tbuckley/cabot-search huggingface dataset:
HGG-37. CLINICAL AND MOLECULAR FEATURES OF BITHALAMIC GLIOMAS IN CHILDREN AND ADOLESCENTS: MULTICENTRIC STUDY AND META-ANALYSIS
Authors: Marta Perez-Somarriba, Anoop Cherungonath, Ajla Wasti, Erika Pace, Philip Benjamin, Guillermo Villacampa, Zita Reisz, Safa Al-Sarraj, Leslie Bridges, Thomas Jacques, Cinzia Lavarino, Nagore Gene, Rita Pereira, Yura Grabovska, Alan Mackay, Ketty Kessler, Matthew Clarke, Vicente Santa-Maria, Ofelia Cruz, Andres Morales La Madrid, Anna Llort, Alvaro Lassaletta, Felisa Vazquez-Gomez, Elena Carceller, Carmen Garrido, Palma Solano-Paez, Eduardo Quiroga, Bassel Zebian, Samantha Hettige, Julia Cockle, Henry Mandeville, Paola Angelini, Kavitha Srivatsa, Sucheta Vaidya, Lynley Marshall, Chris Jones, Fernando Carceller
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Bithalamic gliomas (BTG) are rare brain tumors with dismal prognosis. Optimal management and role of novel therapies have not been established yet. This study aimed to improve our understanding of BTG to guide adapted treatments. METHODS Retrospective case series across 6 Pediatric Neuro-Oncology Units (United Kingdom, Spain) of ≤18-year-old patients with BTG between 2000-2022. Clinical, pathological, and molecular data were derived and reviewed. A systematic review of the literature, meta-analysis, and survival analysis were performed. RESULTS Overall, 148 BTG cases were evaluated (study=25; literature=123). Of those, 97/148 (65%) had individual survival data. Median overall survival (mOS) (95%CI/range) was 13.2 months (12-16.8/0.6-262.2). mOS stratified by histological grading: 21.0 months (low-grade, n=32) versus 12.0 months (high-grade, n=55); hazard ratio (HR) 0.37 (95%CI 0.20-0.68), p-value=0.001. Molecular analyses (n=70) showed EGFR alterations (56%), TP53 mutations (30%), and H3K27M mutations (23%). mOS of EGFR-altered BTG based on targeted therapy was 13.2 months (no EGFR-inhibitors, n=26) versus 21.6 months (EGFR-inhibitors, n=9); HR 0.36 (95CI% 0.11-1.22). Methylation array data was generated for 4 patients and combined with 10 previously available profiles. Integrated MNP12.8 and mutation information classified 57% as DMG_EGFR and 21% as pedHGG_RTK2B. The remaining cases were classified as DMG_K27M (2/14) or pedHGG_A (1/14). Work is underway to establish a patient-derived EGFR-mutated BTG cell culture and further studies. CONCLUSIONS BTG have distinct radiological, and molecular features. EGFR alterations are seen in approximately half of BTG and H3K27M mutations are less frequent than in other midline high-grade gliomas (HGG). Low-grade histology is associated with a survival advantage, although still poor compared to pediatric low-grade gliomas. Therefore, treatment as per HGG guidelines should be considered for all BTG regardless of histological grading. EGFR-altered BTG patients can derive survival benefit from EGFR inhibitors, indicating that these should be considered as part of future treatment protocols.
