between primary versus second (p = 0.973) or third-time resections (p = 0.312). The use of diffusion tensor imaging (DTI) guided resection was associated with reduced post-operative neurological deficit (RR 0.37, p = 0.002), as was use of intraoperative ultrasound (iUSS) (RR 0.45, p = 0.04). CONCLUSIONS: This study demonstrates potential prolongation of survival for rGB patients undergoing repeat resection, without significant increase in complication rates with repeat resections. Achieving a more complete repeat resection improved survival. Moreover, the use of intraoperative imaging adjuncts can maximise tumour resection, whilst minimising the risk of neurological deficit.

Incidence and Risk Factors of Surgical Site Infection After Cranial Surgery for Patients with Brain Tumors: A Systematic Review and Meta-analysis.

BACKGROUND: Surgical site infections after craniotomy (SSI-CRANs) are a serious adverse event given the proximity of the wound to the central nervous system. SSI-CRANs are associated with substantial patient morbidity and mortality. Despite the importance and recognition of this event in other surgical fields, there is a paucity of evidence in the neurosurgical literature devoted to SSI-CRAN specifically in patients after brain tumor surgery. METHODS: Systematic searches of Medline, Embase, and Cochrane Central were undertaken. The primary outcome was the incidence of SSI-CRAN at 30 and 90 days. Secondary outcomes were risk factors for SSI-CRAN. RESULTS: Thirty-seven studies reporting 91,907 patients with brain tumors who underwent cranial surgery were included in the meta-analysis. Pooled incidence of SSI-CRAN at 30 and 90 days was 4.03% (95% CI: 2.94%-5.28%, I2 = 97.3) and 6.17% (95% CI: 3.16%-10.07%, I2 = 97.3), respectively. Specifically, incidence of SSI-CRAN following surgery for posterior fossa tumors was the highest at 9.67% (95% CI: 5.98%-14.09%, I2 = 75.5). Overall pooled incidence of readmission within 30 days and reoperation due to SSI-CRAN were 13.9% (95% CI: 12.5%-15.5%, I2 = 0.0) and 16.3% (95% CI: 5.4%-31.3%, I2 = 72.9), respectively. Risk factors for SSI-CRAN included reintervention (risk ratio [RR] 1.58, 95% CI: 1.22-2.04, I2 = 0.0), previous radiotherapy (RR 1.69, 95% CI: 1.20-2.38, I2 = 0.0), longer duration of operation (mean difference 64.18, 95% CI: 3.96-124.40 minutes, I2 = 90.3) and cerebrospinal fluid (CSF) leaks (RR 14.26, 95% CI: 2.14-94.90, I2 = 73.2). CONCLUSIONS: SSI-CRAN affects up to 1 in 14 patients with brain tumors. High-risk groups include those with reintervention, previous radiotherapy, longer duration of operation, and CSF leaks. Further prospective studies should focus on bundles of care that will reduce SSI-CRAN.

Endoscopic 5-Aminolevulinic Acid-Induced Fluorescence-Guided Intraparenchymal Brain Tumor Resection-Can the Endoscope Detect More Fluorescence Than the Microscope?

