tbuckley/cabot-search huggingface dataset:
LMIC-14. MAPPING THE REFERRAL PATH - HURDLES IN PEDIATRIC BRAIN TUMOR DIAGNOSIS: A PERSPECTIVE FROM TERTIARY CANCER CARE CENTRE IN A LOW MIDDLE-INCOME COUNTRY
Authors: Vasudeva Bhat K, Archana M V, Umesh Vellu, Vishnu Bharadwaj, Vinay M V, Harish Varma T, Emine A Rahiman, Swathi P M, Ibrahim Qaddoumi, Zeena Salman, Girish Dhall, Girish Menon
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Delayed referral remains leads to worse outcomes for children with cancer in low- and middle-income countries (LMIC), especially for patients with brain tumors. Delay in treatment could be due to the ignorance from the families to seek health care advice or lack of awareness of primary care physician. METHODS A retrospective study was conducted to delineate the referral path of children with brain tumors who presented to our institution. Patients &amp;lt;18 years with brain tumors registered from June 2022-December 2023 were included. Patients with relapsed disease, second opinion, or partially treated in an outside institute prior to referral were excluded. Data were captured using a proforma after obtaining permission from Institutional ethics committee. RESULTS Thirty-one children were enrolled with a median age of 5 years (range: 0-17) with M: F ratio of 1.58:1. The most common diagnosis in this cohort was medulloblastoma in 13(42%) followed by high grade glioma in 7(22%) and low-grade glioma in 4 patients (13%). Twenty-four (77%) belonged to low socio-economic strata defined by Modified Kuppuswamy classification, of which 22 (71%) were hailing from rural area with median distance from cancer center being 121 miles (range: 4.34 -242). Median of 3 (range: 1-6) consultations were sought prior to being referred to us and about 11 (35%) had visited alternative system of medicine before consulting us. Mean delay from symptom onset to diagnosis was 52 days (range: 2-530) with healthcare seeking delay of 5.4 days (Range: 0-30) and health system delay of 46 days (range: 1-500). The factors influencing delay included rural background (p=0.04) and lower socioeconomic strata (p=0.03). CONCLUSIONS Health system delay was a major cause of delayed referral in our study. By improving awareness of the primary care physicians about symptomatology of pediatric brain tumors, the referral pathway can be expedited thereby improving the outcomes of these children.
EPEN-27. GAINING A CLUE FROM 1Q: A HIGH-RISK CHROMOSOMAL GAIN IN PEDIATRIC POSTERIOR FOSSA EPENDYMOMA
Authors: Cory M Richman, Alexandra Rasnitsyn, David Przelicki, Jacob Torrejon Diaz, Graham Macleod, Srinidhi Varadharajan, John Lee, Stephane Angers, Antony MichealRaj, Olivier Ayrault, Michael D Taylor
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Ependymomas are neuroepithelial tumours that can be classified into distinct molecular subgroups, each exhibiting a unique clinical outcome. Therapeutic efforts against the most aggressive and abundant subgroup of pediatric ependymoma (posterior fossa group A, PFA) have traditionally been hampered by a lack of known recurrent driver mutations. However, approximately 25% of PFA tumours exhibit gains of the chromosome arm 1q which is associated with an extremely poor prognosis despite aggressive treatment. By interrogating the multi-omic landscape of PFAs harbouring this copy number variation, we aimed to uncover genetic dependencies from which actionable therapeutics could be derived. METHODS Transcriptomic (bulk/single-cell RNA sequencing), proteomic (LC-MS/MS) and phosphoproteomic analyses were conducted on patient tissues and primary patient-derived cell lines to gain insight into the pathways that drive 1q gain pathogenesis. Chromatin immunoprecipitation sequencing of H3K27me3 and H3K27ac marked histones was carried out to profile the epigenetic landscape of these tumours, and whole genome CRISPR knockout screens were performed to reveal the contribution of essential genes unique to tumours harboring 1q gains. RESULTS Through the comparison of 1q gain and balanced PFA samples, our multi-omic analyses identified the up-regulation and essentiality of known glioma oncogenic drivers previously uncharacterized in PFA. The investigation of essential candidate genes showed a convergence on pathways related to ciliogenesis, with genetic vulnerabilities informing in vitro drug screening. Candidate genes were further validated by in vivo knockdown using established xenograft mouse models for pre-clinical testing. CONCLUSIONS This combined approach has allowed for the derivation of a functional cancer signature underlying 1q gains in PFA and presents novel therapeutic targets for this high-risk subgroup. PFA ependymoma is a deadly malignancy whose complex biology has so far eluded therapy, and new insights from this project will help to identify the first effective therapies for this vulnerable patient population.