IMG-21. HOW CAN WE BEST UTILISE HISTORICAL IMAGING DATASETS FOR RESEARCH IN PAEDIATRIC NEURO-ONCOLOGY? A REVIEW OF HISTORICAL PRE-OPERATIVE IMAGING PERFORMED FOR 92 PAEDIATRIC BRAIN TUMOUR PATIENTS WITH COMPARISON TO 2021 SIOPE GUIDELINES
Authors: Simon Dockrell, Kate Vaughan, John-Paul Kilday, Ian Kamaly-Asl, Martin McCabe, Stavros Stivaros
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Utilisation of historical imaging is important for studying long-term outcomes in paediatric brain tumours often pooling data across multiple centres retrospectively over many years. Disparities in MRI sequence parameters, imaging planes, fields of view and resolution limit quantitative radiomic analysis and segmentation algorithms. We review historical imaging datasets, analysing the MRI scans performed assessing suitability for modern research techniques. METHODS Retrospective review of presenting MRI scans was performed in 92 paediatric brain tumour patients between 2006-2020. Whether imaging was performed internally at our paediatric neurosciences centre or externally at their referring hospitals was recorded. Image sequences, planes and slice thickness were compared with 2021 SIOPE guidelines for paediatric brain tumour imaging. T2 signal intensities for tumour, white and grey matter were compared for scans completed in different centres. Statistical testing was performed with T-Test and Paired T-Test. RESULTS 75% of patients had all SIOPE essential sequences and 60.9% were in the recommended planes. Only 1 patient had the desired slice thickness in all sequences recommended for 1.5T scanners. 38.5% had T1 and 27.8% had post-contrast T1 in the ≤1mm slice thickness recommended for 3T scanners. Comparison between 62 internal and 30 external scans revealed statistically significant differences in T2 signal intensities for regions of interest (ROI) within tumour, white and grey matter (p&amp;lt;0.01). Comparison of matched ROI for 12 patients imaged internally and externally demonstrated statistically significant differences in T2 signal intensities (p&amp;lt;0.05). Differences persisted despite normalisation of T2 signal intensity as ratios between tumour and the weighted mean of white and grey matter (p&amp;lt;0.01). CONCLUSIONS This study highlights the challenges of non-standardisation of imaging resolution and acquisition parameters in historical imaging. One approach to utilise these datasets is to use qualitative classifications where human experts label imaging features and encode data for future statistical or machine learning analysis.
MODL-01. IN VITRO MODELING OF AND AUTOMATED DRUG SCREENING IN EMBRYONAL BRAIN TUMORS USING TUMOR-BRAIN ORGANOIDS
Authors: Nicole C Riedel, Carolin Walter, Paula Aust, Flavia de Faria, Lea Altendorf, Carolin Göbel, Archana Verma, Rajanya Roy, Christian Thomas, Ulrich Schüller, Jan M Bruder, Kornelius Kerl
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Embryonal brain tumors (EBTs) such as medulloblastoma, atypical teratoid rhabdoid tumor (AT/RT), and embryonal tumor with multilayered rosettes (ETMR) uniquely arise in the developing brain. Traditional 2D models often fall short in capturing the tumoral microenvironment (TME) and intratumoral heterogeneity, which may limit their translational potential. METHODS To address this, we co-aggregated EBT cells from AT/RT (Chla02 and SHH310) and ETMR (BT183 and murine GEMM cells) with forebrain organoids derived from human induced pluripotent stem cells and developed an automated, screening-ready in vitro model (EBT-FBO). We used immunohistochemistry, whole-mount immunostaining, and single-cell RNA sequencing to characterize our model and compared it with a developmental forebrain atlas. We further used our model for cell type-specific drug screening and validated the results in vivo. RESULTS Our EBT-FBO model mimicked the differentiation states of a mid-gestational fetal forebrain, providing a natural immature neuronal environment for supratentorial EBT cells. This environment allowed the EBT cells from both AT/RT and ETMR to mimic in vivo tumor cell states and avoided the cycling cell selection common in other models. We screened over 160 drugs in ETMR-FBO and identified antracyclines and Triptolide as having anti-tumor, yet non-neurotoxic effects. Our in-depth transcriptomic analysis identified new therapeutic targets, including PDGFR-signaling for ETMR. Building on this insight, we disrupted tumor-TME interactions and observed significant anti-tumor effects both in vitro and in vivo. CONCLUSIONS EBT-FBO provide embryonal brain tumors like ETMR or AT/RT with their intrinsic, immature neuronal microenvironment essential for recapitulating natural tumor heterogeneity. This marks a significant advancement towards targeted therapy and patient-specific models in precision medicine.
