tbuckley/cabot-search huggingface dataset:
OTHR-12. GENERATING A COMPREHENSIVE INTERACTIVE PEDIATRIC BRAIN TUMOR VISUALIZATION PORTAL FROM MOLECULAR AND CLINICAL DATA DERIVED FROM TWO MULTI-INSTITUTIONAL PROTOCOLS (SJMB03, SJYC07) AND NON-PROTOCOL PATIENTS TREATED AT ST JUDE CHILDREN’S RESEARCH HOSPITAL
Authors: Sandeep K Dhanda, Congyu Lu, Edgar Sioson, Anthony P Y Liu, Santhosh A Upadhyaya, Aditi Bagchi, Jason Chiang, Brent A Orr, Amar Gajjar, Kyle S Smith, Paul A Northcott, Qian Li, Xin Zhou, Giles W Robinson
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric central nervous system (CNS) tumors represent a diverse group of neoplasms with heterogeneous molecular and clinical characteristics. The need for well-organized, searchable datasets is paramount to enhance our understanding and improve the treatment approaches for these devastating diseases. To illustrate this, we have organized multifaceted data from patients into an interactive portal equipped with cutting-edge visualization tools. METHODS Clinical and molecular data from the SJMB03 and SJYC07 protocols and select published non-protocol St. Jude patients were collated and harmonized. A data dictionary was constructed to record demographic information, treatment details, histology, methylation classification, mutations, chromosomal aberrations, and outcomes. We implemented five visualization techniques - summary plots, sample view, scatter plots, sample matrix, and survival plots. These techniques are interconnected, enabling interaction and “crosstalk”. RESULTS Data from 710 patients with CNS tumors were incorporated: 386 Medulloblastomas (MB); 88 Atypical teratoid Rhabdoid Tumors (ATRT); 54 Ependymomas (EPN); 49 Pineoblastomas (PB); 28 Embryonal Tumors with Multilayered Rosettes (ETMR), 22 Infant-type hemispheric glioma (IHG), 16 High grade glioma (HGG), 13 Choroid Plexus Tumors (CPT); 11 CNS Sarcoma; 8 CNS tumor with BCOR internal tandem duplication (CNS BCOR); 6 CNS neuroblastoma FOXR2 activated (CNS NB FOXR2); 5 Low grade glioma (LGG); and 24 other entities or unclassified tumors. The portal features enabled the creation of custom cohorts. For example, patients with TP53 mutations (n=32; 15 MB, 7 CPT, 6 HGG, 1 CNS Sarcoma, 1 CNS NB FOXR2, 1 PB, 1 unclassified tumor) or DICER1 mutations (n=10; 7 PB, 2 CNS Sarcoma, and 1 ETMR) could be identified, cross-compared and analyzed adjusting for variables at users’ choice. CONCLUSION The integration of molecular and clinical data from multiple sources into an interactive visualization portal presents a comprehensive resource for research and clinical practice. Future work will focus on expanding the portal to integrate more cases/cohorts.
