bluuebunny/crossref_metadata_2025_split huggingface dataset:
EXTRACELLULAR VESICLES TRANSFER RESISTANCE TO VINCRISTINE IN SONIC HEDGEHOG MEDULLOBLASTOMA
Authors: Wade Philippa , Hume Alistair , Kerr Ian , Coyle Beth 
Published: September 2023

Abstract

AIMS
• To determine the expression patterns of specific ATP-binding cassette (ABC) transporters in medulloblastoma
• To assess whether ABC transporters play a role in acquired drug resistance in SHH medulloblastoma using drug-tolerant cell line models
• To assess whether extracellular vesicles transfer drug-tolerance in SHH medulloblastoma and determine the mechanism by which they do this

METHOD
Drug-tolerant cell lines were generated by continuous culture in drug-containing culture medium. ABC trans- porter gene and protein expression was assessed via qPCR and western blot. EVs were isolated from EV-depleted medium using size-exclusion chromatography. Nanoparticle tracking analysis was used to quantify and deter- mine size. Cytotoxicity analysis was used to determine EV-mediated transfer of resistance in the presence or absence of an ABC transporter inhibitor. RNA sequencing of EVs from matched vehicle and drug tolerant cell lines was carried out.

RESULTS
Analysis of drug-tolerant cell lines revealed significant increases in specific drug transporter gene expression across medulloblastoma subgroups. ABCB1 protein expression was significantly higher in drug-tolerant sonic- hedgehog (SHH) lines and inhibition of ABCB1 in a drug-tolerant SHH line abolished acquired resistance to vincristine. Cytotoxicity assays on sensitive cells, after pre-treatment with drug-tolerant EVs, showed a significant increase in vincristine resistance, implicating EVs in the transfer of resistance.

CONCLUSIONS
Data to date supports the hypothesis that multidrug transporter carrying extracellular vesicles may transfer their multidrug resistant phenotype to surrounding cells in medulloblastoma. We are currently testing this using inhibitors and knockout lines, in addition to RNA sequencing, with the hopes of providing new therapeutic targets to patients with medulloblastoma.
TESSA JOWELL BRAIN MATRIX PLATFORM STUDY: PRELIMINARY ANALYSIS OF THE PRIMARY FEASIBILITY & PROCESS-CENTRED OBJECTIVE
Authors: Watts Colin , Patel Amit , Savage Joshua , Ansorge Olaf , Wykes Victoria , Wallis Yvonne , Sharpe Rowena , Mant Rhys , Brooks Hannah , Short Susan , Ashkan Keyoumars , Brennan Paul , Chalmers Anthony , Smith Stuart , Jenkinson Michael , McBain Catherine , Waldman Adam , Thompson Gerard , Billingham Lucinda 
Published: September 2023

Abstract

AIMS
The Tessa Jowell BRAIN MATRIX (ISRCTN14218060) is an ongoing platform study, collecting disease, treatment, and outcome data prospectively in glioma patients, across nine UK hospitals. We report a preliminary analysis of the primary feasibility and process-centred objectives.

METHOD
Primary Objective: Test the feasibility of establishing an integrated histological-molecular diagnosis using Whole Genome Sequencing (WGS) and Epigenomic Classification (EC) (‘Heidelberg Classifier’) data in NHS practice within 28 days.
Primary Outcome: Time (from surgery) to integrated histological–molecular diagnosis (TTMD) using WGS and EC.
Secondary Outcome: Time to completion of each node (stage) of the tissue and imaging pathway.

RESULTS
Data snapshot on 23-Feb-2023 confirmed 250 patients recruited. Nine nodes along the tissue & imaging pathway were defined. Twenty-one patients had completed the pathway and time to each node was calculated. Median time to complete the pathway was 404 days (range 124-653). There was a trend of improvement in TTMD in recently recruited patients.