OBJECTIVES: Using a laboratory-based optical setup, we show that 5-aminolevulinic acid (5ALA) fluorescence is better detected using the endoscope than the microscope. Furthermore, we present our case series of fully endoscopic 5ALA-guided resection of intraparenchymal tumors. METHODS: A Zeiss Pentero microscope was compared with the Karl Storz Hopkins endoscope. The spectra and intensity of each blue light source were measured. Quantitative fluorescence detection thresholds were measured using a spectrometer. Subjective fluorescence detection thresholds were measured by 6 blinded neuro-oncology surgeons. Clinical data were prospectively collected for all consecutive cases of fully endoscopic 5ALA-guided resection of intraparenchymal tumors between 2012 and 2023. RESULTS: The intensity of blue light on the sample was greater for the endoscope than the microscope at working distances less than 20 mm. The quantitative fluorescence detection thresholds were lower for the endoscope than the microscope at both 30-/10-mm working distances. Fluorescence detection threshold was 0.65%-0.80% relative 4-dicyanomethylene-2-methyl-6-p-dimethylaminostyryl-4H-pyranthe concentration (3.20 × 10-7 to 3.94 × 10-7mol/dm-3) for the microscope, 0.40%-0.55% relative concentrations (1.97 × 10-7 to 2.71 × 10-7mol/dm-3) for the endoscope at 30 mm, and 0.15%-0.30% relative concentrations (7.40 × 10-8 to 1.48 × 10-7mol/dm-3) for the endoscope at 10 mm. In total, 49 5ALA endoscope-assisted brain tumor resections were carried out on 45 patients (mean age = 41 years, male = 28). Greater than 95% resection was achieved in 80% of cases and gross total resection in 42%. Gross total resection was achieved in 100% of tumors in noneloquent locations. There was 1 new neurologic deficit. CONCLUSIONS: The endoscope provides enhanced visualization/detection of 5ALA-induced fluorescence compared with the microscope. 5ALA endoscopic-assisted resection of intraparenchymal tumors is safe and feasible.

Blunted perception of breathlessness in three cases of low grade insular-glioma.

Better understanding of breathlessness perception addresses an unmet clinical need for more effective treatments for intractable dyspnoea, a prevalent symptom of multiple medical conditions. The insular-cortex is predominantly activated in brain-imaging studies of dyspnoea, but its precise role remains unclear. We measured experimentally-induced hypercapnic air-hunger in three insular-glioma patients before and after surgical resection. Tests involved one-minute increments in inspired CO2, raising end-tidal PCO2 to 7.5 mmHg above baseline (38.5 ± 5.7 mmHg), whilst ventilation was constrained (10.7 ± 2.3 L/min). Patients rated air-hunger on a visual analogue scale (VAS). Patients had lower stimulus-response (2.8 ± 2 vs. 11 ± 4 %VAS/mmHg; p = 0.004), but similar threshold (40.5 ± 3.9 vs. 43.2 ± 5.1 mmHg), compared to healthy individuals. Volunteered comments implicated diminished affective valence. After surgical resection; sensitivity increased in one patient, decreased in another, and other was unable to tolerate the ventilatory limit before any increase in inspired CO2.We suggest that functional insular-cortex is essential to register breathlessness unpleasantness and could be targeted with neuromodulation in chronically-breathless patients. Neurological patients with insula involvement should be monitored for blunted breathlessness to inform clinical management.

Supramaximal versus gross total resection in Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4, effect on overall and progression free survival: systematic review and meta-analysis.

PURPOSE: To synthesize the evidence on the impact on progression-free survival (PFS) and overall survival (OS) of supramaximal resection (SMR) over gross total resection (GTR) in Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4 (Glioblastoma). METHODS: The PubMed, Scopus, Web of Science, Ovid and Cochrane databases were systematically searched (up to November 30, 2022). Studies reporting OS and PFS on adult humans with a suspected Glioblastoma, treated either with a SMR or GTR were included. Hazard ratios were estimated for each study and treatment effects were calculated through DerSimonian and Laird random effects models. RESULTS: The literature search yielded 14 studies published between 2013 and 2022, enrolling a total of 6779 patients. Analysis of the included studies reveals significantly better clinical outcomes favoring SMR over GTR in terms of PFS (HR 0.67; p = 0.0007), and OS (HR 0.7; p = 0.0001). CONCLUSION: Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4, are aggressive tumors with a very short long-term OS. SMR is an effective therapeutic approach contributing to increased PFS and OS in patients with this catastrophic disease.

Temporal trends in the incidence of malignant and nonmalignant primary brain and central nervous system tumors by the method of diagnosis in England, 1993-2017.

