tbuckley/cabot-search huggingface dataset:
EVALUATING GLIOMA PATIENT PERCEPTIONS TOWARDS REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION FOR REHABILITATION
Authors: Mr Ahmad Ali, Mr Jahard Aliaga-Arias, Mr Rasheed Zakaria, Prof Michael Jenkinson, Ms Ana Mirallave Pescador, Mr Francesco Vergani, Mr Jose Lavrador
Journal: Neuro-Oncology (2024)

Abstract AIMS Repetitive Transcranial Magnetic Stimulation (rTMS) is established for depression, chronic pain, and motor rehabilitation after stroke. It is an emerging tool for other purposes including cognitive rehabilitation. Recent evidence supports its use for motor rehabilitation after brain surgery. We sought to evaluate patient perceptions towards rTMS. METHOD Two studies were undertaken. Group 1 – patients who received seven days of rTMS for motor rehabilitation for post-operative weakness (MRC 0-1 in any limb) following resection of a glioma or other resective pathology were prospectively surveyed on the last day of their rTMS treatment, as well as their next of kin (NOK). Group 2 – patients who had previously been treated for a glioma but did not receive rTMS were retrospectively surveyed through two brain tumour charities, as well as their NOK. RESULTS Group1: 21 responses. 11 patients, 10 NOK. Commonest pathology was glioblastoma(n=3). Group2: 24 responses. 16 patients, 8 NOK. Commonest pathology was grade 2 glioma(n=7). Most Group1 respondents reported a positive experience with rTMS(n=15). Group1 patients experienced substantial subjective improvements in motor functioning(n=6), some improvements(n=3), or no change(n=2). None reported worsening. Experiencing adverse symptoms (e.g. headache) was associated with reduced likelihood of motor improvements(p=0.01). Most improvements were in gross rather than ﬁner motor domains. Patients in Group2 were accepting of longer and more frequent rTMS sessions than Group1(p=0.03 and p=0.01 respectively). The commonest concerns raised pertained to seizures, side effects, and geographic availability. The commonest hope raised pertained to cognitive or motor improvements. CONCLUSION rTMS is well-tolerated and patients and their NOK support its use. Respondents would ﬁnd longer and more sessions acceptable. Understandably, there is less tolerance for rTMS in the early post-operative period. However, enthusiasm for rTMS is substantial in the later stable post-operative phases. Our ﬁndings support the further development of rTMS as a tool for improving patient rehabilitation.
RECAPITULATING THE POST-SURGICAL BRAIN MICROENVIRONMENT OF ATYPICAL TERATOID RHABDOID TUMOURS TO IDENTIFY MEMBRANE PROTEINS FOR TARGETED THERAPY
Authors: Mr Shaylen Mistry, Mr Harry Porter, Dr Phoebe McCrorie, Dr Anya Snary, Ms Hannah Bailey, Dr Clare Coveney, Dr David Boocock, Dr Ruman Rahman, Prof Robert Layﬁeld
Journal: Neuro-Oncology (2024)

Abstract AIMS Atypical Teratoid Rhabdoid Tumours (AT/RT) are rare aggressive tumours primarily arising in the hind brain of children under three, conferring median survival of &amp;lt;12 months. Surgery remains the only standard treatment; however tumours recur from post-surgical residual disease. Decellularised human brain cerebellum aim to recapitulate AT/RT post-surgical brain microenvironments which retain extracellular matrix (ECM) ligands, and where AT/RT plasma membrane proteins are hypothesised to represent viable molecular therapy targets. METHOD AT/RT, astrocyte and human brain cerebellum (decellularised and non-decellularised) membrane protein fractions were extracted and analysed using liquid chromatography-mass spectrometry. Proteomic analysis tools were integrated to identify differential expressed proteins and identify shared correlations. RESULTS Decellularised cerebellar ECM exhibited an enriched membrane proteome relative to total proteome, evidence of complete removal of intracellular components. Furthermore, decellularised and non-decellularised cerebellar tissue expressed comparable levels of membrane proteins and protein networks, indicative of ECM ligand retention. AT/RT and astrocyte KEGG Pathway analysis revealed speciﬁc oncology-based pathway expression in membrane protein compared to total protein, reinforcing membrane proteins as more visible therapeutic targets. Between the top 20 expressed proteins, ATP1A1 was the only membrane protein shared exclusively between all AT/RT cells and astrocytes, suggesting a critical functional role. Membrane proteins showing shared expression when normalised against each AT/RT cell line included ATP1A1, HSPD1, GNA13 and SLC3A2, indicating biological similarities between AT/RT molecular subtypes, which may offer candidate ubiquitous therapy targets. Membrane proteins expressed similarly in AT/RT-MYC molecular subtypes include ATP1A1, SLC7A5 and EEF1A1. STRING membrane pathway analysis also identiﬁed shared proteins between AT/RT and astrocyte cell populations. CONCLUSION AT/RT membrane protein pathways provide ideal therapeutic targets directly amenable for drug repurposing. Future work prioritises proteomic analysis utilising 3D AT/RT spheroids and cerebellum brain tissue to maximise accurately recapitulating the AT/RT post-surgical microenvironment. Cerebellum decellularisation still permits retention of essential proteins and ligands.
INTEGRATING ALLIED HEALTH PROFESSIONALS DURING THE ONCOLOGICAL TREATMENT PHASE FOR GLIOBLASTOMA PATIENTS: A CASE STUDY AT A UK CANCER CENTRE
Authors: Mrs Toni Wyatt, Mrs Nicola Peat
Journal: Neuro-Oncology (2024)

