tbuckley/cabot-search huggingface dataset:
QOL-49. BOOKS4BRAINS: PILOTING A COMMUNITY CIRCLE BOOK CLUB TO IMPROVE SELF EXPRESSION
Authors: Kelsey M Knight, Susan Appel, Scott L Coven
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Children with brain or spinal cord tumors often have limited interactions with their primary care providers who focus on developmentally appropriate recommendations, including the assessment of literacy. Additionally, we know that children with brain or spinal cord tumors have neurocognitive disruptions secondary to their diagnosis. Due to their disease process, these children are at high-risk for learning difficulties. We want to assist in building their self-confidence and acceptance. The objective was to provide a monthly virtual experience that utilized books, creative writing, and illustration to build a community centered on trust, shared experiences, and discussions of social emotional tools. METHODS We aimed to enroll 40 total participants diagnosed with a brain or spinal cord tumor who were followed by the Pediatric Neuro-Oncology Program at Riley Hospital for Children. These participants were divided amongst two groups: 1st-3rd grade and 6th-8th grade. After final enrollment, we had a total of 30 participants that received the following supplies: a copy of each months book, an audio recording of each book, and creative writing and craft supplies for each session. RESULTS We held three monthly hour-long virtual sessions for each group on Saturday mornings. Ten total children were available to meet consistently over the two groups. Positive feedback we received included, “we loved it,” “everyone felt included in book time,” and “[it] was so helpful that the books were read out loud and it was amazing to have the read along aspect with it for her visual impairment.” We even heard from one caregiver that “[they] noticed that she has some more tools in her toolbox when she is facing a difficult day.” CONCLUSIONS A pilot community book club is feasible through community partnerships. We plan to build on this experience by focusing on improving consistent attendance in future sessions.
HGG-29. INTEGRATED MOLECULAR PROFILING OF &amp;gt;2000 PAEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMA TUMOURS AND &amp;gt;100 PATIENT-DERIVED MODELS
Authors: Alan Mackay, Yura Grabovska, Diana Carvalho, Anna Burford, Rita Pereira, Sara Temelso, Drenusha Sejdiu, Shauna Crampsie, Valeria Molinari, Rebecca Rogers, Ketty Kessler, Lynn Bjerke, Les Bridges, Zita Reisz, Safa Al-Sarraj, Navneet Singh, Simon Stapleton, Cristina Bleil, Samantha Hittite, Bassel Debian, Julia Cockle, Fernando Carceller, Matthew Clarke, Chris Jones
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Paediatric-type diffuse high-grade glioma (PDHGG) is recognised in the WHO2021 CNS Tumour Classification as biologically distinct from ‘adult-types’, and comprises four major categories based on distinct biology and clinical presentation, though sub-types within these are less well-defined. METHODS Published and unpublished genome/exome/targeted sequencing from n=1593 cases were integrated with n=2027 cases with methylation array profiling, with an overlap of n=761. These were supplemented with varying availability of bulk/single-cell RNAseq, ChIP-seq and ATAC-seq, and analysed alongside data from ~100 patient-derived models representing 16 PDHGG sub-types. RESULTS Around half of cases were diffuse midline glioma with H3K27 alterations (DMG-H3K27), which can be split into sub-types based upon either the specific histone alteration (DMG-H3.3K27M/-H3.1K27M/-EZHIP) or co-segregating pathway activating mutations (DMG-EGFR/-MAPK/-ACVR1). These showed distinct copy number, transcriptomic and epigenetic signatures depending on the anatomical location, replicated in ~50 models established as 2D/3D cultures and CDX/PDX. By contrast, diffuse hemispheric glioma with H3G34 mutations (DHG-H3G34) presented a homogenous genomic landscape (TP53/ATRX/PDGFRA) but with a higher degree of transcriptional diversity in both tumours and models. In high-grade glioma, H3/IDH-wild-type (HGG-WT) samples, receptor tyrosine kinase (RTK) subtypes are split by the presence or absence of co-segregating mutations (BCOR/SETD2/NF1) and copy number changes. Across methylation-based subtypes, genetic drivers are associated with distinct phenotypes or drug responses independent of location. EGFR mutations are largely confined to the highly infiltrative pedHGG_RTK2 hemispheric (enriched in gliomatosis cerebri) and DMG-EGFR (bithalamic glioma) subtypes, whilst PDGFRAmutations span DMG-H3.3K27M, DHG-H3G34, and pedHGG-RTK1, and exhibit a differential drug response to targeted therapies depending on the nature of the alteration. Hypermutant tumours are split between pedHGG-RTK1A and the emerging ‘HGG-E’ subtype. CONCLUSIONS These data aim to catalogue the diversity of PDHGG subtypes in order to identify biologically rational targets, and credential patient-derived models which can be exploited for mechanistic/preclinical studies.