BACKGROUND: Several studies report increases in the incidences of primary central nervous system (CNS) tumors. The reasons for this are unclear. METHODS: Data on all 188 340 individuals diagnosed with a primary CNS tumor in England (1993-2017) were obtained from the National Cancer Registration and Analysis Service. Data on all computerized tomography (CT) head and magnetic resonance imaging (MRI) brain scans in England (2013-2017) were obtained from the National Health Service Digital. Age-sex-standardized annual incidence rates per 100 000 population (ASR) were calculated by calendar year, tumor behavior, tumor location, and method of diagnosis. Temporal trends were quantified using average annual percent change (AAPC). RESULTS: The ASR for all CNS tumors increased from 13.0 in 1993 to 18.6 in 2017 (AAPC: +1.5%, 95% CI: 1.3, 1.7). The ASR for malignant tumors (52% overall) remained stable (AAPC: +0.5%, 95% CI: -0.2, 1.3), while benign tumors (37% overall) increased (AAPC: +2.6%, 95% CI: 1.2, 4.0). Among the 66% of benign tumors that were microscopically confirmed, the ASR increased modestly (AAPC: +1.3%, 95% CI: 0.5, 2.1). However, among the 25% of benign tumors that were radiographically confirmed, the ASR increased substantially (AAPC: 10.2%, 95% CI: 7.9, 12.5), principally driven by large increases in those who are aged 65+ years. The rate of CT head scans in Accident & Emergency (A&E) increased during 2013-2017, with especially large increases in 65-84 and 85+-year-olds (AAPCs: +18.4% and +22.5%). CONCLUSIONS: Increases in CNS tumor incidence in England are largely attributable to the greater detection of benign tumors. This could be the result of the increasing use of neuroimaging, particularly CT head scans in A&E in people who are aged 65+ years.

Differential effects of group III metabotropic glutamate receptors on spontaneous inhibitory synaptic currents in spine-innervating double bouquet and parvalbumin-expressing dendrite-targeting GABAergic interneurons in human neocortex.

Diverse neocortical GABAergic neurons specialize in synaptic targeting and their effects are modulated by presynaptic metabotropic glutamate receptors (mGluRs) suppressing neurotransmitter release in rodents, but their effects in human neocortex are unknown. We tested whether activation of group III mGluRs by L-AP4 changes GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in 2 distinct dendritic spine-innervating GABAergic interneurons recorded in vitro in human neocortex. Calbindin-positive double bouquet cells (DBCs) had columnar "horsetail" axons descending through layers II-V innervating dendritic spines (48%) and shafts, but not somata of pyramidal and nonpyramidal neurons. Parvalbumin-expressing dendrite-targeting cell (PV-DTC) axons extended in all directions innervating dendritic spines (22%), shafts (65%), and somata (13%). As measured, 20% of GABAergic neuropil synapses innervate spines, hence DBCs, but not PV-DTCs, preferentially select spine targets. Group III mGluR activation paradoxically increased the frequency of sIPSCs in DBCs (to median 137% of baseline) but suppressed it in PV-DTCs (median 92%), leaving the amplitude unchanged. The facilitation of sIPSCs in DBCs may result from their unique GABAergic input being disinhibited via network effect. We conclude that dendritic spines receive specialized, diverse GABAergic inputs, and group III mGluRs differentially regulate GABAergic synaptic transmission to distinct GABAergic cell types in human cortex.

Functional MRI applications for intra-axial brain tumours: uses and nuances in surgical practise.

