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.

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.

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.

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.

Tonic GABAA Receptor-Mediated Currents of Human Cortical GABAergic Interneurons Vary Amongst Cell Types.

Persistent anion conductances through GABAA receptors (GABAARs) are important modulators of neuronal excitability. However, it is currently unknown how the amplitudes of these currents vary among different cell types in the human neocortex, particularly among diverse GABAergic interneurons. We have recorded 101 interneurons in and near layer 1 from cortical tissue surgically resected from both male and female patients, visualized 84 of them and measured tonic GABAAR currents in 48 cells with an intracellular [Cl-] of 65 mm and in the presence of 5 µm GABA. We compare these tonic currents among five groups of interneurons divided by firing properties and four types of interneuron defined by axonal distributions; rosehip, neurogliaform, stalked-bouton, layer 2-3 innervating and a pool of other cells. Interestingly, the rosehip cell, a type of interneuron only described thus far in human tissue, and layer 2-3 innervating cells exhibit larger tonic currents than other layer 1 interneurons, such as neurogliaform and stalked-bouton cells; the latter two groups showing no difference. The positive allosteric modulators of GABAARs allopregnanolone and DS2 also induced larger current shifts in the rosehip and layer 2-3 innervating cells, consistent with higher expression of the δ subunit of the GABAAR in these neurons. We have also examined how patient parameters, such as age, seizures, type of cancer and anticonvulsant treatment may alter tonic inhibitory currents in human neurons. The cell type-specific differences in tonic inhibitory currents could potentially be used to selectively modulate cortical circuitry.SIGNIFICANCE STATEMENT Tonic currents through GABAA receptors (GABAARs) are a potential therapeutic target for a number of neurologic and psychiatric conditions. Here, we show that these currents in human cerebral cortical GABAergic neurons display cell type-specific differences in their amplitudes which implies differential modulation of their excitability. Additionally, we examine whether the amplitudes of the tonic currents measured in our study show any differences between patient populations, finding some evidence that age, seizures, type of cancer, and anticonvulsant treatment may alter tonic inhibition in human tissue. These results advance our understanding of how pathology affects neuronal excitability and could potentially be used to selectively modulate cortical circuitry.

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.

Advances in the management of glioblastoma.

Glioblastoma (GB) is the most common and most malignant primary brain tumour in adults. Despite much effort, gold standard therapy has not changed since the introduction of adjuvant temozolomide in 2005 and prognosis remains poor. Despite this, there has been significant improvement in the surgical technology and technique, that has allowed for increased rates of safe maximal resection of the tumour. In addition, our increased knowledge of the biology of GB has revealed more potential targets, especially in the field of immunotherapy, which has been successful in revolutionising treatment of other cancers. We review the current best practice for the treatment of GB and explore some of the more recent advances in GB management from both a surgical and molecular therapeutic perspective.

Diffusion tractography for awake craniotomy: accuracy and factors affecting specificity.

INTRODUCTION: Despite evidence of correspondence with intraoperative stimulation, there remains limited data on MRI diffusion tractography (DT)'s sensitivity to predict morbidity after neurosurgical oncology treatment. Our aims were: (1) evaluate DT against subcortical stimulation mapping and performance changes during and after awake neurosurgery; (2) evaluate utility of early post-operative DT to predict recovery from post-surgical deficits. METHODS: We retrospectively reviewed our first 100 awake neurosurgery procedures using DT- neuronavigation. Intra-operative stimulation and performance outcomes were assessed to classify DT predictions for sensitivity and specificity calculations. Post-operative DT data, available in 51 patients, were inspected for tract damage. RESULTS: 91 adult brain tumor patients (mean 49.2 years, 43 women) underwent 100 awake surgeries with subcortical stimulation between 2014 and 2019. Sensitivity and specificity of pre-operative DT predictions were 92.2% and 69.2%, varying among tracts. Post-operative deficits occurred after 41 procedures (39%), but were prolonged (> 3 months) in only 4 patients (4%). Post-operative DT in general confirmed surgical preservation of tracts. Post-operative DT anticipated complete recovery in a patient with supplementary motor area syndrome, and indicated infarct-related damage to corticospinal fibers associated with delayed, partial recovery in a second patient. CONCLUSIONS: Pre-operative DT provided very accurate predictions of the spatial location of tracts in relation to a tumor. As expected, however, the presence of a tract did not inform its functional status, resulting in variable DT specificity among individual tracts. While prolonged deficits were rare, DT in the immediate post-operative period offered additional potential to monitor neurological deficits and anticipate recovery potential.