OTHR-08. CLINICAL MANAGEMENT OF TWO PEDIATRIC CASES OF INTRACRANIAL MESENCHYMAL TUMORS WITH FET::CREB FUSIONS
Authors: Bryony J Lucas, Susan L McGovern, William E Whitehead, Guillermo Aldave, Carrie A Mohila, Melissa M Blessing, Angshumoy Roy, D Williams Parsons, Murali M Chintagumpala, M Fatih Okcu, Frank Y Lin
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Intracranial mesenchymal tumors (IMTs) with FET::CREB fusion are a newly described provisional entity lacking standard management options. This group of neoplasms occur in children and young adults, and is molecularly characterized by a FET family gene (most commonly EWSR1, rarely FUS) fused with a CREB family transcription factor (ATF1, CREB1, or CREM). Histologically, the Ki-67 index is typically low (&amp;lt;5%) and only rarely elevated (15-20%). Treatment consists of surgical resection. Cases achieving gross total resection (GTR) are observed without adjuvant therapy, while subtotal resection (STR) is followed by radiation therapy. Regardless of resection status, patients are at risk for local recurrence. METHODS Case report. RESULTS We present two patients with IMTs harboring FET::CREB fusions. Patient 1 is a 12-year-old male with a known left choroid plexus lesion and hydrocephalus, who presented with acute loss of balance, headaches, and emesis. CT head revealed progression of the choroid plexus lesion with intraventricular hemorrhage and worsening hydrocephalus. Following GTR of the tumor, pathology revealed an IMT without high-grade features and a Ki-67 index of 5%. RNA-sequencing revealed an EWSR1::ATF1 fusion. In consideration of GTR and the tumor being low-grade, he is being followed with surveillance scans. Patient 2 is a 14-year-old male who presented with headaches and seizures and was found to have an enhancing left occipital lesion on MRI. Following GTR, pathology revealed an IMT with abundant mitotic figures (15 per 10 high power fields), increased Ki-67 index of 30-40%, and a FUS::CREM fusion. Due to the high-grade histopathology, he was treated with focal proton beam radiotherapy (5400 cGyRBE). An MRI three months post-therapy was negative for tumor recurrence. CONCLUSIONS We describe two adolescents with IMTs harboring FET::CREB fusions and their management, including one with high-grade histology managed with upfront radiation therapy, which has not been previously reported in the literature.
MDB-73. INHIBITING THE B7-H3 CHECKPOINT IN MEDULLOBLASTOMA
Authors: Kirsten Moziak, Juliana Pensabene, Natalia Muñoz Perez, Rita Yazejian, Elodie Picarda, Xingxing Zhang, Allison M Martin
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Tumors express immune checkpoints to evade detection and clearance by the immune system. Immune checkpoint inhibition (ICI) allows for tumor clearance. Medulloblastoma (MB) has not seen success with ICI and relapsed/refractory tumors remain incurable. B7-H3 is an immune checkpoint that is highly and specifically expressed by many cancers including MB. It is implicated in immune evasion in cancer. We hypothesize inhibiting B7-H3 in MB will enhance the anti-tumorigenic properties of immune cells. METHODS Murine MB cells, which mimic aggressive disease, were transduced with a CRISPR/Cas9 lentivirus (courtesy of Zhang lab) to create a B7-H3 knockout (B7-H3–). Unsuccessful iterations of the same CRISPR/Cas9 sgRNA were used as a B7-H3+ control. B7-H3+ and B7-H3– cells were co-cultured for 5 days with splenic, bead isolated, CD4-T cells from C57BL/6J mice. Proliferation of the T cells was measured with Cell Trace Violet via flow cytometry using a Cytek Aurora. RESULTS We saw comparable tumor cell inhibition of T cell proliferation when cultured with B7-H3+ and B7-H3– tumor cells, as measured by CTV elution. CONCLUSIONS We saw similar amounts of T cell proliferation inhibition from both B7-H3 – and + tumor cells. This could indicate a few possibilities. First, B7-H3 may not be contributing to CD4-T cell inhibition, in which case it is important to explore its role in other immune cells. Another option is that B7-H3 is targeting the function of these cells, rather than the proliferation. To examine this, we could look at markers of effector function. Lastly, B7-H3 could be mediating inhibition of CD4-T cells via other cell(s) in the tumor microenvironment (TME) of MB, which we could test in vivo. If B7-H3 promotes ant-tumorigenic immune responses, it would be a promising approach relapsed/refractory medulloblastoma that presently has no cure, as well as other cancers that highly express it.