STEM-01. DEVELOPMENT OF A HUMAN-SPECIFIC 3D<i>IN VITRO</i> PAEDIATRIC CEREBELLAR TUMOUR MODEL USING DECELLULARISED BRAIN AUTOPSY TISSUE
Authors: Phoebe McCrorie, Harry Porter, Mohammed Diksin, Cara Moloney, Richard Grundy, Ruman Rahman
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB) and Atypical Teratoid/ Rhabdoid Tumours (ATRT) represent paediatric cerebellar tumours with a dismal prognosis. For ATRT in particular, 5-year survival remains at less than 32%. We have developed a 3D in vitro model termed ‘tumoursphere matrix’ which recapitulates in vivo crosstalk between tumour and reactive brain. METHODS AND RESULTS We co-cultured D283 (Group 3-MYC amplified MB) and BT12 (ATRT-MYC) cells with primary human cerebellar astrocytes within a PEGDA hydrogel containing decellularised cerebellar extracellular matrix (ECM) derived from non-disease human autopsy brain. Cerebellar ECM was extensively characterised, showing a significant reduction in cellular material whilst retaining ECM ligands. Reduction of DNA content to 174 ng/mg was corroborated by an absence of nuclei in immunohistochemical staining. Colorimetric assays indicated collagen and glycosaminoglycan retention in decellularised ECM, and Immunofluorescence confirmed retention of fibronectin, laminin and hyaluronic acid. Detection of all ECM ligands was cross-validated by Orbitrap-Secondary Ion Mass Spectrometry. A solubilised ECM/PEGDA hydrogel was used to coat an AggreWell™ plate. Primary human cerebellar astrocytes, D283 and BT12 cells were cultured as spheroids within the ECM/PEGDA hydrogel for 7 days with no significant decrease in cellular viability. Cytokine and Human Matrix Metalloproteinase (MMP) Antibody Arrays showed cytokine and MMP expression in all three cell lines was retained in the presence of ECM material. Furthermore, D283 and BT12 cells were co-cultured with primary astrocytes for 7 days prior to separation using fluorescence activated cell sorting to generate individual cell populations. CONCLUSIONS We have developed a 3D in vitro model which can co-culture cells for over 7 days, whilst recapitulating the in vivo tumour environment. RNA sequencing is currently in progress to identify differentially expressed genes in cerebellar tumour cells upon astrocytic and brain ECM crosstalk. We hypothesise that biochemical signalling underlying this communication will reveal putative therapeutic vulnerabilities.
NFS-08. CLINICAL AND MOLECULAR FEATURES OF HIGH-GRADE GLIOMA IN CHILDREN AND ADULTS WITH NEUROFIBROMATOSIS TYPE 1: A PRELIMINARY ANALYSIS
Authors: Chelsea Kotch, David A Solomon, Keri Wallace, Peter M de Blank, Yimei Li, Franziska Mbonglou, Alyssa T Reddy, David H Gutmann, Anna F Piotrowski, Michael J Fisher
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Individuals with neurofibromatosis type 1 (NF1) are at increased risk for developing high-grade glioma (HGG) relative to the general population. Despite the elevated incidence in NF1, adequately powered studies of HGG have not been performed to date, limiting understanding of the clinical course, prevalent treatment approaches, recurrent molecular features, and outcomes. METHODS Patients with NF1 and pathologic or molecularly confirmed high grade glioma and high-grade astrocytoma with piloid features at Children’s Hospital of Philadelphia, University of California San Francisco, Washington University, and Cincinnati Children’s Hospital Medical Center diagnosed between 2005 to 2021 were included. Retrospective clinical, molecular, treatment, and imaging data were collated and analyzed. RESULTS Thirty-four patients met eligibility criteria, 13 (38%) were female. The median age at diagnosis was 22.7 years; 10 were pediatric (children &amp;lt;18 years of age). The most common diagnoses included high-grade astrocytoma (7), anaplastic astrocytoma (8), glioblastoma multiforme (5), and high-grade astrocytoma with piloid features (5). Fifteen (44%) of tumors underwent biopsy only and 4 (12%) were gross totally resected. Nine tumors (26%) were considered to have transformed from a pre-existing low-grade lesion. In the 22 cases with molecular testing, the most prevalent genetic variants involved the NF1, CDKN2A/B, ATRX, TP53, and SUZ12 genes. Frontline treatment approach varied; however, 26 individuals (76%) received radiation as part of their initial therapy. Overall survival at 2 years was 52% (95% CI 33-67) across all ages and 70% (95% CI 33-89) in children. There was no significant difference in overall survival at 2 years by extent of tumor resection at diagnosis. CONCLUSIONS High grade glioma in individuals with NF1 demonstrate a high prevalence of alterations in the CDKN2A/B and ATRX genes, with a poor overall survival despite radiation-inclusive treatment regimens. Collection of additional patient data from collaborating institutions is ongoing to support further analyses.
