tbuckley/cabot-search huggingface dataset:
LGG-41. DECIPHERING PEDIATRIC LOW-GRADE GLIOMA TRAJECTORIES: DEEP LEARNING-BASED VOLUMETRICS FOR PATIENTS UNDER SURVEILLANCE
Authors: Juan Carlos Climent Pardo, Anna Zapaishchykova, Aidan Boyd, Divyanshu Tak, Maryamalsadat Mahootiha, Zezhong Ye, Sridhar Vajapeyam, Pratiti Bandopadhayay, Ali Nabavizadeh, Ariana Familiar, Tina Young Poussaint, Hugo Aerts, Daphne A Haas-Kogan, Benjamin H Kann
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric low-grade gliomas (pLGGs) have heterogeneous clinical presentations and prognoses. Given the morbidity of treatment, suspected pLGGs are surveilled without treatment, though the natural histories of these tumors have yet to be systematically studied. METHODS We conducted a pooled, retrospective study of pLGG patients diagnosed between 1992 and 2020 from two sources (Dana-Farber Cancer Institute/Boston Children’s Hospital and the Children’s Brain Tumor Network), who were surveilled untreated for at least one-year post-diagnosis and who had linked clinical data and longitudinal MRI available. We applied a validated pLGG deep learning segmentation algorithm to longitudinal T2-weighted MRIs and calculated the 3-dimensional volumes at each timepoint. We evaluated individual tumor trajectories, treatment initiation, and clinical risk factors for radiographic progression and regression (defined as volumetric change &amp;gt;=25% and &amp;lt;=-25% respectively) with univariable and multivariable logistic regression. Unsupervised time-series K-means and density-based spatial clustering with dynamic time wrapping were conducted to uncover volumetric phenotypes and a statistical time-series algorithm with auto-regressive integrated moving average was evaluated to predict future volumetric changes. RESULTS Of 1774 scans from 129 patients (median follow-up of 4.0 years), baseline tumor median volume was 5.8cm3 (range: 0.01-108.1), with 33 cortical (25.5%), 21 brainstem (16.2%), and 21 (16.2%) cerebellar locations. At the last follow-up, 33.8% of tumors progressed, 35.8% were stable, and 30.2% had regressed. Treatment was initiated for 46.5% of the tumors, of which 70.4% underwent surgery. Risk factors such as adolescent age, larger baseline volume size, cortical location and symptomatic presentation were most associated with progression (p&amp;lt;0.05 for each). Clustering revealed three distinct volumetric phenotypes with diverging natural histories, corresponding to progression, stability or regression. The forecasting showed average root-mean-squared error values of &amp;gt;1cm3 at testing. CONCLUSIONS Deep learning auto-segmentation enables longitudinal, volumetric tracking of pLGG, yielding novel insights into the clinical trajectories of untreated tumors on surveillance.
