tbuckley/cabot-search huggingface dataset:
P27.28.B UPSKILLING AND CONNECTING THE NEURO-ONCOLOGY WORKFORCE THROUGH A FREE, COMMUNITY-LED NATIONAL PLATFORM: REFLECTIONS ON TWO YEARS OF THE TESSA JOWELL ACADEMY
Authors: B Allen, C Goetz, A Wright, N Huskens, K Bushby
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The Tessa Jowell Academy is a community platform that connects and upskills the neuro-oncology workforce through training, educational resources, peer-to-peer learning and networking opportunities. Informed by the findings of the Tessa Jowell Centre of Excellence review process, which identified best practice, variation and common challenges, it uses a grassroots community-led approach to disseminate excellence in treatment, care and research and collaboratively build solutions to national challenges. We reflect on two years of success connecting and training NHS clinicians and researchers. MATERIAL AND METHODS The Academy empowers the neuro-oncology community to jointly tackle challenges by: • Sharing knowledge: through tailored neuro-oncology webinars and training courses, a clinical trial finder, and a charity directory, all designed and delivered by the community in prioritised areas. • Connecting professionals: through networks and working groups, a peer-to-peer connect service and tailored centre support, directly connecting professionals both across the country and between specialties, breaking down siloes and creating a coherent and connected neuro-oncology community. All Academy features are designed and delivered by the community, in response to the most pressing needs facing the UK neuro-oncology workforce. Membership is open for free to all NHS professionals, individuals based in UK academic institutions and partners of the Tessa Jowell Brain Cancer Mission (TJBCM). RESULTS In two years the Academy has supported an unprecedented community-building project, with over 1,200 members from 31 NHS centres, 2,400 workshop registrations, 24 national working groups and networks, and 200 members actively involved in task-and-finish groups. The Academy has tackled siloed working practices, helping doctors, nurses and allied health professionals (AHPs) working in single-handed, isolated settings to connect with peers and learn best practice. The first scenario-based supportive care training for neuro-oncology AHPs was delivered, with three more planned and Academy groups are now developing specialty-specific guidelines in areas such as neuropsychology and physiotherapy to standardise practice across the UK. CONCLUSION The Academy’s success has only been possible due to the extraordinary level of engagement from the adult neuro-oncology community. Through this community-led approach, the Academy will continuously build on the excellence of the community in a solution-focused manner, with an expansion planned for the paediatric neuro-oncology community. The TJBCM will continue working with this community, generating learnings that can easily be applied to other cancers and rare diseases.
P26.02.A AN IN VITRO MULTIDIMENSIONAL DRUG ASSESSMENT TOOL FOR PERSONALIZED PREDICTION OF DRUG RESPONSE AND RESISTANCE IN HUMAN GLIOBLASTOMA ORGANOIDS
Authors: S Camenisch, L Mathews, T Hoch, M Neidert, A Zeitlberger, T Hundsberger, W Jochum, N Vélez Char, V Ayala, P Wick
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is a highly aggressive brain tumor treated with surgery, radiotherapy, and concomitant as well as maintenance temozolomide (TMZ). Despite treatment adherence to this so called Stupp’s regime, patient survival is typically less than 18 months, with high relapse rates. Current pre-clinical drug research is performed with cell line or patient-derived xenografts or with in vitro 2D models. These models lack inter- and intratumoral heterogeneity as well as a tumor microenvironment, thus bench to bed translational issues occur. Using patient-derived glioblastoma organoids (PDOs) the necessary cell heterogeneity can be provid-ed by growing them out of micro-dissected biopsy samples from 3 different GBM tumor sub-regions (pe-riphery, contrast-enhancing zone and tumor core). PDOs are considered in vitro models with high clinical rel-evance to evaluate the anticancer potential of novel preclinical drugs. In this project, we translated the Stupp’s regime to an in vitro multidimensional drug assessment tool using our in vitro GBM model. This tool allows us to monitor drug response over time and predict the performance of preclinical drugs with high predictability. The multidimensional drug assessment tool was initially optimized with TMZ in glioblastoma spheroids and then extended to PDOs. Our assessment included a morphological analysis, 2D &amp; 3D confocal imaging, NGS mutational profiling, apoptotic/necrotic cell fraction assessment, cell metabolic activity assays (XTT), and su-pernatant-based cell toxicity assays (LDH). The apoptotic cell fraction was detected by looking at nuclear morphology in H&amp;E stained tissue slices and detected using a pre-trained AI-driven image readout software. Over the duration of 14 days, GBM spheroid and organoids were treated according to the adapted in vitro Stupp’s regime and TMZ was monitored with our in vitro multidimensional drug assessment tool. Multiple concentrations and time points were evaluated to detected TMZ effect on tumor size reduction, metabolic activity, cytotoxicity, appearance of new drug-induced mutations, and extent of apoptosis and necrosis. GBM models treated with clinically relevant TMZ concentration (100 uM) were approximately 33% smaller after 10 days and metabolic activity decreased by up to 53%. Further preclinical drug candidates will be compared to TMZ performance and clinical data. To conclude, we are confident that this dynamic and multidimensional screening tool using physiologically relevant patient-derived GBM models provides high predictive power in order to assist preclinical anti-GBM drug screening and can address current translational issues persisting in drug development.