CONCLUSIONS
The patient pathway from surgery to clinical feedback through a Genomic Tumour Advisory Board (GTAB) utilises NHS-accredited pathways and protocols. Delays inherent in the pathway emphasise the urgent need for infrastructure and operational delivery improvements of the NHS Genomic Medicine Service for brain cancer patients as the current timeframe is not clinically relevant for informing patient care. These data also highlight geographical inequality in accessing genomic medicine within England, across the seven Genomic Laboratory Hubs, and the devolved nations. Detailed analysis of the delays at each node will identify opportunities and solutions to inform discussions with the NHS and Genomics England.
DIAGNOSTIC ACCURACY AND PROCESS EVALUATION WITH HEALTH ECONOMICS ANALYSIS OF AN ULTRA-FAST DIGITAL CONFOCAL MICROSCOPY SCANNER FOR REAL-TIME INTRA-OPERATIVE BRAIN TUMOUR DIAGNOSIS
Authors: Bolton William , Ramakrishnan Piravin , Reveendran Dharsshini , Crispi Vassili , Adebola Oluwaseyi , Sinha Rohit , Digby Richard , Chakrabarty Aruna , Mathew Ryan 
Published: September 2023

Abstract

AIMS
Real-time intra-operative brain tumour tissue analysis in theatre can shorten turnaround times and facilitate repeated sampling; the latter can improve diagnostic accuracy and guide resection to maximise extent. We were the first team in the world to demonstrate the feasibility of an ultra-fast confocal microscopy scanner (Histolog®, SamanTree Medical SA) for real-time intra-operative brain tumour tissue diagnosis. The aim of this study is to demonstrate the diagnostic accuracy of Histolog® within a larger cohort of patients with brain tumours.

METHOD
An observational study with varying brain tumour types was conducted in a Tessa Jowell Brain Tumour Centre of Excellence. Adult patients undergoing brain biopsies or tumour debulking surgery were included. Multiple, freshly excised tissue samples were stained, and images captured within 60 seconds on Histolog® in the OR in parallel to current diagnostic pathways which included frozen section and smear cytology. Quantitative blinded concordance analysis between Histolog® images and gold standard histopathology was performed by a Consultant Neuropathologist.

RESULTS
A total of 50 cases are included in this analysis. This will include the quantitative analysis of n=50 cases and the concordance rating between Histolog® and gold standard traditional (frozen section and smear cytology) intra- operative histopathological diagnosis. The pilot data (n=12) that led to this larger study indicated a concordance rate of 83%.

CONCLUSIONS
Histolog® demonstrates non-inferior diagnostic accuracy when compared to current gold standard but significantly reduces the intra-operative time to achieve diagnosis. Future studies will investigate the effect of real- time margin zone analysis and explore machine learning for automatic computer aided diagnosis.
NON-CELL AUTONOMOUS INDUCTION OF A CANCER STEM CELL MOLECULAR PHENOTYPE IN AN IN VITRO MODEL OF SONIC HEDGEHOG MEDULLOBLASTOMA
Authors: van Essen Max , Cowley Sally , Becker Esther , Schuster-Böckler Benjamin , Jacob John 
Published: September 2023

Abstract

AIMS
• Design a novel in vitro model of sonic hedgehog (SHH) medulloblastoma (SHH-MB) by co-culture of two distinct human SHH-MB cell lines with wild-type cerebellar organoids derived from human induced pluripotent stem cells.
• Investigate how the phenotype of SHH-MB cells grown in co-culture differs from conventional monolayer or tumour spheroid cultures.

METHOD
DAOY and ONS76 cell lines were cultured as monolayers, tumour spheroids or co-cultured with wild type cerebellar organoids for twenty-five days. Cells were then processed for single cell RNA-seq yielding thousands of sequenced transcriptomes, which were analysed using the R package, Seurat and other software.

