tbuckley/cabot-search huggingface dataset:
MDB-55. LYMPHOID ENHANCER-BINDING FACTOR 1 (LEF1): AN IMMUNOHISTOCHEMICAL PREDICTIVE MARKER FOR WNT-ACTIVATED MEDULLOBLASTOMA
Authors: Manali Ranade, Khushi Naik, Prachi Bapat, Mamta Gurav, Omshree Shetty, Aekta Shah, Ayushi Sahay, Maya Prasad, Vikash Singh, Prakash Shetty, Aliasgar Moiyadi, Archya Dasgupta, Abhishek Chatterjee, Girish Chinnaswamy, Tejpal Gupta, Sridhar Epari
Journal: Neuro-Oncology (2024)

Abstract AIM To evaluate lymphoid enhancer-binding factor 1 (LEF1) immunohistochemical expression in various molecular subtypes of medulloblastoma. MATERIALS AND METHODS Molecular subtyping of medulloblastomas was based on real-time PCR target 12 gene panel. LEF1 immunohistochemistry was performed and its expression was correlated with histological and molecular subtypes. RESULTS The study cohort included 65 cases; comprising 17 WNT-activated, 20 SHH-activated, and 28 non-WNT/non-SHH [group 3: 11, group 4: 10, non-WNT/non-SHH NOS: 7] medulloblastomas. The age range was 1-40 years (≤18 years=54 [WNTa:15, SHHa:13, non-WNT/non-SHH:26], 19-40 years=11) with a median age of 9, and an interquartile range (IQR) of 5-14.5. Forty-one were males and 24 were females (M:F=1.7:1). LEF1 immunostaining was diffuse (≥50% tumour cells) in 13 cases, focal (5-49% tumour cells) in 11 cases, and negative in 41 cases. All cases with diffuse LEF1 immunostaining (n=13) were WNT-activated with classic histology. Twelve of the 13 cases had CTNNB1 mutation on Sanger sequencing and monosomy 6 by fluorescence in-situ hybridization (FISH) while 1 case was uninterpretable for CTNNB1 Sanger sequencing and chromosome 6 FISH. LEF1 staining intensity was strong in 9 cases while heterogenous in 4 cases. No differential staining pattern was observed for paediatric and adult cases. Diffuse LEF1 immunostaining was significantly associated with the WNT-activated subtype of medulloblastoma (p=&amp;lt;0.01). Of 11 focal LEF1 positive cases, 4 were WNT-activated (all having classic histology and CTNNB1 mutation) and 7 were SHH-activated, TP53-wildtype (classic: 2 and desmoplastic nodular [D/N]: 5). None of the WNT-activated, 12 SHH-activated, TP53-wildtype (6 classic, 6 D/N), 1 SHH-activated, TP53-mutant (large-cell/Anaplastic [LC/A]) and all (n=28) non-WNT/non-SHH (classic: 25, LC/A: 3) were LEF1 negative. CONCLUSION Classic histology with diffuse (≥50% tumor cells; including heterogeneous intensity) LEF1 immunostaining is a good predictive marker for the WNT-activated molecular group of medulloblastoma, however focal staining is not.
ETMR-19.<i>BCOR/L1</i>-ALTERATIONS REWIRE HISTONE REGULATION TO INDUCE ONCOGENIC PATHWAYS IN PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS
Authors: Katharina Bruckner, Daniela Lötsch-Gojo, Lisa Gabler, Shanzheng Wang, Dominik Kirchhofer, Jenna Labelle, Sibylle Madlener, Daniel Senfter, Felix Schmitt-Hoffner, Aniello Federico, Jan Koster, Christian Dorfer, Arnault Tauziède-Espariat, Jens Pahnke, Volker Hovestadt, Alexander Beck, Julia Schueler, Christine Haberler, Walter Berger, Mariella G Filbin, Marcel Kool, Johannes Gojo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Central nervous system (CNS) tumors with BCOR internal tandem duplication (ITD) or BCOR/L1 fusions are recently described tumor types with distinct molecular characteristics and poor clinical outcome. BCOR and its homologue BCORL1 are essential components of the non-canonical polycomb repressor complex (PRC) 1.1 thereby acting as epigenetic regulators exerting a profound impact on central cellular mechanisms. However, the influence of BCOR/L1-alterations on the functionality of PRC1.1 in pediatric CNS tumors remains understudied. METHODS We performed bulk as well as single-cell/nucleus RNA sequencing (scRNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) of CNS tumor tissue harboring BCOR-ITD or BCOR/L1 fusions. Additionally, BCOR/L1-altered, patient-derived