tbuckley/cabot-search huggingface dataset:
IMG-32. USER EVALUATION OF AN AI-POWERED WEB APPLICATION TO SUPPORT RADIOGRAPHIC INTERPRETATION OF PATIENTS WITH ADAMANTINOMATOUS CRANIOPHARYNGIOMA
Authors: Eric W Prince, David M Mirsky, Carsten Görg, Todd C Hankinson
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND In neuro-oncology, accurately interpreting radiographic images, especially for diagnosing central nervous system (CNS) tumors like Adamantinomatous Craniopharyngioma (ACP), presents formidable challenges. Even with advanced imaging technologies such as Magnetic Resonance Imaging (MRI) and Computed Tomography (CT), pinpointing features related to ACP invasiveness remains daunting. METHODS We introduced an interactive web application that utilizes a custom AI model to analyze preoperative MRI and CT images of 50 patients with ACP. This application can predict a 12-point radiographic feature profile and rank patients based on similarity, aiming to support clinicians in making more precise diagnoses. We deployed our application on a hospital-grade radiographic reading terminal. Our application’s utility and user-friendliness were evaluated through a user study involving four neurosurgeons and two neuroradiologists, who constructed 12-point radiographic feature profiles for ten patients within a 30-minute timeframe given patient MRI and CT images. RESULTS Our study subjects reported high self-assessed numeracy (SNS scores ranging from 4 to 5.25) despite varied preferences in engaging with numerical data. Subjects could efficiently learn to navigate our software interface, with an average task completion time of approximately 3 minutes and 25 seconds per patient. Introducing AI into the task workflow resulted in a slight, statistically non-significant increase in completion time, indicating that while AI modifies interaction dynamics, it does not significantly hinder efficiency in task performance. We observed distinct agreement patterns between clinicians and AI prediction, utilizing Fleiss’ Kappa for categorization. AI assistance subtly boosted clinicians’ confidence and slightly lessened the perceived difficulty of interpreting radiographic images. However, these benefits were not statistically significant. CONCLUSIONS Our study highlights the promise of AI in improving neuro-oncology diagnostics, showing that clinicians quickly adapted to an AI-enhanced application, which subtly influenced their radiographic interpretation. This finding underscores the potential for AI to enhance decision-making accuracy in challenging cases like ACP.
DEI-05. ASSESSING HOUSEHOLD MATERIAL HARDSHIP IN CHILDREN WITH CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Scott L Coven, Yvette H Tran, Seho Park, Eneida A Mendonça
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Household material hardship (HMH) is defined as unmet basic needs including food, heat, housing, or transportation. Researchers have documented higher rates of poor nutrition, injury, infectious disease, and hospitalization in healthy children living in families with household material hardship. Furthermore, targeted interventions exist to modify these health outcomes. However, little is known regarding the relationship between social determinants of health and their impact on overall and quality of survival for children with brain or spinal cord tumors. The current available information is based upon retrospective and secondary data sources, often limited to basic socioeconomic factors such as race and ethnicity. The objective was to describe the change in household material hardship through patient reported outcome measures from baseline to six-months and explore the association between social determinants of health, including prospective household material hardship data, and clinical outcomes among children with brain and spinal cord tumors. METHODS We aimed to enroll 150 patients with a brain or spinal cord tumors who were followed by the Pediatric Neuro-Oncology Program at Riley Hospital for Children at IU Health. These participants were approached during their routinely scheduled clinic visits by a member of the study team. Written or verbal consent/assent was obtained, and their data was transcribed into a REDCap™ database. RESULTS To date, we have enrolled 118 children onto this study, with 35/76 participants completing their six-month follow-up survey. In line with Kira Bona’s previous work, we have found that around 30% acknowledged one positive domain of household material hardship. Additionally, we have found that almost 40% of our cohort fall below the 200% Federal Poverty Level, which is often considered a cutpoint for lower socioeconomic status. CONCLUSIONS We have shown that collecting prospective patient reported sociodemographic information is feasible in a busy clinical setting.
