bluuebunny/crossref_metadata_2025 huggingface dataset:
First light and reionization epoch simulations (FLARES) IX: the physical mechanisms driving compact galaxy formation and evolution
Authors: Roper William J , Lovell Christopher C , Vijayan Aswin P , Irodotou Dimitrios , Kuusisto Jussi K , Matharu Jasleen , Seeyave Louise T C , Thomas Peter A , Wilkins Stephen M
Published: September 2023

In the First Light And Reionization Epoch Simulations (Flares) suite of hydrodynamical simulations, we find the high-redshift (z > 5) intrinsic size–luminosity relation is, surprisingly, negatively sloped. However, after including the effects of dust attenuation, we find a positively sloped UV observed size–luminosity relation in good agreement with other simulated and observational studies. In this work, we extend this analysis to probe the underlying physical mechanisms driving the formation and evolution of the compact galaxies driving the negative size–mass/size–luminosity relation. We find the majority of compact galaxies (R1/2, ⋆ < 1 pkpc, which drive the negative slope of the size–mass relation, have transitioned from extended to compact sizes via efficient centralized cooling, resulting in high specific star formation rates in their cores. These compact stellar systems are enshrouded by non-star-forming gas distributions as much as 100 times larger than their stellar counterparts. By comparing with galaxies from the Eagle simulation suite, we find that these extended gas distributions ‘turn on’ and begin to form stars between z = 5 and 0 leading to increasing sizes, and thus the evolution of the size–mass relation from a negative to a positive slope. This explicitly demonstrates the process of inside-out galaxy formation in which compact bulges form earlier than the surrounding discs.
Collisional excitation of C2H and C2D by molecular hydrogen
Authors: Pirlot Jankowiak P , Lique F , Dagdigian P J
Published: September 2023

The determination of physical conditions in interstellar clouds requires reliable estimation of radiative and collisional data for molecules detected in space. In this work, rate coefficients for de-excitation of C2H and C2D induced by collisions with both ortho- and para-H2 are presented. Calculations have been carried out using a recently published four-dimensional C2H–H2 potential energy surface. Fine-structure resolved cross-sections were computed with the time-independent close-coupling approach. We report cross-sections for transitions between the first 41 levels of C2H and corresponding rate coefficients up to 500 K. We also computed cross-sections for transitions between the first 31 levels of C2D and corresponding rate coefficients up to 200 K. Then, hyperfine structure resolved cross-sections and rate coefficients were computed using the recoupling technique. The hyperfine structure resolved rate coefficients for C2H–H2 and C2D–H2 are calculated for the first 38 hyperfine C2H energy levels and first 55 hyperfine C2D energy levels both for temperatures up to 100 K. These collisional data were used in a simple radiative transfer modelling.
Optical sparse telescope arrays and scintillation noise
Authors: Hartley Kathryn E , Farley Oliver J D , Townson Matthew J , Osborn James , Wilson Richard W
Published: September 2023

Fresnel propagation of starlight after it passes through high altitude turbulence in the Earth’s atmosphere results in random fluctuations of the intensity at ground level, known as scintillation. This effect adds random noise to photometric measurements with ground-based optical telescopes. Spatial correlation of the intensity fluctuations means that the fractional photometric noise due to scintillation may be substantially smaller for a sparse array of small aperture telescopes than for a single large aperture of the same total area. Assuming that the photometric noise for each telescope is independent, averaging the light curves measured by N telescopes reduces the noise by a factor of $\sqrt{N}$. For example, for bright stars, the signal-to-noise ratio of a 2.54 m telescope can be achieved for an array of thirty 20 cm telescopes if the scintillation noise measured for each telescope is uncorrelated. In this paper, we present results from simulation and from observations at the Isaac Newton Telescope. These explore the impact that several parameters have on the measured correlation of the scintillation noise between neighbouring telescopes. We show that there is significant correlation between neighbouring telescopes with separations parallel to the wind direction of the dominant high altitude turbulent layer. We find that the telescopes in an array should be separated by at least twice their aperture diameter so that there is negligible correlation of the photometric noise. We discuss additional benefits of using sparse telescope arrays, including reduced cost and increased field of view.
Flux density monitoring of 89 millisecond pulsars with MeerKAT
Authors: Gitika P , Bailes M , Shannon R M , Reardon D J , Cameron A D , Shamohammadi M , Miles M T , Flynn C M L , Corongiu A , Kramer M
Published: September 2023