cell models were used for downstream in vitro analyses. RESULTS ChIP-Seq analysis demonstrated binding of both KDM2B and mutant BCOR/L1 at PRC1.1 target genes whereas PRC1/2-mediated histone modifications H3K27me3 and H2AK119ub were absent. In addition, PRC1.1 target gene loci were characterized by high H3K27ac levels indicating increased transcriptional activity in BCOR/L1 mutant samples. Indeed, PRC1.1 targets such as FGFR1, GATA6, and ERBB3 were found to be upregulated in bulk transcriptome (n=37) analyses. Using scRNA-seq (n=10), we resolved a transcriptionally distinct cell population, specific for BCOR/L1-driven CNS tumors, which expressed high levels of PRC1.1 target genes. Besides PRC1.1 target genes, the targetable receptor tyrosine kinases PDGFR/FGFR(1/3), and IGF1R were found to be upregulated in pediatric BCOR/L1-altered CNS cancers. Accordingly, drug screens of patient-derived cell models revealed sensitivity towards small molecule inhibitors targeting the respective pathways. This translated well in anti-tumor effects of the FGFR/PDGFRA inhibitor nintedanib in BCORL1::NUTM2HP-fused patient-derived xenograft bearing mice. CONCLUSIONS Our data demonstrate for the first time that BCOR/L1-altered CNS tumors are driven by dysfunction of PRC1.1 histone modifications inducing profound transcriptomic changes ultimately activating oncogenic pathways. We further identified first feasible therapeutic targets including FGFR and PDGFR which may be leveraged for improved therapy of patients suffering from this aggressive tumor type.
NURS-15. THE ROLE OF THE ADVANCED PRACTICE PROVIDER AND NURSES IN CLINICAL TRIALS
Authors: Cynthia Schmus, Courtney Baker Briamonte, Carly Hoffman, Susan Holtzclaw, Michele McHugh, Ashley Meyer, Shannon Raber, Kasey Rangan, Kenny Seidl, Marylynne Strachan, Kaaren Waters, Lanipua Yeh-Nayre, Micah Higgins
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND For many years clinical trials fell under the umbrella of medicine without much acknowledgement to the role of the nurse, both as advanced practice provider (APP) and staff nurse. Oncology continues to rank as one of the highest subspecialties when it comes to availability and participation in clinical trials. There remain multiple barriers to involvement including availability, lack of education, and medical mistrust. The specialized role and skill set of the APP and RN as part of the clinical trial team is important in overcoming these barriers. METHODS We distributed a survey to members of the Advanced Practice Provider and Nurse Investigator Committee (APPNIC), a group within the Pediatric Neuro-Oncology Consortium (PNOC), in order to identify themes, barriers to care, and opportunities for both the APP and RN within clinical trials. The use of a survey and interviews within our APPNIC cohort allowed us to collaborate on the nursing role, prioritize care in new and amended trials, and share unanticipated adverse effects and effective management. RESULTS APPs are actively involved with clinical trial enrollment, performance of diagnostic exams and procedures, education, and early recognition/management of adverse effects. There is also a growing theme of the APP as sub-investigator which provides value in facilitating consent, impacting accrual, determining eligibility, managing anticipated side effects. The role of the staff nurse in clinical trials is found to be vital in providing consistent communication/support, educating patients and families, and alleviating adherence and medical mistrust. CONCLUSION The APP and nurse have a specialized, relevant skill set, which when included as part of the multi-disciplinary team, has the ability to decrease barriers and increase overall delivery and safety of clinical trials. Our goal is to outline specific roles we feel should be standardized in the international arena for nursing involvement within clinical trials.