Abstract AIMS Primary brain tumour patients should be offered neurological rehabilitation assessment at diagnosis and every stage of follow With only 5% of glioblastoma patients surviving more than 5 years, specialist management that spans across all phases of the Dietz rehabilitation model is required to optimise function, treatment tolerance and Quality-of-life. At Guy’s cancer centre an Allied health multi-disciplinary team (Physiotherapy, Occupational therapy and Speech and language therapy) work alongside the oncologist-led clinic to support this patient group. METHOD Case history A 54-year-old, male, was diagnosed with right parietal Glioblastoma, WHO grade 4, IDH wildtype, MGMT 5.47% methylated (August 2023) on biopsy only. He underwent chemo/radiotherapy - 60gy/90 fractions with Temozolmide (TMZ) on 3/11/2023 Currently C4 of adjuvant TMZ. Dexamethazone 2mg was discontinued on 29/11/2023, he continues with Keppra 500mg twice daily. RESULTS Dietz Intervention approach in phases: PREVENTATIVE Fatigue management was introduced prior to radiotherapy including a physical activity review, advice on pacing, sleep hygiene and relaxation techniques. Given the patient’s history of shift work and altered sleep patterns, managing risks of treatment-related fatigue was of particular importance. Restorative &amp; Supportive: A targeted and periodised exercise programme was initiated, comprising 1:1 gym based physiotherapy sessions. The aims included enhancing exercise conﬁdence, improve balance, endurance, maintain strength, pain management and weight maintenance during chemo/radiotherapy and adjuvant TMZ. Education was deployed on adjusting activity levels based on chemotherapy cycle and day to day side effects, alongside ongoing fatigue management advice around pacing and sleep hygiene. CONCLUSION Learning and Recommendations Implementing tailored rehabilitation interventions early in the patient’s treatment pathway, enables proactive management to mitigate the impact of treatment-related side effects on their QOL. Based on our experience, early engagement with a dedicated therapy team is recommended to foster strong rapport with both the patient and their caregivers. This facilitates timely rehabilitation planning for optimal outcomes.
A NEW INTERNATIONAL ACCELERATOR PROGRAMME FOR NOVEL BRAIN TUMOUR THERAPIES
Authors: Dr Charlotte Aitken, Dr Nicky Huskens, Prof Katie Bushby, Dr Karen Noble, Prof Petra Hamerilk, Dr Edward Kaye, Dr Dione Kobayashi, Mr Ryan Mathew, Dr John McCall, Dr Javad Nazarian, Prof Ruth Plummer, Dr Ruman Rahman, Dr Juanita Lopez, Prof Kanneboyina Nagaraju
Journal: Neuro-Oncology (2024)

