tbuckley/cabot-search huggingface dataset:
GCT-27. Β-HCG STIMULATION WITH RAPIDLY PROGRESSIVE PUBERTY (PP) IN INTRACRANIAL NON-GERMINOMATOUS GCT (NGGCT): CASE REPORT
Authors: Yasin Yilmaz, Hiba Salhah, Emily Mattera, Cecilia Damilano, Shadi Bakjaji, Leena Mamilly, Diana Thomas, Ammar Shaikhouni, Sara Khan
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Intracranial non-germinomatous are rare heterogenous group of Central Nervous System (CNS) tumors that consist of embryonal carcinomas, yolk sac tumors, choriocarcinomas, and teratomas (mature, immature), with or without malignant transformation, as well as mixed types. Presentation frequently includes endocrinopathies, visual changes and signs of raised intracranial pressure. CASE We present a 9-year-old boy with history of headaches, voice changes, increased height and muscle mass, and new onset pubic hair for one month. Examination showed mild papilledema with no cranial nerve palsies, advanced linear growth with height velocity of 15.8 cm/yr with height and weight at 94th and 85th percentile respectively for age. Tanner 2 pubic hair, muscular body habitus and testicles volume of 10-12mLs bilaterally. MRI brain showed a localized pineal region mass with obstructive hydrocephalus. Tumor markers were elevated in serum (β-hCG;69 IU/l and AFP;36.8 ng/ml) with high CSF β-hCG of 41 IU/l with AFP &amp;lt;10ng/ml. Work up for advanced puberty showed bone age of 11.3yrs. Markedly elevated testosterone levels at 929 ng/dl with free testosterone of 135 pg/m. Both LH and FSH were undetectable supporting the diagnosis of peripheral non-gonadotropic puberty (PP). Diagnosis of NGGCT was established on biopsy. He received therapy with chemotherapy, second look surgery and radiation. He remains in remission (negative tumors markers and MRI). Interestingly initiation of therapy resulted in age-appropriate testosterone level and slowing down of rapidly progressive puberty clinically. CONCLUSION We herein present a rare association of β-hCG secreted by NGGCT that cross-reacts with testicular and adrenal LH receptors resulting in increased testosterone levels and rapidly progressive or precocious puberty in males. The incidence of PP in pineal NGGCT remains unknown with very few cases reported in the literature however these are an important consideration in children with advanced puberty in the absence of exogenous hormone exposure and or non-CNS etiologies.
EPEN-25. “CONCERNING EPENDYMOMAS, A FURTHER SUBDIVISION IS NEITHER MORPHOLOGICALLY NOR BIOLOGICALLY NECESSARY”: A NARRATIVE REVIEW OF RESEARCH ON EPENDYMOMAS BETWEEN 1865 AND 2024
Authors: David R Ghasemi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The history of research on ependymomas dates back to the nineteenth century. However, ependymomas have received much less attention than other neuro-oncological diseases. This narrative review investigates the history of ependymoma as a distinct tumour entity. METHODS A comprehensive literature search in German, English and French was carried out for publications from 1850 to 2024 in PubMed, the Internet Archive, and the library of Heidelberg University. Additionally, the evolution of the classification of ependymoma throughout the editions of the WHO classification of CNS tumours was analysed. RESULTS The first major systematic description of ependymal tumours was published in 1865 by Rudolf Virchow, who hypothesized that ependymomas originated from chronic irritations to the ependyma. In 1899, perivascular (pseudo-)rosettes were described for the first time. Subsequently, Percival Bailey and Harvey Cushing’s systematic classification efforts laid the groundwork for new advancements. Debates about the classification of ependymomas can already be found in publications by Percival Bailey or Gustave Roussy in 1924, with a major focus on the definition of ependymoblastoma as an independent entity, which was only resolved in 2016 with the introduction of the new diagnosis ETMR. Klaus Joachim Zülch’s important mid-20th-century work highlighted clinical variations within ependymomas but deemed no further stratification necessary. The WHO’s classifications in 1979, 1993, 2000 and 2007 relied on histopathology, with only minor details being adapted over the years. A new era began in 2016 with the recognition of C11orf95-RELA (ZFTA-RELA) as a defining hallmark of supratentorial ependymomas. The latest WHO classification in 2021 adopted a molecular-anatomical approach, incorporating new subgroups and abandoning histomorphological subtypes due to limited prognostic value. Tumor grading became mostly optional. CONCLUSIONS This review summarises the significant evolution in ependymoma research, particularly in the 2010s. Strikingly, many of the questions that Virchow, Bailey or Roussy investigated, remain unanswered in 2024.
