tbuckley/cabot-search huggingface dataset:
QOL-44. EARLY SEVERE HEARING LOSS IN CANADIAN CHILDREN WITH CENTRAL NERVOUS SYSTEM TUMORS: A POPULATION-BASED COHORT STUDY
Authors: Hallie Coltin, Ofélie Trudeau-Ferrin, Sébastien Perreault, Lucie Lafay-Cousin, Samuele Renzi, Valérie Larouche, Craig Erker, Eric Bouffet, Vijay Ramaswamy
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Severe treatment-related hearing loss (HL) is associated with devastating psychosocial/neurocognitive outcomes. Children with central nervous system (CNS) tumors are highly vulnerable to severe HL due to tumor location and treatment exposures. This is the first study to report national CNS tumor-specific rates and predictors of early severe HL. METHODS We conducted a retrospective, population-based cohort study of all children ≤15yrs at diagnosis with CNS tumors between 2001-2019 using the Cancer in Young People in Canada registry. The primary outcome was Common Terminology Criteria for Adverse Events grade 3/4 HL ≤5yrs following diagnosis. We determined prevalence and probabilities of early HL; predictors were determined using multivariable logistic regression models. RESULTS Among 3,201 children with CNS tumors, 5.1% experienced early HL. Children with medulloblastoma (N=570) and ATRT/other embryonal tumors (N=269) experienced disproportionate rates (16.1%, 15.2%, respectively); 85.4% (medulloblastoma) and 68.8% (ATRT/other embryonal) received cisplatin, 74.6% (medulloblastoma) and 52.1% (ATRT/other embryonal) were irradiated. In children with medulloblastoma, when controlling for follow-up, age &amp;lt;=5yrs at diagnosis [odds ratio (OR) 2.4, 1.5-3.8], radiation (OR 3.5, 1.6-7.6), and cisplatin (OR 20.4, 1.3-329.7) predicted early HL. In children with medulloblastoma post cisplatin, age ≤5yrs at diagnosis doubled the probability of early HL in both irradiated (29.8%, vs 15.3% if &amp;gt;5yrs at diagnosis) and non-irradiated patients (10.6% vs 4.8% if &amp;gt;5yrs at diagnosis). In children with ATRT/other embryonal, cisplatin (OR 28.2, 1.7-472.1) was the only predictor of early HL. CONCLUSIONS In the largest population-based study of early severe HL in children with CNS tumors, we report striking rates in children with embryonal tumors. Younger irradiated children had disproportionate probabilities of early HL, suggesting a novel additive interaction between age at diagnosis and radiation. Standardized otoprotection and research focusing on therapy de-escalation in young children with embryonal tumors are urgently needed.
NFS-09.<i>NF1</i> MUTATION IN OLIGODENDROCYTE PRECURSOR CELLS LEADS TO PRENEOPLASTIC LESION FORMATION IN THE BRAIN
Authors: Yuan Pan, Jared Hysinger, Belgin Yalçın, James Lennon, Youkyeong Gloria Byun, Preethi Raghavan, Nicole Schindler, Corina Anastasaki, Jit Chatterjee, Lijun Ni, Haojun Xu, Karen Malacon, Samin Jahan, Alexis Ivec, Benjamin Aghoghovwia, Christopher Mount, Surya Nagaraja, Suzanne Scheaffer, Laura Attardi, David Gutmann, Michelle Monje
Journal: Neuro-Oncology (2024)

Abstract Oligodendrocyte precursor cells (OPCs) are progenitor cells that give rise to central nervous system oligodendrocytes throughout life. Transcriptomic and lineage tracing studies suggest that OPCs may be the putative cell of origin for many glioma histologic subtypes. While children with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome are prone to low-grade gliomas following bi-allelic NF1 loss, the cellular and molecular etiologies underlying tumorigenesis remain incompletely elucidated. Using a unique collection of genetically engineered Nf1 mouse strains, we identified discrete hyperdense lesions composed of OPCs. The OPCs within the lesions display a transient increase in proliferation and hypercellularity (hyperplasia). This phenotype was not observed following heterozygous mutation in other tumor suppressors (Trp53, Pten, or Rb1). OPC-specific heterozygous Nf1-mutant mice harbored similar lesions, suggesting an OPC-intrinsic phenotype. OPC-specific Nf1 loss resulted in increased OPC density throughout the entire brain, suggesting that the lesions in heterozygous Nf1-mutant mice represent spontaneous OPC Nf1 loss-of-heterozygosity events. Mechanistically, monoallelic KRAS hyperactivation phenocopies OPC hyperdensities in the brain of Nf1+/- mice; however, KRAS hyperactivity is not necessary for lesion formation or expansion. When the brains of mice engineered with heterozygous NF1 patient-derived Nf1 mutations were examined, the development of hyperdense OPC lesions reflected RAS-independent dysregulated PI3K-AKT signaling. Collectively, our study reveals a potential mechanism driving the development of preneoplastic lesions in the brains of individuals with NF1.