PURPOSE: Functional MRI (fMRI) has well-established uses to inform risks and plan maximally safe approaches in neurosurgery. In the field of brain tumour surgery, however, fMRI is currently in a state of clinical equipoise due to debate around both its sensitivity and specificity. MATERIALS AND METHODS: In this review, we summarise the role and our experience of fMRI in neurosurgery for gliomas and metastases. We discuss nuances in the conduct and interpretation of fMRI that, based on our practise, most directly impact fMRI's usefulness in the neurosurgical setting. RESULTS: Illustrated examples in which fMRI in our hands directly influences the neurosurgical treatment of brain tumours include evaluating the probability and nature of functional risks, especially for language functions. These presurgical risk assessments, in turn, help to predict the resectability of tumours, select or deselect patients for awake surgery, indicate the need for neurophysiological monitoring and guide the optimal use of intra-operative stimulation mapping. A further emerging application of fMRI is in measuring functional adaptation of functional networks after (partial) surgery, of potential use in the timing of further surgery. CONCLUSIONS: In appropriately selected patients with a clearly defined surgical question, fMRI offers a valuable complementary tool in the pre-surgical evaluation of brain tumours. However, there is a great need for standards in the administration and analysis of fMRI as much as in the techniques that it is commonly evaluated against. Surprisingly little data exists that evaluates the accuracy of fMRI not just against complementary methods, but in terms of its ultimate clinical aim of minimising post-surgical morbidity.

The role of [18F]fluorodopa positron emission tomography in grading of gliomas.

PURPOSE: Gliomas are the most commonly occurring brain tumour in adults and there remains no cure for these tumours with treatment strategies being based on tumour grade. All treatment options aim to prolong survival, maintain quality of life and slow the inevitable progression from low-grade to high-grade. Despite imaging advancements, the only reliable method to grade a glioma is to perform a biopsy, and even this is fraught with errors associated with under grading. Positron emission tomography (PET) imaging with amino acid tracers such as [18F]fluorodopa (18F-FDOPA), [11C]methionine (11C-MET), [18F]fluoroethyltyrosine (18F-FET), and 18F-FDOPA are being increasingly used in the diagnosis and management of gliomas. METHODS: In this review we discuss the literature available on the ability of 18F-FDOPA-PET to distinguish low- from high-grade in newly diagnosed gliomas. RESULTS: In 2016 the Response Assessment in Neuro-Oncology (RANO) and European Association for Neuro-Oncology (EANO) published recommendations on the clinical use of PET imaging in gliomas. However, since these recommendations there have been a number of studies performed looking at whether 18F-FDOPA-PET can identify areas of high-grade transformation before the typical radiological features of transformation such as contrast enhancement are visible on standard magnetic resonance imaging (MRI). CONCLUSION: Larger studies are needed to validate 18F-FDOPA-PET as a non-invasive marker of glioma grade and prediction of tumour molecular characteristics which could guide decisions surrounding surgical resection.

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.

Modern Solutions for Ancient Pathogens: Direct Pathogen Sequencing for Diagnosis of Lepromatous Leprosy and Cerebral Coenurosis.

Microbes unculturable in vitro remain diagnostically challenging, dependent historically on clinical findings, histology, or targeted molecular detection. We applied whole-genome sequencing directly from tissue to diagnose infections with mycobacteria (leprosy) and parasites (coenurosis). Direct pathogen DNA sequencing provides flexible solutions to diagnosis of difficult pathogens in diverse contexts.

Endoscope-Assisted Resection for Cystic Cerebellar Hemangioblastomas.

BACKGROUND: Hemangioblastomas are benign, often cystic tumors occurring most commonly in the cerebellum. We describe resection of cystic cerebellar hemangioblastomas using an endoscope-assisted technique. METHODS: We present a series of 9 cases and discuss the endoscopic technique for resection of cystic hemangioblastoma. Frameless neuronavigation was used in all cases. A small 1- to 1.5-cm corticotomy lined with Surgicel and patties allows access to the peritumoral cyst. Using bimanual microsurgical techniques and the 30-degree rigid endoscope to provide visualization, the mural nodule can be resected and the cyst cavity inspected. RESULTS: Complete resection of the mural nodule was achieved in all cases. One patient had a postsurgery pseudomeningocele requiring ventriculoperitoneal shunt. Hospital length of stay was short for all the patients. CONCLUSIONS: Endoscope-assisted resection is a safe and effective technique for surgical resection of cystic hemangioblastoma.

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.

Development of 'Core Outcome Sets' for Meningioma in Clinical Studies (The COSMIC Project): protocol for two systematic literature reviews, eDelphi surveys and online consensus meetings.