DIPG-13. TIM-3 TARGETED APTAMER IN COMBINATION WITH LOCO-REGIONAL RADIOTHERAPY IMPROVES SURVIVAL BY MODULATING THE IMMUNE INFILTRATION IN DIFFUSE MIDLINE GLIOMA MODELS
Authors: Iker Ausejo-Mauleon, Daniel de la Nava, Naiara Martinez-Velez, Sara Nuin, Sandra Morales, Daniel Palacios-Alonso, Fernando Pastor, Marta M Alonso
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse midline gliomas (DMG) are the most aggressive pediatric brain tumors. Their meager survival has not changed in the last decades emphasizing the urgent need for effective treatments. TIM-3 has emerged as a new target expressed in multiple immune cell types, regulating adaptive and innate immunity. In this work, we used an aptamer against TIM-3 to modify the tumor microenvironment and enhance the antitumor effect. METHODS For in vivo experiments, DMG murine cells were injected orthotopically into the pons of mice using a screw-guided system. The aptamer was administered intracranially (380pmol) on day 5 with the same system and three times intravenous (320pmol/mouse) 8-11-14 days after tumor implantation. In the radiotherapy experiments, 6Gy was given on day 7. Tumor and immune populations were analyzed by flow cytometry. RESULTS TIM-3 aptamer as monotherapy increases immune infiltration and elicits a specific immune response with a modest tendency to improve overall survival. Interestingly, we observed that radiotherapy, DMG standard of care, significantly induced TIM-3 expression in tumor and immune cells in the tumor microenvironment (TME). The combination of TIM-3 aptamer with radiotherapy increased the overall survival (3-fold), led to long-term survivors (30-50%), and generated immune memory in three different glioma models. Importantly, combination treatment significantly increases the infiltration of immune cells (3-fold) in the TME compared with the control groups. Radiotherapy and TIM-3 Apt treatment significantly increased the number and proliferative state of microglia, dendritic, NK, CD4, and CD8 T-cells. Interestingly, TIM-3 aptamer decreased the number and proliferative state of Tregs increasing the pro-inflammatory ratio of CD8: Tregs in the TME compared to non-treated groups after radiotherapy. CONCLUSIONS In conclusion, we provide evidence that combining radiotherapy with a TIM-3 aptamer increases overall survival, leads to the expansion of myeloid and T-cells in the TME, and generates immune memory in DMG models.
METB-07. FREQUENCY AND OUTCOMES OF CDKN2A/B LOSS IN PEDIATRIC GLIOMA
Authors: Phoebe C Power, Jacquelyn Jones, Susan N Chi, Lissa Baird, Katie P Fehnel, Nicole J Ullrich, Keith L Ligon, Sanda Alexandrescu*, Pratiti Bandopadhayay*, Kee Kiat Yeo*
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Chromosome 9p21 deletions involving the tumor-suppressor genes cyclin-dependent kinase 2A and 2B (CDKN2A/B) have been identified as a poor prognostic factor in various cancer types, including adult low-grade gliomas. The frequency and influence of CDKN2A/B hemi- and homozygous deletions in pediatric glioma are less well defined. Herein, we report a single-institution evaluation of the frequency and clinical outcomes of CDKN2A/B loss in pediatric gliomas. METHOD We performed a retrospective, IRB-approved single institutional study, utilizing an existing institutional data registry to identify pediatric patients (age &amp;lt; 21) diagnosed with a glioma who had undergone targeted DNA next generation panel sequencing (Oncopanel) between 2013-2023. IDH1/2-mutant gliomas were excluded. Clinical features, treatment details and outcome data were collected and analyzed. RESULTS Oncopanel was performed on 510 pediatric gliomas. Of these, 372 (72.9%) had low-grade and 138 (27%) had high-grade gliomas. Sixty-six (12.9%) gliomas harbored CDKN2A/B hemi-/homozygous loss; this included 26/372 (7%) low-grade and 40/138 (29%) high-grade gliomas. Homozygous loss was seen in 13/372 (3.5%) low-grade and 26/138 (18.8%) high-grade gliomas. The most common co-alteration with CDKN2A/B loss was BRAFV600E (28/66, 42%), followed by TP53 (8/66, 12%). Median follow-up time of the entire cohort was 3.2 years (range:0.1-36). The 10-year overall survival for pLGGs with CDKN2A/B wildtype and CDKN2A/B homozygous deletion were 95% and 85%, respectively (p=0.03). There was no significant difference in survival of pLGGs with CDKN2A/B wildtype and CDKN2A/B hemizygous deletion. For pHGGs, there was no difference in survival outcomes based on CDKN2A/B status. Further univariate and multivariable analyses are underway. Central pathology review and methylation subtyping to confirm rates of malignant transformation are also ongoing. CONCLUSION CDKN2A/B loss is identified in a subset of both pediatric low- and high-grade gliomas. Our data suggest that homozygous CDKN2A/B loss in pLGG is associated with poorer long-term survival.