P22.05.B DIFFERENCES IN END-OF-LIFE CARE AND PLACE OF DEATH IN PATIENTS WITH MALIGNANT BRAIN TUMOUR: A SWEDISH REGISTRY STUDY
Authors: A Ozanne, J Öhlén, S Nyblom, A S Jakola, A Smits, C Larsdotter
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The treatment in malignant brain tumour is multimodal and consists of a combination of surgery, radiotherapy, and chemotherapy. The average survival differs depending on e.g. degree of malignancy and location. Potential palliative needs also need attention. This preliminary study seeks to utilize registry data to identify the place of death among adult people with malignant brain tumours in Sweden between 2013 and 2019. It aims to explore potential associations between the place of death and factors such as medical diagnosis, official palliative care status, sociodemographic characteristics, health service utilization, and healthcare service characteristics at the end-of-life. MATERIAL AND METHODS This is a population-level registry study examined the place of death among adults who died of malignant brain tumours in Sweden. Data was retrieved from the Swedish National board of Health and Welfare (NBHW), the Swedish Register of Palliative Care (SRCP), and Statistics Sweden (SCB). Descriptive statistics, univariable and multivariable binary logistic regression analyses are performed. RESULTS Preliminary results show that 3888 adults died of malignant brain tumours between 2013 and 2019 (41.4% female). In total, 64.4% did not have the palliative care diagnosis Z51.5, and this percentage varied depending on location of their death. Additionally, 57.2% did not have access to specialised palliative care at their place of death. Notably, among those who died in a nursing home, 80.0% lacked this access. Among those who died in a hospital, 53.5% had experienced one transfer to the hospital in the last month of life, and 41.8% had undergone two or more transfers. Notably, the odds ratio of dying in a hospital versus at home was higher for patients with more transfers. Additionally, the odds ratio of dying in a hospital compared to dying at home was higher in the Stockholm region but lower in the Western, South-eastern, and the Southern regions. CONCLUSION A minority of patients had access to specialised palliative care, despite being diagnosed with a malignant brain tumour, and this varied depending on the location of their death. Moreover, notable regional disparities were observed between deaths that occurred in hospitals versus at home. These findings underscore the presence of unequal End-of-life palliative care and highlights the need for additional investigation.