MDB-99. SPATIAL AND TEMPORAL DEVELOPMENT OF GLI2-DRIVEN MEDULLOBLASTOMA
Authors: Najiba Murad, Zhenhua Xu, Jiao Zhang, Prathibhani Ramawickrama Gamachchige, Melanie Schoof, Ulrich Schüller, Andrzej Dlugosz, Michael D Taylor, Yanxin Pei
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB) is a highly malignant tumor of the cerebellum predominantly affecting children. It can be classified into four major molecular subgroups: WNT, SHH, Group 3, and Group 4. Among these subgroups, the SHH subgroup MB, characterized by GLI2 amplification, is associated with a poor prognosis. However, while GLI2 alterations have been linked to SHH-MB, evidence demonstrating its role as an oncogenic driver in an animal model is lacking. Understanding the mechanisms underlying GLI2-amplified MB initiation and progression is crucial for developing improved therapeutic strategies. METHODS By utilizing transgenic mouse models, our study aims to elucidate the role of GLI2 in SHH-MB tumorigenesis and uncover the underlying mechanisms driving tumor formation. This research effort seeks to identify novel therapeutic targets for the treatment of this disease. RESULTS We discovered that overexpression of GLI2 in embryonic Math1+ granule neuron precursors (GNPs) led to tumorigenesis within the cerebellum, resulting in 100% mortality in the mice. Importantly, the cellular and molecular characteristics of these tumors faithfully recapitulated those found in human SHH-MB. Further analysis revealed that only Math1+ GNPs specifically between E13.5 and E15.5 are susceptible to GLI2-induced tumorigenesis, while overexpression of GLI2 in embryonic GFAP+ stem cell/progenitors failed to induce tumorigenesis. Additionally, our single-cell RNA-seq analysis unveiled the heterogeneity of Math1+ cells during cerebellar development. Furthermore, we demonstrated that the MAPK signaling pathway was involved in the tumorigenesis of embryonic Math1+ GNPs by preventing cell apoptosis. CONCLUSIONS Our findings establish a pivotal oncogenic role of GLI2 in SHH-MB tumorigenesis, with GLI2-driven tumors developing within a specific spatial-temporal window from a distinct cell population during cerebellar development. Targeting the MAPK signaling pathway holds promise in preventing tumorigenesis and progression of GLI2-amplified MB.
HGG-36. ASSESSMENT OF CHROMOSOMAL ABERRATIONS IN DIFFUSE ASTROCYTOMAS OF CHILDHOOD USING THE ARRAY COMPARATIVE GENOMIC HYBRIDIZATION (ACGH+SNP) TECHNIQUE – PRELIMINARY STUDY
Authors: Laura Maryńczak, Katarzyna Szewczyk, Stanisław Kwiatkowski, Dariusz Adamek, Mirosław Bik-Multanowski
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Comprehensive knowledge of the genomic changes underlying cancer is a key basis for diagnosis, prognosis and targeted therapies. With recent advances, the technique of comparative genomic hybridization (aCGH+SNP) facilitates genome-wide screening for genome copy number changes and rapid examination of numerical and structural chromosomal changes, as well as loss of heterozygosity at high resolution down to several tens of kilobases. METHODS The study included 12 patients aged 6 months to 15 years, operated on at the Department of Pediatric Neurosurgery in Krakow due to paediatric-type diffuse gliomas (according to WHO classification 5th Ed). Tumor tissue samples were collected from all included participants as remnants of routine examination. Pangenomic profiling of diffuse astrocytomas was performed with using SurePrint G3 Cancer CGH+SNP Kit 4x180K (Agilent, Santa Clara USA) at the Molecular Genetics Laboratory of the University Children’s Hospital in Krakow. Genomic DNA was extracted automatically from deep-frozen tumor tissue. Descriptive statistics were used to describe the basic characteristics of the data included in the study due to the small number of participants. RESULTS Of the 12 tumors examined by microarray, 5 patients had abnormalities in the form of diffuse high grade gliomas. In 1 patient, only numerical changes in chromosomes were observed, in 1 case only structural chromosomal abnormalities were detected. Combined numerical and structural aberrations were presented in 3 samples. Additionally, we detected 1 case of triploidy and 1 case of loss of heterozygosity. CONCLUSIONS Significant changes were observed in paediatric-type diffuse high-grade gliomas. Interestingly, we detected new undescribed alterations that were not only of a chromosomal nature, but also concerned individual genes. This may constitute the basis for further research aimed at establishing new diagnostic and prognostic markers, as well as effective therapy. A limitation of this study is the small patient sample, and further research is recommended.