CP-17. NKX3.1 AS A PROGNOSTIC MARKER IN PEDIATRIC CRANIOPHARYNGIOMA
Authors: Shehbeel Arif, Ammar S Naqvi, Anne M Coyle, Madison L Hollawell, Phillip B Storm, Adam C Resnick, Mateusz P Koptyra, Peter J Madsen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Craniopharyngiomas are rare, low histologic grade neoplasms of the suprasellar region. Despite their benign histology, these tumors can be challenging to manage due to the morbidities associated with surgery or radiation and their tendency to recur after treatment. In this study, we set out to identify transcriptional factors that may influence or predict recurrence. METHODS We analyzed RNA-sequencing data of 77 craniopharyngioma tissue samples from the Open Pediatric Brain Tumor Atlas cohort and corresponding clinical data. Kaplan-Meier survival analysis was performed using R. Differential expression analysis and gene set enrichment analysis (GSEA) of hallmark pathways was performed. RESULTS The transcription factor NKX3.1 was found to be markedly upregulated in craniopharyngioma relative to other brain tumor histologies (p&amp;lt;0.05). NKX3.1 is a well-studied tumor suppressor in prostate cancer and its reduction or loss of expression is seen with disease progression. Patients with higher NKX3.1 expression had better event-free survival (p=0.0049) and had an average of 530 days longer event-free survival (p=0.036). There was no statistically significant difference in age, sex, tumor location, and extent of tumor resection between high and low NKX3.1 expression groups. There was no significant difference in overall survival (p=0.23). GSEA revealed that patients with high NKX3.1 expression had decreased activation of the Epithelial-Mesenchymal Transition pathway (NES=-1.84, adj. p&amp;lt;0.001) and reduced activation of inflammatory pathways, including the complement, inflammatory response, and IL6-JAK-STAT3 pathways (NES&amp;lt;-1.6, adj. p&amp;lt;0.001). CONCLUSION These findings reveal NKX3.1 as a potential prognostic marker for craniopharyngioma recurrence. Low NKX3.1 expression also correlated with inflammatory pathway activation, a factor that has been previously associated with more aggressive behavior and worse prognosis. Future work is planned to validate NKX3.1 protein expression in patient specimens.
