bluuebunny/crossref_metadata_2025_split huggingface dataset:
MODELLING GBM RECURRENCE: THE INﬂUENCE OF PERI-LESIONAL OEDEMA AND THE DISCONNECTOME
Authors: Tariq Ms Manaal , Ruﬄe Dr James , Mohinta Ms Samia , Brothwell Dr Morag , Brandner Prof Sebastian , Nachev Prof Parashkev , Hyare Harpreet 
Published: October 2024

Abstract

AIMS
Residual tumour burden after surgery in GBM patients is a prognostic imaging biomarker, often involving the area of T2 signal elevation surrounding the tumour core, histopathologically representing inﬁltrative oedema with tumour cells. We present the ﬁrst stage of a model to improve the prediction GBM recurrence by speciﬁcally investigating the peri-lesional oedema compartment.

METHOD
UK-wide sample of histologically proven IDHwt GBMs with MRIs at the time of diagnosis underwent state-of- the-art in-house tumour segmentation pipeline and radiomic feature extraction of whole-tumour, enhancing, non-enhancing and oedema components, and masked disconnectome map components. Of these, early GBM recurrence, within 6 months after completion of radiotherapy, was curated and distribution mapped across the brain.

RESULTS
1464 patients were identiﬁed: male = 901, median age 63 years, average overall survival 597 days. The radiomic features: Compactness 1 and 2, Surface Area, Spherical Disproportion, Sphericity, and Maximum 2D Diameter column of the disconnectome-related perilesional oedema compartment were most predictive of survival outcome (p value &lt;0.01). Of these, 47 patients with average overall survival 357 days and average time from end of radiotherapy to progression of 131 days were identiﬁed.

CONCLUSION
Our early results reveal the relationship between perilesional oedema MRI features and survival, with disconnectome-related perilesional oedema features most predictive. This suggests that extended brain network aberrations caused by gliomas may also inﬂuence tumour recurrence. Further work will focus on the development of more robust predictive models of tumour recurrence that have potential for signiﬁcant impact on surgical and radiotherapy planning.
FROM VEIN TO BRAIN: ENHANCING TRAﬃCKING OF CAR T-CELLS IN DIFFUSE MIDLINE GLIOMA
Authors: Saukila Dr Louise Steele , Hotblack Dr Alastair , Burke Dr Christina , Rodriguez Ms Carmen , Righi Dr Matteo , Kalber Dr Tammy , De-Cola Dr Antonia , McNicholas Mr Michael , Pathania Dr Manav , Pule Dr Martin , Straathof Dr Karin 
Published: October 2024

Abstract

AIMS
H3K27M-altered diffuse midline glioma (DMG) is the deadliest childhood brain tumour, with treatment limited by anatomical location and chemoresistance; palliative radiotherapy remains the mainstay of treatment. Chimeric antigen receptor (CAR) T-cell therapy produces promising pre-clinical results in treating these tumours whilst leaving interspersed normal brain cells intact. Early clinical outcomes of GD2-CAR T-cell therapy for H3K27M-altered DMG demonstrate short-lived neurological and radiological improvement. Enhancing traﬃcking to and inﬁltration into the tumour core may enhance CAR T-cell eﬃcacy. Here, advanced T-cell engineering modules are tested for their ability to improve CAR T-cell traﬃcking.

METHOD
A library of T-cell engineering modules was created each with a unique DNA barcode to allow identiﬁcation of CAR T-cells expressing a given module. The library includes chemokine receptors (CCR) to improve tumour homing by chemotaxis towards tumour-secreted chemokines, adhesion molecules to increase extravasation across the blood-brain-barrier, and molecules to degrade upregulated tumour extracellular matrix (ECM) components to improve CAR T-cell motility through the tumour. Murine T-cells were co-transduced with a CAR and barcoded advanced T-cell engineering modules and administrated intravenously in syngeneic models of high-grade glioma (HGG)/DMG. Tumour, normal brain, bone marrow, spleen and liver tissue were collected at several time points post CAR T-cell administration to assess presence of CAR T-cells using genetic barcodes.

RESULTS
Co-expression of advanced T-cell engineering modules did not impair CAR T-cell function in vitro. CARs co-expressing selected CCRs were preferentially detected in tumour tissue in mice with GL261-EGFRvIII or H3.3K27Mp53LOFPDGFRAWT-engrafted tumours. Findings were further validated by ﬂow cytometry detection of selected CCR-expressing CAR T-cells as compared to CAR T-cells without additional engineering components. Similar experiments for adhesion molecules and ECM modiﬁers are planned.