P14.21.B ROLE OF 11C-METHIONINE POSITRON EMISSION TOMOGRAPHY EMPLOY BEYOND THAT ADVANCED MAGNETIC RESONANCE IMAGING FOR TARGET VOLUME DELINEATION IN PATIENTS UNDERWENT RE-IRRADIATION FOR RECURRENT GLIOBLASTOMA
Authors: P Navarria, F Pessina, L Bellu, E Clerici, V Vernier, L Politi, L Raspagliesi, L Di Cristina, M Simonelli, A Di Pasquale, B Bono, A Franzini, L Evangelista, M Scorsetti
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Reirradiation for recurrent glioblastoma patients is a challenging and important topic under investigation. No clear evidences exists regarding indications, sequences with other therapeutic approach, optimal dose to delivered, and fractionation to use. But even more, the critical point is reaching correct tumor delineation based on imaging. The contrast enhancement T1-weighted-MRI usually outlines the most aggressive tumor area, and T2-weighted FLAIR-MRI allows a more accurate definition of the infiltrating microscopic disease growing outside the enhanced area on T1 MRI. More recently, different reports suggest that the use of carbon-11-methionine positron emission tomography ([11C]-methionine PET ([11C]METPET) improves diagnostic accuracy for treatment planning allowing more precise viable tumor cell identification. Evidence regarding the predictive, and prognostic value is still lacking, and its use in planning radiation therapy, is debated. For this reason, we investigated the role of [11C]-Methionine PET (PET-MET) in a cohort of adults patients with recurrent GBM treated with adiation therapy aiming to evaluate how it could modify target volume delineation, and if it could detect eventually tumor cells not otherwise visible. MATERIAL AND METHODS Patients with recurrent GBM, and an interval time (IT) from previous RT &amp;gt; 6 months were included. Simulation CT scan, MRI with different sequences and a 11CMETPET were performed in all patients, and images were co-registrated one with each other to define the target volume. Two different target volume were defined: Biological Target Volume (BTV) corresponded to the pathological uptake on METPET, and Clinical Target Volume (CTV) defined as the abnormalities volume on postcontrast T1 MRI. Correlation between BTV and CTV were recorded. RESULTS From September 2013 to January 2024, 121 patients received reirradiation for recurrent GBM. The median age was 52 years, and majority had KPS 90-100. In all cases, the whole BTV was inside the CTV, and in 10 (11%) patients, part of the BTV was outside the CTV into the FLAIR abnormalities area. The overlap between BTV and CTV showed low correlation between the two volumes, with CTV not always fully included in BTV. According to the 11CMETPET uptake, CTV was modified. CONCLUSION 11CPET-MET allowed to detect areas at higher risk of recurrent. A challenging issue is represented by integration of morphological, and functional imaging to define CTV in the setting of reirradiation. This results are promising and could permit to better define the tumor volume, to reduce the dose at organs at risk, and potentially to allow a dose escalation for a better local control improving patients outcome in recurrent glioblastoma patients.
P18.03.B ANTIBIOTIC EXPOSURE DURING RADIOTHERAPY FOR GLIOBLASTOMA MULTIFORME IMPACTS SURVIVAL
Authors: S Main, A Swampillai, J Lavrador, O Al-Salihi, K Chia, L Brazil, V Manik, J Ching, E Clarke, M Reis Ferreira
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND IDH wildtype Glioblastoma multiforme (GBM) is an aggressive primary brain tumour. Despite treatment with surgical resection, radiotherapy (± chemotherapy) and adjuvant chemotherapy median survival remains poor. Antibiotics influence the human microbiota and alter treatment efficacy in other tumours. This study addresses antibiotic exposure in GBM. MATERIAL AND METHODS A retrospective observational study based on electronic patient records March 2016-May 2022 in a large UK tertiary centre (N=234) and replicated for validation purposes in a second UK tertiary centre (N=179) over the same time period. All patients received radiotherapy 54-60Gy/30 fractions or 40Gy/15 fractions ± concurrent/adjuvant temozolomide chemotherapy. Prophylactic antibiotics with co-trimoxazole were used during concurrent chemoradiotherapy as per the Stupp protocol. Peri-operative, prophylactic and antibiotic exposures within 30 days of death were excluded. Additional antibiotic exposures were recorded from 4 weeks prior to radiotherapy to the completion/discontinuation of adjuvant temozolomide chemotherapy. Survival analysis was conducted with Kaplan-Meier methodology and Cox proportional hazard modelling using R language for statistical programming. RESULTS 99 (42.3%) patients in the principal study cohort and 44 (31.7%) patients in the validation cohort received antibiotics. They were most commonly prescribed for respiratory infections (40.2% and 37.3%) and broad-spectrum penicillin-based (60.5% and 49.3%). There was no clear indication for prescriptions in 15.6% and 9.3% of the principal and validation cohorts respectively. Antibiotic exposure has a negative impact on survival in the principal and validation cohorts: median overall survival (mOS) 12.0 months(mo) vs 15.2 mo (P= 0.0062); mOS 12.5mo vs 19.2mo(P=0.0023). This effect is greater in those with better predictors of prognosis (i.e. MGMT promoter methylation receiving Stupp chemoradiotherapy): mOS 15.2mo vs 33.3mo (P=0.013) and mOS 9.3mo vs 27.7mo (P=0.001) in principal and validation cohorts respectively. The association of antibiotic exposure and survival compromise was resilient in multivariate analysis with established risk factors in both cohorts: hazard ratio 1.52(P=0.017) in principal cohort and 2.81(P=0.023) in validation cohort. CONCLUSION Antibiotic exposure reduces treatment efficacy in GBM. The human microbiome (gut/intratumoural) may well underpin the mechanism of this observed effect. Ongoing work will explore the presence and influence of the tumoural and gut microbiome in GBM. These results pose a challenge to the use of prophylactic antibiotics with chemoradiotherapy. We recommend multi-centre validation and that clinicians consider to use prophylactic antibiotics only in those with a high risk of PJP (low lymphocyte count, prolonged high dose corticosteroids).