MDB-104. TARGETING Y BOX BINDING PROTEIN (YBX1) IN PEDIATRIC MEDULLOBLASTOMA
Authors: Stephen Carney, John Hemenway, Ashmita Rajendran, Matthew Hathaway, Eric Nealy, Christian Bonatto Paese, Dhanir Tailor, Sanjay Malhotra, Myron Evans II
Journal: Neuro-Oncology (2024)

Abstract Medulloblastoma is the most common malignant pediatric brain tumor, with some patients having abysmal survival despite an intense therapeutic regimen. A significant barrier to effective outcomes is cell-intrinsic resistance to chemo- and radio- therapy. Using a batch-normalized bulk RNA-seq dataset (GSE124814) comprised of 1350 MB samples and 291 normal cerebella, we reveal upregulation of Y-box binding protein 1 (YBX1) in MB compared to normal cerebellum. Further analysis of this dataset and others demonstrates a significant correlation between MYC and YBX1 expression in G3 tumors. Proteomics analysis also reveals higher YBX1 in G3 tumors characterized by hyperstability of MYC. Using a well-established ex vivo model, we demonstrate increased YBX1 expression as normal cerebellar progenitor cells transition to tumorigenic G3 MB stem-like cells. Deletion of YBX1 in these progenitor cells limits tumorigenesis suggesting a requirement for YBX1 in tumor initiation. We utilized an orthogonal pharmacogenetic approach to inhibit YBX1 and determine its effects on G3 MB tumor biology. Genetic depletion of YBX1 significantly reduced cellular proliferation and antagonized MYC expression in vitro. Orthotopic implantation of these YBX1KO G3 MB cells leads to increased tumor latency and animal survival. Transcriptomic analysis reveals a de-repression of neuronal target genes as well as suppression of MYC-activated genes. Evaluation of SU056, a YBX1 targeting small molecule, revealed both single agent efficacy as well as synergism with chemo- and radio- therapy. Further analysis revealed efficacy in SHH MB, even in tumors with mutant p53, suggesting cross-subgroup use for SU056. In silico docking identified binding of SU056 in the mRNA recognition domain of YBX1. Disruption of YBX1-RNA binding impacts the stability of known oncogenic transcripts, important for tumorigenesis and progression. Our findings corroborate previous identification of YBX1 as a chemoresistance factor and validate pre-clinical targeting of YBX1 to improve patient outcomes.
MODL-04. ZEBRAFISH: THE FUTURE OF PEDIATRIC BRAIN CANCER RESEARCH
Authors: Debasish Roy, Bavani Subramaniam, Wai Chin Chong, Javad Nazarian
Journal: Neuro-Oncology (2024)

Abstract Pediatric brain cancers cause the highest rate of mortality amongst all childhood cancers. Most high-grade gliomas are difficult to treat mainly due to impermeability across the blood-brain barrier, or systemic toxicity. Here, we explore the benefits of zebrafish to assess drug toxicity, orthotopic pediatric brain cancer model development and drug screening. We assessed the toxicity of eight anti-cancer drugs with diverse mechanisms of action. In addition to the survival assay (LC50), we analyzed other teratogenic characteristics to demonstrate the detrimental developmental toxicity, which was critical in determining drug safety for future human usage. To develop fast and reproducible orthotopically xenografted pediatric brain cancer models, we injected approximately 80-100 mCherry expressing JHH-NF1-PA1 and TM-31 cells into the midbrain of 2 days post-fertilization (dpf) zebrafish embryos and imaged daily for next 4 days to monitor the survival, progression, and invasion of the injected cells. Our results show that both cell types were engrafted successfully and multiplied inside the developing zebrafish brain. As compared to JHH-NF1-PA1 cells, which mostly migrated caudally within the developing spinal cord, TM-31 migrated in multiple directions and metastasized five times more rapidly. To check the efficiency of VAL-083 and AZD-1775 in high-grade glioma, 2 dpf zebrafish embryos were injected with mCherry expressing HGG cells, SF8628. At one day post-injection (dpi), the xenografted embryos were exposed to different combinations of Val-083 and AZD-1775 for 72 hours. After 4 dpi, tumor cell invasion and migration in zebrafish were quantified. We found that the combination group had the lowest tumor burden with significantly lower fluorescence intensity, total area of migration, and reduced number of metastatic cells (p&amp;lt;0.001) compared to single or no drug treatment groups. Our study showed that zebrafish is a valuable, rapid, and cost-effective in-vivo pediatric brain cancer pre-clinical model to assess tumor proliferation, metastasis, and rapid drug screening.