NURS-14. DEVELOPMENT OF A CLINICAL PRACTICE INTERVENTION TO SUPPORT NURSES CARING FOR PATIENTS WITH DIABETES INSIPIDUS (DI) DURING CHEMOTHERAPY HYDRATION
Authors: Cynthia Schmus, Concetta DiDomenico, Jessica McWhorter
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric neuro-oncology patients with germ cell tumors (GCT) and diabetes insipidus (DI) often require management with vasopressin (DDAVP). Fluid and sodium balance, ordinarily managed successfully with DDAVP, can be disrupted during chemotherapy and associated hydration. Patients with an intact thirst mechanism may be able to self-regulate fluid and salt balance under the right conditions, whereas patients without an intact thirst may experience sodium fluctuations if intravenous hydration exceeds the amount they drink independently. Patients may be unable to maintain adequate hydration and sodium levels due to nausea and/or sedating antiemetics. These factors create a unique clinical challenge for nurses. Nurses sought guidance in understanding DI and its impact on hydration during chemotherapy. METHODS Two nursing education sessions were held and focused on DI management. Nurses were surveyed pre and post education. The goals of the intervention were that the oncology nurse will be to describe the pathophysiology of diabetes insipidus, the role of desmopressin, the ability to differentiate between management of patients with and without an intact thirst mechanism, and the special care of a DI patient receiving chemotherapy. RESULTS Nurses reported an increased awareness post education of the need to closely assess patients and manage their DI in collaboration with clinicians. Routine chemotherapy management does not apply to this population, because drastic fluctuations in sodium and water balance put them at risk of other complications. Nurses identified the need to closely manage hydration, DDAVP, recording strict intake/output, monitoring sodium levels, assessing for nausea/vomiting and the degree of sedation from antiemetics. CONCLUSION Outcomes from this educational intervention were that nurses had an increased understanding of DI management in patients with GCT receiving chemotherapy. Future goals would be to implement a standard approach to hydration, DDAVP administration, and monitoring sodium levels in patients with GCT and DI.
METB-14. INTEGRATED GERMLINE AND SOMATIC PROFILING OF PEDIATRIC BRAIN TUMORS REVEALS INCIDENTAL FINDINGS AND NOVEL TUMOR BIOLOGY
Authors: Ryan J Corbett, Rebecca Kaufman, Shelly W McQuaid, Zalman Vaksman, Saksham Phul, Miguel A Brown, Jennifer L Mason, Heena Desai, Ryan Hausler, Ammar S Naqvi, Antonia Chroni, Zhuangzhuang Geng, Bo Zhang, Chuwei Zhong, Yuankun Zhu, Allison P Heath, Marilyn Li, Phillip B Storm, Adam C Resnick, Kara N Maxwell, Miriam Bornhorst, Kristina A Cole, Angela J Waanders, Suzanne P MacFarland, Jo Lynne Rokita, Sharon J Diskin
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The contribution of rare pathogenic germline variation to central nervous system (CNS) tumor formation in pediatric patients without a family history of cancer remains unclear. METHODS We characterized the prevalence of pathogenic germline variants in 214 cancer predisposition genes (CPGs) in 837 patients profiled in the Pediatric Brain Tumor Atlas by whole genome or exome sequencing (n=820 and n=17, respectively). Rare SNVs and small INDELs were annotated as pathogenic (P) or likely pathogenic (LP) consistent with American College of Medical Genetics criteria using AutoGVP, our open-source automated pathogenicity assessment tool. We classified pathogenicity of germline structural variants (SVs) using ClassifyCNV and AnnotSV. Somatic alterations and mutational signatures from matched tumor sequencing were integrated to identify functional consequences associated with germline pathogenic variation. RESULTS We observed 206 germline P/LP SNVs/small INDELs and 18 SVs (16 deletions, 2 duplications) within 78 unique CPGs in 195 patients (23.3%). We detected syndrome-associated P/LP variants in 45/58 patients with a clinically-reported cancer predisposition syndrome and incidentally in 41 patients. Ninety-five (42%) germline P/LP variants co-occurred with at least one somatic alteration in the same gene in matched tumors: n=6 oncogenic SNVs, n=28 CNVs, n=54 loss of heterozygosity (LOH), n=26 differential gene or protein expression, and n=18 alternative splicing. NF1, TSC1, and TSC2 germline P/LP carriers exhibited significantly higher tumor LOH scores and lower gene expression in tumors relative to non-P/LP carriers. Patients with germline splice region P/LP variants exhibited significantly increased skipping of most the proximal exon in matched tumor relative to patients with non-splice region P/LP variants (W=401, p=1.1E-04). CONCLUSION We have identified rare germline P/LP variants associated with cancer predisposition syndromes and diverse functional consequences in pediatric CNS tumor patients. Efforts are underway to extend this work to include 1,801 additional probands and 1,105 parents to further characterize the prevalence and heritability of germline pathogenic variation in children diagnosed with CNS tumors.