P17.29.B UNVEILING MEMORY DECLINE POST-SRS: DIFFERENTIAL EFFECTS OF HIPPOCAMPAL DOSE ON COGNITIVE FUNCTION IN PATIENTS WITH BRAIN METASTASES
Authors: E E van Grinsven, F Cialdella, S David, J J C Verhoeff, M E P Philippens, M J E van Zandvoort
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain metastases (BMs) occur in ten to thirty percent of the adult cancer population and are often treated with stereotactic radiosurgery (SRS). Even with high dose fall-off at tumor borders, such as in SRS, some radiotherapy dose gradient will fall outside the BMs to ensure adequate tumor coverage. This may include radiation to the neural stem cell regions, like the subventricular zone (SVZ) and the hippocampus (HPC), which can possibly play a role in neurocognitive functioning (NCF). Patients with BMs commonly experience radiation-induced cognitive decline, yet the underlying mechanisms remain incompletely understood. In this retrospective study, we aimed to elucidate the impact of radiotherapy dose on the SVZ and HPC and subsequent cognitive changes three months post-SRS, focusing on memory and information processing speed (IPS). MATERIAL AND METHODS The study population consisted of 36 adult patients with BMs that were referred for SRS. Neurocognitive assessments were performed before and three months post-SRS and reliable change indices were calculated to asses cognitive changes. The SVZ and HPC regions were acquired via nonlinear registration of brain atlases (COBRA and SVZ atlas) on pre-SRS T1 MRI images using CAT12 and median radiotherapy dose per region was calculated. RESULTS Multivariable linear regression analyses corrected for age, previous radiotherapy, number of brain metastases, and previous systemic therapy indicated a significant association between higher radiotherapy dose to the HPC and decline in memory performance, specifically in HVLT-R immediate recall (β = -0.787, p =.011) and delayed recall (β = -0.587, p =.036), and ROCFT delayed copy (β = -0.700, p =.046). Conversely, no significant association was found between radiation dose to the SVZ and memory, nor between dose to either region and IPS (p &amp;gt;.05). CONCLUSION These results suggest potential benefits of minimizing radiation exposure to the HPC, even with SRS, to help preserve memory function in patients with BMs. Further prospective evaluation is warranted to validate these findings and inform clinical decision-making regarding radiation therapy protocols for preserving NCF in this patient population.
