bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Application of Polygenic Risk Scores Identifies Biomarkers for Early Detection of Glioma
Authors: Andrews Lily , Robinson Jamie , Kurian Kathreena , Kar Siddhartha 
Published: October 2022

Abstract

AIMS
In the UK, brain, other CNS and intracranial tumours incidence rates are increasing with over 12,200 new cases diagnosed each year. The overall survival rate over 5 years in these tumours is approximately 12%. There is a need for predictive biomarkers to detect the presence of gliomas to improve prognosis for such patients. A novel modified Mendelian randomization (MR)-based technique has been proposed to discover predictive biomarkers for diagnostic applications. The aim of this project is to identify circulating blood biomarkers that are genetically liable to all gliomas, glioblastoma (GB), or non-GBs.

METHOD
We generated polygenic scores for genetic liability to glioma and a separate GWAS of plasma protein levels from the INTERVAL study. We used sensitivity analyses methods to further assess our findings. The results were then validated by the plasma pQTL GWAS data from the Fenland cohort.

RESULTS
We identified a potential blood biomarker called erythroblast membrane associated protein (ERMAP) which showed consistent results across all sensitivity analyses in our discovery cohort [β: -0.0778, P-value: 2.1E-04]. We identified that decreased levels of ERMAP [β: -0.078 SD of ERMAP abundance per SD increase in glioma risk, 95% confidence interval (CI) 0.037 to 0.119, P-value: 2.1E-04] in the blood are associated with increased risk of glioma.

CONCLUSION
ERMAP protein is found to have a potential genetic liability for all gliomas. Predictive biomarkers are novel to glioma research and could be important for diagnostic applications and population screening in early detection. However, further clinical research is required to validate these findings.
Systemic Inflammation Is Implicated in De Novo Seizures Following Meningioma Resection
Authors: Bakhsh Ali , Gillespie Conor , Kumar Siddhant , Richardson George , Mustafa Arish , Mirza Nasir , Jenkinson Michael 
Published: October 2022

Abstract

AIMS
To investigate the association between perioperative peripheral blood inflammatory markers and seizures in patients who have undergone meningioma resection.

METHOD
A single neurosurgery tertiary centre blood bank database was screened to extract pre-operative and post-operative white cell count (WCC), neutrophils, lymphocytes, monocytes, platelets and neutrophil-lymphocyte ratio (NLR) and derived NLR (dNLR). All patients who underwent resection of meningioma from 2012 to 2020 were eligible. Patients were excluded if they had an inflammatory condition, peri-operative infection, medical illness or operative complication.

RESULTS
30 patients suffered pre-operative seizures only, 16 experienced de novo post-operative seizures within 1 year and 42 patients did not experience seizures throughout their treatment timeline. In those who had never had a seizure, there was a significant increase in WCC post-operatively (15.2 vs. 10.6 × 109/L (95% CI 2.1-8.2), p=0.02). Patients who suffered de novo seizures had a significantly higher post-operative day 1 to 4 WCC than those with no seizures (21.1 vs. 14.8 × 109/L (2.1-12.6), p=0.48). However, this difference of WCC was poorly predictive of de novo seizures at one year (AUC 0.61). There was no difference in pre-operative inflammatory markers between pre-operative seizure patients, de novo seizure or never seizure patients.

CONCLUSION
There is a significantly higher post-operative systemic inflammatory response in patients who suffered de novoseizures after meningioma resection. Peripheral blood markers have the potential to predict seizures in patients with meningioma.
CLIC1 and CLIC4 Ion Channel Deficiency Confers Increased Sensitivity to Tumour Treating Fields and Improved Survival in Paediatric Glioblastoma
Authors: Griffin Michaela , Basu Surajit , Khan Raheela , Smith Stuart 
Published: October 2022

Abstract

AIMS
(1) To determine if specific and unique chloride intracellular channel (CLIC) expression patterns exist in paediatric glioblastoma. (2) To assess if these expression patterns can be exploited as a treatment strategy. (3) To assess the combination of ion channel manipulation with Tumour Treating Fields (TTFields).

METHOD
CLIC channel expression patterns were identified via multivariate analysis of in-house and publicly available data sets and RNA sequencing of in-house patient tumour samples. siRNA depletion or inhibition via IAA94 of CLIC1 and CLIC4 was assessed using cell cycle, clonogenic, migration and proliferation assays, alone and in combination with TTFields. Whole transcriptome gene expression analysis (Human Clairom™ Array) of pGBM cells treated with TTFields was carried out.