INTRODUCTION: Meningioma is the most common primary intracranial tumour in adults. The majority are non-malignant, but a proportion behave more aggressively. Incidental/minimally symptomatic meningioma are often managed by serial imaging. Symptomatic meningioma, those that threaten neurovascular structures, or demonstrate radiological growth, are usually resected as first-line management strategy. For patients in poor clinical condition, or with inoperable, residual or recurrent disease, radiotherapy is often used as primary or adjuvant treatment. Effective pharmacotherapy treatments do not currently exist. There is heterogeneity in the outcomes measured and reported in meningioma clinical studies. Two 'Core Outcome Sets' (COS) will be developed: (COSMIC: Intervention) for use in meningioma clinical effectiveness trials and (COSMIC: Observation) for use in clinical studies of incidental/untreated meningioma. METHODS AND ANALYSIS: Two systematic literature reviews and trial registry searches will identify outcomes measured and reported in published and ongoing (1) meningioma clinical effectiveness trials, and (2) clinical studies of incidental/untreated meningioma. Outcomes include those that are clinician reported, patient reported, caregiver reported and based on objective tests (eg, neurocognitive tests), as well as measures of progression and survival. Outcomes will be deduplicated and categorised to generate two long lists. The two long lists will be prioritised through two, two-round, international, modified eDelphi surveys including patients with meningioma, healthcare professionals, researchers and those in caring/supporting roles. The two final COS will be ratified through two 1-day online consensus meetings, with representation from all stakeholder groups. ETHICS AND DISSEMINATION: Institutional review board (University of Liverpool) approval was obtained for the conduct of this study. Participant eConsent will be obtained prior to participation in the eDelphi surveys and consensus meetings. The two systematic literature reviews and two final COS will be published and freely available. TRIAL REGISTRATION NUMBER: COMET study ID 1508.

Decitabine increases neoantigen and cancer testis antigen expression to enhance T-cell-mediated toxicity against glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Despite maximal treatment, median survival remains dismal at 14-24 months. Immunotherapies, such as checkpoint inhibition, have revolutionized management of some cancers but have little benefit for GBM patients. This is, in part, due to the low mutational and neoantigen burden in this immunogenically "cold" tumor. METHODS: U87MG and patient-derived cell lines were treated with 5-aza-2'-deoxycytidine (DAC) and underwent whole-exome and transcriptome sequencing. Cell lines were then subjected to cellular assays with neoantigen and cancer testis antigen (CTA) specific T cells. RESULTS: We demonstrate that DAC increases neoantigen and CTA mRNA expression through DNA hypomethylation. This results in increased neoantigen presentation by MHC class I in tumor cells, leading to increased neoantigen- and CTA-specific T-cell activation and killing of DAC-treated cancer cells. In addition, we show that patients have endogenous cancer-specific T cells in both tumor and blood, which show increased tumor-specific activation in the presence of DAC-treated cells. CONCLUSIONS: Our work shows that DAC increases GBM immunogenicity and consequent susceptibility to T-cell responses in vitro. Our results support a potential use of DAC as a sensitizing agent for immunotherapy.

Surgical and oncological score to estimate the survival benefit of resection and chemoradiotherapy in elderly (≥70 years) glioblastoma patients: A preliminary analysis.