RESULTS
Tumour cells in co-culture could be distinguished from non-malignant cells by their distinct transcriptional profiles. Subpopulations of both cancer cell lines in co-culture upregulated neuronal differentiation genes. In co-culture only, a distinct subset of DAOY cells expressed multiple cancer stem cell markers including SOX2, OTX2, GLI2 and NES. The upregulation of SOX2 by these cells correlated with the co-expression of ERBB4, which encodes a tyrosine kinase receptor.

CONCLUSIONS
SHH-MB cells exhibited striking differences in their phenotype when grown under physiological conditions in co-culture. First, subpopulations of both types of cancer cells expressed a neuronal differentiation programme. Second, a cancer stem cell phenotype is revealed in TP53 mutant tumour cells that is centred on SOX2. Signalling by ERBB4 is a candidate in the upregulation of SOX2 in these cells and has previously been implicated in the pathogenesis of Group 4 medulloblastoma. Future experiments will test whether SOX2 and ERBB4 are co-expressed in patient tumour cells.
GENOMIC LANDSCAPE AND ACTIONABLE MUTATIONS OF BRAIN METASTASES IN NON-SMALL CELL LUNG CANCER: A SYSTEMATIC REVIEW
Authors: Andrews Lily , Thornton Zak , Saleh Ruqiya , Dawson Sarah , Daly Richard , Higgins Julian , Davies Philippa , Kurian Kathreena 
Published: September 2023

Abstract

AIMS
Lung cancer causes the most deaths worldwide due to cancer. Non-small cell lung cancer (NSCLC) represents the largest subgroup (80-90%), with most patients presenting at an advanced stage of disease. Brain metastases (BM) develop in about 27% of these cases, leading to a poor survival outcome. Previous literature has suggested that BM derived from NSCLC have a different genomic profile compared to the primary NSCLC. We aim to review the literature to discover the genomic landscape of BM derived from NSCLC.

METHOD
Embase, MEDLINE, Web of Science, and BIOSIS were searched, and any records found were assessed for eligibility. For the included papers, patient information, smoking status, genomic data, matched primary NSCLC, and PD-L1 expression was extracted.

RESULTS
72 papers were included in the review, with data on 2,340 patients. The most mutated genes were EGFR (n=560), TP53 (n=331), KRAS (n=328), CDKN2A (n=97), STK11 (n=72). Frequently mutated missense mutations included L858R (n=80) in EGFR and G12C (n=17) in KRAS. Ever versus never smokers were found to have differing mis- sense mutations in TP53 and EGFR, with the expectation of L858R and T790M. BM were suggested to have a different genomic landscape compared to the primary NSCLC. PD-L1 expression was found to be low in BM derived from NSCLC.

CONCLUSIONS
To our knowledge, this is the first systematic review which assessed the genomic landscape of BM derived from NSCLC. This review highlights the most mutated genes, missense mutations, and their clinical actionability. Differing genomic profiles were suggested in primary compared to BM and smoking status.
TUMOUR TREATING FIELDS WITH DDR INHIBITORS EFFECTIVELY LEADS TO CHEMO-/RADIO-SENSITISATION OF GLIOMAS
Authors: Jones Callum , Vanderlinden Aurelie , Myers Katie , McGarrity-Cottrell Connor , Rominiyi Ola , Collis Spencer 
Published: September 2023

Abstract

AIMS
High grade gliomas are the most common CNS malignancies and cause ~200,000 deaths/year globally. Glioblastoma (WHO grade IV) confer the worst prognoses with their treatment being hindered by glioma stem cell-like (GSC) tumour sub-regions and high intratumoural spatio-heterogeneity. Tumour Treating Fields (TTFields) exert clinically approved alternating electric fields of intermediate frequency which induces anti-mitotic effects within concomitant deleterious effects on cellular responses to DNA damage (DDR). Therefore, treatment resistance could be overcome with TTFields with clinically developed DDR inhibitors (DDRi) to cause chemo-/radio- sensitisation.