EPID-05. 60 YEARS OF CENTRAL NERVOUS SYSTEM TUMOURS IN THE WEST MIDLANDS, UK
Authors: Helen Curry, Jenny Adamski, Martin English, Mike Hawkins, Raoul Reulen, Helena Gleeson, Helen Jenkinson
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The West Midlands Regional Children’s Tumour Registry is a specialist paediatric cancer registry in the West Midlands region of England, representing 9% of the national population. Our aim was to produce an historical, regional overview of central nervous system (CNS) tumour incidence and survival from 1957 onwards. METHODS Paediatric CNS tumour records included in the Registry from 01/01/57 to 31/12/16 were reviewed. There were 1945 cases: 1066 males and 879 females (M:F ratio 1.2:1) aged 0-14 years, resident in the West Midlands and diagnosed with a malignant, uncertain, or benign tumour. Patients were categorised according to the International Classification of Childhood Cancer, Third Edition (ICCC-3). Age and sex-specific incidence rates per million and directly age standardised incidence rates were calculated. Survival by decade of diagnosis was calculated using Kaplan-Meier survival analysis. RESULTS Incidence rates were broadly comparable to national data. Five-year survival for all CNS tumours combined increased from 38.0% [CI 32.2-43.8%] during 1957-1966 to 79.8% [CI 75.4-83.5] for diagnoses 2007-2016. Five-year survival for patients with ependymoma, astrocytoma and medulloblastoma diagnosed 2007-2016 was 95.7% [CI 72.9-99.4], 86.9% [CI 80.3-91.3] and 68.0% [CI 52.0-79.7] respectively: substantially above equivalent national figures. Five-year survival for groups including ‘Other Gliomas’ and Atypical teratoid/rhabdoid tumour (ATRT) had lower than nationally reported survival rates at 53.3% [CI 37.6-66.8] and 9.1% [0.5-33.3] however, small numbers and wide confidence intervals must be considered. CONCLUSIONS Huge improvements in survival, nationally and in the West Midlands, over the past 60 years are attributable to a greater understanding of tumour biology, intensification of multi-agent chemotherapy and new treatments. Despite these gains, certain diagnoses - most prominently ATRT - remain resistant to cure with five-year survival below 10%. Certain diagnoses showed a notable rise in late mortality, demonstrating the importance of long-term follow-up for detecting late effects and subsequent malignancies.
MDB-60. CDK7 INHIBITION DISRUPTS ACQUIRED RESISTANCE MECHANISMS IN MYC-MB
Authors: Bethany Veo, Dong Wang, Joshua Michlin, Genevieve Wimsatt, Rajeev Vibhakar
Journal: Neuro-Oncology (2024)

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children, accounting for 20% of all pediatric brain tumors. Medulloblastoma manifests as a clinically heterogeneous tumor with varying prognoses depending on the molecular subgroup. Group 3 tumors have the worst overall prognosis, and are associated with MYC gene amplification, higher rates of metastasis, and increased likelihood of recurrence. Our prior work demonstrated that WEE1 is upregulated in all MB subtypes and is a critical mediator of MB cell viability. We have established that Myc-driven MB is particularly sensitive to the WEE1 inhibitor AZD1775. Although AZD1775 showed promising results in combination with other genotoxic agents, tumor cells frequently acquire resistance to small molecule inhibitors. Thus, to identify regulators of resistance in Myc-MB we performed a Kinome scale RNAi screen in isogenic parental and resistant cells and identified CDK7 as a key mediator of AZD1775 resistance that restored sensitivity to WEE1 inhibition when depleted. CDK7 controls transcriptional initiation by phosphorylating the c-terminal domain of RNA Pol II. CDK7 has been implicated in several Myc-associated malignancies and is frequently enriched at Super Enhancers. Enhancer-promoter interactions (EPIs) are dynamic and can facilitate resistance mechanisms by inducing additional enhancer elements to promote transcription. Here, we investigated 3D chromatin interactions by HiChIP and further assessed CTCF and H3K27ac patterns after treatment with the CDK7 inhibitor, THZ1, by Cut and Run. Our analysis suggests that AZD1775-resistant cells are reorganized to establish alternate cis-acting elements that reinforce transcription of DNA repair and proliferation genes, circumventing AZD1775 treatment. We further examine cisplatin-resistant MB cells to determine if the mechanism is consistent in Myc-MB cell lines or therapy specific. Overall, we suggest that reorganized chromatin structure aids resistance development and that inhibition of CDK7 intervenes in this process, restoring sensitivity to standard therapies.