Background: Elderly patients with glioblastoma are perceived to face a poor prognosis with perceptions surrounding older age and a relative lack of randomized data contributing. This study evaluated survival prognosticators in elderly glioblastoma patients to more accurately guide their treatment. Methods: The records of 169 elderly (≥70 years) patients with a new diagnosis of glioblastoma who had undergone neurosurgical intervention were retrospectively examined for patient sex, age, performance status, comorbidities, MGMT promoter methylation, surgical intervention, and chemoradiation regime. The adjusted survival impact of these factors was determined using Cox proportional hazards model and used to devise a two-stage scoring system to estimate patient survival at the stage of surgical (Elderly Glioblastoma Surgical Score, EGSS) and oncological management (Elderly Glioblastoma Oncological Score, EGOS). Results: The median overall survival (mOS) of the cohort was 28.8 weeks. Gross-total and subtotal resection were associated with improved survival compared to biopsy alone (respective mOS 65.3 and 28.1 vs 15.7 weeks, P < .001). Hypofractionated radiotherapy (40Gy in 15 fractions) with Temozolomide was noninferior to the Stupp protocol, P = .72. Exploratory subgroup analysis revealed a significant benefit of Temozolomide-based approaches in MGMT-methylated patients as well as a trend towards improved survival in MGMT-unmethylated patients. Our EGSS and EGOS scores successfully estimated survival in this retrospective cohort with 65% and 73% accuracy. Conclusions: Where appropriate and safe, elderly glioblastoma patients may benefit from surgical resection and combined chemoradiotherapy with Temozolomide. The proposed EGSS and EGOS scores take into account important prognostic factors to help guide which patients should receive such treatment.

VCAM-1-targeted MRI Improves Detection of the Tumor-brain Interface.

PURPOSE: Despite optimal local therapy, tumor cell invasion into normal brain parenchyma frequently results in recurrence in patients with solid tumors. The aim of this study was to determine whether microvascular inflammation can be targeted to better delineate the tumor-brain interface through vascular cell adhesion molecule-1 (VCAM-1)-targeted MRI. EXPERIMENTAL DESIGN: Intracerebral xenograft rat models of MDA231Br-GFP (breast cancer) brain metastasis and U87MG (glioblastoma) were used to histologically examine the tumor-brain interface and to test the efficacy of VCAM-1-targeted MRI in detecting this region. Human biopsy samples of the brain metastasis and glioblastoma margins were examined for endothelial VCAM-1 expression. RESULTS: The interface between tumor and surrounding normal brain tissue exhibited elevated endothelial VCAM-1 expression and increased microvessel density. Tumor proliferation and stemness markers were also significantly upregulated at the tumor rim in the brain metastasis model. T2*-weighted MRI, following intravenous administration of VCAM-MPIO, highlighted the tumor-brain interface of both tumor models more extensively than gadolinium-DTPA-enhanced T1-weighted MRI. Sites of VCAM-MPIO binding, evident as hypointense signals on MR images, correlated spatially with endothelial VCAM-1 upregulation and bound VCAM-MPIO beads detected histologically. These findings were further validated in an orthotopic medulloblastoma model. Finally, the tumor-brain interface in human brain metastasis and glioblastoma samples was similarly characterized by microvascular inflammation, extending beyond the region detectable using conventional MRI. CONCLUSIONS: This work illustrates the potential of VCAM-1-targeted MRI for improved delineation of the tumor-brain interface in both primary and secondary brain tumors.

Opportunities and challenges for the development of "core outcome sets" in neuro-oncology.

Core Outcome Sets (COS) define minimum outcomes to be measured and reported in clinical effectiveness trials for a particular health condition/health area. Despite recognition as critical to clinical research design for other health areas, none have been developed for neuro-oncology. COS development projects should carefully consider: scope (how the COS should be used), stakeholders involved in development (including patients as both research partners and participants), and consensus methodologies used (typically a Delphi survey and consensus meeting), as well as dissemination plans. Developing COS for neuro-oncology is potentially challenging due to extensive tumor subclassification (including molecular stratification), different symptoms related to anatomical tumor location, and variation in treatment options. Development of a COS specific to tumor subtype, in a specific location, for a particular intervention may be too narrow and would be unlikely to be used. Equally, a COS that is applicable across a wider area of neuro-oncology may be too broad and therefore lack specificity. This review describes why and how a COS may be developed, and discusses challenges for their development, specific to neuro-oncology. The COS under development are briefly described, including: adult glioma, incidental/untreated meningioma, meningioma requiring intervention, and adverse events from surgical intervention for pediatric brain tumors.