SURG-04. COMPARABLE SAFETY OF INTRATHECAL CHEMOTHERAPY GIVEN VIA LUMBAR PUNCTURE OR INTRAVENTRICULAR RESERVOIRS FOR PEDIATRIC CENTRAL NERVOUS SYSTEM (CNS) TUMORS: A SINGLE-INSTITUTION EXPERIENCE
Authors: Caleb Richmond, Mary Ann Zimmerman, Christine Chordas, Jessica Helt, Caroline Fitzgerald, Kathryn Matson, Karen D Wright, Kee Kiat Yeo, Susan N Chi, Tom Rosenberg
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Intrathecal (IT) delivery of chemotherapy is utilized for the treatment of pediatric cancers, particularly leukemia and CNS tumors, either via lumbar puncture (LP) or intraventricular reservoir (IR). While the latter allows easier administration and more frequent IT dosing, data are lacking on the comparative safety and efficacy between these administration routes. We now present the IT chemotherapy experience from a single high-volume pediatric neuro-oncology center. METHODS We performed a retrospective chart review of patients with primary CNS tumors treated with IT chemotherapy between the years 2004-2022 at Dana-Farber/Boston Children’s Hospital. We collected demographic, clinical and outcome data. Safety evaluation included review of immediate (procedural) and short-term post-procedural assessments. RESULTS We identified 74 patients who received a total of 1,211 IT chemotherapy administrations. Excluding patients with insufficient data, we report on 38 patients who received 717 administrations (LP, n=207; IR, n=510). Median age was 26.5 months (range, 0.1-14.5), and diagnoses included medulloblastoma (n=14), ATRT (n=14) and others (n=10). Immediate events were reported in 11 (0.2%) IR and 1 (0.4%) LP administrations, i.e technical (n=5), high ICP (n=3), and immediate adverse side effects (n=3). Short-term events were reported in 16 (3%) IR and 12 (5.8%) LP administrations, i.e. fever (n=6), seizures (n=6), arachnoiditis (n=4), and others (n=10). No grade 4-5 adverse events were reported. No statistically significant difference was found between routes of administration and the rate of immediate or short-term events. Of note, 14/18 (78%) patients with CSF-positive disease achieved CSF clearance, with median time to response of 57 days (range, 27-446). CONCLUSIONS IT chemotherapy shows an excellent safety profile in children with malignant CNS tumors, with no differences between IR and LP administration. IT delivery can be efficacious in CFS clearance for patients with metastatic disease, lending support to inclusion of IT chemotherapy in current treatment regimens.
LGG-02. ELUCIDATING THE ROLE OF FGFR1 ALTERATIONS IN PEDIATRIC GLIOMAS
Authors: April A Apfelbaum, Eric Morin, Sher Bahadur, Dominik Sturm, Dana Novikov, Jeromy DiGiacomo, Amy Cameron, Patrick Rechter, Margaret M Cusick, Sehee Oh, Hyesung Jeon, Jayne Vogelzang, Jacquelyn Jones, Connor Bossi, Quang- De Nguyen, David T W Jones, Michael J Eck, Eric S Fischer, Keith L Ligon, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric brain cancers are the leading cause of cancer-related deaths in children. We (and others) have recently found that close to 10% of all pediatric gliomas, encompassing low-grade gliomas (LGGs) and high-grade gliomas (HGGs), harbor recurrent driver alterations in FGFR proteins, most frequently FGFR1, the gene encoding Fibroblast Growth Factor Receptor 1. In pediatric gliomas, FGFR1 alterations present as either structural variants (SVs), including kinase duplications and fusion proteins, or kinase-activating single nucleotide variants (SNVs). Recurrent FGFR1 alterations represent a promising therapeutic target for precision medicine approaches, however a challenge has been the lack of clinical trials for FGFR inhibitors. A major goal of this project is to identify preclinical FGFR inhibitor candidates for FGFR1-altered pediatric gliomas. METHODS We have generated isogenic mouse and human neural stem cell (NSC) models driven by FGFR1 and BRAF alterations commonly seen in pediatric gliomas to test the oncogenic properties and therapeutic capacities of these alterations. RESULTS We found that NSC lines grow independent of growth factors and form tumors in mice. RNA-sequencing of these lines revealed the FGFR1-altered lines are enriched in neuronal gene programs. The FGFR1-altered models are exquisitely sensitive to the four FDA-approved panFGFR inhibitors Infigratinib, Erdafitinib, Pemigatinib, and Futibatinib. However, the FGFR1 SNV + PTPN11 co-occurring SNV line is the least sensitive to FGFR inhibition, which suggests combination therapies may be needed. Combination drug studies with FGFR inhibition in our FGFR1-altered lines reveal the best synergy with mTOR inhibition. Finally, we present examples of case studies of patients with FGFR1-altered tumors treated with targeted inhibitors. CONCLUSIONS Taken together, our studies have established models that have generated key insights into the biology of FGFR1-altered gliomas and how to best target them therapeutically.