DIPG-17. DYSREGULATED PURINE METABOLISM IN A LETHAL CHILDHOOD BRAINSTEM TUMOR REVEALS NEW TREATMENT STRATEGIES WITH OLD DRUGS
Authors: Ian Mersich, Sunny Congrove, Matthew Horchar, Roman Caceres, Janki Desai, Pankaj Desai, Larry Sallans, Julie Haines, Ranjith Menon, Charles Stevenson, Peter de Blank, Natasha Pillay-Smiley, Trent Hummel, Ali Tavassoli, Angelo D’Alessandro, Timothy Phoenix, Biplab Dasgupta
Journal: Neuro-Oncology (2024)

Abstract The median survival of children with Diffuse Intrinsic Pontine Glioma (DIPG), an incurable brainstem cancer is less than 1 year. Radiation therapy is the only treatment that offers a transient benefit. The preclusion of surgery and biopsy due to the anatomical location of the tumor impeded our understanding of tumor biology for a long time. Genomic analysis during the past decade revealed that over 80% of DIPGs harbor an oncogenic histone H3K27M point mutation. However, the pathways altered by the mutation are still poorly understood. Metabolites serve as proxies to the state of biochemical pathways in a tissue. Given that unbiased a priori knowledge about metabolic alterations in DIPG is limited, we set out for the first time to identify metabolic dependencies intrinsic to DIPGs by leveraging untargeted and targeted metabolomics, transcriptomics, ChiP-Seq and ATAC-seq and integrating multi-omics datasets. We discovered that the mutant histone reprograms chromatin landscape causing aberrant misregulation of genes including a family of transcription factors that in turn causes misregulation of purine biosynthesis and folate metabolism. Specifically, the mutation alone is sufficient to upregulate a rate limiting bifunctional enzyme of de novo purine biosynthesis called ATIC, and the reduced folate carrier SLC19A1 to enhance purine synthesis and folate import, respectively, causing antifolate resistance. Genetic or pharmacological inhibition of ATIC greatly reduced tumor burden and extended survival in mice. Finally, folate removal from the microenvironment sensitized DIPGs to the antifolate methotrexate. Our studies identify ATIC as a novel target in DIPG and reveal a potential treatment strategy with antifolates in children with this lethal brain tumor.
DIPG-24. COMBINED EPIGENETIC THERAPY WITH FACT AND BET INHIBITORS REMODELS CHROMATIN AND DISRUPTS ONCOGENIC TRANSCRIPTION IN DIFFUSE MIDLINE GLIOMA
Authors: Holly Holliday, Aaminah Khan, Nisitha Jayatilleke, Chelsea Mayoh, Samuel E Ross, Xinyi Guo, Yolanda Colino Sanguino, Anjana Gopalakrishnan, Anahid Ehteda, Maria Tsoli, David S Ziegler
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Aberrant epigenetic regulation is a hallmark of Diffuse Midline Glioma (DMG), an incurable pediatric brain tumor. The H3K27M driver histone mutation leads to transcriptional dysregulation, indicating that targeting the epigenome and transcription may be a key therapeutic strategy against this aggressive cancer. One such target is the Facilitates Chromatin Transcription (FACT) histone chaperone. FACT is targeted by the curaxin compound CBL0137 which is currently in Phase I/II Children’s Oncology Group clinical trial as a single agent for pediatric cancer patients (NCT04870944). METHODS We applied a multi-omics approach by integrating epigenetic profiling with transcriptomics (CUT&amp;RUN, ATAC-seq and RNA-seq) to interrogate the role of FACT in DMG. We then employed in vitro cytotoxicity assays and in vivo orthotopic patient-derived xenograft (PDX) pre-clinical models to test a novel, mechanistic-anchored epigenetic combination therapy. RESULTS We found FACT to be enriched at developmental gene promoters, coinciding with regions of open chromatin and binding motifs of core DMG regulatory transcription factors (OLIG2, TCF12, and SNAI1). FACT interacted and co-localized with the Bromodomain and Extra-Terminal Domain (BET) protein BRD4 at active promoters and enhancers, suggesting functional cooperation between FACT and BRD4 in DMG. Investigating the combination of CBL0137 with two BET inhibitors (JQ1 and trotabresib) revealed potent cytotoxicity in vitro, particularly against H3K27M-mutant cells. Furthermore, this approach was recapitulated in vivo, significantly extending the survival of three independent orthotopic PDX models of DMG. Mechanistically, CBL0137 decreased chromatin accessibility, synergising with BET inhibition to disrupt transcription, leading to transcriptional silencing of several key oncogenes (MYC, PDGFRA and MDM4) as well as causing alterations to the splicing landscape. CONCLUSIONS This study highlights the therapeutic promise of simultaneously targeting FACT and BRD4 in DMG, and provides the rationale for a combination clinical trial, currently in development.