CONCLUSION
Results to date indicate that CAR T-cells co-expressing selected CCRs enhance their homing to HGG/DMG tumours, encouraging further in vivo research to assess impact on CAR T-cell eﬃcacy.
CHARACTERISATION OF THE RESPONSE OF PRE-CLINICAL MODELS OF GLIOMA TO METABOLIC THERAPIES USING IN VIVO MAGNETIC RESONANCE SPECTROSCOPY
Authors: Perryman Dr Richard , Baxan Dr Nicoleta , Syed Dr Nelofer 
Published: October 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.
APPLICATION OF IN VITRO MODELS: INCORPORATING BLOOD BRAIN BARRIER MODELS WITH GLIOMA, AND THE USE OF MICROﬂUIDICS
Authors: Taylor-Chilton Ms Eleanor , Baldwin Dr Lydia , Stead Dr Lucy , Greenman Prof John , Wade Dr Mark , Rabie Dr Tamer , Alder Dr Jane 
Published: October 2024

Abstract

AIMS
The blood brain barrier (BBB) presents one of the main obstacles for the development of novel glioblastoma treatments. The various transporters and enzymes within the BBB reduce the disposition of novel therapies into the brain. There is a need for an in vitro BBB-glioma model with proven eﬃcacy of predicting CNS delivery at earlier stages in the drug discovery pipeline.

METHOD
A BBB-glioma lab-on-a-chip model could enable rapid identiﬁcation of novel therapies that can cross the BBB at earlier stages of the drug development process, before going to clinical trials. The application of microﬂuidic technology allows for the detection of soluble tissue-derived factors and the assessment of the levels of soluble markers released from malignant tissue. Adding ‘ﬂow’ to the model, is more reﬂective of the dynamic ﬂow present at the BBB.

RESULTS
Validation studies of the current BBB model and converting this model over to a lab-on-a-chip model have shown the presence of an endothelial cell barrier and the tight junction proteins Zo-1 and Claudin-1, through western blotting, immunocytochemistry, and permeability experiments using varying molecular weights of FitC-dextran. These validation studies have been completed using brain endothelial monolayers on polycarbonate transwell inserts, with the immortalised cell line HCMEC/d3, and the short-term culture cells HBMEC. Also, validation studies using a co-culture of endothelial cells, astrocytes and pericytes have begun, using the same techniques to show a barrier has formed, on both the current BBB model and the lab-on-a-chip model.

CONCLUSION
The aim of this study is to combine the use of an all-human BBB-glioma model with lab-on-a-chip technology to produce a high throughput model to test novel therapies at an earlier stage. The lab-on-a-chip model will be validated for the purpose of measuring permeability and drug response and to investigate the expression of novel targets verses expression in conventional models.
TARGETING RESIDUAL CANCER FROM THE INVASIVE MARGIN OF GLIOBLASTOMA USING COMPUTATIONAL TOOLKITS
Authors: Shah Ms Maria , Smith Dr Stuart , Bakker Dr Emyr , Rahman Dr Ruman 
Published: October 2024

Abstract

AIMS
Inﬁltrative margin GBM, as a proxy for residual disease post-surgery, can be identiﬁed by 5-aminolevulininc acid (5ALA) to facilitate the discovery of uniquely expressed or upregulated molecular pathways. Complementary bioinformatics approaches offer reproducible ways to enable interoperability of heterogenous data sources towards identiﬁcation of therapeutic targets associated with GBM inﬁltration.

METHOD
RNA-seq primary tumour data was ﬁrst categorised as: 5ALA+ (inﬁltrative margin) vs tumour core and 5ALA+ vs 5ALA- (reactive brain). Two levels of ﬁltration (genes with adjusted p-value &lt;0.05; degree of fold change with log2&gt;1.5) were applied to genes, creating two separate gene lists. Cross-referencing gene lists identiﬁed transcripts upregulated in both 5ALA+ vs core and 5ALA+ vs 5ALA-. This candidate gene list was inputted into STRING to generate an uncurated protein-protein interaction (PPI) network, which returned a signiﬁcant PPI enrichment p-value to conﬁrm network connectivity, and next inputted into Metascape to elucidate biological processes associated with tumour inﬁltration.