We present a flux density study of 89 millisecond pulsars (MSPs) regularly monitored as part of the MeerKAT Pulsar Timing Array (MPTA) using the L-Band receiver with an approximately two week cadence between 2019 and 2022. For each pulsar, we have determined the mean flux densities at each epoch in eight ∼97 MHz sub-bands ranging from 944 to 1625 MHz. From these we have derived their modulation indices, their average and peak-to-median flux densities in each sub-band, as well as their mean spectral indices across the entire frequency range. We find that the vast majority of the MSPs have spectra that are well described by a simple power law, with a mean spectral index of –1.86(6). Using the temporal variation of the flux densities, we measured the structure functions and determined the refractive scintillation time-scale for seven. The structure functions provide strong evidence that the intrinsic radio luminosities of MSPs are stable. As a population, the average modulation index at 20 cm wavelengths peaks near unity at dispersion measures (DMs) of ∼20 pc cm−3 and by a DM of 100 pc cm−3 are closer to 0.2, due to refractive scintillation. We find that timing arrays can improve their observing efficiency by reacting to scintillation maxima, and that 20 cm FRB surveys should prioritize highly scintillating mid-latitude regions of the Galactic sky where they will find ∼30 per cent more events and bursts at greater distances.
Spectral study of neutron star low-mass X-ray binary source 1A 1744−361
Authors: Tobrej Mohammed , Rai Binay , Ghising Manoj , Tamang Ruchi , Paul Bikash Chandra
Published: September 2023

We present X-ray observations of the recent outburst of 2022 from the neutron star low-mass X-ray binary source 1A 1744−361. Spectral properties of the source have been analysed using joint Nuclear Spectroscopic Telescope Array and Neutron Star Interior Composition Explorer observations. During our observations, the source happens to be in the banana state (soft state) of the hardness–intensity diagram. In addition to a power law with a high-energy cut-off, the spectrum is found to exhibit broad iron Kα emission along with distinct absorption features. A prominent absorption feature observed at 6.92 keV may be interpreted as Kα absorption line from hydrogen-like iron. The absorption feature observed at 7.98 keV may be interpreted as a blend of Fe xxv and Ni xxvii transitions. We have summarized the evidence of variability of the spectral features observed in the X-ray continuum by time-resolved spectroscopy.
Temperature-dependent convective parameters for RRc 1D models
Authors: Kovács Gábor B , Nuspl János , Szabó Róbert
Published: September 2023

Non-linear pulsation modelling of classical variable stars is among the first topics that were developed at the beginning of the computational era. Various developments were made, and many questions were answered in the past 60 yr, and the models became more complex, describing the genuinely 3D convection in a single dimension. Despite its successes, the recent public availability of the mesa radial stellar pulsations (mesa rsp) module and the emerging results from multidimensional codes made clear that the eight free convective parameters, unique to these models, together with the underlying physical models need calibration. This could be done by comparing them against multidimensional codes, but before that, it is important to scrutinize the free parameters of the 1D codes using observations. This is a follow-up work of our previous calibration on the convective parameters of the budapest-florida and mesa rsp pulsation codes for RRab stars. In this letter, we extend the previous calibration to the RRc stars and the RR Lyrae stars in general. We found that correlations of some of the parameters are present in RRc stars as well but have a different nature, while high-temperature RRc stars’ pulsation properties are very sensitive to the chosen parameter sets.
IMAGING HABITAT CHANGES AFTER PREOPERATIVE RADIOTHERAPY FOR GLIOBLASTOMA: UTILISATION OF A BIOINFORMATICS AND MACHINE LEARNING PIPELINE TO CHARACTERISE REGIONAL TREATMENT RESPONSE
Authors: Waqar Mueez , Van-Houdt Petra , Hessen Eline , Lewis Daniel , Li Ka-loh , Zhu Xiaoping , Jackson Alan , Iqbal Mudassar , Roncaroli Federico , Djoukhadar Ibrahim , Coope David , Borst Gerben
Published: September 2023