P18.35.B RBFOX1 GENE INFLUENCES NEURONAL SUBTYPE PLASTICITY IN INVASIVE HIGH GRADE GLIOMA CELLS
Authors: M Flick, V Stevens, C P Sereduk, C L Plaisier, R F Barajas, L Hu, K Kannan, N Tran
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND High-grade glioma (HGG) is the most common and aggressive form of primary brain cancer with poor prognosis. Standard of care surgery employs Magnetic Resonance Imaging (MRI) to identify the contrast enhancing (CE) core for resection, leaving behind an unresected non-enhancing (NE) invasive rim of tumor which borders healthy brain tissue and invariably contributes to recurrence. Recent multi-omic analyses identified predominant neuronal and immune signatures within NE tumor; understanding these signatures could provide key insights to combatting recurrence and improving patient outcomes. To this end, we utilized a novel graph database method to integrate multi-omic data from a unique dataset of multi-regional spatially-localized biopsies from the CE core and invasive NE rim from a large cohort of patients with HGG. MATERIAL AND METHODS 159 IDH-wildtype tumor biopsy samples from the NE and CE regions of 74 glioma patients were profiled by bulk RNA sequencing. Differentially expressed genes (DEG) (n=1159) across NE and CE samples were selected using EdgeR. Samples were hierarchically clustered (method = median) for each DEG and represented as nodes in a Neo4j graph network. Edges were generated between nodes sharing ≥ 1 sample. Modularity optimization was used to identify communities of densely connected nodes. Genes occurring exclusively within NE communities were localized by cell type using external single-cell RNA sequencing datasets and selected as candidate source nodes for NE network random walks. RBFOX1 was selected as a source (walk length = 5; 10,000 walks/source node). Random walks traversing samples with significantly elevated RBFOX1 expression (one-tailed test) were kept for analysis. Genes occurring at significantly high frequency (one-tailed test) within random walks were ranked by correlation with RBFOX1 expression in NE samples and analyzed by gene set enrichment analysis (GSEA) for biological processes using clusterProfiler. RESULTS RBFOX1, a neurodevelopmental regulator, was upregulated (logFC = 1.85) in NE samples and uniquely occurred in NE communities. We show RBFOX1 is differential expressed in the aggressive Neuronal glioma subtype and enriched in neuroepithelial/astrocyte subpopulations across single cell HGG datasets. NE network random walks identified 201 DEGs associated with RBFOX1. GSEA revealed upregulation of neurodevelopmental signatures and downregulation of proliferative pathways amongst RBFOX1’s network. CONCLUSION RBFOX1’s genetic network within NE tumor represents neurodevelopmental processes potentially underlying glioma invasiveness within the NE region. As such, understanding the mechanistic role of key genes within the RBFOX1 network may provide insight into novel strategies for targeting these invasive cells within an aggressive subtype of glioma in the NE rim.
P13.03.B CLINICAL APPLICATION OF HYPER ARC TECHNOLOGY FOR BRAIN METASTASES: INSIGHTS FROM A SINGLE INSTITUTION EXPERIENCE
Authors: M Skoblar Vidmar, U Smrdel
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Hyper Arc is an innovative software introduced at the Institute of Oncology Ljubljana in June 2020. It enables high-precision treatment of multiple brain lesions with a single isocenter and with the potential to address an unlimited number of targets. This software is particularly useful in the local treatment of brain metastases, which are increasingly common causes of morbidity and mortality in patients with malignant diseases. Based on the latest research and guidelines, stereotactic radiosurgery is considered the primary choice to improve survival and may be the best treatment choice for multiple brain metastases. MATERIAL AND METHODS From June 2020 to December 2023, a total of 525 stereotactic radiosurgeries for brain metastases were performed. We analyzed all irradiated patients. RESULTS The most common metastases treated were from lung cancer (45.7%), followed by breast cancer (17.7%), malignant melanoma (16.6%), kidney (13.5%), digestive tract (3.8%), testes (1.1%), thyroid (1%) and ovaries (0.6%). The number of procedures increased over the years, with 24 in 2020, 121 in 2021, 172 in 2022, and 203 in 2023. 68.4% of patients are still alive. The highest number of irradiated metastases was 19, completed in just 20 minutes. Before the introduction of this technique, only 5 to 6 metastases could be treated due to the need for individual isocenters for each lesion. With the new technology, the same amount of time is required whether treating one or multiple metastases. CONCLUSION The treatment of brain metastases has become an increasingly complex field that requires multidisciplinary decisions regarding local and systemic treatment strategies as well as follow-up care. In the past two decades, the role of radiotherapy evolved from being solely palliative to offering ablative local treatments that can potentially improve survival rates. Hyper Arc is an innovative software for implementing stereotactic radiosurgery allowing monoisocentric irradiation of multiple lesions in a short time. This has led to an increase in the number of stereotactic radiosurgery performed at the Institute of Oncology Ljubljana.