RESULTS
Of 141 upregulated 5ALA+ genes TCP10L3, HELT, MGAM, ALOX5 and FOXI1 exhibited the greatest fold change. The most prevalent 5ALA+ biological processes were primitive streak formation, disaccharide metabolic process and sodium ion transmembrane transport. LOC157273, LINC00200, LINC00656, LOC285626 and LINC01568 were identiﬁed as long non-coding RNAs (lncRNA) most abundant in the inﬁltrative margin of GBM relative to tumour core and reactive brain. Regulatory associations between candidate 5ALA+ lncRNA and genes, and in silico drug repurposing via molecular docking, are being investigated.

CONCLUSION
The plasticity of GBM warrants analysis of the GBM inﬁltrative margin via computational toolkits to enhance understanding of upregulated molecular pathways, functionally associated with an invasive phenotype.
AN EX-VIVO SPECTRAL AND LIFETIME-DECAY ANALYSIS OF 5-ALA DERIVED PPIX ﬂUORESCENCE: OBJECTIVE ﬂUORESCENCE MAPPING IN GLIOMA SURGERY
Authors: Elliot Mr Matthew , Segaud Dr Silvere , MacCormac Mr Oscar , Patel Ms Sabina , Reisz Dr Zita , Lavrador Mr Jose , Vergani Mr Francesco , Bhangoo Mr Ranjeev , Ashkan Prof Keyoumars , Al-Sarraj Prof Safa , Stasiuk Dr Graeme , Xie Dr Yijing , Vercauteren Prof Tom , Shapey Mr Jonathan 
Published: October 2024

Abstract

AIMS
5ALA/Protoporphyrin IX (PpIX) ﬂuorescence guided surgery (FGS) in high-grade glioma has been shown to increase resection and survival, despite this beneﬁts are limited in low-grade glioma by low emission and subjective interpretation. Quantitative ﬂuorescence could address these issues, however is challenging due to photobleaching and variations in tissue induced distortion and PpIX photochemical state that are poorly understood. Lifetime-decay measures intrinsic ﬂuorophore properties and is not inﬂuenced by these factors, but is diﬃcult to measure intra-operatively. We used paired optical and ﬂuorescence spectroscopy with lifetime decay mapping to characterise PpIX emission within the glioma tissue microenvironment.

METHOD
Biopsies were collected from 20 patients undergoing glioma FGS, along with 4 controls from partial temporal lobectomies. Paired measurements of emission and lifetime were matched with optical property readings. Lifetime and emission ratios at 635 and 620nm were calculated (PpIX635/620), corresponding to the primary emission peak for the photochemical states of PpIX in tissue. Raw and optically corrected emission was correlated with lifetime decay.

RESULTS
205 specimens were analysed by WHO grade (56 Grade4, 66 Grade3, 37 Grade2, 20 control). PpIX635/620 emission was 0.93 in control (CI 0.91-0.95), 1.03 in grade 2 tumours (CI 0.95-1.26), 1.56 in grade 3 (CI 1.22-1.91) and 6.99 (CI 5.78-8.20) in grade 4. PpIX635/620 lifetime correlated with emission (R2 =0.98, range 0.94-1.57). Correlation of emission with lifetime readings improved signiﬁcantly following optical correction at 635nm (raw R2 =0.81, corrected R2 =0.90) and 620nm (raw R2 =0.44, corrected R2 =0.86).

CONCLUSION
PpIX620 and PpIX635 photochemical states are present in human glioma, with an increase in PpIX635/620 suggesting increased WHO grade. The ability to distinguish these forms holds the potential to provide real-time data for tumour differentiation and pathology. Accurate characterisation and correction of tissue induced distortion signiﬁcantly improves the ability to detect, characterise and quantify PpIX intra-operatively.
PATTERNS OF RADIOTHERAPY PRACTICE FOR FUNCTIONING PITUITARY TUMOURS - A SURVEY OF UK CENTRES
Authors: Pilar Dr Avinash , Ronneberger Dr Ruth , Tyson Ms Charlotte , Baldeweg Prof Stephanie , Kosmin Dr Michael 
Published: October 2024

Abstract

AIMS
Pituitary adenomas are benign tumours that are classiﬁed as functioning or non-functioning based on the production of excess pituitary hormones. Functioning adenomas (FA) typically present as hypersecretory syndromes including acromegaly and Cushing’s disease. In FA, radiotherapy is used when surgery fails to achieve hormone normalisation and/or when medical treatment does not control hormone excess. In the absence of prospective studies that clearly deﬁne the optimal radiotherapy technique in FA, it is expected that there will be variability in practice. A survey of UK neuro-oncology centres was undertaken, aiming to establish the extent of this variability in FA.