NFS-11. PHASE II STUDY OF AXITINIB IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 2-RELATED SCHWANNOMATOSIS AND PROGRESSIVE VESTIBULAR SCHWANNOMAS
Authors: Mekka R Garcia, Mari Hagiwara, Anna Yaffe, Carole Mitchell, Srivandana Akshintala, Theodore Nicolaides, Sheetal S Phadnis, Kaleb Yohay, Yang Feng, Judith D Goldberg, Jeffrey C Allen, Matthias A Karajannis
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Axitinib is an oral multi-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), and c-KIT. These represent a clinically and/or preclinically validated molecular targets in vestibular schwannoma (VS). METHODS Eligible participants were age &amp;gt;5 years with a clinical diagnosis of neurofibromatosis type 2-related schwannomatosis (NF2-SWN) and at least one volumetrically measurable, progressive VS. Axitinib was given continuously in 28-day cycles for up to of 12 cycles. Primary endpoint was objective volumetric response rate to axitinib, hearing response was a secondary endpoint, along with validated quality of life assessments (NFTI-QOL). RESULTS Twelve participants were enrolled and eight completed 12 cycles, including two pediatric patients. Two patients were non-evaluable due to coming off study prior to the first scheduled response evaluation: one withdrew from the study for personal reasons and one for non-compliance. Due to slowing accrual, the study closed prior to meeting planned enrollment of 17 evaluable patients. Ten patients were evaluable for the primary endpoint, defined as ≥20% decrease in VS volume, with two volumetric responses observed; both were reached after three cycles and sustained during treatment. Best volumetric response was −53.9% after nine cycles. Hearing response was evaluable in nine participants, with three hearing responses observed, one of which was sustained during treatment. All participants experienced drug-related toxicities, the most common were diarrhea, hematuria and skin toxicity, not exceeding grade 2, as well as hypertension, not exceeding grade 3. NFTI-QOL scores remained stable or improved during treatment in all participants. CONCLUSIONS Axitinib therapy targeting VEGFR, PDGFR and c-KIT is feasible in this population and associated with volumetric and hearing responses in a subset of patients. The convenience of oral administration appears to be offset, however, by increased toxicity and lower response rates compared to VEGF-A targeted therapy with bevacizumab.