METHOD
Surgically resected samples derived from the tumour core and invasive edge were processed to create GSC cell lines, offering highly clinically relevant models. These were grown in either 2D or in 3D-printed AlvetexTM scaffolds, treated with DDRi, subjected to chemo-/radio-therapy and then placed under TTFields (200 kHz, 48- 72 hrs). Survival was measured by clonogenic assays after 3 weeks. Immunofluorescence and western blot analysis were used to analyse the combination treatment effects on the DDR.

RESULTS
TTFields with DDRi led to significant chemo/radio-sensitisation in both 2D and 3D intratumoral core/edge GSC models. Western blot and immunofluorescence analyses revealed that DNA damage was heightened by the combination treatments with lesion resolution being impaired.

CONCLUSIONS
DDRi with concurrent TTFields effectively leads to significant chemo-/radio-sensitisation in clinically relevant 3D GSCs which model spatio-heterogeneity which is thought to impede treatment effcacy. Given that all the DDRi used are BBB penetrable and are either clinically approved or in clinical trials, TTFields could additionally compliment these treatment regimens in gliomas to boost their effcacy.
PSYCHOLOGY EDUCATION WORKSHOPS ARE AN INNOVATIVE METHOD OF OFFERING PSYCHOLOGICAL INPUT TO A WIDER POPULATION
Authors: Hurwitz Victoria , Groves Mark , Butler Carly , Kostick Ellie , La Jessica , Hedges Sarah , Delacroix Louise , Suarez Aeron , Robinson Charlotte , Chia Kazumi , Brazil Lucy , Al-Salihi Omar , Swampillai Angela 
Published: September 2023

Abstract

AIMS
People diagnosed with brain tumours are well recognised as needing psychological support. Service provision is limited and can be diffcult to gain engagement. Providing psychology education workshops aims to be inclusive, bring patients and loved ones together and offer an opportunity for peer support.

METHOD
Patients who had finished or were coming to the end of their current treatment were invited to attend a psychology education workshop. Their loved ones were also invited to attend via the patient’s invitation letter. A clinic code was set up to enable us to monitor who was invited, who attended and importantly who did not. This also aimed to integrate the workshop into standard of care on completion of treatment. Feedback was obtained from attendees at the end of the workshop verbally as well as offering the opportunity to give anonymous written feedback.

RESULTS
On average a third of people invited attended each group. Half of these attended with one or more loved ones. 100% of attendees found the workshop helpful. Feedback included “Useful to realise that my emotions are similar to his” – Carer and “Having the shared experience of being here with (loved one) has started to open things up for us as a family” – Family member.

CONCLUSIONS
Patients and carers valued the workshop. This format offered a more accessible introduction to psychology. The workshop was enough to provide some patients and carers with strategies to look after their psychological well-being and served as a method of identifying those with greater need.
RADIOGENOMIC DATASETS IN GLIOBLASTOMA: AN ESSENTIAL HURDLE
Authors: Ghimire Prajwal , Karami Golestan , Modat Marc , Booth Thomas 
Published: September 2023

Abstract

AIMS
To evaluate current available datasets for radiogenomic analysis in glioblastoma

METHOD
A scoping review was performed in the literature from 2000-2023. List of datasets (open access, controlled, paid) available in the literature were tabulated. Qualitative analysis was performed.

RESULTS
Multiple datasets and data portals were available. Clinical data was available on all portals. MRI and Radiomics datasets were available on The Cancer Imaging Archive(TCIA). Genomics datasets were available in Genomics England (DNA sequencing reads and variants), The Cancer Genome atlas(TCGA) data portal, Chinese cancer genome atlas (CCGA) data portal and The Georgetown Database of Cancer (G-DOC) (sequencing reads, Tran- scriptome profiling, simple nucleotide variation, copy number variation, DNA methylation). Raw datasets were controlled with permission-only access whereas rest were available for access and download on registration. Datasets were available in UK Biobank with a fee.