METHOD
A survey was distributed electronically to 20 neuro-oncology departments across the UK. Data were collected on patient numbers, radiotherapy indications, techniques, dosing, and target volume delineation.

RESULTS
Responses were received from eight centres (40% response rate), treating a total of approximately 32 FA per annum. There was variability in techniques employed to treat FA. While four centres treated most FA with IMRT, two treat most with stereotactic radiosurgery (SRS), and two with fractionated stereotactic radiotherapy (fSRT). The most common dose used for IMRT treatment was 45Gy in 25 fractions (n=7), with 50.4Gy in 28 fractions, 50Gy in 30 fractions and 54Gy in 30 fractions also reported. Use of margins around residual disease (n=5) and inclusion of involved cavernous sinuses and surgical tract (n=3) within clinical target volumes also varied. Most centres (n=7) would agree to a change in target volume delineation practices for the purpose of a clinical trial in FA.

CONCLUSION
This survey found that there is variability in radiotherapy dosing, technique, and target volume delineation practices for radiotherapy to FA across the UK. All centres but one would accept changes in their practice within the context of a prospective clinical trial of radiotherapy for FA.
NEURONAL INJURY DRIVES GLIOBLASTOMA INITIATION
Authors: Baronik Mr Zan Florjanic , Clements Dr Melanie , Tang Dr Wenhao , Ragdale Dr Holly Simpson , Lindsay Ms Rachel , Marguerat Dr Sam , Hill Mr Ciaran , Parrinello Prof Simona 
Published: October 2024

Abstract

AIMS
Glioblastoma (GBM), the most common primary brain malignancy in adults, remains incurable. Pervasive heterogeneity and plasticity underpin therapy resistance and lethal recurrence, suggesting that prevention or earlier intervention may be required. Improved understanding of GBM initiation is a prerequisite for achieving this goal. GBM frequently originates from neural stem cells (NSCs) of the subventricular zone, which, upon acquisition of mutations, migrate away from their niche and form tumours at distal sites through unknown mechanisms. Here, we explored GBM initiation and its microenvironment.

METHOD
We combined a murine somatic GBM model which faithfully recapitulates the human disease with PDX models and patient tissue datasets. We used immunohistochemistry, scRNA-sequencing, immuno-phenotyping, behavioural and survival studies and in vivo gain- and loss-of-function experiments in Sarm1-/- lines.

RESULTS
Time-course analysis of tumour development identiﬁed neuronal degeneration as an early event in GBM tumourigenesis, occurring preferentially in white matter, where we ﬁnd mutated NSCs are immediately rerouted. Axonal loss was accompanied by a robust inﬂammatory response, marked by microglial and astrocytic activation. Neuronal degeneration played a causative role, in that transection injury of corpus callosum axons accelerated tumourigenesis and, conversely, GBM development was delayed in Sarm1-/- mice with impaired Wallerian degeneration, a major mode of neuronal death following injury. Consistently, terminal Sarm1-/- tumours were more diffuse, contained more immature tumour cells and were less immune-inﬁltrated than their WT counterparts. Strikingly, behavioural studies revealed that Sarm1-/- tumour-bearing mice also retained improved motor performance compared to WT mice, even at terminal disease stages.

CONCLUSION
Our work provides important insights into GBM development, identifying white matter injury as a key initiating event, elicited by early tumour cells and orchestrated by neuronal degeneration. It identiﬁes Wallerian degeneration, a druggable pathway already in clinical trials for neurodegenerative diseases, as a therapeutic target for GBM, with the potential to extend survival and ameliorate cognition.
PROLONGED SURVIVAL IN IDH-WILDTYPE GLIOBLASTOMA: CASE REPORTS, LITERATURE REVIEW AND CURRENT PERSPECTIVES OF MOLECULAR BEHAVIOR
Authors: Batista Mr Ruben , Hajra Mr Debasish , Nazar Mr Thaaqib , Dardis Mr Ronan , Mukherjee Mr Soumya 
Published: October 2024

Abstract

AIMS
Glioblastoma remains one of the most aggressive primary brain tumours, with a median survival of around 12 months despite advances in treatment. However, rare cases of long-term survival challenge this prognosis. The evaluation of age, tumour location, surgical approach and strategies, adjuvant therapy, and molecular behavior provides valuable prognostic and predictive information in patients with glioblastoma.