Abstract AIMS Developing a comprehensive translational programme for brain tumours involves navigating numerous challenges, including preclinical study robustness, safety, clinical trial design, understanding and addressing regulatory requirements, and commercialisation. Recognising the diﬃculty of this journey, the Brain Tumour Research Novel Therapeutics Accelerator (BTR-NTA) was launched in 2023. The BTR-NTA is an accelerator programme providing independent expert guidance to de-risk drug or device development through systematic evaluation. The international, multidisciplinary BTR-NTA Committee spans expertise across the entire therapeutic development pathway. Supported by Brain Tumour Research, BTR-NTA is free for academics and available at nominal cost for industry. METHOD Researchers at any stage of therapeutic development may apply to BTR-NTA. Accepted applicants proceed as follows: 1. Applicants complete a form highlighting their current and prospective data and ﬁndings. All materials are covered under a conﬁdentiality agreement that protects their intellectual property; 2. Applicants’ proposals are reviewed by the BTR-NTA Committee; 3. The Applicants and BTR-NTA Committee meet in-person to constructively evaluate the work; and 4. Applicants receive a comprehensive report with feedback on strengths, identiﬁcation of potential risks, and guidance on next steps. The BTR-NTA Committee dedicates time for in-person meetings with each applicant, and extensive time pre and post-meeting. RESULTS Since the launch of BTR-NTA, 13 international groups have applied to the programme and three groups have had their therapies reviewed in-person by the BTR-NTA committee to date. Of the groups who provided feedback on the programme, 100% intended to adjust or reﬁne their future work based on the BTR-NTA Committee’s input and the average rating of the programme’s helpfulness was 9.5/10. CONCLUSION The ultimate goal of BTR-NTA is to help researchers with a potential therapy for brain tumours navigate the development journey and reach the clinic in an eﬃcient way. This programme will support development of novel therapies to improve outcomes for brain tumour patients.
MITOCHONDRIAL MEMBRANE POTENTIAL IS A FUNCTIONALLY RELEVANT AXIS OF NON-GENETIC CELLULAR HETEROGENEITY IN GLIOBLASTOMA
Authors: Dr Ruth Robinson, Ms Emily Gaizley, Dr Elitza Deltcheva, Dr Sam Marguerat, Dr Jason Wray, Prof Tariq Enver
Journal: Neuro-Oncology (2024)

Abstract AIMS Glioma stem cells (GSCs) are believed to underpin treatment resistance in glioblastoma by virtue of their self- renewal capabilities and presumed transcriptional plasticity. Understanding how cell state diversity is established and maintained is crucial to make therapeutic gains. We have previously shown mitochondrial membrane potential (MMP) to be a functionally relevant source of extrinsic noise in embryonic and haematopoietic stem cells. This study evaluates cellular MMP as an axis of variability in GSCs. METHOD MMP was measured by ﬂow cytometry in patient-derived GSC lines using cationic dyes that diffuse reversibly across the mitochondrial membrane in a voltage dependent manner. MMP-high and low populations (top and bottom 10-20%) were fractionated and subjected to RNA-sequencing and assays of proliferation and clonogenicity. Correlation between MMP and global transcription rate was investigated through a uridine analogue (5-EU) incorporation assay. The relationship between MMP and quiescence was assessed, with quiescence deﬁned as inducible histone2B-GFP label retention after 10 days. Timecourse data for MMP was obtained through sequential staining. RESULTS RNA sequencing identiﬁed differential gene expression and exon utilization according to MMP status. MMP- high cells upregulated cell cycle genes, while MMP-low cells exhibited a diverse signature suggestive of a more differentiated state. A greater proportion of MMP-high cells were in cycle, but MMP-low cells formed more colonies. MMP positively correlated with global transcription rate in both cycling and quiescent GSCs. Time- course experiments revealed dynamic periodicity in cellular MMP. CONCLUSION The MMP axis reveals transcriptional and functional heterogeneity in GSCs and importantly unmasks phenotypic variability within the treatment-refractory quiescent compartment. The positive correlation between MMP and transcription rate, along with splicing differences, suggests a mechanism underlying functional diversity. Given the oscillatory dynamics of MMP, we postulate that stable-low MMP may deﬁne a deeply quiescent, therapy-resistant state. Evaluating MMP as a tractable regulator of GSC fate is warranted.
CHARACTERISATION OF THE RESPONSE OF PRE-CLINICAL MODELS OF GLIOMA TO METABOLIC THERAPIES USING IN VIVO MAGNETIC RESONANCE SPECTROSCOPY
Authors: Dr Richard Perryman, Dr Nicoleta Baxan, Dr Nelofer Syed
Journal: Neuro-Oncology (2024)