AIMS

Imaging of tumour habitats is a novel technique to assess regional treatment response by defining tumour ‘habitats’, which are regions with shared imaging characteristics. Here, we describe a novel pipeline to characterise imaging habitats in glioblastoma using bioinformatics and machine learning. We apply this pipeline to glioblastoma patients in the Preoperative Brain Irradiation in Glioblastoma (POBIG) trial that received preoperative radiotherapy for the first time.

METHOD

Glioblastoma patients underwent preoperative diffusion/perfusion MRI. A two- stage clustering pipeline was developed to define imaging habitats using relative cerebral blood volume (rCBV) and apparent diffusion co- effcient (ADC). 6 habitats were defined that occupied 10.6-21.5% of tumour volume. Treatment response was evaluated using Ktrans permeability.

RESULTS

In newly diagnosed cases the commonest habitats included those with a medium and high rCBV. In contrast, recurrent cases had significantly greater proportion of low rCBV habitats (p = 0.026). Two patients in the POBIG trial received 8 Gy preoperative radiotherapy. Within 24 hours of treatment there was a global decrease in vascularity with a decrease in high rCBV habitats (-3.7%) and increase in low rCBV habitats (+8.2%) in irradiated regions. Habitats demonstrated a heterogeneous response to preoperative radiotherapy, with a greater increase in Ktrans in high rCBV habitats (mean +83%) versus low rCBV habitats (mean +40%).

CONCLUSIONS

We have developed a unique pipeline to delineate imaging habitats in glioblastoma and applied it to a novel trial. Imaging habitats can allow regional monitoring of treatment response and could allow more targeted treatment in future.
LONGITUDINAL WGS AND WES OF GLIOBLASTOMA REVEAL POTENTIAL PATHWAY TARGETS
Authors: Alghamdi Yousef , Tanner Georgette , Finetti Martina , Pollock Steven , Chakrabarty Aruna , Ismail Azzam , Poulter James , Stead Lucy
Published: September 2023

AIMS

Treating glioblastoma (GBM) patients remains challenging as the current regimens result in the recurrence of a treatment-resistant and fatal tumour. We aimed to identify candidate pathways that, when mutated, confer treatment resistance. Targeting these pathways may improve GBM treatment effcacy.

METHOD

We performed WGS and WES on 46 matched primary and recurrent GBMs (the Discovery cohort) and used data from additional 188 samples from the Glioma Longitudinal AnalySiS consortium (GLASS: Validation cohort). First, we identified variants that were shared between primary and recurrent GBMs. We then highlighted those most likely to be involved in treatment resistance, i.e. with: 1) low allele fractions at primary and high in recurrent, 2) high allele fractions in both primary and recurrent. Finally, we performed enrichment analysis using these variants to identify pathways that may drive clonal expansion from primary to recurrent.

RESULTS

The analysis of variants that increased from primary to recurrent revealed three significant disrupted path- ways in the Discovery cohort; “Activation of BH3 Only Proteins” (Reactome), “P53 pathway” (BIOCARTA), and “Intrinsic Pathway for Apoptosis” (REACTOME). Six distinct genes caused the aberration of these pathways. The same pathways were significantly disrupted in the recurrent variants group of the Validation cohort but were solely caused by TP53 alterations. In the Discovery cohort, “Activation of BH3 Only Proteins” was altered in 24% of the patients.