METB-05. CSF LIQUID BIOPSY: PAVING THE WAY FOR MINIMALLY INVASIVE BRAIN TUMOR SURVEILLANCE USING LOW-PASS WHOLE GENOME SEQUENCING
Authors: Lydia T Tam, Grace Rossi, Jeff Stevens, Rebecca Ronsley, Nicholas A Vitanza, Bonnie L Cole, Vera A Paulson, Christina M Lockwood, Sarah E S Leary, Erin E Crotty
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE We describe a clinical liquid biopsy platform for disease detection and surveillance in pediatric patients with primary central nervous system (CNS) tumors using low-pass whole genome sequencing (LP-WGS) on cell-free DNA (cfDNA) isolated from cerebrospinal fluid (CSF). METHODS CSF samples were collected during routine clinical procedures. cfDNA was extracted and LP-WGS performed using a validated Illumina NextSeq sequencing with a 37 bp paired-end read configuration. Sequencing results were compared to tumor molecular profiling performed by UW-Oncoplex™, a targeted DNA-based next-generation sequencing panel. RESULTS Sixty-one CSF specimens were collected from 29 individual patients with primary brain tumors across 7 institutions, with samples obtained at initial diagnosis or staging (n=17), during treatment (n=29), at therapy completion (n=4), or at disease recurrence (n=11). Patients with medulloblastoma (n=13), ATRT (n=3), high-grade glioma (n=3), low-grade glioma (n=6), ependymoma (n=1), and high-grade neuroepithelial tumor/ embryonal tumors (n=3) were included. Copy number variants consistent with tumor were detected in 24 samples from a median CSF volume of 2.5 mL (range: 1-8 mL) and 54.6 pg/ul of cfDNA (median, range: 1.3-5,220). 31/61 samples yielded enough DNA for LP-WGS while 30 were insufficient due to absence of tumor DNA (true negatives) or low DNA quantity (technical insufficiency). Among the 10 diagnostic samples collected from patients with MRI evidence of disease at initial staging, LP-WGS was positive in 8/10 (80%), compared to 2/10 (20%) positive by cytologic analysis for malignant cells. All 4 staging samples from patients with leptomeningeal metastasis were positive by LP-WGS. At recurrence, LP-WGS was positive for tumor in 6/8 (75%) of MRI-positive patients. CONCLUSIONS LP-WGS of CSF-derived cfDNA can identify clinically relevant somatic copy number variants, offering a minimally invasive liquid biopsy option for ongoing surveillance in pediatric CNS tumors. Further prospective analysis is needed to mitigate interpretation error and refine clinical applications.