RESULTS
Clinical correlation determined that CLIC4 and CLIC1 deficiency was associated with increased overall survival, with siRNA depletion propagating a reduction in the proliferation, migration and invasion of pHGG cell lines associated with cell cycle arrest. Furthermore, CLIC1 and CLIC4 deficiency exacerbated the killing capacity of TTFields, reducing clonogenic and proliferative capabilities. Whole transcriptome gene expression analysis of paediatric GBM cell lines treated with TTFields and found that cells treated with TTfields exhibited a down-regulation in CLIC1 and CLIC4 compared to untreated cells.

CONCLUSION
These data provide rationale that genetic, electrical, and pharmacological manipulation of ion channels can reduce the capacity of childhood brain tumours to proliferate and invade. CLIC channels may be a suitable target for combination therapy to enhance the treatment efficacy of TTfields and help bring this non-invasive therapy to paediatric patients.
Health-Related Quality of Life in Patients With High-Grade Glioma: A Systematic Review
Authors: Sanpher Elen , Mitchell Layla , Keshwara Sumirat , Islim Abdurrahman , Jenkinson Michael , Millward Christopher 
Published: October 2022

Abstract

AIMS
Several studies have evaluated health-related quality of life (HRQoL) through patient-reported outcomes (PROs) in high-grade glioma (HGG) patients. No systematic review has summarised this increasingly important research area.

METHOD
Seven electronic databases were systematically searched. Primary research articles evaluating HRQoL in HGG patients through PRO assessment were included. Global, physical, mental, and social health were summarised descriptively. Risk of bias (RoB) of included studies was assessed using The Joanna Briggs Institute Critical Appraisal tool or Newcastle Ottawa Scale. Quality of study reporting was assessed using a modified ISOQOL checklist.

RESULTS
Twenty-six studies were included (4,451 patients): cross-sectional (n=14), longitudinal (n=12). RoB and quality of reporting were satisfactory. Ten PRO measurement instruments were identified, of which EORTC-QLQ-C30 (n=15) was utilised most frequently. Fatigue significantly impacted both physical and global health. HRQoL improved after surgery but recurrence, fatigue, and difficulties with activities of daily living were associated with worsening HRQoL. HGG patients had higher anxiety and depression scores than the general population, negatively impacting overall HRQoL. Social health was superior for patients with good supportive networks, but a majority do not return to full-time employment post-diagnosis. Long-term survivors reported improvements in their physical, social and emotional functioning over time.

CONCLUSION
With HGG life expectancy less than 12 months post-diagnosis, HRQoL is of paramount importance to patients. PRO assessment of HRQoL can be used to evaluate self-reported functioning and well-being in both routine practice and clinical trial settings and provide opportunities for timely intervention.
Usability of Mixed Reality in Awake Craniotomy Planning
Authors: Moon Richard , Barua Neil 
Published: October 2022

Abstract

AIMS
This study aimed to describe our institutional use of a commercially available mixed reality viewer within a multi-disciplinary planning workflow for awake craniotomy surgery and to report an assessment of its usability.

METHOD
Three Tesla MRI scans, including 32-direction diffusion tensor sequences, were reconstructed with BrainLab Elements auto-segmentation software. Magic Leap mixed reality viewer headsets were registered to a shared virtual viewing space to display image reconstructions. System Usability Scale was used to assess the usability of the mixed reality system.

RESULTS
The awake craniotomy planning workflow utilises the mixed reality viewer to facilitate a stepwise discussion through four progressive anatomical layers; skin, cerebral cortex, subcortical white matter tracts and tumour with surrounding vasculature. At each stage relevant members of the multi-disciplinary team reviewed key operative considerations, including patient positioning, cortical and subcortical speech mapping protocols and surgical approaches to the tumour. The mixed reality system was used in 10 consecutive awake craniotomy procedures over a 5-month period. Ten participants (2 Anaesthetists, 5 Neurosurgical trainees, 2 Speech therapists, 1 Neuropsychologist) completed System Usability Scale assessments, reporting a mean score of 71.5. Feedback highlighted the benefit of being able to rehearse important steps in the procedure, including patient positioning and anaesthetic access and visualising the testing protocol for cortical and subcortical speech mapping.