CONCLUSIONS

Investigating how pathway mutations alter in GBM through treatment has led to identifying potential candidate mechanisms to be further studied in the laboratory.
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

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 (>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 <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

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

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

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

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 >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 >20% pts receiving VOR vs PBO were alanine aminotransferase increased, COVID-19, fatigue, aspartate aminotransferase increase, headache, diarrhea, nausea. Common grade ≥3 AEs (>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

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<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

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

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

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

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

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.
A RANDOMISED TRIAL TO OPTIMISE OUTCOMES IN PATIENTS WITH BRAIN METASTASES (AROMA): TRIAL PROPOSAL
Authors: Ho Andrew , Pakzad-Shahabi Lillie , Chen Jiarong , Williams Matthew
Published: September 2023

AIMS

Brain metastases carry significant morbidity and mortality. The survival of patients with metastatic disease has improved due to systemic therapy advances conferring greater extracranial control. Optimal intracranial local control is probably surgical resection or stereotactic radiosurgery. However, there is a cohort for whom this is inappropriate, either for disease or patient fitness reasons. Traditionally, treatment has included whole brain radiotherapy although this has not been convincingly shown to improve survival or quality of life.

AROMA is a single-arm phase II study investigating the feasibility of delivering a novel radiotherapy technique and measuring quality of life.

METHOD

We have developed a modern technique to deliver dose-escalated internal PTV (DE-iPTV) in patients with metas- tases too large for SRS. Our previously-published planning study demonstrates dosimetric improvements in 5 fractions versus WBRT, with higher lesion dose and lower normal tissue dose. It is delivered using a standard linear accelerator.

In AROMA, patients for whom their oncologist would normally consider WBRT instead receive DE-iPTV. QoL measures (EQ5D-3L, Barthel, PS) are collected weekly for 8 weeks then monthly to 6 months. There is an MRI at 6 weeks post-radiotherapy. We are also collecting retrospective observational data on participating centres’ WBRT cohort.

RESULTS

The primary outcome is completion of treatment and completion of QoL at 8 weeks. Secondary outcomes include lesional response, survival, QoL and steroid use.

CONCLUSIONS

AROMA is a phase II study looking at the feasibility of DE-iPTV for patients with brain metastases not suitable for SRS or neurosurgery. It is currently in the design and setup phase.
AN EVALUATION OF THE USE OF TARGETED GENE PANELS TO IDENTIFY TARGETED TREATMENTS IN PATIENTS WITH BRAIN TUMOURS
Authors: Hussain Sana , Hughes Jane , Collinson Fi , Short Susan
Published: September 2023

AIMS

• To assess the impact of undertaking targeted gene panel testing in brain tumour patients outside clinical studies

• To assess if novel treatments have impacted management decisions and/or prognosis

Testing for specific mutations in brain tumours may give opportunities for using targeted drugs. It is not well established how much patients benefit from this approach since routine panel testing has not been widely applied.

METHOD

We reviewed patients who had a known brain tumour and were referred to the early phase research clinic at St James’s for consideration of further treatment in the 6-month period [08/2022 – 02/2023]. We identified ten patients and reviewed their records in detail. Ad hoc testing was done on 6 patients, and SPARTA trial screening on 4 patients.

RESULTS

There were 7 males, 3 females with a mean age of 42 years (24-59). 3 were eligible for clinical trials using agents targeting mutations in the FGFR gene or RET fusion positive status (for the FIGHT 209 and TAPISTRY trials respectively). In 3 patients, there were no targetable mutations. One patient died whilst awaiting results and another is currently under palliative care. Two patients have outstanding molecular data. The data are too early to be able to assess effects on disease trajectory in any patient.

CONCLUSIONS

These data confirm that gene panel testing may suggest novel treatment options in a subset of brain tumour patients and support efforts to ensure that potentially suitable patients have access to appropriate molecular pathology and genomic testing.
SPATIAL DISTRIBUTION AND FUNCTIONAL RELEVANCE OF FGFR1 AND FGFR2 EXPRESSION FOR GLIOBLASTOMA TUMOUR INVASION
Authors: Begum Ayesha , Alshahrany Nawal , Jimenez-Pascual Ana , Siebzehnrubl Florian
Published: September 2023

AIMS

Glioblastoma (GBM) is the most common brain tumour in adults. The GBM microenvironment is made up of heterogeneous GBM cell populations, but how microenvironmental signalling pathways contribute to GBM het- erogeneity and specific GBM pathological features remains incompletely understood. Here, we compare expression of fibroblast growth factor receptors (FGFRs) within the tumour core and the invasion front, specifically investigating the functional relevance of FGFR1 and FGFR2 for in GBM invasion in vitro and in vivo.