IMG-34. THE UTILITY OF [18F]FET PET IMAGING IN PAEDIATRIC CNS TUMOURS: A SINGLE INSTITUTION EXPERIENCE IN SYDNEY, AUSTRALIA
Authors: Dinisha Govender, David Chung
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND MRI remains the standard imaging modality in paediatric CNS tumours. Whilst Positron emission tomography (PET) with O-(2-[18F]fluoroethyl)-L-tyrosine ([18F-FET) is a well-established tool in adult central nervous system (CNS) tumours, established data on its diagnostic utility and impact on clinical management in children and adolescents remain limited. METHODS Single centre retrospective review of database of all paediatric and adolescent patients (age 0-19years) who underwent 18F]FET-PET imaging with cross referencing of patient electronic medical records. Conducted at the Children’s Hospital at Westmead in Sydney, Australia. RESULTS 116 patients underwent 18F-FET PET imaging between October 2012 and January 2024. 28 patients had additional comparative fluorodeoxyglucose (FDG) CNS dedicated PET imaging. Primary indications for FET PET imaging included differentiating between a neoplastic versus non-neoplastic process (23.3%), identifying active residual tumour (14.7%), characterising tumour grade in patients including in those with the known tumour predisposition syndromes (6%), distinguishing between progression pseudo-progression (2.5%) and providing additional localisation or biopsy guidance (8.6%). Malignant transformation, gliomatosis and extent of disease was also noted as indications. 15 patients were able to avoid a biopsy or invasive surgery. Nearly 60% of FET PET imaging was considered clinically useful with the management of 52/112 (46%) patients being supported or changed. Management changes included change second look surgery, change of radiation field, change of treatment and access to a clinical trial. Only 3 scans were reported to have technical challenges in resolution or poor spatial correlation with MRI. Further analysis is currently being conducted, reviewing standard uptake values (SUV’s) of histologically proven low/high grade tumours and T2 enhancing/non-enhancing lesions. CONCLUSIONS This small study demonstrated the clinical benefit and utility of 18F-FET PET imaging in paediatric CNS tumours. Our experience has demonstrated significant surgical and diagnostic advantage in tumour localisation as well as avoiding surgery where able.
PATH-14. A CLINICAL CONUNDRUM - INFANTILE POSTERIOR FOSSA EPENDYMOMA WITH YAP1:MAML FUSION?
Authors: Dinisha Govender, Robert Goetti, Young-Jun Kim, Nicole Graf
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Ependymomas of infancy (0-18months) have been reported to comprise distinct clinical, pathological and genetic entities. Young age is typically associated with posterior fossa group A (PF-A) tumours and therefore a poor prognosis. Treatment of these infants is challenging with limited therapeutic options that have significant long-term sequelae. METHOD We report a single case of a 4-month old baby girl who presented with obstructive hydrocephalus and a presumed posterior fossa mass. RESULTS Imaging demonstrated a large fairly well-defined solid lesion with multiple T1 high and corresponding T2 intermediate signal intensity foci scattered throughout the lesion and marked mass effect on the cerebellum and fourth ventricle. The lesion was inseparable from the pineal gland, habenula and tectum and only mild diffusion restriction. Whilst initially considered to be a posterior fossa tumour, the presence of a claw sign with the tectal plate, favoured a tectal origin. Histological appearances, together with immunohistochemistry findings (GFAP positive and EMA patchy perinuclear dot expression) were consistent with classic ependymoma. Grading was difficult as mitotic activity was relatively low, although focal areas of high ki67 proliferation index were noted suggesting at least focal grade 3 areas. Retained expression of tumour cells for H3K27me3 on immunohistochemistry suggested the likely posterior fossa group B (PF-B) ependymoma. Local SNP chromosome microarray found no acquired clonal abnormality; with no detection of gain chromosome 1q; loss/LOH 6q; Loss/LOH 9p21.3 [CDKN2A, CDKN2B], chromothripsis 11q [ZFTA::RELA], Loss/LOH 17p13 [TP53] or Loss/LOH 22q [NF2]. Additional NGS sequencing identified a YAP1::MAML2 fusion (confirmed with targeted RT-PCR followed by subsequent Sanger sequencing). CONCLUSION This case highlights the challenges with overlapping clinical, pathological and radiological features in an infant with ependymoma, necessitating a molecular diagnosis. After 21months, the patient remains in complete remission following surgery alone.