DIPG-87. TARGETING GENE-REPRESSIVE EPIGENETIC REGULATION TO INDUCE INTERFERON SIGNALING IN DIFFUSE MIDLINE GLIOMA
Authors: Jordyn Craig-Schwartz, Ashley R Tetens, Kayleigh Lunsford, Athanasia Liapodimitri, Michael A Koldobskiy
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brainstem tumor with no known effective treatment. DIPG is driven by the H3K27M mutant histone, which promotes epigenetic dysregulation, leading to loss of gene-repressive H3K27me3 marks, global DNA hypomethylation, and a distinct gene expression profile. DIPG cells retain histone methylation at histone H3 lysine 9 (H3K9me2/3), suggesting that the tumor may rely on these marks to repress unwanted expression. Our prior work has demonstrated that treatment with the DNA hypomethylating agent decitabine (DAC) elicits expression of cancer-specific antigens and immune activation, including activation of interferon signaling, but modulating gene-repressive H3K9 methylation in DIPG has not been extensively investigated. METHODS We treated four primary patient-derived DIPG neurosphere cell lines with BIX01294 and UNC0642, inhibitors of H3K9 methyltransferases G9a/GLP, and analyzed gene expression changes by RNA-sequencing and Western blot. We assessed the effect of combination treatments on these four cell lines with both DAC and either BIX01294 or UNC0642 and evaluated impact on gene expression, innate immune signaling, and interferon pathway activation. RESULTS We found that treatment with either of the G9a/GLP inhibitors resulted in the upregulation of genes involved in immune signaling. Given the similarities in the immune signaling response elicited from treatment with DAC and the G9a/GLP inhibitors, we evaluated the effect of combination treatments with both DAC and either BIX01294 or UNC0642. These combinations resulted in an increased induction of genes involved in immune signaling, including STING. CONCLUSIONS Pharmacologic inhibition of DNA methylation and histone H3K9 methylation elicits immune activation in DIPG cells. Upregulation of interferon and STING signaling with this combination treatment may be significant in enhancing the immunogenicity of DIPG cells to allow effective immunotherapy.
CP-09. HTDS ON NOVEL CELL LINES IDENTIFIED BETA-CATENIN INHIBITOR TEGATRABETAN AND PROTEASOME INHIBITOR BORTEZOMIB AS TWO NOVEL POTENTIAL AGENTS AGAINST ADAMANTINOMATOUS CRANIOPHARYNGIOMA
Authors: Carolina Cocito, Christopher C Padilla, David J Pisapia, Charli Ann J Hertz, Nadia Dahmane, Jeffrey P Greenfield
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Adamantinomatous craniopharyngiomas (ACPs) are rare intracranial suprasellar tumors, primarily affecting pediatric population. ACPs are histologically benign but their location makes them highly debilitating and clinically challenging with no standard of care available. Mutations in exon 3 of the CTNNB1 gene, codifying for β-catenin, are pathognomonic hallmark of ACPs. Although several cell lines and patient-derived models have been sporadically described, no reproducible pre-clinical models are available for these tumors. METHODS Eight ACP patients underwent gross total resections and we were able to generate novel cell lines from four of them. The lines, named CBTP-77, CBTP-97, CBTP-101 and CBTP-119, grow consistently and have been passaged more than 15 times. Immunocytochemistry and RNA sequencing were performed, highlighting inter- and intra-line heterogeneity, typical of ACP tumors. To identify new therapeutic targets, High Throughput Drug Screening (HTDS) was performed on two lines. RESULTS β-catenin inhibitor tegatrabetan, FGFR inhibitor erdafitinib, and the proteasome inhibitor bortezomib resulted as top effective agents. In vitro validation of the three agents confirmed strong cytotoxicity and on target activity shown by downregulation of the WNT and PI3K/AKT/mTOR pathways. The limited CNS permeability of these agents, makes them great candidates for local intra-cystic delivery, as described for other therapeutic options for ACP. CONCLUSIONS Our study represents the first large scale screening for new therapeutic agents for ACP, highlighting the importance of establishing consistent cell lines and preclinical models for these rare and devastating tumors.