MODL-03. THERAPEUTIC EFFICACY OF IMIPIRIDONES IN LYNCH SYNDROME-ASSOCIATED GLIOMAS
Authors: Wai Chin Chong, Ethan Putnam, Bavani Subramaniam, Ayda Woldegerima, Sean Mizoguchi, Steve Cerna, Sridevi Yadavilli, Miriam Bornhorst, Roger Packer, Javad Nazarian
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Lynch Syndrome, a hereditary cancer syndrome linked to DNA mismatch repair gene mutations (MMRD), predisposes individuals to various cancers, including high grade gliomas (Lynch-HGG). Effective treatments for Lynch-HGGs are scarce, and suitable pre-clinical models are needed to identify novel therapeutic combinations. METHODS In this study, we generated patient-derived cell line models of Lynch-HGGs (n=3), characterized them through Western blot analysis for MMRD gene markers, and conducted genome and transcriptomic analyses. Murine models were then generated via intracranial injection of cultured cells expressing mCherry-luciferase reporter genes. Drug screening based on transcriptomic analysis was performed to identify potential therapeutic agents. RESULTS Our findings showed loss of MMRD protein consistent with the primary mutation, and a constant loss of P53, a tumor suppressor protein. One cell line, 7316-3058, exhibited an absence of NF1 expression, another critical tumor suppressor protein. Transcriptomic analysis unveiled upregulation in cell cycle processes and SUMOylation of DNA damage response and repair proteins. In vitro treatment with imipiridone compounds (ONC201 and ONC206) demonstrated varying degrees of drug response, with 7316-3058 displaying high sensitivity to the targeted inhibitor. Unfortunately, this therapeutic efficacy did not translate to the in vivo murine model, suggesting underlying mechanisms that impede drug efficiency. CONCLUSION In summary, we developed effective pre-clinical models of Lynch-HGG that can be used to screen different drug combinations targeted to treat these tumors. Furthermore, despite promising in-vitro data, we demonstrated the limited efficacy of imipiridones in treating Lynch-HGG in vivo, emphasizing the challenges in translating in vitro findings to in vivo contexts. This study contributes valuable insights to the development of effective therapeutic strategies for Lynch Syndrome-associated gliomas.
OTHR-06. A NEW INTERNATIONAL, MULTIDISCIPLINARY ACCELERATOR PROGRAMME FOR NOVEL BRAIN TUMOUR THERAPIES
Authors: Charlotte Aitken, Nicky Huskens, Katie Bushby, Karen Noble, Petra Hamerlik, Edward Kaye, Dione Kobayashi, Ryan Matthew, John McCall, Javad Nazarian, Ruth Plummer, Ruman Rahman, Juanita Lopez, Kanneboyina Nagaraju
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Developing a comprehensive translational programme for brain tumours involves navigating numerous challenges, including robustness of preclinical studies, safety, clinical trial design, regulatory issues, and commercialisation. Recognising this journey can be difficult, the Brain Tumour Research Novel Therapeutics Accelerator (BTR-NTA) was launched. The BTR-NTA is an accelerator programme that provides independent guidance to de-risk drug or device development through systematic evaluation. The international, multidisciplinary BTR-NTA Committee spans the entire therapeutic development pathway to avoid a siloed approach to therapeutic development. Thanks to Brain Tumour Research funding, the BTR-NTA is free for academics and available at nominal cost for industry. METHODS Researchers at any stage of therapeutic development are invited to apply to BTR-NTA, and, if accepted, their application proceeds as follows: 1. The Applicant completes an application form covering work to date and future plans under a confidentiality agreement that protects the Applicant’s intellectual property; 2. The Applicant’s therapeutic is reviewed by the BTR-NTA Committee 3. The Applicant and BTR-NTA Committee meet in-person to discuss the Applicant’s work; and 4. The Applicant receives a comprehensive report with feedback on strengths, identification of potential risks, and guidance on next steps. The BTR-NTA Committee dedicates half a day to reviewing the Applicant’s work in-person, and extensive time pre- and post-meeting. RESULTS Following the launch of BTR-NTA in 2023 and review of the first therapies, we will report on impact to date, early learnings, and how we hope to grow BTR-NTA to accelerate novel brain tumour therapies globally. CONCLUSIONS The ultimate goal of BTR-NTA is to enable researchers with a potential therapy for brain tumours to navigate the development journey and successfully reach the clinic in an efficient way. It is hoped this programme will strengthen international collaboration and support the development of novel therapies to improve outcomes for brain tumour patients.