OTHR-03. DEVELOPMENT OF PANORAMA: AN ASSESSMENT TOOL FOR PEDIATRIC NEURO-ONCOLOGY SERVICE DELIVERY CAPACITY
Authors: Revathi Rajagopal, Rosdali Diaz-Coronado, Syed Ahmer Hamid, Regina M Navarro-Martin del Campo, Frederick Boop, Asim Bag, Alma Benito Reséndiz, Kalya Vasudeva Bhat, Danny Campos, Kenneth T E Chang, Ramona Cirt, Ludi Dhyani Rahmartani, Jen Chun Foo, Julieta Hoveyan, John T Lucas Jr., Thandeka Ngcana, Rahat Ul Ain, Nuha Omran, Diana Osorio, Bilal Mazhar Qureshi, Noah Sabin, Ernestina Schandorf, Patrick Bankah, Mary-Ann Dadzie, Hafisatu Gbadamosi, Hend Sharafeldin, Mahendra Somathilaka, Peiyi Yang, Yao Atteby Jean-Jacques, Anan Zhang, Zeena Salman, Miriam Gonzalez, Paola Friedrich, Ibrahim Qaddoumi, Daniel C Moreira
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND To enhance the quality of care available for children with central nervous system (CNS) tumors across the world, a systematic evaluation of service delivery capacity is needed to identify gaps in pediatric neuro-oncology and prioritize interventions. To that end, we created the PediAtric Neuro-Oncology Resource AssesMent Aid (PANORAMA) tool. METHODS PANORAMA development consisted of three phases: operationalization, consensus building, and piloting. PANORAMA was designed to have domains that capture the elements of the pediatric neuro-oncology care continuum using assessments which were weighted according to their importance. Responses were ordinally scored to reflect adequacy of satisfaction. PANORAMA was revised based on feedback at various phases to improve its relevance, usability, and clarity. RESULTS The operationalization phase identified thirteen domains using 252 questions. The consensus phase included validating the identified domains, questions, and scoring by fifteen experts (six pediatric oncologists, three radiation oncologists, two neurosurgeons, two radiologists, and two pathologists). The validated PANORAMA domains were national context, hospital infrastructure, organization and service integration, human resources, financing, laboratory, neurosurgery, diagnostic imaging, pathology, chemotherapy, radiotherapy, supportive care, and patient outcomes. Seventy-six questions were added during the expert review. PANORAMA was piloted at thirteen institutions in twelve countries, representing diverse patient care contexts. Face validity was assessed using the correlation between the estimated score by respondents and calculated PANORAMA scores for each domain (r = 0.67, p &amp;lt;0.0001). Piloting eliminated two questions. CONCLUSIONS PANORAMA was developed following a systematic approach, leading to a relevant tool to evaluate the core elements of pediatric neuro-oncology service capacity. PANORAMA will be distributed to facilitate quantitative evaluation of institutional services, allowing for prioritization and benchmarking with centers at the local, regional, and international levels.