IMMU-19. COMBINATION IMMUNOTHERAPY SEQUENCE MATTERS: VACCINE PRIOR TO ONCOLYTIC HSV VIROTHERAPY ENHANCES TUMOR-SPECIFIC T CELL RESPONSES AND EFFICACY
Authors: Kyung-Don Kang, Stacie K Totsch, Andrew S Ishizuka, Sam E Gary, Abbey Rocco, Aaron Fan, Li Zhou, Pablo A Valdes, SeungHo Lee, Jason Li, Luca Peruzzotti-Jametti, Sarah Blitz, Christopher M Garliss, James M Johnston, James M Markert, Geoffrey M Lynn, Joshua D Bernstock, Gregory K Friedman
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Safety and preliminary efficacy have been demonstrated with intratumoral oncolytic, engineered HSV immunotherapy; however, few responses have been durable, suggesting that augmented, prolonged anti-tumor T cell responses are likely required to maintain tumor remission. We hypothesized that combining the direct oncolytic effect and innate immune stimulus of oHSV with a vaccine that fosters T cell mediated immunity would lead to more prolonged tumor responses. METHODS We examined the preclinical efficacy of combining intratumoral oHSV with an intravenous (via tail vein) self-assembling nanoparticle vaccine co-delivering peptide antigen to E7 and Toll-like receptor-7 and -8 agonists (TLR-7/8a), termed ‘SNAPvax™’, compared to either therapy alone or control in a TC-1 E7-expressing tumor model in immunocompetent mice. We also assessed how SNAPvax™ timing (before or after oHSV) affected efficacy, viral replication by viral recovery assay, and T cell activation and responses via intracellular cytokine staining of CD8+ T cells in the blood and tetramer staining. RESULTS The oHSV-vaccine combination prolonged survival compared to control or either agent alone. Critically, survival was significantly enhanced when SNAPvax was given before oHSV compared to after oHSV. Increased effectiveness was associated with reduced tumor volume, increased tumor antigen specific CD8+ T cells, and amplified viral recovery. CONCLUSIONS These results demonstrate the criticalness of combination immunotherapy timing with improved efficacy seen when vaccine was given prior to oHSV, which was mediated by tumor specific CD8+ T cells and increased viral replication. Our data provide preclinical support for translation of this novel combination therapy to clinical trial.
