bluuebunny/crossref_metadata_2025_split huggingface dataset:
LONG-TERM POST-MARKETING SURVEILLANCE DATA FROM ELDERLY PATIENTS WITH CENTRAL NERVOUS SYSTEM MALIGNANCIES TREATED WITH TUMOR TREATING FIELDS (TTFIELDS) THERAPY
Authors: Mrugala Maciej M , Shi Wenyin , Iwamoto Fabio M , Heidemann Martina , Lukas Rimas V , Palmer Joshua D , Suh John H , Glas Martin 
Published: September 2023

Abstract

AIMS
Glioblastoma (GBM) has a poor prognosis, which is compounded by an increase in treatment-related toxicity with age. TTFields are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability. Subgroup analysis of the phase 3 EF-14 study demonstrated TTFields therapy to be well-tolerated in patients ≥65 years with newly diagnosed (nd) GBM. We report safety data in elderly patients from a global post- marketing surveillance (PMS) analysis of patients with central nervous system (CNS) malignancies receiving TTFields.

METHOD
PMS data was collected from patients receiving TTFields (October 2011–March 2022) in North America, Europe, Middle East, Africa, and Japan. Adverse events (AEs) were categorized using MedDRA version 25.1.

RESULTS
Overall, 25,898 patients were included (diagnoses: ndGBM [68%], recurrent GBM [26%], anaplastic astrocytoma/oligodendroglioma [4%], other [2%]). Of these, 7808 patients (30%) were elderly (&gt;65 years). 75% of elderly patients experienced ≥1 AE, with 57% related to TTFields; comparable frequencies to the overall population (73% and 56%, respectively). The most common treatment-related AE in elderly patients was skin reaction (45%; overall population: 43%). Incidence of treatment-related fall and fracture in elderly patients was 1% and &lt;1%, respectively. Incidence of treatment-related ‘quality-of-life decreased’ was 2% (elderly and overall). No systemic toxicities were reported, regardless of age group.

CONCLUSIONS
These real-world data demonstrate TTFields has a tolerable safety profile in elderly patients with CNS malignancies, consistent with elderly subgroup data from EF-14, and with no new safety signals. Most AEs were localised, manageable, mild–moderate skin reactions.
PATTERNS OF INfiLTRATION AND RELAPSE OF GLIOBLASTOMA INVOLVING THE ANTERIOR TEMPORAL LOBE: IMPLICATIONS FOR RADIATION THERAPY TARGET VOLUME DELINEATION
Authors: Back Michael , Horsley Patrick , Yim Jackie , Drummond James 
Published: September 2023

Abstract

AIMS
To characterise specific patterns of infiltration and recurrence for IDH-wildtype Glioblastoma (GBMwt) involving the anterior temporal lobe (ATL)

METHOD
Patients managed for GBMwt involving ATL between 1/2008-12/2020 were identified. Tumour was segmentated on T1-gadolinium-enhanced(T1gd) and T2-weighted(T2) sequences at baseline and initial relapse.
Involvement of adjacent normal structures was assessed: superior temporal gyrus (STG), middle temporal gyrus (MTG), medial occipito-temporal gyrus (MOTG), amygdala, and uncus. Abnormalities in para- hippocampal region (PHG) and sub-insular regions were recorded; as well as distant sites of insular cortex, extreme/external/internal capsule, and frontal lobe.
Two major neural pathways were also assessed: the uncinate fasciculus-inferior fronto-occipital fasciculus (UF- IFOF) and hippocampal formation (HP-PHG).

RESULTS
Of 562 patients 53 involved ATL with 47 included for analysis. Median volume at diagnosis on T1gd and T2 was 36cm3(IQR 12-54) and 51cm3(IQR 23-73) respectively.
Adjacent sites involved on T1gd were STG/MTG (87%), amygdala (45%), uncus (8%), MOTG (4%). T2 abnormality extended into insular region in 91%, and hippocampal region in 17% patients. The temporal horn was involved in 21% and compressed/displaced in 63% of patients.
Forty patients relapsed with relapse-free survival of 11.4 months. Thirty-five (87%) had T1gd relapse involving a neural pathway: UF-IFOF (74%), HP-PHG (14%), combined (9%), optic tract (3%). Twenty relapses (50%) involved distant sites in external capsule or frontal lobe.
Although adjacent to ATL, no relapse occurred posterior to temporal horn or along HP-PHG unless evidence of T2 abnormality was present at diagnosis. All 8 relapses involving the HP-PHG, and none of 26 relapses involving UF-IFOF alone, had T2 involvement of HP-PHG at diagnosis.