QOL-50. THE ROLE OF TUMOR SIZE IN COGNITIVE FUNCTIONING AMONG SURVIVORS TREATED FOR MEDULLOBLASTOMA
Authors: Kimberly P Raghubar, Krystal Christopher, Se-Kang Kim, Lisa Mash, Heather Stancel, Kelley Parsons, Natasha Feuerbach, Maheen Rizvi, Arnold Paulino, David Grosshans, M Fatih Okcu, Lisa S Kahalley, Murali Chintagumpala
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medical and treatment variables, including presence of post-operative cerebellar mutism syndrome (CMS), shunt placement, craniospinal radiation, and total radiotherapy (RT) dose, have been evaluated as potential risk factors for adverse cognitive effects among pediatric patients diagnosed and treated for medulloblastoma. Larger brain tumor size is associated with increased risk of medical complications, but cognitive risk of larger tumor size remains unknown. METHODS Cognitive scores were examined for 40 participants diagnosed and treated for medulloblastoma. The age-appropriate Wechsler Intelligence Scale was administered at the start of RT and up to 10 years post-RT (M=4.96, SD=3.78). A total of 162 evaluations were examined across participants. Linear mixed models examined change in Wechsler Index scores over time since RT based on tumor size, which was dichotomized at the median diameter (small ≤4.6cm versus large &amp;gt;4.6cm), covarying for maternal education, total RT dose, and presence of CMS. RESULTS Patients (72.5% male) were diagnosed with medulloblastoma and began RT at a mean age of 8.89 years. Groups did not differ on demographic or medical variables with the exception of presence/absence of CMS, with a higher proportion of patients diagnosed with CMS having large-size tumors (40%) versus small-size tumors (5%). Tumor size did not predict change in IQ, working memory, or processing speed performance over time since RT after accounting for covariates. CMS was associated with significant decline in processing speed (p&amp;lt;.001) and IQ over time (p&amp;lt;.05); RT dose was associated with significant working memory and IQ decline (both p&amp;lt;.05); and maternal education was associated with decline in processing speed, working memory, and IQ (all p&amp;lt;.05). CONCLUSIONS While tumor size may be associated with treatment intensity and other medical risk factors, CMS and RT dose significantly increase cognitive risk, independent of tumor size. Lower socioeconomic status also increases cognitive risk post-RT, which may illuminate pathways for prevention and intervention efforts.
DIPG-92. IMMUNE ACTIVATION STUDIES WITH THE NEOANTIGEN-BASED PEPTIDE VACCINE RHSC-DIPGVAX DEMONSTRATE ANTIBODY-MEDIATED RESPONSES AND EPITOPE SPREADING IN PEDIATRIC PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPG)
Authors: Patrick Sipila, Lauren Boland, Jason M Miska, Susan N Chi, Mariko Sato, Ashley S Plant-Fox, Aru Narendran
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Approximately 80% of DIPGs carry gain-of-function lysine-to-methionine (K27M) mutations in histone H3 proteins that frequently co-occur with other protein aberrations, including p53, ACVR1, and PDGFRA. Because the DIPG microenvironment has few infiltrating immune cells, resolution of negative regulatory mechanisms through checkpoint blockade may be necessary to promote vaccine-induced anti-tumor responses. Accordingly, rHSC-DIPGVax is a neoantigen-based peptide vaccine combined with checkpoint inhibitors currently under investigation in clinical trial, NCT04943848. The vaccine contains 16 neoantigen peptides, QS-21 adjuvant, and recombinant heat shock protein, Hsc70. In this study, we investigate vaccine-induced antibody-mediated immunity and the phenomenon of epitope spreading, an extension of the immune response to secondary epitopes not directly targeted by the therapy, thus promoting distinct, individualized responses. METHODS rHSC-DIPGVax is administered every two weeks to patients with DIPG and blood is collected pre-treatment and prior to each dose. To investigate vaccine-induced immunoreactivity to neoantigens targeted by rHSC-DIPGVax, DIPG lysates resolved by two-dimensional gel electrophoresis are immunoblotted with pre- and post-vaccine patient plasma containing antibodies against vaccine antigens. Proteins are immunoprecipitated (IP) from DIPG lysates, followed by mass spectrometry (MS) identification and validation. RESULTS In eight subjects to date, vaccination with rHSC-DIPGVax consistently induces IgM and IgG antibodies against proteins directly targeted by the vaccine, including strong immunoreactivity to ACVR1. Furthermore, antibodies against several secondary proteins are also detected in post-vaccination plasma. Immunoblotting and IP-MS analysis identified several distinct candidates of epitope spreading, including the tumor antigens CEP290, DNAH3, HRNR, KDM6B, LAMA5, and TRPA1. CONCLUSIONS rHSC-DIPGVax induces antibody-mediated tumor-specific responses to DIPG neoantigens, including direct vaccine targets and secondary targets via intra- and inter-molecular epitope spreading. We also present an experimental protocol to investigate vaccine-induced immune activation. Our ongoing studies aim to validate epitope spreading candidates and determine the important biological correlates between antibody responses and clinical outcomes.