METB-04. UTILITY OF OPTICAL GENOME MAPPING IN THE CHARACTERIZATION OF PAEDIATRIC CENTRAL NERVOUS SYSTEM TUMOURS: ANALYSIS OF A MONO-INSTITUTIONAL SERIES OF 26 CASES
Authors: viola alesi, Silvia Genovese, Serena Russo, Isabella Giovannoni, Sabina Barresi, Chantal Tancredi, Lucia Pedace, Antonietta Lombardo, Piera Bontempo, Emanuele Agolini, Chiara Calacci, Alessandra Morgia, Giusy Calvieri, Chiara Puggioni, Antonello Cardoni, Antonella Cacchione, Giada Del Baldo, Giovanna Stefania Colafati, Andrea Carai, Angela Mastronuzzi, Evelina Miele, Damiano Abeni, Franco Locatelli, Andrea Onetti Muda, Antonio Novelli, Rita Alaggio, Sabrina Rossi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Optical Genome Mapping (OGM) is a recent platform which enables the detection of genome-wide balanced and unbalanced structural rearrangements (SR), providing a genome complexity overview. METHODS This study explores OGM implementation in the context of paediatric central nervous system (CNS) tumours by analyzing a series of 26 cases. RESULTS OGM equaled Chromosomal Microarray Analysis in detecting aneuploidies and copy number alterations (CNA), and, although less sensitive than RNAseq in identifying gene-fusions (15/19), enabled the definition of their causative mechanism. The assessment of SR and CNA allowed the distinction of different groups. Amount and distribution of SR identified 4 groups: HIGH_SR with &amp;gt;10 breakpoints (BP) distributed in ≥5 chromosomes (8 cases), SR_CHROMOTHRIPSIS with ≥10BP in &amp;lt;5 chromosomes with the most affected chromosome presenting with &amp;gt;10 BP (9 cases), and LOW_SR with &amp;lt;10BP (9 cases). CNA non-associated with chromothripsis (nCthCNA) stratified the series in NO_nCthCNA, LOW_nCthCNA, INT_nCthCNA, HIGH_nCthCNA group, where the alterations were absent (9 cases), &amp;lt;10 (9 cases), 10-49 (2 cases) and ≥50 (6 cases), respectively. nCthCNA directly correlated with the mean number of chromosomes harboring SR, i.e. 10.2 in HIGH_/INT_nCthCNA vs 2.5 in NO_/LOW_nCthCNA (p=0.001), and inversely with chromothripsis (9/18 in NO_/LOW_nCthCNA vs 0/8 in HIGH_/INT_nCthCNA, p=0.015). CONCLUSIONS High complexity groups associated with biological aggressiveness, with HIGH_nCthCNA including only high-grade tumours (p=0.004) and disease progression mostly occurring in HIGH_SR (6/7 cases vs 1/17, p&amp;lt;0.001) and HIGH_nCthCNA (4/5 vs 2/12 cases, p=0.013). Low-complexity groups were enriched of low/intermediate-grade tumours (13/15 in NO_/LOW_nCthCNA vs 5/11 in INT_/HIGH_nCthCNA, p=0.024). SR_CHROMOTHRIPSIS cases were all low/intermediate-grade fusion-driven tumours, did not harbour TP53 mutations or high-impact CNA (0/9 vs 7/17, p=0.030), and did not progress (0/9 vs 7/16, p=0.030). This study suggests a possible value of OGM assessment of genome complexity in prognostication of paediatric CNS tumours.