CONCLUSIONS
Infiltration and relapse of GBMwt involving ATL correlates with distinct neural pathways.
MULTI-OMICS MENDELIAN RANDOMISATION USING EXPRESSION, PROTEIN AND SPLICING QUANTITATIVE TRAIT LOCI: IDENTIfiCATION OF NOVEL DRUG TARGETS ASSOCIATED WITH RISK OF GLIOMAGENESIS
Authors: Thornton Zak , Andrews Lily , Zhao Huiling , Zheng Chris , Paternoster Lavinia , Robinson Jamie , Kurian Kathreena 
Published: September 2023

Abstract

AIMS
Genetic variants associated with molecular traits are also associated with liability to glioma. We sought to pro- vide causal evidence for the prioritization of these traits using triangulation of several causal inference approaches.

METHOD
We performed two-sample Mendelian randomization and genetic colocalization of molecular traits on glioma. Molecular data were taken from studies of expression quantitative trait loci (QTL) [11,803 genes]; protein QTL [7,376 proteins] and splicing QTL [13,285 genes]) derived from 15 brain tissues. Glioma data were taken from a genome-wide association meta-analysis (12,496 cases and 18,190 controls).

RESULTS
The MR analysis showed evidence for a causal effect of 25 molecular traits on glioma. Of these, 19 (all gene expression) were robust according to colocalization and Steiger filtering. 18/19 (95%) of these genes were previously implicated in genome-wide and transcriptome-wide association studies with glioma risk. We identified one novel locus with causal evidence in cortex tissue: HBEGF (5q31.3). HBEGF expression has been found to be significantly increased in many human cancer types, including glioma. We found genetically predicted in- creased expression of HBEGF associated with an increased risk of all glioma [OR 1.53 (95%CI 1.28 to 1.82); P =2.66 x 10-6] and the glioblastoma subtype [OR 1.68 (95%CI 1.35 to 2.08); P = 2.97 x 10-6].

CONCLUSIONS
We provide robust causal evidence as validation for genes previously implicated with glioma risk in genome- wide association studies. Additionally, we show for the first-time evidence for a causal relationship between HBEGF expression and glioma risk.
SPATIAL TRANSCRIPTOMICS REVEALS TRANSLATIONAL AND INflAMMATORY CHANGES UPON ARGININE DEPRIVATION IN GLIOBLASTOMA
Authors: Symington Jake , Huang Huan , Thorne Tom , O’Neill Kevin , Want Elizabeth , Syed Nelofer 
Published: September 2023

Abstract

AIMS
Glioblastoma is a primary brain malignancy with poor prognosis. The immunosuppressive microenvironment, molecular heterogeneity and the blood-brain barrier makes this tumour diffcult to treat. Targeted and immune therapies have shown limited success, highlighting the need for novel therapies. We previously demonstrated the effectiveness of arginine deprivation using ADI-PEG20 when combined with radiation. The aim of this study was to investigate transcriptomic changes initiated by ADI-PEG20 to potentiate the effects of radiation.

METHOD
To investigate this hypothesis, the CT2A syngeneic mouse model was used. To systemically deplete arginine, mice with brain tumours were treated with 5IU of ADI-PEG20 subcutaneously. Brains were harvested 6 days after treatment with ADI-PEG20 and analyzed by 10x Genomics Spatial Transcriptomics to investigate changes in the transcriptome. PartekFlow, GOFigure, PathfindR and EnrichR were used for bioinformatic analysis.

RESULTS
Arginine deprivation downregulated genes encoding ribosomal subunits. Gene Ontology and KEGG pathway analysis indicated an overall decrease in genes involved in transcription, translation and ribosomal biogenesis which were targets for the Myc transcription factor. Arginine Deprivation upregulated pro-inflammatory genes, including genes under the influence of IFN-y (GBPs and ISGs), indicating involvement of the STAT1 and NFkB transcription factors upon ADI-PEG20 administration.