OTHR-09. HEALTHCARE PROVIDERS’ PERSPECTIVES ON MALAYSIA-SINGAPORE VIRTUAL PEDIATRIC NEURO-ONCOLOGY TUMOR BOARD MEETING
Authors: Revathi Rajagopal, Jen Chun Foo, Jillian Chui Lin Teo, Rafikah Sawal, Vida Jawin, Ana Patricia Alcasabas, Thi Kim Nguyen Ho, C-Khai Loh, Shweta Bansal, Kok Hoi Teh, Sharon Low, Dharmendra Ganesan, Kenneth Chang, Shui Yen Soh, Mohamed S Abdelbaki, Eric Bouffet, Nicholas G Gottardo, Enrica Tan
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Virtual pediatric neuro-oncology tumor board meetings have been reported to be highly beneficial in improving the delivery of high-quality care for childhood central nervous system (CNS) tumors. However, such meetings are lacking in the Asia Pacific region. Hence, we initiated the first pediatric neuro-oncology online platform in the Asia Pacific region in January 2019, and we aimed to describe the participants’ perception of the virtual tumor board meetings. METHODS We retrospectively reviewed all cases from January 2019 to December 2023 and conducted a web-based survey to all participants in December 2023. Centers that presented more than five cases were invited to assess the impact of virtual meetings. RESULTS Fifty-four meetings have been conducted over five years. A total of 160 cases were presented by 20 institutions from six Asian countries, which include Malaysia, Singapore, Philippines, Vietnam, India, and Taiwan. Thirty participants responded to the survey. Majority of them attended the meetings to enhance their knowledge in pediatric neuro-oncology (96.7%), to learn evidence-based management (83.3%), and to build connections with regional colleagues and international experts (53.3%). Almost all concluded that tumor board meetings improved treatment decisions, addressed challenges of complex CNS tumor cases, and promoted continuity of care with appropriate post-surgical chemotherapy administration and surveillance investigations after completion of treatment. The main reason for case discussion was diagnostic difficulties followed by multimodal treatment advice (85.7%). More than 25% of management changes were observed in pathological diagnosis and treatment approaches. All the hospitals reported that the online case discussions improved pediatric neuro-oncology service delivery capacity and increased local team competence. CONCLUSION Virtual pediatric neuro-oncology tumor board meetings facilitated improvement in pathological diagnosis and multimodal treatment approach. The establishment of virtual CNS tumor board meetings is an effective way to seek international expert advice and promote pediatric neuro-oncology education in our region.
MDB-81. THE ROLE OF SURVEILLANCE IMAGING IN DETECTING RECURRENCE OF MEDULLOBLASTOMA
Authors: Archya Dasgupta, Rudrani Dhele, Arpita Sahu, Abhishek Chatterjee, Girish Chinnaswamy, Maya Prasad, Amit Choudhary, Kajari Bhattacharya, Sridhar Epari, Ayushi Sahay, Aekta Shah, Aliasgar Moiyadi, Prakash Shetty, Vikas Singh, Nandini Menon, Tejpal Gupta
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND In patients with medulloblastoma, imaging with magnetic resonance imaging (MRI) of the brain and spine plays an integral role in surveillance following treatment completion. The primary objective of imaging surveillance is to detect early recurrences, possibly leading to better salvage treatment. However, there is a lack of data to demonstrate the utility of imaging with possible demerits associated with increased resource utilization, scan-related anxiety, and lead or length time bias. METHODS Patients with histopathological confirmation of medulloblastoma treated in our institute between 2005 and 2022 were screened to identify patients with image-detected recurrences and corresponding documentation of symptoms and imaging intent (surveillance or directed by symptoms). RESULTS From a cohort of 545 patients treated during the period, 212 had disease recurrence, of which 153 had known symptomatology during the first recurrence. A total of 114 patients (75%) were having recurrence detected prompted by symptoms. Group 4 medulloblastomas were commonly seen to have recurrence detected on surveillance imaging (35%) compared to the SHH subgroup (25%) and group 3 (12%). During the final analysis, 141 of 153 patients had died. The median survival of patients detected to have asymptomatic relapse was 14 months compared to 5 months for symptomatic recurrences (p=0.03). The overall survival (calculated from index diagnosis) was not statistically significant between the two groups, with a 3-year survival of 53% (asymptomatic) vs 46% (symptomatic) (p=0.51). CONCLUSION In most patients, recurrences were detected by unplanned imaging ahead of scheduled surveillance imaging prompted by symptoms. Although the survival after recurrence is better in patients diagnosed on surveillance imaging, the overall survival was not different between the two groups, suggesting the possibility of lead time bias. Prospective studies are warranted to determine the role and appropriate frequency of surveillance imaging in patients with medulloblastoma.