CONCLUSIONS
Non-uniformity in datasets is a huge hurdle in pre-processing of the datasets and analysis. Collaborative data portals with user friendly interface are likely to provide uniformity and resolve biases as a part of the hurdle in analysis of these datasets.
OUTCOMES OF STEREOTACTIC RADIOSURGERY/RADIOTHERAPY (SRST) IN MALIGNANT MELANOMA WITH CRANIAL METASTASES - THE WESSEX EXPERIENCE
Authors: Ah-Chuen Jonathan , Johnson Emma , Conibear Isobel , Carr Ruth , Simpson Eleni , Sinclair Georges , Clarke Enrico , Ching Jeng 
Published: September 2023

Abstract

AIMS
To assess overall survival in malignant melanoma with cranial metastases following stereotactic radio- surgery/radiotherapy (SRST).

METHOD
Patients with metastatic melanoma who received SRST for their cranial metastases at the Wessex Neuro- Oncology Unit were evaluated between January 2017 and January 2023. Subtype analysis based on BRAF mutation was also performed. Their overall survival (OS) was plotted using Kaplan-Meier graph.

RESULTS
121 patients were identified. The mean age at referral was 62 years (range 30-90). 50 patients had a BRAF mutation while 71 were BRAF wild type. This is a heterogenous cohort of patients, ranging from cranial-only disease to widespread disease, receiving one to two lines of systemic treatment. The median OS in patients with malignant melanoma with cranial metastases following SRST is 15 months (similar in both BRAF mutant and BRAF wildtype subgroups). The 3-year survival rate is 22.8% (BRAF mutant – 27.3%, BRAF wildtype - 20.3%). There is a small group of patients (28%) that died within six months of SRST.

CONCLUSIONS
Limitations were the small number of patients, short follow up period and heterogeneity in terms of systemic therapy. Our experience reveals in malignant melanoma, the median OS is 15 months after SRST to their cranial metastases. We found that BRAF mutation is non-discriminatory when predicting response to SRST and not the sole factor in predicting OS. A small cohort did not benefit from SRST as they survived for 6 months or less. Further analysis of this subgroup is needed to improve patient selection and treatment personalisation.
PREDICTING GLIOBLASTOMA GENE EXPRESSION THERAPY RESPONSE WITH MACHINE LEARNING
Authors: Thomas Morgan , Theophanous Stelios , Whittle Isabelle , Finetti Martina , Pollock Steven , Ahmed Nazia , Tanner Georgette , Chakrabarty Aruna , Ismail Azzam , Bulpitt Andrew , Stead Lucy 
Published: September 2023

Abstract

AIMS
The rapid recurrence of therapy-resistant glioblastoma leaves patients with a dismal 2-year survival rate of just 16%, highlighting the need to develop treatments that combat or prevent glioblastoma recurrence. Recently, glioblastoma patients have been stratified by their gene expression response to therapy. Specifically, genes with JARID2 binding sites in their promoter (JBS-genes) either become up- or down-regulated on progression from the primary to the recurrent tumour. Importantly, these two responses appear to employ different mechanisms of therapy resistance. Using gene expression data from primary tumours, we aim to predict the direction of JBS- gene dysregulation. Ultimately, this prediction could guide treatment decisions that prevent the acquisition of therapy resistance in glioblastoma.

METHOD
We used gene expression data from 84 primary glioblastoma tumours that had been labelled as either ‘Up’ or ‘Down’ responders based on the direction of JBS-gene dysregulation in matched recurrent tumours. We converted the RNA-sequencing data from the primary tumours to single-sample pathway scores, which were used to train several binary classification machine learning models.

RESULTS
A ridge regression model achieved an accuracy of 73.9% in predicting the direction of JBS-gene dysregulation in an independent set of 23 primary glioblastoma tumours.