LGG-51. SYSTEMIC IMMUNE TOXICITY OF BRAF AND MEK-INHIBITORS IN CHILDREN: A PAN-CANADIAN SERIES
Authors: Tara McKeown, Samuele Renzi, Valerie Larouche, Rae Yeung, Cynthia Hawkins, Ute Bartels, Vijay Ramaswamy, Eric Bouffet, Uri Tabori, Julie Bennett, Anirban Das
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND BRAF/MEK-inhibitors have been transformative for pediatric gliomas with RAS/MAPK pathway aberrations. The RAS/MAPK pathway has a complex role in immune regulation. Though well-known in adults, the systemic immune-related adverse effects (irAE) of BRAF/MEKi in children are not widely reported. METHODS We performed a retrospective chart review for irAE following BRAF/MEKi in children treated at SickKids between 2016-2023. Additional patients were included through a pan-Canadian survey. RESULTS 136 patients on BRAF/MEKi were included (MEKi: 74%, BRAFi: 13%, BRAF+MEKi: 13%); irAE was reported in 6/136 (4.5%). One additional patient was included through the national survey. Median age was 14 years (range: 7-16). Male:female was 3:4. Three patients were on BRAFi, and two each on MEKi, and BRAF+MEKi. Early events developing within weeks of drug initiation included hyper-immune systemic inflammatory responses in three children on BRAFi and one child on MEKi. There was no evidence of any concomitant infection. Two children needed intensive care and showed evidence of multi-organ dysfunction. Delayed irAE developing after months to years on therapy included multi-systemic sarcoid-like reaction, parasympathetic dysautonomia (both on BRAF+MEKi) and brachial neuritis/Parsonage-Turner syndrome (MEKi). Management included drug holidays, dose reductions, and immunosuppressive treatment with steroids. Long-term steroids were needed in two of these seven patients. CONCLUSIONS Pediatric oncologists need to be aware of rare yet possibly under-reported systemic immune toxicity in children treated with BRAF/MEKi. They can present acutely, or while on chronic therapy. Management may be challenging in view of issues with rebound tumor growth on stopping some of these drugs, with select patients needing concomitant, long-term immunosuppressive therapy. Genetic susceptibility and biomarkers may need to be systematically studied in future clinical trials of novel RAS/MAPK inhibitors. Continued surveillance and reporting are needed for the marketed compounds, especially for children on long-term use of these inhibitors.
METB-09. VARIANT WORKBENCH IN THE KIDS FIRST PROGRAM FACILITATES GENOMIC DISCOVERIES IN PEDIATRIC NEURO-ONCOLOGY RESEARCH
Authors: Yiran Guo, Qi Li, Jare Rozowsky, Jeremy Costanza, Michele Mattioni, Jean-Philippe Thibert, Miguel Brown, David Higgins, Yuankun Zhu, Allison Heath, Adam Resnick, Vincent Ferretti
Journal: Neuro-Oncology (2024)

Abstract The Gabriella Miller Kids First Pediatric Research Program (Kids First) aims at facilitating researchers to uncover new insights into the biology of childhood cancer and structural birth defects, including the discovery of shared genetic pathways between these disorders. Kids First Data Resource Center developed the Kids First Data Resource Portal (KFDRP), which is a centralized data platform for both Kids First and collaborative cohorts. Currently, KFDRP facilitates data access for 40 studies with over 35,500 participants. To assist researchers and clinicians in identifying potential disease-causing germline variants in the human genome, KFDRP released the Variant WorkBench (VWB), which facilitates variant querying, manipulation, analysis, and visualization. Cavatica is a widely used bioinformatics analysis platform developed by Velsera. Compared to a previous version, the Cavatica-based VWB has better support for data import/export, more convenient sharing of notebooks and data, and easier billing details, with the same level of scalable, cloud-based computing. Additionally, Cavatica-based VWB has incorporated multiple public reference databases, including Cancer Hotspots, ClinVar, COSMIC, dbNSFP, gnomAD, TOPMed, as well as gene-phenotype links provided by OMIM, HPO, Orphanet, and the Deciphering Developmental Disorders Project. These databases have been converted to parquet files, reducing process time and memory usage compared to regular text files, thus speeding up data retrieval and querying. Furthermore, Cavatica empowers users to create and share custom analysis workflows tailored to specific research questions and datasets, enhancing data utility and analysis accuracy. Here we present a gene-based variant filtering workflow that aggregates information from dbNSFP, HGMD, TOPMed, gnomAD, and ClinVar. We identified 1202 pathogenic/likely pathogenic variants in NF1, a gene that helps regulate cell growth, across 582 pediatric brain tumor samples within 6 mins. Among the variants, there are 21 protein-altering variants. Overall, the upgraded VWB is more powerful, user-friendly, and adaptable.