NFS-06. MANAGEMENT TRENDS OF MEK INHIBITOR DERMATOLOGIC ADVERSE EVENTS FOR NEUROFIBROMATOSIS PATIENTS
Authors: Rose Parisi, Sanjana Dhulipalla, Brigitte Widemann, Dominique C Pichard, Andrea Gross, Lauren Weintraub
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Selumetinib, a MEK inhibitor (MEKi), is approved for the treatment of plexiform neurofibromas (PN) in pediatric neurofibromatosis (NF) patients. In pivotal trials, nearly 70% of participants had PN shrinkage; however, 93% experienced a rash. This is the first study to characterize management trends of MEKi induced dermatologic adverse events (DAEs). METHODS Physicians treating NF patients were surveyed to assess MEKi DAE frequency, treatment, and effect on MEKi therapy. The survey was distributed using the Children’s Tumor Foundation listserv. RESULTS The survey was completed by MD/DOs (n=15) who were pediatric hematologists/oncologists (n=13) and pediatric neurologists (n=2). Physicians treated pediatric patients (n=8), adult patients (n=2), or both (n=5). Common DAEs included folliculitis (range:10-50% of treated patients; n=11), xerosis (range:1-80%;n=8), acneiform eruptions (range: 20-80%;n=10), eczematous dermatitis (range: 10-80%;n=12), paronychia (range: 10-80%;n=12), and seborrheic dermatitis (range:1-60%;n=8). Approximately half of physicians (n=8) used prophylactic DAE treatment. Prophylaxis for pre-pubertal patients included emollients (n=4), bleach baths (n=2), topical clindamycin (n=1), and doxycycline (n=1). Post-pubertal prophylaxis included emollients (n=5), doxycycline (n=5), topical clindamycin (n=4), bleach baths (n=1), and topical hydrocortisone (n=1). Almost all physicians modified MEKi treatment at least once because of a DAE (n=14), including dose hold (range: 1-25%;n=10), dose reduction (range:1-25%;n=10), and MEKi discontinuation (range:1-25%;n=8). Of the 10 physicians who reported dose holds, 6 were from physicians utilizing prophylactic therapy. Of the 8 physicians who reported MEKi discontinuations, only 3 were reported by physicians utilizing prophylactic therapy. CONCLUSIONS Most physicians modified MEKi treatment for DAEs, and many started prophylactic DAE therapy. The benefit of prophylactic treatment cannot yet be determined. Given the low response rate, future research will be aimed at collecting more data. There is a need for more studies to establish standardized treatment guidelines to reduce the frequency of MEKi modifications secondary to DAEs.
QOL-53. EXPLORING HEADACHES IN PEDIATRIC NEURO-ONCOLOGY PATIENTS: A SINGLE INSTITUTION RETROSPECTIVE CHART REVIEW
Authors: Samantha J DeMarsh, Elizabeth R Ackley, Alyse Staley, Kathleen M Dorris
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Despite the high prevalence of headaches in pediatric patients with brain tumors, very little research has been done to characterize their traits and to assess current management practices. Effective and efficient treatment of these headaches is critical to the optimization of brain tumor survivors’ quality of life. Foundational knowledge of any clinical associations likely would be beneficial to develop rational management strategies. METHODS A retrospective single-institution chart review of pediatric patients seen in the Children’s Hospital Colorado (CHCO) Neuro-oncology clinic from 1/1/22-12/31/22 is underway. Information is being collected via manual chart review including basic demographic information, oncologic diagnosis and tumor location, surgical interventions, and tumor-directed treatments. Headache characteristics, including timing of onset, associated symptoms, severity and frequency, referral to CHCO Neurology Headache Clinic and any headache therapies attempted will be sought. Additional information will include the number of emergency department visits and unplanned MRIs obtained as part of headache management. RESULTS 384 patients (53% male; median age 12 years, range 2-24 years) received care in the CHCO Neuro-oncology clinic in 2022. The majority of these patients were Caucasian/Non-Hispanic (61.7%), followed by Caucasian/Hispanic (13.8%) and African American/Non-Hispanic (4.2%). In this cohort, the preferred language for 93% was English and for 6% was Spanish. The majority (55%) of patients had a low-grade glioma/ glioneuronal tumor as their oncologic diagnosis. Patients with referrals to CHCO Headache clinic made up 13% of this cohort. Data collection and analysis are ongoing. CONCLUSIONS This data set will help to characterize the prevalence and features of headaches in pediatric patients with CNS tumors. This information will serve as the foundation for planned prospective studies that will collect more comprehensive and consistent data related to headaches in the pediatric neuro-oncology population and to formalize processes that will identify appropriate patients for referral to specialized headache providers.