CONCLUSION
This study supports the use of mixed reality for multi-disciplinary planning for awake craniotomy surgery, with an acceptable degree of interface usability. We highlight the need to consider the requirements of non-technical, non-neurosurgical team members when involving mixed reality activities.
Analytic Approaches to Clinical Validation of Results From Preclinical Models of Glioblastoma: A Systematic Review
Authors: Fitt Beth , Loy Grace , Christopher Edward , Brennan Paul , Poon Michael T C 
Published: October 2022

Abstract

AIMS
Analytic approaches to clinical validation of results from preclinical models are important in assessment of their relevance to human disease. This systematic review examined consistency in reporting of glioblastoma cohorts from The Cancer Genome Atlas (TCGA) or Chinese Glioma Genome Atlas (CGGA) and assessed whether studies included patient characteristics in their survival analyses.

METHOD
We searched Embase and Medline on 02Feb21 for studies using preclinical models of glioblastoma published after Jan2008 that used data from TCGA or CGGA to validate the association between ≥1 molecular marker and overall survival in adult patients with glioblastoma. Main data items included cohort characteristics, statistical significance of the survival analysis, and model covariates.

RESULTS
There were 58 eligible studies from 1,751 non-duplicate records investigating 126 individual molecular markers. In 14 studies published between 2017 and 2020 using TCGA RNA microarray data that should have the same cohort, the median number of patients was 464.5 (interquartile range 220.5–525). Of the 15 molecular markers that underwent more than one univariable or multivariable survival analyses, five had discrepancies between studies. Covariates used in the 17 studies that used multivariable survival analyses were age (76.5%), pre-operative functional status (35.3%), sex (29.4%) MGMT promoter methylation (29.4%), radiotherapy (23.5%), chemotherapy (17.6%), IDH mutation (17.6%) and extent of resection (5.9%).

CONCLUSION
Preclinical glioblastoma studies that used TCGA for validation did not provide sufficient information about their cohort selection and there were inconsistent results. Transparency in reporting and the use of analytic approaches that adjust for clinical variables can improve the reproducibility between studies.
Computer-aided Design of Novel CDK5 Inhibitors; Towards New Treatments of Glioblastoma
Authors: Khan Zahra , Stasik Izabela , Hayes Joseph 
Published: October 2022

Abstract

AIMS
Design and statistically optimize an in silico screening protocol; apply the screening protocol to a compound database; in vitro validation of selected inhibitors (isolated CDK5 enzyme binding assay).

METHOD
Two large compound databases, ZINC15 and Analyticon Discovery, were used to screen for potential CDK5 ATP-binding site inhibitors. They were first filtered using a generated pharmacophore model and then virtually screened using Glide SP docking with a solved CDK5-p25 structure (PDB: 3O0G). The selected candidates were validated using enzyme binding assays to determine their inhibitory activity on CDK5, as well as against a panel of kinases.

RESULTS
Over 17,000 compounds were screened during molecular docking studies and of these, ~11,600 compounds returned which are predicted to bind to CDK5. The top 10% of docked compounds were analysed and 30 candidates were selected for single concentration screening at 50 µM concentrations. The 9 most potent compounds were selected for IC50 determinations and revealed 6 compounds with IC50 &lt;10 µM. The selected novel compounds were also screened against a panel of kinases (CDK2, CDK5, CDK9, GSK-3β) with varying selective profiles observed.

CONCLUSION
Low micromolar potent compounds have been identified through in silico screening and validated in using in vitro binding assays. One flavonoid compound in particular, cirsiliol (IC50 = 5.90 µM), displayed best selectivity towards CDK5, a challenge in kinase inhibitor design. The identified compounds will now pass to cellular studies to determine their effect on Glioblastoma cell lines.
The Outcomes Measured and Reported in Meningioma Clinical Effectiveness Trials Are Heterogeneous and Preclude Comparative Analysis of Results: A Systematic Review
Authors: Millward Christopher , Islim Abdurrahman , Keshwara Sumirat , Srikandarajah Nisaharan , Brodbelt Andrew , Marson Anthony , Williamson Paula , Jenkinson Michael 
Published: October 2022

Abstract

AIMS
Meningioma clinical trials have assessed interventions including surgery, radiotherapy, and pharmacotherapy, but heterogeneity of outcome measurement and reporting often precludes comparative analysis of trial results. This systematic review aimed to summarise the outcomes measured and reported in such trials.