DIPG-23. SAFETY AND TECHNICAL YIELD OF BRAINSTEM BIOPSIES IN CHILDREN – AN UPDATED META-ANALYSIS OF 1000 CASES
Authors: Shehryar R Sheikh, Neha J Patel, Violette Recinos
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brainstem tumors represent ~10% of pediatric brain tumors, ~80% of these are diffuse intrapontine gliomas (DIPG, primarily WHO Grade 4 midline glioma, H3 K27M-mutant). Given invariably poor prognosis in these cases, there continues to be immense variation (across the US and internationally) in performing biopsy of these lesions as opposed to making a presumptive diagnosis based on MRI. Several multi-center studies in recent years have aimed to show the safety profile of biopsy but an updated meta-analysis is lacking. METHODS We found 29 studies of pediatric brainstem biopsy in the last 20 years (2003-2023), representing data from 1002 children. We applied meta-analysis of proportions using a random-effects model to generate point estimates, confidence intervals, and measures of heterogeneity. RESULTS 87% of procedures were stereotactic needle biopsies (of these, 62% with a frame, 14% without frame, and 24% robotic.) Biopsy yield (i.e. the rate at which biopsy resulted in a tissue diagnosis) was 94% (95% CI 92-97). Temporary complications were seen in 6% (95 CI 4-8), most commonly including 1) radiographic evidence of bleeding or air without an associated fixed neurological deficit, 2) cranial nerve dysfunction, and 3) delayed awakening. Permanent complications (excluding death) were seen in 1% (95% CI 0.5-2), most commonly including cranial nerve dysfunction and limb weakness. 5 deaths were reported in the entire pooled cohort of 1002 children (0.5%). Gliomas represented 92% of tumors (95% CI 89-95). Of the gliomas for which WHO grading was provided, 68% were high grade (III/IV). CONCLUSION When counseling families on the merits of brainstem biopsy in children, it is reasonable to state that permanent morbidity is rare (&amp;lt; 2%). If biopsy is performed specifically to facilitate enrollment in clinical trials requiring a molecular diagnosis, the risks of biopsy outlined here should be weighed against potential benefits of trial enrollment.
IMG-27. ASSESSMENT OF VARIABILITY OF PEDIATRIC BRAIN TUMOR IMAGING PROTOCOLS ACROSS INSTITUTIONS: ARE WE FOLLOWING RECOMMENDATIONS?
Authors: Apoorva kotha, David L Yang, Mariam Aboian, Usha D Nagaraj, Aashim Bhatia, Adam Ezra Goldman-Yassen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Evaluating pediatric brain tumors requires imaging children with tailored MRI protocols. Considerable variation in pediatric brain tumor imaging protocols exist across institutions, which can cause inaccuracies in staging. Although recently consensus guidelines for pediatric brain tumor imaging protocols have been established, adherence to these guidelines across institutions is unknown. Institutions may perceive guidelines as applicable for research purposes rather than routine clinical practice. We aim to explore variability in pediatric brain tumor imaging protocols across institutions and determine the factors influencing guideline divergence. METHODS AND METHODOLOGY Faculty at institutions routinely imaging pediatric patients with brain tumors were invited to share brain tumor MRI protocols and complete a structured survey. The survey included multiple choice and open-ended queries concerning practice type, the presence of an institutional imaging protocol for pediatric brain tumors and if the protocol was based on specific consensus recommendations. We assessed if protocols included the 7 minimum recommended MRI sequences by the Children’s Oncology Group (COG) guidelines, including slice thickness and gap. RESULTS Twenty emails were sent and responses were received from 12 institutions (the data collection is still ongoing). 2 institutions did not have dedicated protocols for pediatric brain tumors. On average, institutions had 5.7 out of the 7 minimum COG-recommended sequences. All 10 institutions included 3D T1 IR-GRE/TSE, DWI or DTI, and SWI sequences in their protocols. 9 (90%) included post-contrast 3D T1 IR-GRE/TSE, 7 (70%) included T2 TSE/FSE, 7 (70%) included either 3D T2 FLAIR or T2 FLAIR TSE/FSE, and 4 (40%) included T1/TSE/FSE. Across all sequences in all protocols, adherence to recommended imaging parameters was 87% for plane, 71% for slice thickness, and 85% for gap. CONCLUSION Significant variability in pediatric brain tumor imaging protocols exists across institutions Standardizing imaging protocols through collaboration is vital in ensuring uniformity in care.