CONCLUSIONS
Arginine deprivation reduced overall protein synthesis, conserving energy to favour translation and transcription of components of the pro-inflammatory immune response. Our study provides some insights into the mechanisms of action of ADI-PEG20 in enhancing the effects of standard of care for GBM.
INDIGO: A GLOBAL, RANDOMIZED, DOUBLE-BLINDED, PHASE 3 STUDY OF VORASIDENIB VERSUS PLACEBO IN PATIENTS WITH RESIDUAL OR RECURRENT GRADE 2 GLIOMA WITH AN IDH1/2 MUTATION
Authors: McBain Catherine , Mellinghoff Ingo K , van den Bent Martin J , Blumenthal Deborah T , Touat Mehdi , Peters Katherine B , Clarke Jennifer , Mendez Joe , Welsh Liam , Mason Warren P , Hottinger Andreas F , Sepulveda Juan M , Wick Wolfgang , Soffetti Riccardo , Wen Patrick Y , Cloughesy Timothy F 
Published: September 2023

Abstract

AIMS
Current treatments grade 2 gliomas are not curative and can be associated with short- and long-term toxicities. Vorasidenib (VOR), an oral, brain-penetrant, dual inhibitor of mutant (m)IDH1/2 enzymes, has shown a tolerable safety profile and preliminary clinical activity in phase 1 studies.

METHOD
In the phase 3 INDIGO study (NCT04164901), patients (pts) were randomized 1:1 to receive VOR 40 mg daily or placebo (PBO) daily in 28-day cycles. Patients were stratified by 1p19q status and baseline tumor size. Key eligibility criteria included: age ≥12; KPS &gt;80; residual or recurrent grade 2 IDH1m or IDH2m oligodendroglioma or astrocytoma; measurable non-enhancing disease; no prior treatment for glioma with most recent surgery 1-5 years from randomization; and not in immediate need of chemotherapy/radiation. Primary endpoint: radiographic progression-free survival (PFS) by blinded independent radiology committee (BIRC). Key secondary endpoint: time to next intervention (TTNI).

RESULTS
As of 06 Sep2022, 331 pts were randomized across 10 countries: 168 to VOR and 163 to PBO. Median PFS by BIRC was 27.7 mos with VOR and 11.1 with PBO (HR, 0.39; 95% CI, 0.27, 0.56; 1-sided P=0.000000067). Median TTNI was not reached with VOR and 17.8 mos with PBO (HR, 0.26; 95% CI, 0.15, 0.43; 1-sided P=0.000000019). All-grade adverse events (AEs) occurring in &gt;20% pts receiving VOR vs PBO were alanine aminotransferase increased, COVID-19, fatigue, aspartate aminotransferase increase, headache, diarrhea, nausea. Common grade ≥3 AEs (&gt;5%): ALT increased (9.6% vs 0%).

CONCLUSIONS
VOR significantly improved PFS by BIRC versus PBO with a manageable safety profile.
© 2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Annual Meeting. All rights reserved.
BIOPSY VS BEST SUPPORTIVE CARE IN GLIOBLASTOMA: IMPACT OF NO POST-OP RADIOTHERAPY ON OVERALL SURVIVAL
Authors: Kannan Siddarth , Phang Isaac 
Published: September 2023

Abstract

AIMS
Best supportive care (BSC) is a management option generally considered glioblastoma patients with poor performance status, multiple co-morbidities or extensive disease. Navigated biopsy is recommended if there are multi- focal or multicentric disease. Patients are considered for biopsy based on performance score and co-morbidities with the aim of delivering post-operative radiotherapy. However, some patients are not offered radiotherapy. We examined patients who underwent biopsy and BSC to determine their overall outcomes

METHOD
Data from the neuro-oncology database and electronic patient records between 01/01/2018- 31/12/2022 were analyzed using GraphPad.

RESULTS
A total of 112 glioblastoma patients were included, 73 (median age: 65 years) patients underwent biopsy with 39 for best supportive care (median age: 80 years). The median overall survival for biopsy patients was 22.1 weeks (0.6-258) compared to 7.9 weeks (0.7-65.4) for BSC. 38 underwent post-operative radiotherapy. We further looked at biopsy patients that did not receive post-operation radiotherapy, 35 were identified and compared to BSC patients. There was a significant difference observed in overall survival between BSC (7.9 weeks) and No radiotherapy (14.7 weeks) groups (p&lt;0.05).

CONCLUSIONS
We hypothesize that difference in overall survival between BSC and No radiotherapy patients could be due to 79.5% of BSC patients having significant co-morbidities compared to only 57% No radiotherapy patients. The group of BSC patients were also slightly older compared to patients that underwent biopsy. An interesting finding is that about 46% of BSC patients were not prescribed any dexamethasone compared to 11% of biopsy patients.
HULL’S MAGIC BOX: BUILDING THE CASE FOR CLINICAL TRIALS USING ARGININE METHYLATION INHIBITORS AGAINST GBM
Authors: Barry Antonia , Samuel Sabrina , Moursi Amr , Deepak Srihari , Rajaraman Chittoor , Achawal Shailendra , Akinkuolie Ricky , Feugere Lauric , Iles Alexander , Green Vicky , Stead Lucy , Wade Mark , Greenman John , Beltran-Alvarez Pedro 
Published: September 2023

Abstract

AIMS
• Assess/evaluate transcriptomic changes in GBM, maintained on a microfluidics system, in response to treatment with arginine methylation inhibitor GSK3368715, currently in clinical trials, to identify novel therapeutic strategies, synergising with personalised patient care and precision medicine
• Investigate molecular differences between healthy brain and GBM maintained on-chip in response to GSK3368715, including proliferation, apoptosis and splicing.