LMIC-02. FREQUENCY OF NTRK FUSIONS IN PEDIATRIC LOW GRADE GLIOMAS. DATA FROM A SINGLE CENTER IN MONTERREY, MEXICO
Authors: Carlos A Leal-Cavazos, Jose A Arenas-Ruiz, Oscar Vidal-Gutierrez
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Neurotrophic tyrosine receptor kinases (NTRK 1-3)fusions have been identified in a range of pediatric cancer. Among children with cancer NTRK fusions can be detected in less than 1% of cases. Low grade gliomas (LGG) are the most pediatric brain tumors and the frequency of NTRK fusions reported is between 0.4 -4.3%. NTRK2 fusions are the most commonly reported in pediatric brain tumors. METHOD We describe the characteristics of patients analysed. Due to limited access to Next Generation Sequencing (NGS) only patients with recurrent, progressive, metastatic or midline location LGG were tested during 2021-2022. Positivity to Pan-Trk immunohistochemistry was needed to proceed to confirmation with NGS. 10 patients with LGG were included. Median age of patients at baseline was 4.7 (range,1-12) years. 10/10 showed positivity to Pan-Trk stain and NTRK fusions were detected in 6/10 patients, 3/6 had NTRK1 fusions, 2/6 NTRK2 fusion and 1 with NTRK3 fusion.. All 4 patients without NTRK fusions are off therapy (more than 1 year survellaince) and 2/4 were treated with surgery only. All patients with NTRK fusions are still on treatment due to progressive disease, 4/6 patients have required 2 or more surgeries and 5/6 patients have needed 2 or more chemotherapy regimens. CONCLUSION This small cohort of patients represents a highly selected population with LGG and the frequency of NTRK fusions resulted significantly higher than expected (6 out of 10 patients tested). This finding could reflect a clinical or prognostic significance, it will be important to analyze a larger cohort of patients that share these same clinical characteristics to determine its real value as a prognostic marker in these heavily treated patients. There is well known molecular alterations that predict outcome in patients with LGG. NTRK targeted therapy already exists with proven efficacy although access may limits its use.
MDB-100. RETROSPECTIVE ANALYSIS OF CUMULATIVE DOSING OF CHEMOTHERAPY AGENTS AND THE EFFECT ON SURVIVAL IN PATIENTS WITH AVERAGE RISK MEDULLOBLASTOMA TREATED ON CHILDRENS ONCOLOGY GROUP STUDY ACNS0331
Authors: Erin N Wright, Catherine Billups, Yimei Li, Sarah Rush, Ralph Salloum, Peter de Blank
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Although survival outcomes for average risk (AR) medulloblastoma remain good, patients may experience significant acute and long-term toxicities from therapy. To evaluate the effect of dose modifications among children with AR medulloblastoma, we examined the effect of cumulative chemotherapy dose on overall and event-free survival. METHODS We retrospectively examined the association between the proportion of scheduled chemotherapy dose received on survival outcomes (OS and EFS) using Cox regression models and log-rank tests for patients treated on ACNS0331. We evaluated all chemotherapy agents for the group as a whole and within the four major subgroups. Dose intensity was analyzed continuously and categorically (&amp;gt;75% or &amp;lt;75% of planned dose) for each agent. RESULTS 274 evaluable children (medulloblastoma by methylation, received standard dose craniospinal radiation and chemotherapy) were followed for a median of 9.3 years (range, 7.0-10.4 years). Vincristine and cisplatin showed the most variable dose intensity (25.2% and 31.8% of patients received &amp;lt;75% of expected dosing, respectively). Cyclophosphamide and lomustine were not examined due to low dose variability (17.2% and 11.7%, respectively). The effect of dose intensity was evaluated in 235 patients who completed planned therapy. Molecular subgroup remained a significant predictor of outcome in AR medulloblastoma (EFS (p=0.012) and OS (p=0.008)). Although survival curves were lower for less dose intense treatments, no significant difference in EFS or OS was found due to reduced dose intensity for vincristine (p=0.36 EFS, p=0.35 OS) or cisplatin (p=0.49 EFS, p=0.52 OS). The hazard ratio [95% confidence interval] for chemotherapy proportion and EFS was 0.998[0.977-1.019] (vincristine) and 0.989[0.966-1.012] (cisplatin). There was no difference in the effect of dose reductions by molecular subgroup. CONCLUSIONS Moderate reductions in vincristine and cisplatin dose intensity do not significantly affect survival in AR medulloblastoma. It is unknown whether this reduction would reduce chemotherapy-related toxicity.