LGG-15. DEEP LEARNING ENABLES LONGITUDINAL RISK PREDICTION FOR PEDIATRIC LOW-GRADE GLIOMAS AFTER SURGERY
Authors: Divyanshu Tak, Biniam Amsalu Garomsa, Anna Zapaishchykova, Zezhong Ye, Sridhar Vajapeyam, Maryamalsadat Mahootiha, Juan Carlos Climent Pardo, Ariana Familiar, Kevin Liu, Pratiti Bandopadhayay, Ali Nabavizadeh, Sabine Mueller, Hugo Aerts, Daphne Haas-Kogan, Tina Young Poussaint, Benjamin Harris Kann
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Disease progression is challenging to predict following surgery for pediatric low-grade glioma (pLGG), and early progression indicators on MRI surveillance imaging would help guide management. Longitudinal surveillance imaging data may capture subtle temporal tumor changes and patterns that could inform recurrence risk but are difficult to synthesize clinically. We applied deep, self-supervised learning to longitudinal surveillance MRI to predict short-interval event-free-survival (EFS) risk from time-of-scan. METHODS We retrospectively collected data from 278 patients (2,174 scans) who underwent surgical resection for pLGG at Dana-Farber Cancer Institute/Boston Children’s Hospital (DFCI/BCH) from 1990-2022. A deep-learning model was pretrained with T2-FLAIR sequences to determine the chronological scan order for each patient (temporal pretraining). The model was fine-tuned to predict 1-year EFS from point-of-scan using a subset of scans from DFCI/BCH and then validated on a hold-out dataset (511 scans, 67 patients). Separately, the model was fine-tuned on an external dataset from the Children’s Brain Tumor Network (CBTN) and validated on a hold-out set (204 scans, 61 patients). Results were compared to a model trained without temporal pretraining. RESULTS Median follow-up and interval between scans were 73 and 6.3 months for DFCI/BCH and 20 and 5.8 months for CBTN. Temporal pretraining improved performance for 1-year EFS, for DFCI/BCH (AUC: 0.83 [0.71-0.90] vs. 0.78 [0.62-0.91]; F1-score: 0.80 vs. 0.67), and CBTN hold-out sets (AUC: 0.75 [0.58-0.90] vs. 0.53 [0.35-0.70], p=0.01; F1-score: 0.65 vs. 0.55). Increasing the number of longitudinal scans available to the model incrementally improved performance up to 7 scans/patient for DFCI/BCH and 10 scans/patient for CBTN. CONCLUSIONS Deep-learning with temporal pretraining improves the predictive analysis of tumor growth patterns in postoperative pLGG surveillance MRI, enabling accurate short-interval EFS prediction. This model could help inform patients and clinicians regarding surveillance regimen and initiation of adjuvant therapy.