HGG-41. COMBINATORIAL BH3-MIMETIC STRATEGY FOR OVERCOMING RADIORESISTANCE IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Krishna Madhavan, Sahiti Donthula, Faye M Walker, Lays Martin Sobral, Ilango Balakrishnan, Angela Pierce, Sana D Karam, Natalie J Serkova, Sujatha Venkataraman, Nathan A Dahl
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND High-grade gliomas (HGGs) are a leading cause of cancer-associated death in children. Radiation therapy (RT) continues to be the only standard-of-care treatment across HGG subtypes, but disease frequently recurs following only a transient response. We have recently identified that HGGs utilize the pro-survival BCL-2 family of proteins to evade cell death after radiation, and we demonstrated that effective inhibition of BCL-2 with the CNS-penetrant drug venetoclax could be utilized to disrupt this resistance and augment radiation-induced cell killing. While this treatment significantly prolonged survival in orthotopic mouse models of pediatric HGG, tumors invariably developed resistance to single-agent venetoclax and recurred. METHODS We profiled tumors from venetoclax-resistant animals for alternate BCL-2 family binding. We then assessed susceptibility to MCL1 inhibition in venetoclax-treated or treatment naïve culture models. Synergy was tested in vitro, and mitochondrial ROS production and induction of apoptosis was assessed using the MCL1-specific agent S63845. Finally, venetoclax and S63845 were tested in combination following fractionated radiotherapy in orthotopic models of DIPG. RESULTS MCL1 is an acquired dependency following treatment with RT + venetoclax. S63845 synergizes with venetoclax following RT to drive mitochondrial ROS production and apoptosis. The combination of venetoclax and S63845 significantly prolongs survival in xenograft models of DIPG. CONCLUSIONS Combinatorial targeting with BH3 mimetics augments radiation-induced cell killing and may open new therapeutic avenues for pediatric HGG.
NFS-12. CHOROID PLEXUS CARCINOMA IN PEDIATRIC PATIENTS WITH LI FRAUMENI SYNDROME (LFS) – CLINICAL COURSE AND THERAPEUTIC STRATEGIES
Authors: Thomas Perwein, Gunther Nussbaumer, Iwona Filipek, Gianluca Piccolo, Maria Luisa Garrè, Serafin Castellano, Alvaro Lassaletta, Hector Salvador, Lorena Baroni, Elvis Terci Valera, Carlos Scrideli, Ólafur G Jónsson, Katrin Scheinemann, John-Paul Kilday, Christian Thomas, Martin Hasselblatt, Uwe R Kordes, Jenny Adamski, Martin Benesch, Denise Obrecht-Sturm
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Choroid plexus carcinoma (CPC) is a rare pediatric brain tumor occuring predominantly in infancy. It is commonly associated with the cancer predisposition Li-Fraumeni syndrome (LFS). Management of CPC patients with LFS is challenging and there is no accepted standard treatment. This multinational retrospective analysis aimed to describe the clinical characteristics and outcome of pediatric patients with LFS-associated CPC. METHODS We identified 32 patients (male, n=24; median age at diagnosis 2.1 years [range, 0.3-13.2]) with CPC (CNS WHO grade 3), and LFS confirmed by the presence of (likely) pathogenic TP53 germline variants. In 29 patients, LFS was diagnosed after CPC. Seventeen patients (53%) had a positive family history of LFS. CPC arose from the lateral ventricles in 30 patients, 14 had metastases at diagnosis. RESULTS Gross total resection was achieved in 21 patients during first-line treatment, as was subtotal resection in 9 and partial resection/biopsy in 2 patients. Thirty-one patients received first-line chemotherapy, with carboplatin/etoposide/vincristine most commonly used (n=9). Eight patients received upfront irradiation (CSI, n=5). Complete remission (CR) and partial remission (PR)/stable disease (SD) was achieved in 20 and 5 patients, respectively. Six patients did not respond to first-line treatment and one patient died during initial surgery. Nineteen patients experienced relapse or progressive disease (PD) with a median progression-free survival of 2.2±1.0 years and with metastases in 79%. At a median follow-up of 1.9 (0.1-17.7) years, fourteen patients were alive in CR (n=10), SD (n=1) or PD (n=3) and eighteen patients died (CPC-related, n=14; other malignancies, n=4). Progression-free and overall survival at 2 and 5 years were 52.2±9.1%/32.8±8.9% and 65.6±8.9%/51.8±10%, respectively. CONCLUSIONS LFS-related CPC carries a poor prognosis but should not be considered incurable. Outcomes are not dissimilar to non-LFS-related TP53-mutated CPC. International collaboration is the prerequisite for treatment standardization.