METHOD

Quantification of the relative expression levels of FGFR1 and FGFR2 was determined in GBM primary patient- derived cell lines and xenograft models. Additional transcriptional profiling using RNA sequencing identified potential gene-regulatory networks involved in FGFR1-driven GBM tumour invasion.

RESULTS

We found FGFR1 distributed across the tumour mass and expressed in invasive GBM cells, while FGFR2 expression is confined to the tumour mass only. Loss of FGFR1, but not FGFR2, significantly reduced cell migration in vitro and tumour invasion in human GBM xenografts. Comparative analysis of RNA-sequencing data of FGFR1 and FGFR2 knockdown GBM cells revealed a FGFR1-specific gene regulatory network associated with tumour invasion.

CONCLUSIONS

Differential expression of FGFR1 and FGFR2 on invasive GBM cells identified FGFR1 is functionally relevant for tumour invasion in GBM. New gene candidates linked to FGFR1-mediated GBM invasion have been revealed and warrant further investigation to identify how FGFR1 regulates GBM invasion.
PREDICTING INPATIENT LENGTH OF STAY FOR PATIENTS UNDERGOING NEURO-ONCOLOGICAL OPERATIONS: A MACHINE LEARNING PERSPECTIVE FROM A 10-YEAR STUDY AT A NATIONAL TERTIARY NEUROSURGICAL CENTRE
Authors: Snowdon Ella , Biswas Sayan , MacArthur Joshua , Sarkar Ved , Tetlow Callum , George K Joshi
Published: September 2023

AIMS

Length of stay (LOS) following neuro-oncological (NO) operations is essential information for both clinicians, patients and hospital administrators. This study aimed to analyse the LOS of patients following the most common NO surgeries over time and subsequently create a machine learning (ML) algorithm to predict LOS.

METHOD

Retrospective case series analysis of all NO operations at a tertiary neurosurgical centre from 2012 to 2022. A total of 4700 patients were identified and classified based on 40 operation types. 3 regression ML models were developed to predict the inpatient LOS: XGBoost Regressor, Huber Regressor and Support Vector Machine. Models were trained using 25 stratified KFold cross-validation with an 80:20 train-test split. All models were evaluated via model coverage score, mean absolute error (MAE), mean squared error (MSE) and root mean squared error (RMSE) metrics. All analysis was conducted in R and Python.

RESULTS

The average patient age was 53.5±15.7 years, with a mean overall LOS of 160.7hrs. The most common operation was an excision of lesion of brain with 2735 operations. The operation with the longest average LOS was extirpation of lesion of meninges of spinal cord at 268.9hrs, with the shortest being biopsy of lesion of brain at 48.1hrs. The best performing model was the XGBoost Regressor with a mean coverage score=0.885 [0.966, 0.803], RMSE=0.784, MAE=0.594, MSE=0.615.

CONCLUSIONS

ML models can accurately predict LOS and have potential for use in clinical practice to help clinical decision making. Further studies are needed to validate these models on prospective data and additional predictor variables.
STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES FROM GASTROINTESTINAL PRIMARIES: ANALYSIS OF OUTCOMES
Authors: Lynch Sophie , Al-Salihi Omar , Manik Vishal , Qureshi Asad , Hassan Sheila , Forner Samantha , Durve Meeta , Chia Kazumi
Published: September 2023

AIMS

Brain metastases from gastrointestinal primaries are uncommon with poor reported outcomes following SRS. We evaluated clinical outcomes for patients diagnosed with metastatic brain tumours from a gastrointestinal primary treated with stereotactic radiosurgery (SRS).

METHOD

A single institutional retrospective review of patients treated with LINAC-based SRS at our institution between 2017 and 2022. Median survival was calculated from the time of SRS.