HGG-25. IDENTIFYING YB1 AND NPM1 AS PART OF THE MUTANT HISTONE 3 PROTEIN INTERACTOME IN H3 MUTATED PHGG
Authors: Mehar Dhillon, Eleanor Read, Rob Layfeild, Farhana Haque
Journal: Neuro-Oncology (2024)

Abstract Paediatric high-grade gliomas (pHGG) are the leading cause of childhood cancer deaths, accounting for over 40% of deaths in the UK. pHGG tumours harbour histone H3 mutations, defining 50% of pHGG cases. Studies show prominent mutations as being H3.3K27M and H3.3G34R/V. Our previous proteomic research on H3 intercatomes, identified unique and common interacting binding partners of H3-G34R and H3-G34V mutant proteins relative to wild type H3. Among these proteins we have focused on YB-1 and Nucleophosmin 1 (NPM1). YB-1, is multifunctional transcription factor and a well-characterised oncogenic protein. NPM1 is a molecular chaperone and frequently overexpressed in cancers. Our aim is to analyse the role of YB-1 and NPM1 in H3 mutated pHGG, in order to identify targeted therapeutic options for these difficult to treat tumours. H3 mutated glioma cell lines, H3 wild type pHGG cells and control cells were cultured and then subjected to comparative immunofluorescence microscopy, and western blot analyses to investigate YB-1 and NPM1 expression. Results showed statistically significant altered protein expression and localisation of YB-1 and NPM1 in H3 mutated pHGG in comparison to wild type and control cells. YB-1 expression was increased in H3 mutated cells and NPM1 showed increased cytoplasmic localization in H3 mutated cells in comparison to H3 WT glioma and control cells. Results of the study support that YB-1 and NPM1 are important interacting proteins in H3G34-mutated pHGGs and can be explored as potential therapeutic targets in H3 mutated pHGG.
DIPG-91. CLINICAL, RADIOGRAPHIC, HISTOPATHOLOGIC, AND MOLECULAR CHARACTERISTICS OF LONG-TERM SURVIVORS OF DIFFUSE INTRINSIC PONTINE GLIOMA-AN UPDATE FROM THE INTERNATIONAL AND EUROPEAN SOCIETY FOR PEDIATRIC ONCOLOGY DIPG REGISTRIES (IDIPGR/SIOPE-DIPGR)
Authors: Natasha Pillay-Smiley, Gunther Nussbaumer, Carin Damen-Corbijn, Joshua Baugh, Aaron Webster, Adam Lane, T C Godschalk, Jacques Grill, Cynthia Hawkins, James Leach, Geert Janssens, Blaise Jones, Maura Massimino, Michael Karremann, Dannis G van Vuurden, Simon Bailey, Anirban Das, Ulrich-Wilhelm Thomale, Stewart Goldman, Sebastien Perreault, Veronica Biassoni, Jane Minturn, Trent Hummel, Christof Kramm, Sophie Veldhuijzen van Zanten, Lindsey M Hoffman
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a childhood tumor with median survival of &amp;lt; 1 year. Survival-associated factors for this rare disease are poorly understood. METHODS Clinical, radiological, and histo-molecular data were abstracted from databases of the IDIPGR and SIOPE-DIPGR and analyzed using descriptive statistics. Survival was estimated by the Kaplan Meier method. Short term survivors (STS) were defined as overall survival (OS) &amp;lt; 2 years, and long term survivors (LTS) had OS &amp;gt;2 years. We present data from the IDIPGR with additional analyses