HGG-27.<i>IDH</i>- AND H3-WILDTYPE HIGH-GRADE GLIOMAS OCCURRING IN TEENAGERS AND YOUNG ADULT PATIENTS COMPRISE NOVEL MOLECULAR SUBGROUPS
Authors: Rita Pereira, Alan Mackay, Yura Grabovska, Amelia Clarke, Tabitha Bloom, James Nicoll, Delphine Boche, John Procter, Andrew Moore, Johanna Schagen, Liam Walker, Federico Roncaroli, Olumide Ogunbigi, Thijs van Dalen, David Ziegler, Zhi-Feng Shi, Darren Hargrave, Thomas S Jacques, Bassel Zebian, Cristina Bleil, Joseph Yates, Emma Norton, Henry Mandeville, Antonia Creak, Liam Welsh, Lynley Marshall, Ferndando Carceller, Zita Reisz, Safa Al-Sarraj, Angela Mastronuzzi, Andrea Carai, Maria Vinci, Kathreena Kurian, Ho-Keung Ng, Sebastian Brandner, Chris Jones, Matthew Clarke
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND High-grade gliomas (HGG) arise in any CNS location with a poor prognosis. HGGs in teenagers/young adults (TYA) are understudied; this project aimed to characterise these tumours and identify therapeutic targets. METHODS HGG samples (histone/IDH-wildtype, n=207, FFPE/FF, 13-30 years) were collected from national/international collaborators. DNA methylation profiling (Illumina EPIC BeadArrays, brain tumour classifier (MNPv12.5 R package)) classified cases against reference cohorts. Calibrated scores guided workflows to characterise mutational landscapes (RNA-based ArcherDx fusion panel (n=92), whole exome sequencing (n=107), histological review). RESULTS Of cases scoring &amp;gt;0.5, n=25 classified as PXA and n=8 as HGAP, differing from primary diagnoses. 53.4% (n=86) classified as paediatric-type subgroups ((pedHGG-RTK1A/B/C, 31.7%, n=51, associated with frequent PDGFRA, CDKN2A/B, SETD2, NF1 alterations), pedHGG-MYCN (8.1%, n=13, MYCN/ID2 amplifications), and pedHGG-RTK2A/B (7.5%, n=12)). 18.0% (n=29) classified as subgroups frequently seen in adults including GBM-MES (15.5%, n=25, enriched for RB1, PTEN, NF1 alterations) and GBM-RTK1/2 (2.5%, n=4, CDK4 amplifications). 16 cases were assigned to novel, poorly-characterised subgroups with distinct methylation profiles and molecular features including paediatric-specific pedHGG-A/B (n=10 6.2%) and HGG-E (n=6 3.7%) subgroups, and HGG-B (n=2 1.0%), and GBM-CBM (n=5 3.1%, frequent cerebellar location) subgroups, associated with variable histological morphology. 8 cases showed hypermutator phenotypes, enriched in HGG-E. Age-distribution/molecular profile comparisons using publicly available methylation and sequencing data for HGG-B (n=9), GBM-CBM (n=26) and GBM-MES-ATYP (n=53), irrespective of age, shows they are TYA-specific subgroups with the latter containing fewer chr7 gains and chr10 losses, and more CDKN2A/B deletions and MET amplifications, compared with adult-specific GBM-MES-TYP. Across the cohort, other frequent copy number changes included gains in chr1q (54%, frequent in pedHGG-RTK1B/C/MYCN, pedHGG-A/B), chr2 (22%, pedHGG-MYCN), and chr13 losses (64%, pedHGG-RTK1B/C). Focal amplifications included CDK6 (1.4%, n=3) and EGFR (1.0%, n=2). CONCLUSION TYA HGG comprise well-characterised, novel methylation subgroups with distinct methylation profiles and molecular characteristics, representing opportunities to refine treatment.