METHOD
We present a case report of two patients diagnosed with wild-type glioblastoma who have survived over 10 years post-primary surgery. A review of epidemiological data, preoperative and postoperative radiological reports, surgical approach, and histology reports were studied. Additionally, we review the current literature to explore current nuances in High-Grade Glioma Wild Type prognosis and potential future directions. Three major medical database engines, PubMed (Medline), Scopus (ELSEVIER), and Cochrane were used to conduct a thorough literature search.

RESULTS
Both patients underwent maximal safe resection followed by the Stupp Protocol, comprising adjuvant chemotherapy with temozolomide and radiotherapy. Our case report highlights two exceptional cases of prolonged survival in Glioblastoma patients, both under 51 years-old at the moment of diagnosis, early diagnosis with isolated lobar lesions, no compromise of deep white matter, and achieving maximal safe resection and functional independence. Molecular analysis revealed speciﬁc genetic in common, including IDH Wild Type, p53 mutation, retained ATRX expression, TERT mutation, and MGMT promoter methylation, consistent with a favourable prognosis. Moreover, patients without recurrence often exhibit distinct molecular proﬁles, such as MGMT promoter methylation, suggesting a potential subtype associated with prolonged survival.

CONCLUSION
Our case reports and literature review highlight the possibility of prolonged survival in Glioblastoma patients. The age, tumor location at the time of diagnosis, comprehensive treatment approaches, may contribute to improved outcomes. Molecular proﬁling, particularly assessing genetic mutations and MGMT promoter methylation, holds promise for identifying patients with a higher likelihood of prolonged survival.
ABNORMAL CORTICAL EXCITABILITY IS ASSOCIATED WITH DECREASED OVERALL SURVIVAL IN PATIENTS WITH GLIOBLASTOMA
Authors: Lavrador Mr Jose , Pescador Ms Ana Mirallave , Patel Ms Sabina , Banna Dr Qusai Al , Rajwani Mr Kapil , Marchi Mr Francesco , Elhag Mr Ali , Baamonde Mr Alba Diaz , Mosquera Mr Jose , Ashkan Prof Keyoumars , Bhangoo Mr Ranjeev , Vergani Mr Francesco 
Published: October 2024

Abstract

AIMS
Navigated transcranial magnetic stimulation (nTMS) is a well-established technique for motor cortex mapping and assessing motor tract integrity in patients with brain tumours. Pre-surgical nTMS mapping in patients with glioma has shown an altered interhemispheric excitability that correlates well with WHO grade. The aim of this study is to correlate the preoperative nTMS ﬁndings with overall survival (OS) in patients with motor-eloquent brain tumours operated at our institution.

METHOD
We conducted a retrospective cohort study using electronic patient records to search for all patients with a motor-eloquent brain tumour resected between 2017 and 2023. We included all adult patients (&gt;18 years) with pre-operative nTMS mapping and a tissue diagnosis. Two nTMS measures of cortical excitability were assessed; cortical excitability score (CES) and the intraM1 excitability score (IMES). Our outcome measure was OS.

RESULTS
160 patients fulﬁlled the inclusion criteria (mean age 48.34 years). The commonest tumour histology was glioblastoma (n=51; 32%). Among patients with diffuse gliomas, IDH was mutated in 59% patients and MGMT was methylated in 61%. Majority of patients (62.5%) underwent gross total resection. Resting motor thresholds (RMTs) for both upper and lower limbs between the tumour and healthy side were not signiﬁcantly different. Interhemispheric RMT ratio in the upper limbs was abnormal in 60.93% patients and in the LLs was abnormal in 57.14%. A higher CES was related to lower overall survival (p=0.04). A subgroup analysis showed this was particularly the case among patients with a diagnosis of Glioblastoma (p=0.015). When adjusted for cofounding factors EOR, MGMT methylation and age, both CES and IMES were inversely related to OS (p=0.002).

CONCLUSION
A higher CES and IMES is related with poor overall survival in patients with Glioblastoma even when other cofounding factors affecting OS are considered. This information can be used when counselling patients and planning surgical approach to motor-eloquent tumours.