METHOD
GBM biopsies from Hull Royal Infirmary, or healthy mouse brain tissues, were maintained on-chip for 8- days and perfused with GSK3368715-treated media, at 3 μl/min, mimicking the in vivo environment. RNA- sequencing determined thousands of differentially expressed genes and alternative splicing (AS) events resulting from GSK3368715 treatment. Immunohistochemistry displayed the effect of GSK3368715 on healthy mouse brain tissue to ascertain the specificity of the arginine methylation inhibitor in leading to GBM apoptosis.

RESULTS
RNA-sequencing showed highly significant GO-term-enrichment in ribosome and translation pathways, suggesting decreased protein synthesis capacity after GSK3368715 treatment. Additionally, several hundreds of genes were found to be undergoing AS, compatible with a mechanism where changes in the arginine methylation pattern of spliceosome member FUS, upon GSK3368715 treatment, contribute to AS. Of these events, 136 (more than expected by chance, χ2 = 7.16, p = 0.007) were known FUS splicing targets. GO-term-enrichment of these AS events was found in DNA damage and cell death . Together these results are consistent with immunohistological findings that GSK3368715 causes apoptosis in GBM-on-chip tissue, in a specific manner.

CONCLUSIONS
Our results highlight an exciting potential therapeutic target for GBM, via induction of alternative splicing path- ways, through arginine methylation inhibition with GSK3368715.
MULTIDIMENSIONAL PROfiLES OF COGNITIVE DETERIORATION AND RECOVERY ASSOCIATED WITH GLIOBLASTOMA SURGERY
Authors: Wan Yizhou , Halai Ajay , Zheng Haiyan , Sinha Rohitashwa , Santarius Thomas , Mair Richard , Morris Robert , Lambon-Ralph Matt , Price Stephen J 
Published: September 2023

Abstract

AIMS
Patients with glioblastoma suffer a high incidence of cognitive deficits. Cognition is the result of multiple neural mechanisms and glioblastoma is diffusely infiltrative with the capacity to invade multiple functional areas in the brain.
We hypothesise that cognitive deterioration and recovery in these patients will be multidimensional in nature and therefore different components of cognition will show distinct recovery profiles following surgery.

METHOD
28 patients with high-grade glioma, recruited at a single centre underwent preoperative (T0), early postoperative (within one week) (T1) and delayed (six to eight weeks) (T2) testing of their cognition with a neurocognitive screening tests; Oxford Cognitive Screen and Cambridge Attention, Memory and Perception Screen (OCS-Bridge) tool.
Varimax principal component analysis was performed to determine if there are low-dimensional domains of cognition examined by the tests. Changes in cognitive scores between time points was calculated and correlated with principal component scores (PCs).

RESULTS
We found six principal components which explained 71% of the variance in OCS scores. and six different com- ponents explained 63% of the variance in Bridge scores.
Cognitive deterioration was largely multidimensional with few significant correlations between PC change scores at T1 except tests loading on to visual field and spatial neglect. Cognitive recovery measured with T2 change scores were not significantly correlated between attention, praxis and language domains and between verbal working memory and visual memory and attention.

CONCLUSIONS
Longitudinal cognitive signatures of deterioration and recovery are heterogenous between patients. This high- lights the importance of targeting potentially distinct neural mechanisms for the rehabilitation of these patients.
AN ANALYSIS OF THE EFFECTIVENESS OF CURRENT PROVISION OF FATIGUE MANAGEMENT STRATEGIES WITHIN A NEURO-ONCOLOGY MDT CLINIC
Authors: Africa Olivia , Clark Rebecca , Sellwood Bethany 
Published: September 2023

Abstract

AIMS
Cancer-related fatigue (CRF) is known to have a distressing impact on a patient’s function and quality of life, with as many as 9 out of 10 people with cancer (90%) experiencing CRF (Macmillan 2021). Management of CFR for patients with a Glioblastoma diagnosis is additionally complex given associated neurological affect.
Physiotherapy and Occupational Therapy (PT & OT) have an important role addressing CRF through interventions such as, graded exercise programmes, fatigue education, self-management strategies, cognitive rehab and sleep hygiene advice. Intervention varies depending on when the patient is being referred or logistics of the clinic setting.