Abstract AIMS Magnetic resonance imaging (MRI) is routinely used to diagnose and monitor brain tumours. Magnetic resonance spectroscopy (MRS) allows us to record the metabolic proﬁle of tumours in situ. This provides a non-invasive method to monitor the response of tumours to metabolic therapies. We aimed to characterise the response of pre-clinical models of glioma to metabolic therapies such as arginine deprivation and the ketogenic diet (KD) by MRS, to better understand what metabolic changes are occurring in the tumour. METHOD We performed orthotopic injection of three different cell lines, including the syngeneic models GL261 and CT2A, as well as a primary GBM cell line, into the striatum of C57BL/6 and athymic nude mice respectively. Mice were randomised to either arginine deprivation treatment using pegylated arginine deiminase (ADI), or KD, plus controls. In each animal, we collected single voxel MRS data using STEAM on both the tumour itself, and healthy brain. MRS data was exported in jMRUI format and analysed in R using the spant package, followed by PCA and OPLS-DA. RESULTS PCA showed that there is clear distinction between healthy and tumour spectra across all models. OPLS-DA indicated that the lipid and choline spectral regions were signiﬁcantly associated with tumour, whereas the NAA and glutamine/glutamate regions were signiﬁcantly associated with healthy brain. Integration of speciﬁc peaks associated with these metabolites conﬁrmed these results. Subset analysis indicated distinct metabolic signatures between the syngeneic models and the primary GBM model. Furthermore, there is evidence to suggest that tumours in animals treated with arginine deprivation have a unique metabolic signature. CONCLUSION This data indicates that the tumour speciﬁc response to metabolic therapies can be measured by routine MRS screening. This would allow a non-invasive method by which clinicians could monitor the effectiveness of metabolic therapies in patients with gliomas.
SURGICAL OUTCOMES OF TUBULAR RETRACTOR SYSTEMS IN THE MANAGEMENT OF BRAIN TUMOURS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Mr Amir Rafati Fard, Mr Oliver Mowforth, Dr Owen Hibberd, Mr Isaac Akinduro, Mr Kieran Smith, Dr Reece Patel, Mrs Zainab Bhatti, Mrs Sejal Karmarkar, Mr Ciaran Hill
Journal: Neuro-Oncology (2024)

Abstract AIMS Retraction is a critical step in surgical removal of brain tumours, enabling visualisation and resection. Conventional retraction applies focal pressure to overlying tissue, potentially resulting in retraction-induced injury. Tubular retractors (minimally invasive parafascicular surgery) circumferentially distribute pressure to theoretically minimise injury. Whilst previous reviews have provided insight into their potential, the literature has since signiﬁcantly expanded, necessitating an update. The objective was to synthesise all current evidence regarding surgical outcomes of tubular retractors in resection of brain tumours. METHOD Studies reporting on use of tubular retractors to resect brain tumours in adult patients were eligible. PRISMA guidelines were followed. MEDLINE, Embase and the Cochrane Library were searched to 18th October 2023. Duplicate title/abstract screening, data extraction and risk of bias assessments were conducted. RESULTS Of the 2453 studies screened, 49 were included in the ﬁnal synthesis, involving 690 patients. Tubular retractor systems assessed were: BrainPath (n=199), VBAS (n=198), METRx (n=63) and other (n=230). Pooled estimate of gross total resection rate was 75% (95% CI 0.65-0.84; I2=83%), whilst pooled estimate of complication rate was 17% (95% CI 0.11-0.24; I2=75%). Sub-group analysis of gross total resection rate was conducted for: glioma (150 patients, pooled prevalence 47%, 95% CI 0.36-0.57; I2=29%), colloid cyst (121 patients, pooled prevalence 100%, CI 0.99-1.00; I2=0%), and metastasis (114 patients, pooled prevalence 82%, 95% CI 0.67-0.94; I2=64%). There was no signiﬁcant difference between tubular retractor systems with regards to gross total resection or complication rate (p&amp;gt;0.05). CONCLUSION There is mounting evidence for the utility of tubular retractors in resection of brain tumours. However, this evidence remains largely in the form of low-quality case-series, providing proof-of-concept, but limited in its ability to draw more robust comparisons to conventional retraction. Future studies with greater sample sizes and inclusion of control groups are now needed to consolidate the position of tubular retractors in neuro-oncology.
MULTI-OMIC INTEGRATION REVEAL INTRA-TUMOUR HETEROGENEITY AND IDENTIFY DISULﬁRAM AND COPPER AS A SYNERGISTIC THERAPY IN PAEDIATRIC EPENDYMOMA
Authors: Dr Alina Pandele, Dr Alison Whitby, Ms Sophie Lankford, Mr Donald Macarthur, Mr Ian Kamaly-Asl, Prof David Barrett, Prof Richard Grundy, Dr Dong-Hyun Kim, Dr Ruman Rahman
Journal: Neuro-Oncology (2024)