EPEN-07. USP7 IS AN INTERACTION PARTNER OF EZHIP AND POTENTIAL DRUGGABLE TARGET IN PFA EPENDYMOMAS
Authors: Anne Jenseit, Aylin Camgöz, Monika Mauermann, Norman Mack, Benjamin Schwalm, Jacqueline Mohr, Sophie Wittenburg, Christian Steinebach, Michael Gütschow, Heike Peterziel, Aileen Friedenauer, Carola Jaunecker, Daniela Lötsch-Gojo, Ina Oehme, Stefan M Pfister, Marcel Kool
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Ependymomas (EPN) arise in the supratentorial brain (ST-EPN), posterior fossa (PF-EPN), or the spinal cord (SP-EPN), in children and adults. Among the three molecular PF-EPN groups, PFAs are characterized by young median age at diagnosis, a balanced genome and poor outcome. Recently, enhancer of zeste inhibiting protein (EZHIP) has been identified as potential driver of PFAs. By inhibiting EZH2, EZHIP prevents the distribution of the epigenetic repressor mark H3K27me3. Without known enzymatic functions though, EZHIP isn´t the urgently needed drug target. We therefore focused on essential and potentially druggable interaction partners. METHODS We investigated protein-protein interactions using co-immunofluorescence, co- immunoprecipitation and proximity-based assays. We utilized CRIPSR/Cas9 and shRNAs-based methods, mutagenesis and PROTAC treatments followed by Western Blot or mass spectrometry for functional analyses. Viability and apoptosis after drug treatments was assessed in vitro by metabolic readouts, synergy was determined using matrix layouts. RESULTS We identified ubiquitin-specific protease 7 (USP7), a known cancer regulator with multiple inhibitors available as direct interaction partner of EZHIP in PFA. We confirmed their interaction in PFA cells and showed that the EZHIP-USP7 interaction is independent of EZH2, a separate interactor of both. Functionally, we show that USP7 de-ubiquitinates EZHIP, preventing its degradation and thus stabilizing it, mediated via the six lysine residues present in EZHIP. We reveal a vulnerability of PFA cells to genetically engineered losses of EZHIP and USP7. Moreover, USP7 inhibitors highly affected the survival and induced apoptosis in different PFA cell lines at a low micromolar IC50 in vitro. Mid-throughput drug library screens additionally identified BET inhibitors as synergistic partners. In vivo treatments with the combination of USP7 and clinically achievable doses of BET inhibitors in PFA PDX models are ongoing. CONCLUSIONS USP7 de-ubiquitinates and thus stabilizes EZHIP, which qualifies it as a candidate therapeutic target in pediatric PFA ependymoma.
EPEN-05. SURGERY FOR CHILDHOOD EPENDYMOMA: THE EPENDYMOMA MULTIDISCIPLINARY ADVISORY GROUP (EMAG) CLINICAL TRIAL EXPERIENCE
Authors: Timothy A Ritzmann, Rebecca J Chapman, Rheanne Leatherland, John Goodden, Donald Macarthur, Conor Mallucci, Ian Kamaly, Barry Pizer, Richard G Grundy
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION The National Ependymoma Multidisciplinary Advisory Group (EMAG) is the central review mechanism for the SIOP Ependymoma II clinical trial in the UK. EMAG is a multiprofessional group which meets weekly to support decision making. We report detailed surgical outcomes for children with confirmed intracranial ependymoma, discussed through EMAG between January 2020 and November 2022. METHODS Data was collected on resection status, surgical outcomes, reasons for not achieving Gross Total Resection (GTR), number of surgeries and adjuvant therapies. Data was analysed descriptively. RESULTS After first surgery, GTR or near total resection (NTR) rate was 69/105 (66%) rising to 83/105 (79%) following repeated surgeries. 17 patients underwent second-look surgery prior to further therapy, whilst 9 underwent second-look surgery after chemotherapy but before radiotherapy. Eight (17%) posterior fossa (PF) surgeries were not completed due to factors including patient instability and tumour attachments. Most post-operative problems were seen in PF tumours with 26/60 (43%) bulbar palsy, 13/60 (22%) focal weakness and 12/60 (20%) cerebellar mutism. Incomplete PF resections were associated with increased bulbar palsy risk (p=0.02, Chi-Square test). 73% of PF patients required hydrocephalus management with external ventricular drainage, endoscopic third ventriculostomy (ETV) or shunt. Longer term hydrocephalus management with ETV or shunt was required in 29% and was more common in those with subtotal resection (R3-RX, 8/16, 50%) compared to GTR or NTR (R0-R2, 9/43, 21%, p=0.03). 27/60 (45%) received post-op NG feeding and 2/60 (3%) needed tracheostomies. Second surgery was associated with lower complication rates. DISCUSSION Our National MDT approach supports collaborative surgical decision making without a need for centralisation of the surgery itself. There was no evidence of increased complication rates compared to historical trials despite a more aggressive surgical approach. We argue for continued centralisation of EPN evaluation to support optimal care for children with this devastating disease.