RESULTS

A total of 24 patients were treated with primary malignancy locations as follows: 10 colon, 7 rectum and 7 oesophageal. Median survival was 6.4 months for the overall cohort and 4.5 months for colon, 6.1 months for rectum and 14 months for oesophagus. 44% and 14% of patients had undergone surgical resection with colorectal cancer (CRC) and oesophageal cancer respectively. Median survival in CRC patients receiving SRS post-operatively was 6.8 months compared with 11.5 months for patients with non-gastrointestinal primaries. Time from diagnosis of the primary malignancy to diagnosis of brain metastases showed an inverse correlation with survival: 48 months colon, 21 months rectum and 13 months oesophagus. Compared to oesophageal patients, CRC patients were more likely to have extra-cranial disease at the time of SRS (57% vs. 18%).

CONCLUSIONS

Survival after SRS to brain metastases from gastrointestinal primaries is poor, but we demonstrate important differences in outcome depending on the location of the primary malignancy. Oesophageal cancer patients had the best survival with colon cancer patients having the worst. Although our findings are likely to influenced by patient selection bias, these differences are worthy of further investigation.
SURVIVAL OVER A DECADE IN A CASE OF GLIOBLASTOMA
Authors: Shawki Omar , Shaikh Salman , Mukherjee Soumya , El-Maghraby Hussien , Dardis Ronan
Published: September 2023

AIMS

Glioblastoma multiforme is the most aggressive type of primary brain tumours, but there is a small percentage of patients who have a long-term survival and some exceptional cases who survive decades after surgical removal of tumour along with adjuvant therapy.

METHOD

In 2011, a 40-year-old man, presented with headaches & confusion and underwent gliolan guided resection of a right frontal glioblastoma WHO grade IV. He received 30# of 60Gy Radiotherapy with TMZ. Chemotherapy was continued with interval scans in 2016 and 2018 showing stable disease. MRI scan in October 2022 showed contrast enhancing foci for which redo surgery was eventually performed 5 months later. The repeat histology is pending. 12 years after the primary diagnosis, the patient is clinically well.

RESULTS

Only a very handful cases of glioblastoma show prolonged survival of over 10 years. The long-survival for glioblastoma multiforme can be linked to age, surgical resection, molecular profile and good performance score before surgery.

CONCLUSIONS

These extremely rare scenarios of prolonged survival in glioblastoma serves as a motivation to continue incessant research in this field with the hope of improving life expectancy in grade 4 tumours.
PROGNOSTIC FACTORS IN NON-SMALL CELL LUNG CANCER METASTATIC TO THE BRAIN
Authors: Shelley Daniel , Gkogkou Pinelopi
Published: September 2023

AIMS

To identify prognostic factors significantly associated with overall survival in patients with non-small cell lung cancer (NSCLC) metastatic to the brain. To identify whether intracranial or extracranial factors had greater influence on overall survival in this cohort.

METHOD

Retrospective review of 21 patients from a single UK centre with NSCLC metastatic to the brain was undertaken. Hazard ratios were obtained from the Cox proportional hazards model, and survival curves plotted via the Kaplan-Meier method.

RESULTS

On univariate analysis, higher Karnofsky Performance Status (KPS) was significantly associated with improved overall survival compared to lower (HR 0.112; 95% CI 0.029 – 0.438) as was stable primary disease relative to progressive primary disease (HR 0.088; 95% CI 0.017 – 0.459). Surgical resection of primary disease was also associated with longer overall survival relative to no resection (HR 0.2713; 95% CI 0.075 – 0.980). Local treatment to brain metastases with either surgery or stereotactic radiosurgery prolonged overall survival relative to no local metastatic treatment (HR 0.1422; 95% CI 0.031 – 0.656). Notable variables not significantly associated with overall survival include number, size and location of metastases as markers of intracranial metastatic burden.

CONCLUSIONS

Primary disease activity (p = 0.004), KPS (p = 0.002), surgical resection of thoracic disease (p = 0.046) and treatment modality of brain metastasis (p = 0.012) were significant prognostic covariates in this cohort of 21 patients. Extracranial disease and patient factors appear to have greater prognostic significance than intracranial metastatic burden in this patient population.