forthcoming. RESULTS Analysis included 1123 patients with DIPG, with 476 undergoing central radiographic review. Median OS for the entire cohort was 11 months (IQR 7-15 months), with 2 yr OS 6.9% (5.6% to 8.6%). Median age at diagnosis was 6.6 years (5-9.7 years) for 1045 STS (93.1%) and 6.8 years (3.7-13 years) for 78 LTS (6.9%). Factors significantly associated with LTS included longer symptom duration (STS 73.7% vs LTS 42%; p&amp;lt;0.001), age &amp;lt; 3 and &amp;gt; 10 years (STS 4.5 and 22.8% vs LTS 17.9 and 35.9%; p&amp;lt;0.0001), and receipt of chemotherapy at any time during therapy (STS 54.7% vs LTS 67.9%; p=0.025). A similar percentage of STS and LTS received EGFR, MTOR, PI3K, HDAC, local delivery and immunotherapy, although more LTS used VEGF inhibition (20.5 % vs 8.6%; p = 0.002). Of 104 patients with molecular data, 69 harbored the H3.3 histone mutations (7 LTS, 62 STS), and 15 had H3.1(3 LTS, 12 STS). CONCLUSION Early analysis of factors associated with survival in patients with DIPG reveal similar findings as the prior IDIPGR/SIOPE-DIPGR study in 2018. These findings will be updated for the final presentation to include ~400 more cases and additional radiological and molecular data.
HGG-23. MAPPING GENETIC DEPENDENCIES IN PAEDIATRIC HIGH GRADE GLIOMAS AT GENOME-SCALE
Authors: Vanessa Tsui, Yuqing Liang, Hanbyeol Lee, Yichen Zhou, Claire Sun, Paul Daniel, Ron Firestein
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric high-grade gliomas (HGGs) present a therapeutic challenge due to their aggressive behavior and limited treatment options. Traditional treatments often fall short in addressing the genetic complexity and aggressiveness of pediatric HGGs, urging the search for and validation of novel genetic dependencies as potential therapeutic targets. METHODS Loss of function CRISPR screens enable the systematic investigation of gene function by selectively disrupting gene expression, offering invaluable insights into the genetic dependencies fuelling tumor growth and survival. Herein, we conducted genome-scale, loss of function CRISPR/Cas12 screens across genetically-defined subtypes of pediatric HGG, including diffuse midline gliomas (n=30 cell lines). RESULTS Distinct genetic dependencies exclusive to pediatric high-grade gliomas (pHGG) are uncovered compared to their adult counterparts, particularly within druggable pathways. These dependencies are associated with specific pathways such as cellular metabolism, epigenetics, and tissue development. Notably, histone-altered subtypes of pHGG exhibit dependency on distinct gene sets for growth. Furthermore, machine learning techniques are applied to correlate various -omics features (RNA, DNA, epigenomics, proteomics) with genetic dependencies, facilitating the identification of biomarkers predictive of therapeutic response. CONCLUSION Our work provides a comprehensive genetic dependency map of pHGG. We expect this data to serve as a springboard for enriching our biological understanding of pHGG, ultimately improving clinical outcomes and quality of life.