METHOD
Systematic literature and trial registry searches were performed to identify published and ongoing intracranial meningioma clinical effectiveness trials. Reported outcomes were extracted verbatim, along with an associated definition and method of measurement if provided. Deduplication, grouping, and classification of verbatim outcomes was performed to identify unique outcomes reported in the literature.

RESULTS
Thirty published articles and 18 ongoing studies were included, describing 47 unique studies: phase II n=33, phase III n=14. Common interventions included: surgery n=13, radiotherapy n=8, and pharmacotherapy n=20. 660 verbatim outcomes were reported, of which 85 were defined. Following deduplication, 416 unique verbatim outcomes remained and were grouped into 119 unique ‘non-verbatim’ outcomes. Those reported most frequently included: blood loss n=15, need for blood transfusion n=12, radiographic response to treatment n=19, eye toxicity after radiotherapy, gastrointestinal toxicity from pharmacotherapy n=40, haematological toxicity from pharmacotherapy n=31, metabolic and nutrition toxicity from pharmacotherapy n=42, progression-free survival n=46, and overall survival n=37.

CONCLUSION
Outcome measurement and reporting across meningioma clinical trials is heterogeneous and may preclude comparative analysis of trial results. The unique outcomes identified from this systematic literature review will be prioritised through an eDelphi survey and consensus meeting of key stakeholders (including patients), in order to develop a Core Outcome Set (COS) for use in future meningioma clinical trials.
Impact of the Neuro-Radiologist and Neuro-Surgeon in Contouring With the Neuro-Oncologist on Local Relapse Rates for Brain Metastases Treated With Stereotactic Radiosurgery
Authors: Robinson Maxwell , Sayal Karen , Tunstall Clare , Padmanaban Sriram , Watson Rhona , Pretorious Pieter , Joseph Robin , Jeyaretna Sanjeeva , Hobbs Claire 
Published: October 2022

Abstract

AIMS
The audit evaluates the value of MDT, including neuro-radiologist and neuro-surgeon, review of contouring carried out by a clinical oncologist in stereotactic radiosurgery (SRS).

METHOD
Lesions were contoured first by clinical oncologist then reviewed/edited by MDT. Iinitial contour was compared with final using Jaccard conformity and geographical miss indices. Dosimetric impact of contouring change was assessed using plan metrics to both original and final contour. The impact of contouring review on local relapse, overall survival and radio necrosis rate was evaluated with at least 24 months follow up.

RESULTS
113 patients and 142 lesions treated over 22 months were identified. Mean JCI was 0.92 (0.32-1.00) and 38% needed significant editing (JCI&lt;0.95). Mean GMI was 0.03 (0.0-0.65) and 17% showed significant miss (GMI&gt;0.05). Resection cavities showed more changes, with lower JCI and higher GMI (p&lt;0.05). Dosimetric analysis indicated a strong association of conformity with PTV dose metrics. Greater association was seen in resection cavity, i.e. geographical nature of a typical contouring error gives rise to greater potential change in dose. Clinical outcomes compared well with published series. Median survival was 20 months and local relapse free rate of 0.89 (0.8-0.94) at 40 months. Radio-necrosis free rate 0.9 (0.83-0.95) at 40 months with median 17 months to developing radionecrosis for those that did.

CONCLUSION
MDT contour review adds significant value to SRS resulting in reduced local recurrence rates. No improvement in clinical oncologist contouring over time was shown indicating a collaborative approach is needed regardless of experience of clinical oncologist - particularly for resection cavities.
Retrospective Review of Carcinomatous Meningitis Management at a Tertiary Centre: Reflections on Current and Future Management
Authors: Williams Simon , Topping Oliver , Sanghera Paul , Hassan-Smith Ghaniah 
Published: October 2022

Abstract

AIMS
Carcinomatous meningitis (CM) arises following metastatic deposition of neoplastic cells in the meninges triggering a complex series of pathological changes, typically representing a terminal complication of underlying malignancy. No uniform management strategy exists for CM patients, despite research highlighting numerous treatment modalities. We present a single centre retrospective study of CM patients managed over a ten year period, along with analysis of current and future treatment modalities for CM.

METHOD
Patient datasets were identified using diagnostic codes. Inclusion criteria were patients with malignant cells identified in CSF, or those with radiological features consistent with CM with a background of cancer and supporting clinical features. Data regarding patient symptomatology, management, and outcome were then gathered from electronic patient records.