COVID-legal study: neurosurgeon experience in Britain during the first phase of the COVID-19 pandemic - medico-legal considerations.

Introduction: The COVID-19 pandemic has resulted in a significant number of changes to elective and emergency neurosurgical practice.Materials and Methods: This paper reports the results of an online survey of Society of British Neurological Surgeons (SBNS) members undertaken between 10th and 24th of June 2020 regarding changes in consent practice in response to COVID-19, as well as the physical challenges experienced while operating under higher levels of personal protective equipment (PPE).Results: Despite the real and substantial risks associated with COVID-19, 23% of surgeons reported they were not made any changes to their usual consent process, and 54% of surgeons indicated that they made reference to COVID-19-associated risks in their written consent documentation. 93% of neurosurgeons reported physical difficulties operating using PPE; 62% reported visors/goggles fogging up, 55% experienced 'overheating', 62% reported fatigue, and 82% of surgeons reported difficulty communicating with the theatre staff.Conclusions: This survey highlights discrepancies in the consent practice between neurosurgeons which needs to be addressed at both local and national levels. The PPE being used in neurosurgical operations is not designed for use with specialist equipment (82% of respondents reported having to remove PPE to use the microscope) and the reported physical difficulties using PPE intraoperatively could significantly impact on both neurosurgeon performance and patient outcomes. This requires urgent attention by NHS procurement and management and should be urgently escalated to trust occupational health authorities as a workplace safety concern.

A comparison of 2-hydroxyglutarate detection at 3 and 7 T with long-TE semi-LASER.

Abnormally high levels of the 'oncometabolite' 2-hydroxyglutarate (2-HG) occur in many grade II and III gliomas, and correlate with mutations in the genes of isocitrate dehydrogenase (IDH) isoforms. In vivo measurement of 2-HG in patients, using magnetic resonance spectroscopy (MRS), has largely been carried out at 3 T, yet signal overlap continues to pose a challenge for 2-HG detection. To combat this, several groups have proposed MRS methods at ultra-high field (≥7 T) where theoretical increases in signal-to-noise ratio and spectral resolution could improve 2-HG detection. Long echo time (long-TE) semi-localization by adiabatic selective refocusing (semi-LASER) (TE = 110 ms) is a promising method for improved 2-HG detection in vivo at either 3 or 7 T owing to the use of broad-band adiabatic localization. Using previously published semi-LASER methods at 3 and 7 T, this study directly compares the detectability of 2-HG in phantoms and in vivo across nine patients. Cramér-Rao lower bounds (CRLBs) of 2-HG fitting were found to be significantly lower at 7 T (6 ± 2%) relative to 3 T (15 ± 7%) (p = 0.0019), yet were larger at 7 T in an IDH wild-type patient. Although no increase in SNR was detected at 7 T (77 ± 26) relative to 3 T (77 ± 30), the detection of 2-HG was greatly enhanced through an improved spectral profile and increased resolution at 7 T. 7 T had a large effect on pairwise fitting correlations between γ-aminobutyric acid (GABA) and 2-HG (p = 0.004), and resulted in smaller coefficients. The increased sensitivity for 2-HG detection using long-TE acquisition at 7 T may allow for more rapid estimation of 2-HG (within a few spectral averages) together with other associated metabolic markers in glioma.

Brain white matter fibre tracts: a review of functional neuro-oncological relevance.