OTHR-15. POSTMORTEM TISSUE BIOBANKING AND COLLABORATIVE EFFORTS: A SINGLE INSTITUTION REPORT
Authors: Sydney N Peck, Brittany Lebert, Julia Hegert, Avery Wright, Claudia Zapata, Blaine Pitts, Ana Aguilar- Bonilla, Amy A Smith
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Post-mortem tissue donation holds significant value to researchers, clinicians and bereaved families however it is an underutilized tool. Initiatives in pediatric neuro-oncology allow new insights into tumors such as DIPG and is becoming more widespread. Barriers include treating physicians lack of knowledge, lack of resources, religious beliefs and more. Postmortem tissue gives insight into the evolving biology of cancer and failed treatments. Postmortem tissue donation offers some understanding to families and empower them to help others. Surgical tissue collection used for diagnosis, leaves limited amounts for research. METHODS Since 2012, we have contributed to pediatric cancer research by offering postmortem donation to 48 patients. We have consented and facilitated 35 autopsies. In 2020, Arnold Palmer Hospital for Children became a lead institution for the COG’s Project:EveryChild. In 2021, we became a Center of Excellence for Gift From A Child. Our local Translational Protocol, IRB-approved, allowing us to collect and store our surgical and postmortem samples. To date, we have collected over 839 postmortem samples from 35 patients. In our Translational Laboratory, we have access to 207 postmortem samples from 13 patients. Through collaborative research initiatives, we have successfully sent over 368 samples from 11 patients and 14 parents to GFAC. Through Project:EveryChild we have shared 218 samples from 7 patients. RESULTS To explore the quality of postmortem tissues, we tested the integrity of our samples through DNA and RNA sequencing. The DNA quality is excellent across specimens and equivalent to surgical specimens however the RNA quality from autopsy specimens has degraded 7.5% RINe factor &amp;gt; 8 (excellent) and 38% RINe factor &amp;gt; 6 (mildly degraded) compared to surgical specimens, 85% with RINe factor &amp;gt; 8, 14.3% RINe factor &amp;gt; 6. CONCLUSION The platform of postmortem tissue donation can lead to further advancements in understanding the evolution and resistance of cancer.
LMIC-23. PEDIATRIC CRANIOPHARYNGIOMA SURVIVAL OUTCOMES IN THE US-MEXICO BORDER: RESULTS FROM A CROSS-BORDER NEURO-ONCOLOGY PROGRAM
Authors: John R Crawford, Alexander Tenorio, Michael G Brandel, Gautam R Produturi, Rebeca Rivera Gomez, William Roberts, David Gonda, Michael L Levy, Paula Aristizabal
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Management of pediatric craniopharyngioma requires complex, multidisciplinary care. Data on outcomes in low- and middle-income countries (LMIC) are lacking. To improve survival for children with brain tumors in the US-Mexico border, we established the Cross-Border Neuro-Oncology Program (CBNP) and facilitated access to high-complexity neuro-oncology for Mexican children. METHODS We retrospectively assessed clinical and surgical characteristics and progression-free survival (PFS) and overall survival (OS) in US and Mexican children who received neurosurgical intervention for craniopharyngiomas at Rady Children’s Hospital, San Diego (RCHSD) between January 2010 and December 2022. Patients either received follow-up care at RCHSD (RCHSD cohort) or returned to Hospital General, Tijuana (HGT), Mexico (HGT cohort) to continue care. RESULTS Thirty-five children with craniopharyngioma were included; 30 patients (mean age 8.7 years, 60% male) in the RCHSD cohort and five (mean age 14 years, 20% male) in the HGT cohort. The HGT cohort had longer symptom duration at presentation compared to the RCHSD cohort (24 weeks vs. 4 weeks, p=0.011). Pituitary dysfunction at diagnosis was observed in 20 (57%) patients, with growth hormone deficiency (n=17, 47%) being most common. Gross total resection was achieved in 32 (94%) patients. Seven (23%) patients in the RCHSD cohort received adjuvant therapies, compared to none in the HGT cohort (p = 0.6). Endocrine treatment compliance was lower in the HGT cohort vs..RCHSD cohort (50% vs. 100%, p=0.012). OS was significantly lower in the HGT cohort compared to the RCHSD cohort (67.3 months vs. N/A __ months, p&amp;lt; 0.001), whereas PFS was not different between cohorts. CONCLUSION Despite providing access to complex neurosurgical care through the CBNP for Mexican children with craniopharyngioma, we demonstrated lower survival. To address this inequity, delayed presentation and post-operative endocrine management will be addressed through infrastructure enhancements, engaging a pediatric endocrinologist at HGT, and providing training in early-detection and management of complications.