QOL-40. FAMILY MENTAL HEALTH SCREENING EARLY AFTER A DIAGNOSIS OF PEDIATRIC BRAIN TUMOR
Authors: Ashley Rodemann, Mary E Hartman, Mohamed Abdelbaki, Andrew S Cluster
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION A new diagnosis of a brain tumor in a child has significant emotional consequences for every member of the family. Despite this, early phases of oncologic care rarely provide formal mental health screening. METHODS In 2021, we implemented a mental health screening protocol for patients with a newly diagnosed brain tumor admitted to our pediatric intensive care unit (PICU) at the time of diagnosis, and their parents. Screening instruments were selected based on previous validation and relevance to both a brain tumor diagnosis and PICU admission. Parents were contacted by our team shortly after their child’s diagnosis and completed the screening within a month via an online interface. Parent proxy reports for children were used when necessary. Scores were shared with the family and neuro-oncology team. When indicated, supportive counseling and care coordination were offered. RESULTS Since 2021, 97 new brain tumor patients have met criteria for mental health screening. Of these, 72 patient and parent dyads were provided the screening protocol, and 31 fully completed the screening (mean patient age 7.3 yrs; 81% white; 58% male). Of the families that completed the evaluation, most parents (83%) reported their child’s diagnosis negatively impacted their health-related quality of life (HRQL), while 75% of children themselves reported a lower HRQL than population norms. Nearly half of children (44%) self-reported having symptoms outside of normal range for anger, anxiety or depression and 33% had abnormal scores for pain interference with their daily lives. More than half (65%) of families reported lower family functioning than population norms. CONCLUSION Families of children with a new diagnosis of brain tumor are at risk for impaired mental health and quality of life early after diagnosis. A systematic approach to assess and address these concerns early after diagnosis is needed.
NURS-16. CREATING A STANDARDISED DOCUMENT FOR EDUCATION SETTINGS ACROSS THE UNITED KINGDOM FOR CHILDREN WITH CENTRAL NERVOUS SYSTEM TUMOURS
Authors: Melissa Hayes, Nicola Blount, Louise Robinson, Gabrielle Reynolds, Jade Ryles
Journal: Neuro-Oncology (2024)

Abstract There are currently nineteen Principle Treatment Centres (PTC) in the UK delivering care to children, aged 0-19, following diagnosis of a Central Nervous System (CNS) tumour. Every centre promotes inclusivity and the safe and successful return to education, however reintegration can be a challenging process for this complex group of patients and there is a vast amount of information available. At present each PTC provides their own personalised document, including a list of resources, to signpost the education setting to appropriate information. With the collaboration of participating PTC’s, our aim was to create a standardised document for education settings to utilise following a child’s CNS diagnosis. Each of the nineteen PTC’s were approached, requesting representation from a neuro oncology nurse specialist and the sharing of their bespoke information. Following this, benchmarking criteria were created and each document reviewed and evaluated. The review and evaluation process also included websites and information leaflets that centres currently signpost to, from charities and other relevant organisations. By working closely together as a national group of neuro oncology nurses, we have created a standardised document and list of suitable resources for education settings. The finalised document will be shared with each PTC, with the intention of promoting a smooth transition back into education and quality and equity of information for all children, irrespective of where they live in the UK. Auditing of the document will be part of the ongoing work of the group.
LGG-22. INVESTIGATING THE EFFICACY OF BELVARAFENIB, A TYPE II PAN-RAF INHIBITOR, AS A POTENTIAL THERAPEUTIC AGENT TO TREAT PEDIATRIC LOW-GRADE GLIOMAS HARBORING<i>BRAF</i> FUSIONS
Authors: Brittany M Lebert, Maxine Gonzalez-Vega, Ryan Jafrani, Ana Aguilar-Bonilla, Amy A Smith
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Low-grade gliomas (LGGs) are the most common central nervous system (CNS) tumor found in children, comprising nearly one-third of all diagnoses. Fifteen to twenty percent of pediatric LGGs arise due to mutations in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway, most commonly at the B-Raf proto-oncogene (BRAF) gene. Modern advances in personalized medicine have led to widespread use of targeted therapies to treat pediatric LGGs, specifically pan-RAF inhibitors that target BRAF V600E missense mutations and KIAA1549:BRAF fusions. However, to date, very few RAF inhibitors have been approved for use in children. METHODS The present study utilized patient-derived pediatric LGG cell lines to investigate the efficacy of Belvarafenib (0.5nM to 5nM), a type II pan-RAF inhibitor, as a potential therapeutic agent to treat BRAF-altered pediatric LGGs. A recent study demonstrated Belvarafenib’s ability to cross the blood-brain barrier, leading to an interest in its potential use in BRAF-mutated pediatric brain tumors. Belvarafenib has already shown promise in treating BRAF V600E-mutated melanomas and other solid tumors in adults, although its ability to effectively target BRAF fusions is unclear. Hence, three pediatric patient-derived cell lines with BRAF fusions will help elucidate any effect from Belvarafenib. RESULTS When treated with Belvarafenib, the cell lines harboring BRAF fusions demonstrated the compound’s inability to significantly decrease tumor cell viability. CONCLUSIONS This preliminary data highlights the possible limitations associated with using Belvarafenib as a single agent to treat pediatric LGGs with BRAF fusions.