RESULTS
Ten cases of carcinomatous meningitis were identified. The most common primary tumour site was breast (30%). The most common presenting symptoms were headache (70%), weakness (60%), vomiting (50%), and confusion (50%). Radiological evidence of CM in the form of leptomeningeal enhancement was noted in 60% of cases. Management of CM cases was variable – six patients underwent no further anti-cancer treatment, two patients underwent chemotherapy, and two patients were planned for radiotherapy. Median length of survival from time of CM diagnosis was 30 days (IQR 15 – 63).

CONCLUSION
CM patients have a poor prognosis, and significant variability exists in management. New therapeutic options are emerging, particularly in the field of targeted biologic therapies, and engagement with specialist oncology teams is recommended. Early palliative care support is essential in the management of CM patients.
Stereotactic Radiosurgery for Brainstem Metastases
Authors: Hickman Mitchell , Benghiat Helen , Meade Sara , Hayes Geoff , Hartley Andrew , Sanghera Paul 
Published: October 2022

Abstract

AIMS
Limited data exists on outcomes following SRS for brainstem metastases (BSM). The purpose of this audit was to explore the use of SRS using Cyberknife for BSM at a single centre; reporting rates of toxicity and survival outcomes.

METHOD
Patients undergoing SRS for BSM from 2013 to 2021 were identified from a prospective database. Clinical characteristics were collected including; gender, age, histology and KPS. The use of previous WBRT, the volume and the dose delivered to the BSM were also recorded. All target volumes were peer reviewed by a neuro-radiologist.

RESULTS
41 patients with a BSM were identified. The median age was 62 years (range 35-78). Histology was lung 15 (36.6%), breast 13 (31.7%) and other 13(31.7%). The median brainstem target volume was 0.36cc (range 0.01 – 5.63cc). 32 patients had single fraction (dose range 14.5 to 18Gy) and 9 patients had 3 fractions (dose range 17-24Gy). 7 patients had previous WBRT. Median overall survival was 242 days (range 19-1213). A radiological response or stable disease was seen in 26 out of 30 patients with post SRS imaging available for review. 2 patients developed a 6th nerve palsy. 12 patients required a prolonged course of dexamethasone. No statistically significant relationship was observed between patient age, brainstem lesion size or fractionation and the need for prolonged use of dexamethasone but there was a trend with lung cancer patients requiring prolonged dexamethasone (p=0.06).

CONCLUSION
Brainstem SRS is viable option with an acceptable late toxicity profile. Updated information on survival and local control will be presented.
Motor Seizures Confer Overall Survival Benefit in WHO Grade 2 Glioma
Authors: Fairclough Sam , Mathew Ryan , Goodden John , Chumas Paul , Maguire Melissa 
Published: October 2022

Abstract

AIMS
The prevalence of epilepsy in WHO grade 2 glioma is high, with seizures often being the presenting symptom. We explore the epidemiology of seizures in this patient population in a regional neurosurgical centre.

METHOD
Electronic health records of patients with histologically-proven WHO grade 2 glioma (n=227) were reviewed with data collected including patient demographics, epilepsy prevalence and seizure semiology. Relationships between epilepsy and overall survival were calculated using a Cox proportional hazards model in the statistical software “R,” controlling for all other variables – including histological diagnosis.

RESULTS
Overall, 196/227 (86.3%) patients were diagnosed with epilepsy - either at presentation (179/196, 91.3%), or during the course of their disease (17/196, 8.7%) . Mean follow-up was 7.0 years. Diffuse astrocytoma histology was associated with reduced overall 10-year survival (HR 4.68, p&lt;0.001) compared with oligodendroglioma. The majority of patients experienced focal onset seizures (n=118) as their predominant seizure type, with generalised (n=64) and unknown onset seizures (n=14) less likely. Almost two-thirds (64.8%) of those with epilepsy had experienced at least one generalised tonic-clonic seizure. During seizures, loss of awareness (n=132) and presence of motor activity (n=147) were frequently encountered. Predominantly experiencing seizures without any motor activity also appeared to confer poorer survival outcomes (HR 2.39, p&lt;0.05), even when controlled for histology.

CONCLUSION
Most WHO Grade 2 glioma patients experience focal seizures, though generalised tonic-clonic seizures are common. Motor seizure activity is a frequent feature in WHO Grade 2 glioma and may confer a survival benefit, when compared to patients that have primarily non-motor seizure activity.