State-of-the-art glioma treatment aims to maximise neuro-oncological benefit while minimising losses in quality of life. Optimising this balance remains hindered by our still limited understanding of information processing in the human brain. To help understand individual differences in functional outcomes following neuro-oncological treatment, we review mounting evidence demonstrating the fundamental role that white matter connections play in complex human behaviour. We focus on selected fibre tracts whose destruction is recognised to elicit predictable behavioural deficits and consider specific indications for non-invasive diffusion MRI tractography, the only existing method to map these fibre tracts in vivo, in the selection and planning of neuro-oncological treatments. Despite remaining challenges, longitudinal tract imaging, in combination with intraoperative testing and neuropsychological evaluation, offers unique opportunities to refine our understanding of human brain organisation in the quest to predict and ultimately reduce the quality of life burden of both surgical and non-surgical first-line neuro-oncological therapies.

Implementing novel trial methods to evaluate surgery for essential tremor.

INTRODUCTION: Deep brain stimulation (DBS) can provide dramatic essential tremor (ET) relief, however no Class I evidence exists. MATERIALS AND METHODS: Analysis methods: I) traditional cohort analysis; II) N-of-1 single patient randomised control trial and III) signal-to-noise (S/N) analysis. 20 DBS electrodes in ET patients were switched on and off for 3-min periods. Six pairs of on and off periods in each case, with the pair order determined randomly. Tremor severity was quantified with tremor evaluator and patient was blinded to stimulation. Patients also stated whether they perceived the stimulation to be on after each trial. RESULTS: I) Mean end-of-trial tremor severity 0.84 out of 10 on, 6.62 Off, t = - 13.218, p < 0.0005. II) N-of-1: 60% of cases had 12 correct perceptions (p = 0.001), 20% had 11 correct perceptions (p = 0.013). III) S/N: > 80% tremor reduction occurred in 99/114 'On' trials (87%), and 3/114 'Off' trials (3%). S/N ratio for 80% improvement with DBS versus spontaneous improvement was 487,757-to-1. CONCLUSIONS: DBS treatment effect on ET is too large for bias to be a plausible explanation. Formal N-of-1 trial design, and S/N ratio method for presenting results, allows this to be demonstrated convincingly where conventional randomised controlled trials are not possible. CLASSIFICATION OF EVIDENCE: This study is the first to provide Class I evidence for the efficacy of DBS for ET.

Transsphenoidal pituitary surgery in the elderly is safe and effective.

OBJECT: With an increasingly ageing population, the number of elderly people diagnosed with pituitary tumours continues to rise. There is a concern that with increasing age and comorbidities, there is higher anaesthetic risk, as well as peri-operative morbidity and mortality from pituitary surgery. This study aimed to audit the benefits and complications of transsphenoidal surgery performed in a large pituitary centre in elderly patients. METHODS: Data on all elderly patients (age: ≥ 70 years) undergoing transsphenoidal surgery at a large tertiary referral centre between November 2003 and August 2012 were collected retrospectively. RESULTS: A total of 104 operations were performed on 102 patients during 106 months. Median age was 75.2 years (range: 70-94) and 63 (61%) of the patients were male. Median follow-up was 15.2 months (range: 2.3-84.4). The majority presented with either peripheral visual field defects (26.4%) or pituitary hormone deficits (17.9%). A significant number (21.7%) of tumours were incidental radiological findings while investigating other diagnoses like stroke and dementia. 48.1% of operations were undertaken microscopically and the remaining 51.9% were endoscopic. Median hospital stay was 4 days (range: 3-18). Intra-operative complications included hypotension (1.9%) and blood loss requiring transfusion (2.9%). The 30-day complications included transient diabetes insipidus (9.6%), syndrome of inappropriate anti-diuretic hormone secretion (8.7%), delayed cerebrospinal fluid leak requiring lumbar drainage (0.9%) with no patient requiring formal repair. There were no peri-operative deaths. Long-term assessment suggested 79% had improved or stable endocrine function with 7% achieving biochemical cure and 91% showed improved or stable visual fields. CONCLUSIONS: Pituitary surgery in the elderly, whether microscopic or endoscopic, has low morbidity and mortality and is a safe and effective intervention for both symptom control and functional outcomes.

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.

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.