IMG-02. USING MRI RADIOMICS AND MACHINE LEARNING TO PREDICT OVERALL SURVIVAL FOR PEDIATRIC DIFFUSE MIDLINE GLIOMAS
Authors: Xinyang Liu, Zhifan Jiang, Holger R Roth, Syed M Anwar, Erin R Bonner, Roger J Packer, Anahita F Kazerooni, Miriam Bornhorst, Marius George Linguraru
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric diffuse midline gliomas (DMG) are aggressive central nervous system tumors with a median overall survival (OS) of less than one year from diagnosis. There is no curative therapy for DMG, and radiation therapy (RT) is the standard treatment. Magnetic resonance imaging (MRI) is the common noninvasive tool for DMG diagnosis and monitoring of tumor response to therapy. We developed an automatic pipeline to segment subregions of DMG and select MRI features that predict patient OS. METHODS We acquired diagnostic and post-RT multisequence MRI (T1, T1ce, T2, T2 FLAIR) and manual segmentations of pediatric DMG patients from two centers: 53 from Children’s National Hospital (internal) and 16 from Children’s Hospital of Philadelphia (external). We pretrained a deep learning model on a public adult brain tumor dataset, and finetuned the model to segment tumor core (TC) and whole tumor (WT) of DMG. We used PyRadiomics and sequential feature selection to select discriminative features based on the segmented volumes. Two machine learning models were trained on our internal cohort to predict patient 1-year survival from diagnosis. One model used only diagnostic tumor features and the other used both diagnostic and post-RT features. RESULTS For segmentation, Dice score (mean [median]±SD) was 0.91 (0.94)±0.12 and 0.74 (0.83)±0.32 for TC, and 0.88 (0.91)±0.07 and 0.86 (0.89)±0.06 for WT for internal and external cohorts, respectively. For OS prediction, accuracy was 77% and 81% at time of diagnosis, and 85% and 78% post-RT for internal and external cohorts, respectively. Heterogeneous WT intensity in baseline T2 FLAIR and smaller post-RT TC/WT volume ratio indicate longer OS. CONCLUSIONS Our method accurately predict OS for DMG patients and can be extended to other rare pediatric brain tumors. With automated and standardized analysis, early prognostication of OS can guide patient risk stratification and clinical decisions.
EPEN-28. NOVEL TARGET IDENTIFICATION IN RECURRENT POSTERIOR FOSSA EPENDYMOMA GROUP A
Authors: David Przelicki, Alex Rasnitsyn, Cory Richman, Graham MacLeod, Jacob Torrejon Diaz, Stephane Angers, Olivier Ayrault, Kulandaimanuvel A Michealraj, Michael D Taylor
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Posterior fossa ependymoma group A (PF-EPN-A) are an aggressive subgroup of ependymal tumors which occur predominantly in infants and possess a poor prognosis. Treatment is limited to surgical resection and adjuvant radiation with no approved chemotherapies or targeted therapies available. Despite treatment efforts, nearly half of all PF-EPN-A cases will experience tumor recurrence within a decade of initial diagnosis. Our current understanding of relapse is limited to clinical risk stratification based on subtotal resection of the primary tumor, male sex and specific chromosomal copy number aberrations. In an effort to overcome the shortcomings of current literature on PF-EPN-A recurrence, we present a concerted effort to investigate the biology of both recurrent human tissue specimens and patient-derived cell models to identify novel drivers of recurrence. METHODS Utilizing a multi-omics approach, we have conducted transcriptomic (bulk RNA-Seq), proteomic and phosphoproteomic (LC-MS/MS) analyses in order to identify molecular pathways that are enriched in recurrent disease as compared to primaries. We have also performed genome-wide CRISPR essentiality screens to further pinpoint essential genes and pathways with therapeutic potential. RESULTS Through the comparison of primary and recurrent PF-EPN-A samples, we have identified both previously implicated and novel genes and pathways in recurrent disease. Our multi-omic analyses identified the upregulation of genes involved in DNA repair, DNA damage response and cell cycle pathways in recurrent PF-EPN-A. CONCLUSIONS Our combined approach has enabled the identification of novel targets with therapeutic potential in the treatment of recurrent PF-EPN-A. The identified targets will be validated using a combination of drug screening and knockdown approaches in vitro. Top candidates will be further validated in vivo with established recurrent xenograft mouse models. PF-EPN-A is an aggressive disease with limited treatment options and the identification of novel targets with potential therapeutic utility will allow us to better treat this patient population.