CONCLUSIONS
Our classifier performs better than random chance demonstrating that gene expression data is informative and molecular features influence this gene expression response to therapy. However, there remains scope for improvement. This suggests further studies may benefit from integrating multiple data types such as genomics, epigenomics, tumour architecture, or clinical variables.
GLIOBLASTOMA CELL INVASION IS TARGETABLE BY COMBINATION TREATMENT WITH MIGRASTATIC INHIBITORS
Authors: Prior Sally , Senior Jessica , Jaworska Kayley , Burns Eryn , Ahmed Zara , Butler Hayley , Brüning-Richardson Anke 
Published: September 2023

Abstract

AIMS
One of the hallmarks of cancer is cell migration and invasion, a striking feature of glioblastoma (GBM). The highly migratory potential of tumour cells enables recurrence of GBM tumours leading to poor survival and patient death. We recently characterised a panel of migrastatic inhibitors and reported on the ability of glioma cells to overcome drug activity by employing a mesenchymal to amoeboid migratory switch. Here we demonstrate that targeting different signalling pathways involved in cell migration induces synergistic drug activity of single inhibitors.

METHOD
The previously described inhibitors CCG-1423 and Rhosin Hydrochloride were used singly or in combination to target cell migration in established glioma cell lines. Characterisation of drug activity was achieved by 2D and 3D migration and invasion assays and cytoskeletal and morphological changes were assessed by immunofluorescence assays.

RESULTS
When used in single applications, the inhibitors did not have a significant effect on cell migration in 2D and 3D. However, combination treatments led to significantly reduced migration in both 2D and 3D with notable effects on the cytoskeleton as evidenced by changes in focal adhesion dynamics and in actin localisation. Cellular features also changed in response to combination treatment as noted by increase in cell size and adhesion to neighbouring cells.

CONCLUSIONS
The observed effects are in keeping with targeting two distinct signalling pathways driving cells to either adopt amoeboid or mesenchymal cell migration/invasion mechanisms. We propose that a ‘cocktail’ of migrastatic inhibitors should be included in future experimental designs for consideration as novel, complementary treatment strategies in GBM.
TUMOUR TREATING FIELDS (TTFIELDS) THERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA: A META-ANALYSIS AND SYSTEMATIC REVIEW OF REAL-WORLD SURVIVAL DATA
Authors: Ballo Matthew , Conlon Patrick , Lavy-Shahaf Gitit , Urman Noa , Kinzel Adrian , Vyamzal Josef , Rulseh Aaron 
Published: September 2023

Abstract

AIMS
Tumour Treating Fields (TTFields) are electric fields that disrupt processes required for cancer cell viability and tumour progression. TTFields therapy gained FDA approval and CE accreditation for newly diagnosed glioblastoma (ndGBM) following the EF-14 study (NCT00916409). We aimed to determine the real-world survival benefit of TTFields therapy.

METHOD
Survival data from clinical studies in TTFields therapy-treated patients with ndGBM were identified using a literature search and analysed. The Cochran Q test and Higgins I2 statistic were used to assess and quantify inter-study heterogeneity. Survival curves were pooled using a distribution-free random-effects method.

RESULTS
Among studies evaluating the clinical effcacy of TTFields therapy in ndGBM, six studies were identified which compared the addition of TTFields therapy to standard of care (SOC) vs SOC alone. The meta-analysis showed a significant improvement in OS for TTFields therapy-treated patients vs SOC alone (P &lt; 0.001). The pooled effect was robust and independent of any individual study. In post-approval studies, the pooled median OS was 22.2 months (95% CI, 17.3–42.6) and 17.3 months (95% CI, 13.6–22.0) for TTFields therapy-treated patients and SOC, respectively. Rates of gross total resection were generally higher in the real-world setting, irrespective of TTFields therapy use. Average device usage of ≥75% was associated with prolonged survival vs &lt;75% usage (pooled HR: 0.63; 95% CI, 0.48–0.83; P = 0.001).

CONCLUSIONS
Data suggest a significant survival benefit when TTFields therapy is added to SOC for patients with ndGBM. Usage of ≥75% may be meaningful in the real-world setting.