Abstract AIMS Ependymoma (EPN) is the second most malignant paediatric brain tumour. The PF-A subgroup, associated with a hypoxic microenvironment, has a dismal survival rate of 50% with clinical trials failing to demonstrate a signiﬁcant survival advantage from chemotherapy to date. As the lack of genomic alterations makes it diﬃcult to uncover novel therapeutic targets, we present a multi-omic integration investigating whether spatially-distinct tumour microenvironments represent targetable metabolic niches in PF-A EPN. METHOD Surgical sampling of spatially-distinct regions was performed on eight PF-A patients. Metabolites and RNA were simultaneously extracted from the same cellular population and analysed using liquid chromatography-mass spectrometry (LC-MS) and RNAseq. Multi-omic integration was performed using Metscape3 and functional assays evaluating proliferation, invasion and siRNA-mediated knockdown were performed in 2D and 3D models of intra-tumour region patient-derived cell lines. Selected single and drug combination therapy was performed in normoxia and hypoxia, and synergy assessed using the Chou-Talalay method. RESULTS Multi-omic integration revealed 124 dysregulated metabolic pathways, encompassing 156 genes and 49 metabolites with the largest number of interactions occurring in the gluconeogenesis pathway. Each anatomical region also presented at least one unique gene-metabolite interaction demonstrating heterogeneity within and across PF-A EPN tumours. Four selected drug targets (Disulﬁram, Vandetanib, Mildronate and FBP1 inhibitor) based on metabolically relevant genes (ALDH3A1, FMO3, BBOX1, FBP1) showed impairment of metabolic viability in vitro, with limited chemosensitivity observed in control human cerebellar astrocytes. The addition of Cu2+ signiﬁcantly sensitized cells to Disulﬁram, particularly under hypoxic conditions. This synergistic combination signiﬁcantly impaired invasion in both normoxia and hypoxia. CONCLUSION This is the ﬁrst instance where multi-omic data integration and intra-tumour heterogeneity has been investigated for paediatric EPN revealing novel therapeutic targets in the context of gene-metabolite correlations. Drug tolerability will be further assessed in vivo using the previously characterised PF-A EPN orthotopic mouse xenograft MAF-928.
DEXAMETHASONE WEAN POST CRANIOTOMY FOR MENINGIOMA- A CASE STUDY
Authors: Ms Laura Mullens, Mrs Victoria Hurwitz, Mrs Sarah Hedges, Ms Ellie Kostick, Mr Aeron Suarez, Ms Pat Sabido, Ms Nicola Harding, Mr Jose Lavrador, Prof Keyoumars Ashkan, Mr Francesco Vergani, Mrs Katia Cikurel, Mr Richard Gullan
Journal: Neuro-Oncology (2024)

Abstract AIMS Case review/analysis of dexamethasone wean post craniotomy for meningioma. To identify any quality of life issues experienced during the wean, how and why steroid wean was adjusted and any impact steroid use had on serum cortisol level causing adrenal insuﬃciency. METHOD Review of documentation to identify steroid related side effects, how and when this impacted on the patient’s quality of life. Collection of data; steroid doses, length of time on steroids (pre-surgery and post-surgery), serum cortisol result. Clinical choices regarding dose/timings of dexamethasone reviewed and compared to literature. RESULTS Delays/changes with theatre dates, capacity, neurological symptoms on presentation led this individual to a four month pre-surgical dose of dexamethasone which led to weight gain, pre-diabetes and insomnia. Quality of life pre and post-surgically affected by steroid use namely mental health, employment and social belonging. This case study conﬁrms adrenal insuﬃciency was precipitated by the prolonged pre-surgical use of dexamethasone. Clinical nurse specialists are integral in adjusting steroid dose to manage neurological recovery and safely wean steroids to zero as well as identifying adrenal insuﬃciency. CONCLUSION Data collection from a large sample size is required to conﬁrm how many patients coming through the neurooncology surgical pathway have conﬁrmed adrenal insuﬃciency post neurosurgery secondary to Dexamethasone. Once data is collected guidance on how to manage a safe post surgical steroid wean and minimise impact of quality of life can be formalised.