MDB-74. SERINE/GLYCINE METABOLISM REPRESENTS A NOVEL TARGETABLE THERAPEUTIC VULNERABILITY IN MYC-AMPLIFIED MEDULLOBLASTOMA
Authors: Magretta Adiamah, Bethany Poole, Janet C Lindsey, Shanel Swartz, Alaide Morcavallo, Samantha Jepson Gosling, Mankaran Singh, Helen J Blair, Sarah Kohe, Tong Zhang, Oliver Maddocks, Andrew Peet, Louis Chesler, Ian Hickson, Ross Maxwell, Rebecca M Hill, Steven C Clifford
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma is the most frequent malignant brain tumour of childhood. Whilst advances in risk-stratification and upfront multimodal therapy have led to five-year survival rates around 70%, a subset of tumours remain refractory to current therapies. Group 3 medulloblastomas (MBGRP3) are enriched for amplification or overexpression of the proto-oncogene MYC which conveys a dismal prognosis (&amp;lt;10% survival), highlighting the urgent need for novel therapeutic strategies. Recent advances have revealed a role for metabolic reprogramming in MYC-amplified MBGRP3 tumorigenesis, providing novel opportunities for selective therapeutic targeting. METHODS &amp; RESULTS To investigate MYC-dependent metabolic alterations in MBGRP3, we generated three independent isogenic MBGRP3 cell-based models with regulable MYC expression (iMBGRP3-MYC) using a doxycycline-inducible shRNA system. Using 1H high-resolution magic angle spectroscopy and stable isotope-resolved metabolomics, we identified upregulation of the de novo serine/glycine biosynthesis pathway (SGP), attributable to elevated expression of the rate-limiting enzyme PHGDH, as a novel therapeutic target. Genetic and pharmacological (NCT-503) inhibition of PHGDH induced greater cell death in MYC-expressing cells compared to MYC knockdown cells and increased survival across two independent MYC-amplified MBGRP3 mouse models. The decrease in tumour growth observed was moderate; we therefore hypothesised that a compensatory reliance on exogenous serine/glycine may play a role in sustaining tumour progression under therapy. To explore this, we investigated the impact of exogenous serine/glycine starvation on MBGRP3-MYC tumour development. Starvation resulted in a marked MYC-dependent reduction in cell viability in vitro across independent iMBGRP3-MYC models. Notably, dietary serine/glycine starvation was well-tolerated, delayed tumour progression, and increased survival (by 50%) in an MBGRP3-MYC mouse model (p=0.005), highlighting the metabolic plasticity of MYC-amplified tumours to utilise both de novo and exogenous serine/glycine sources to survive and proliferate. CONCLUSIONS These findings identify serine/glycine metabolism as a targetable therapeutic vulnerability within MYC-amplified MBGroup3 and a novel therapeutic strategy to treat this poor-prognosis disease group.
OTHR-14. AN ADOLESCENT WITH A RARE SCHWANNOMA LOCALIZATION AND THE IMPORTANCE OF METHYLATION STUDIES
Authors: Inês Romão Luz, Raquel Gonçalves, Rita Sousa, Sílvia Carvalho, Ana Margarida Novo, Olinda Rebelo, João Pinheiro, Gustavo Soares, Stephan Frank, Jürgen Hench, Alice Carvalho
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Schwannomas are benign nerve sheath tumours, accounting for about 8% of intracranial tumours, with different histologic patterns described. Olfactory nerves are not expected to have Schwann cells, several theories exist about the origin of these tumours. METHODS/RESULTS A 16-year-old boy was admitted to the emergency department due to a first, self-limited, isolated epileptic event. He scored 15 in the GCS and no focal neurological deficits were observed. At that time, he complained about headaches, lasting for 3 months. Brain CT showed a frontobasal heterogeneous mass. MR characterized it as a 43X34X38 mm well-circumscribed mass, with solid and cystic areas, having an intimate relationship with lamina cribosa, with extensive vasogenic oedema surrounding it, causing deviation of adjacent structures. At that time, he was COVID-19 positive. He was submitted to a craniotomy with a transcortical approach, with an apparent total resection. Retrospectively, he became aware of an improved sense of smell after intervention. The histopathological study revealed a tumour composed of sheets and lobules of large, round cells showing immunopositivity for SOX-10 and S100 and with a Ki-67 index of 5-6%. We proceed to a molecular diagnosis, as the morphology was elusive, finding a methylation pattern highly close to those of schwannomas. With this presumptive diagnosis, clinical and radiological follow-up has been done. After two years, he is doing well, without signs of recurrence. CONCLUSIONS Although rare, an olfactory nerve schwannoma should be considered when there is a frontobasal tumour and impaired sense of smell, although in this case, the COVID-19 infection could be responsible for hyposmia. The clinical picture, imaging and histopathology description were not enough to make the diagnosis and, therefore, to plan the post-surgical approach. We emphasize the importance of a comprehensive molecular study, with a methylation classifier, as this tumour exhibits a typical DNA methylation pattern.