METHOD
A 12-month review of the OT & PT caseload (January 2022 – December 2022) is under evaluation to establish the number of patients reporting CRF at initial assessment or at follow up review. Clinic notes of patients reporting CRF have been reviewed to determine the oncological treatment time point that CRF was identified – pre, mid or post treatment. Data collection also includes patient and clinical characteristics, and the rehabilitation intervention type offered correlated to treatment phase.

RESULTS
49 datasets are under evaluation, with the key aims to explore 1) the prevalence of CRF in patients referred to the Cancer Specialist OT and PT team, 2) correlation of reporting’s of CRF with treatment phase 3) the Rehabilitation Treatment Taxonomy deployed in the management of CRF.

CONCLUSIONS
Our evaluation will explore patients CRF needs and how they may change through the treatment pathway, leading to future recommendations for service quality improvement and implementation change.
EVALUATION OF PATIENT REPORTED TOXICITIES AND THE INFORMATION WE PROVIDE TO GLIOBLASTOMA PATIENTS
Authors: Fernandez Sharon , Boele Florien , Short Susan 
Published: September 2023

Abstract

AIMS
To collect prospective, real- time data and lived experiences to determine if the chemo-radiotherapy pre- treatment information materials we provide to our patients need to be updated.

METHOD
A repeat cross-sectional, qualitative design was followed whereby individuals were interviewed at specific time points. These were defined as prior to radiotherapy (following planning scan and mould room); during radio- therapy (week 2) and post radiotherapy (4-6 weeks post radiotherapy). Patients and their caregivers were invited to participate in face-to-face, semi-structured interviews. Interviews were recorded, transcribed verbatim and thematically analysed.

RESULTS
Eighteen patients with confirmed diagnosis of glioblastoma and eleven caregivers consented for interview (n=9/n=5 prior to RT, n=5/n=4 during RT, n=4/n=2 post RT). Three main themes emerged. (1) Enhancing public awareness. Responses indicated that headway could be made in educating patients more effciently in terms of what chemo-radiotherapy related toxicities to expect. (2) Individual patient expectation. The majority of patients raised concern regarding insuffcient detail of chemo-radiotherapy related toxicities, with some patients expressing fear of the unexpected. (3) Impact of cancer treatment on daily life. Generally, patients and caregivers indicated that information booklets should provide clearer information on the impact of toxicities on patients’ and caregivers’ daily lives, at differing stages of treatment.

CONCLUSIONS
Patients and their caregivers provided constructive responses in relation to wanting more enhanced detail surrounding expected toxicities, toxicity severity and impact on daily life. All participants expressed wanting more information on the probability of likely toxicities to be experienced during and after chemo-radiotherapy, as current pre-treatment information given might be too generalised.
THE LINK BETWEEN M6A RNA METHYLATION AND R LOOPS IN PAEDIATRIC HIGH-GRADE GLIOMAS AND EPENDYMOMAS
Authors: Walker Lauryn , Radhi Masar , Knight Helen , Smith Stuart 
Published: September 2023

Abstract

AIMS
Paediatric high-grade glioma (HGG) and ependymoma (EPN) are two devastating malignant tumours of the central nervous system that unfortunately carry a poor prognosis. As R loops are a known source of genomic instability in eukaryotic cells and have previously been revealed to undergo m6A RNA methylation, we sought to investigate the potential link between m6A methylation and R loops in relation to the pathogenesis of paediatric gliomas.

METHOD
Paediatric HGG cell lines including KNS42, GCE62 and SF188, and paediatric EPN cell lines including BXD- 1425EPN and EPN9, were utilised for experimental analysis, in addition to normal human astrocytes. Immuno- cytochemistry was performed to assess m6A and R loop levels in tumour cell lines compared to normal human astrocytes. Moreover, DNA damage levels and the effects of anti-cancer drugs on R loop levels were also examined.

RESULTS
Immunocytochemistry analysis revealed that overall m6A and R loop levels were higher in tumour cell lines compared to normal human astrocytes. Furthermore, differences in R loop levels were observed as a result of pharmacological and biological manipulation, including reduction in R loop abundance with PARP inhibitors.

CONCLUSIONS
The link between m6A methylation and R loops in relation to the pathogenesis of paediatric HGG and EPN is being investigated. The results of these experiments will be presented.