RADT-11. PROTON BEAM THERAPY (PBT) FOR CENTRAL NERVOUS SYSTEM (CNS) TUMOURS IN CHILDREN: A CANADIAN PEDIATRIC BRAIN TUMOUR CONSORTIUM STUDY
Authors: Kendrew S K Wong, Samir Patel, Lucie Lafay-Cousin, Natalie Logie, Paul D’Alessandro, Vanan Magimairajan, Chantel Cacciotti, Sebastien Perreault, Melanie Alves, Marie Galopin, Éloise Poirier, Sonia Skamene, Samuel Bergeron-Gravel, Simon Lagacé, Anne-Marie Charpentier, Craig Erker, Bruce Crooks, Rob Rutledge, Ash Sandhu, Beth Brooks, Andrea C Lo, Derek S Tsang, Sylvia Cheng
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Radiotherapy is important for treating pediatric CNS tumours. The main modalities include photon therapy and PBT. PBT offers potential advantages over photon therapy in children since its precise dose control can limit long-term side effects. However, Canadian patients needing PBT are referred to the United States (US) because PBT is unavailable in Canada. We aimed to describe PBT use and outcomes over time for Canadian pediatric patients with CNS tumours. METHODS Patient demographics, treatment characteristics, and outcomes were extracted from medical records of patients from 10/13 Canadian provinces/territories. Patients diagnosed with a CNS tumour at ≤20 years old between 2001-2021 who received curative-intent PBT were included. PBT plans were compared using Fisher’s exact or Kruskal-Wallis rank sum tests. Overall survival (OS) was estimated using the Kaplan-Meier method. RESULTS Of 195 patients (59.0% male) included in the study, majority were from Alberta (28.7%), Quebec (26.7%), British Columbia (22.6%), and Ontario (20.5%). Median age at diagnosis was 8.0 years. Most tumours (77.9%) were non-metastatic. Medulloblastoma was the most common diagnosis (30.8%). Provinces/territories referred patients to proton centres in the same geographical regions, except Alberta (74.5% referred to Florida). Referral numbers have increased ~180%/year since 2011. Median time from diagnosis to PBT was 126 days [11-5236] for all patients, and 36 days [21-1313] for medulloblastoma. Radiation doses, irradiation site, therapy duration, and time to treatment were not different (p≥0.2) across all PBT facilities for medulloblastoma. 5-year OS were 86.8% and 73.0% for the PBT study population and the Cancer in Young People-Canada reference population, respectively, in those aged &amp;lt;15 years. CONCLUSIONS Given the unavailability of PBT in Canada, pediatric CNS tumour patients were referred to US PBT facilities close in proximity. Further studies are needed to better understand provincial referral patterns and barriers to equitable PBT access across Canada.
NFS-04. GENETIC COUNSELLING IN A MULTI-TUMOR PREDISPOSITION SYNDROME: A NOVEL FOUR-GENERATION TUNISIAN PEDIGREE
Authors: Nouha Bouayed Abdelmoula, Balkiss Abdelmoula
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Cancer predisposition syndromes associated with an increased risk of CNS tumors and colorectal polyposis are heterogeneous inherited disorders associated with multiples genes. The delineation of the inheritance pattern and the management of the genetic testing are recommended for optimal care of patients and their families. Our aim was to report a cancer predisposition brain tumor-polyposis syndrome in a four-generation Tunisian consanguineous pedigree characterized by uncommon tumors localizations. METHODS The index case was a 43-year-old infertile woman presented to our genetic counselling because of a suspected familial cancer predisposition syndrome. She consulted for digestive symptoms with epigastralgia. Six adenomatous polyposis of the colon were confirmed histologically. Her sister died of colon cancer at the age of 50. She developed a malignant mesenteric recurrence after surgical resection of a moderately differentiated adenocarcinoma infiltrating the meso fat with lymph node metastases. Their three sisters and brother did not have any cancer. From the same third generation, only one cousin died of a brain cancer identified as a glioblastoma at the age of 43. Their maternal grandmother and her two brothers died of respectively breast, laryngeal and urothelial cancers. The second generation and fourth generation involved healthy members. RESULTS Analysis of the pedigree of this family indicated an autosomal recessive mode of inheritance of the brain tumor-polyposis syndrome. Clinically, there was uncommon association with breast, laryngeal and urothelial cancers in the first generation and brain/colon cancers in the third generation. CONCLUSIONS A recessive multi-tumor predisposition syndrome related to high microsatellite instability resulting in a mismatch repair deficiency seems to be the most reliable diagnosis in this family. Familial NTHL1 tumor and MUTYH associated polyposis syndromes were also suspected. NGS-based testing, from whole exome sequencing to multigene panel testing, is suggested as the most accurate genetic testing in such heterogeneous multi-tumor predisposition syndromes.