QOL-30. NEUROPSYCHOLOGICAL FUNCTIONING AFTER WHOLE VENTRICULAR OR CRANIOSPINAL PROTON RADIATION FOR PEDIATRIC INTRACRANIAL GERM CELL TUMORS
Authors: Iris Paltin, Meghan K O’Brien
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND In Western countries, intracranial germ cell tumors (ICGT) represent 3-5% of central nervous system tumors, with peak incidence in the second decade of life. Compared to those receiving photon radiation therapy, pediatric patients receiving proton radiation therapy demonstrate stronger neurocognitive outcomes, particularly in verbal and visual reasoning. Ongoing treatment advances aim to reduce morbidity, such as neurocognitive late effects. This study characterizes memory functioning for patients with intracranial germinoma treated with either whole ventricular (WV) or craniospinal (CSI) proton radiation therapy. METHODS 29 patients received proton radiation therapy (17 WV, 12 CSI) for an ICGT (20 germinoma, 8 NGGCT, 1 mixed GCT; 3 disseminated at diagnosis). Age at diagnosis was 5-21 years (M=14.14; SD=3.91) with age at neuropsychological evaluation 8-25 years (M=17.66, SD=4.11). Evaluations occurred 0.71-7.85 years after diagnosis (M=3.52; SD=2.02). Patients (82.8% male, 65.5% white, 44.8% Very High Childhood Opportunity Index [COI]) had multiple additional interventions (surgeries, chemotherapy) prior to neuropsychological evaluation. RESULTS Patients in the WV group did not differ from patients in the CSI group on sex, COI, race, or ethnicity. Mean performance was stronger in the WV group than the CSI group for Full Scale IQ (FSIQ; t(27)=2.50, p=.019, Cohen’s d =0.94), Verbal Reasoning (VCI; t(24)=2.52, p=.019, d=1.0), Visual Memory (WRAML-2 Picture Memory Recognition; t(14)=2.51, p=.025, d=1.26), and Verbal Memory [(WRAML-2 Story Memory Delay, t(15.32)=2.82, p=.013, d=1.25); (WRAML-2 Story Memory Recognition, t(20)=2.34, p=.03, d=1.0)], all with large effect sizes. CONCLUSIONS Within this small ICGT sample with various medical treatments and comorbidities, demographic factors did not differ between groups, and WV proton radiation therapy appears to have less negative impact on aspects of reasoning and memory abilities compared to CSI proton radiation therapy.
QOL-28. NEUROCOGNITIVE DEFICITS, EMOTIONAL DISTURBANCES, PSYCHOSOMATIC COMPLAINS – ADDITIONAL SYMPTOMS OR COMORBID DIAGNOSIS IN CNS GERMINOMA? OVERVIEW OF GROUP AND CASE STUDIES
Authors: Justyna Korzeniewska
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND CNS Germinoma cases are associated with good medical prognosis, low risk for neurological deficits and high cognitive functioning. Deeper psychological and neuropsychological examination and longitudinal observation shows also neurocognitive problems and emotional disturbances. The purpose of the study was to assess patients with CNS Germinoma (during and after anticancer treatment), expressed specific psychological and physical symptoms and to find the reason for this. METHODS Since 1998 all patients treated at our center are under psychological control and care. From these group 78 patients with CNS Germinoma with additional significant symptoms, seriously affected their quality of life and everyday activity, were selected for psychological and neuropsychological assessment. Age at psychological intervention ranged from 6 5/12 to 34 8/12 yrs. The patients have no pre-diagnosis history of neurological, developmental or psychiatric disorder. They were examined using a battery of standardized psychological and neuropsychological methods. RESULTS In our sample FIQ (full-scale intelligence quotient) score ranged from 59 to 139. The most patients presented average level of intelligence. However, cognitive functioning was often reduced due to emotional disturbances and psychosomatic complains. 2 patients showed memory disorders, one of them TGA (transient global amnesia) at the time of diagnosis. All patients struggled with emotional disturbances at different grades, especially internalizing type of problems (immaturity, depression, anxiety, instability, inhibition, negative attitude) or were considered to be at risk for psychological adjustment difficulties and tendency to somatization. Analyzed group of patients showed also social competences deficits. They may exhibit deficit in age-appropriate social competence and peers relations. CONCLUSIONS Although CNS Germinoma patients shows similar behavioral and emotional phenotype, there are significant differences between them in terms of cognitive functions. The range of results is wide, from high levels to neurocognitive disorders. Therefore, risk factors, diagnostic criteria and effective neuropsychological intervention, will also be presented and discussed.