ATRT-14. TARGETING ATYPICAL TERATOID RHABDOID TUMORS USING A NOVEL BI-FUNCTIONAL COREST INHIBITOR
Authors: Anupa Geethadevi, Marianne Collard, Tyler Findlay, Robert Fisher, Nikhil Vaidya, Yiming Deng, Charles Eberhart, Philip Cole, Rhoda Alani, Jeffrey Rubens, Eric Raabe
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (ATRT) are deadly infantile brain tumors driven by a loss-of-function mutation of SMARCB1, a critical component of the SWI-SNF chromatin remodeling complex. However, residual SWI-SNF activity inhibits EZH2 at all loci except where CoREST colocalizes with these complexes, specifically contributing to ATRT pathogenesis. This results in hypermethylation and subsequent repression of genes coding for neuronal differentiation and tumor suppressors, accounting for ATRTs’ stem-like state, aggressive growth, and therapy resistance. We functionally inhibited the CoREST complex in ATRT cells by targeting its core enzymes LSD1 and HDAC1/2 using a bi-functional inhibitor, corin. METHODS We evaluated the efficacy of corin to target ATRT cells (BT37, CHLA05 and CHLA06) by measuring cell proliferation (BrdU immunofluorescence/IF), apoptosis (CC3 IF, cPARP Western blotting/WB, MUSE Annexin V), histone modifications (WB) and neuronal differentiation (WB, IF). Whole mRNA sequencing and ATAC-Seq were performed to see the global transcriptomic and chromatin changes driven by corin. Further, we examined the long-term survival advantage rendered by corin in an in-vivo orthotopic xenograft model of ATRT. RESULTS Corin reprogrammed the chromatin structure in ATRT cells in favor of pathways related to neuronal differentiation, cell differentiation, and axonal development while downregulating pathways related to proliferation and cell cycle (mRNA Seq, ATAC-Seq). Corin inhibited AT/RT cell growth and proliferation (p&amp;lt;0.05), increased apoptosis (p&amp;lt;0.05), increased H3K4me1 and H3K9Ac levels (p &amp;lt; 0.001), and induced neuronal differentiation (IF: Beta-3-tubulin, MAP2, Synaptophysin). Intratumoral delivery of corin increased the median survival of mice bearing aggressive orthotopic CHLA06 tumors from 14 to 35 days compared to control (p=0.02, Log Rank test). CONCLUSIONS Targeting the CoREST complex with corin disrupts ATRT’s epigenetic abnormalities, reversing their stem-like state and slowing tumor growth, thus presenting a promising new strategy that may translate into the clinical setting to help improve ATRT’s dismal survival.
MDB-90. PRIMARY LEPTOMENINGEAL MEDULLOBLASTOMA: A SINGLE-SITE RETROSPECTIVE STUDY OF 5 CASES
Authors: Olivia Wells, Kanika Bhatia, Marty Campbell, Jordan R Hansford, Michael Sullivan, Molly Williams, Cristina Mignone, Colleen D’Arcy, David D Eisenstat, Dong-Anh Khuong-Quang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Primary leptomeningeal medulloblastoma without mass is a rare entity with fewer than 10 reported paediatric cases. Establishing an accurate diagnosis is challenging and reported outcomes are very poor. METHODS We conducted a retrospective analysis of cases presenting to the Royal Children’s Hospital Melbourne between 2013 and 2023. RESULTS Between 2013 and 2023 five patients, all male, were identified, with an average age of 6.6 years [1.9 - 12.2 years]. The presenting history was short in all cases (2-3 weeks) and all had symptoms of raised intracranial pressure. Diagnostic imaging (MRI brain and spine) showed non-specific leptomeningeal thickening and enhancement with no primary posterior fossa mass seen; interestingly only two imaging reports considered malignancy in the differential diagnosis. Surgical biopsy confirmed the diagnosis of medulloblastoma on histology; 3 anaplastic and 2 with classic histology. Subgrouping by IHC, available for 4 patients, showed non-WNT/non-SHH, with one reclassified as SHH by DNA methylation (performed in 2 patients). MYC was amplified in one patient (assessed by FISH in all tumours). Four patients were treated with craniospinal irradiation (36-39.6Gy with 18Gy boost), followed by chemotherapy as per SJMB12 stratum N3 (n=3) or HeadStart III (n=1). One case, an infant, was treated according to COG ACNS0334 with concurrent intraventricular topotecan, followed by maintenance with irinotecan/temozolomide/IVent topotecan. At follow up (average 54 months; 11 – 126 months), four children with residual disease on end of treatment MRI are alive without disease progression. One patient with classical SHH medulloblastoma and MYCN amplification progressed on treatment and died of disease 11 months after diagnosis. CONCLUSIONS Contrary to the historical literature, our case series suggests a more favourable outcome if this disease is recognised early. Further studies are warranted to better understand the molecular profile of these tumours.
IMG-03. PRE-TREATMENT EVIDENCE OF ABNORMAL SUPRATENTORIAL WHITE MATTER IN CHILDREN WITH POSTERIOR FOSSA TUMOURS USING DIFFUSION MRI
Authors: Emily Drabek-Maunder, Kshitij Mankad, Kristian Aquilina, Jamie A Dean, Andrew Nisbet, Chris A Clark
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Over half of childhood brain tumours originate in the posterior fossa, which includes low-grade (e.g. pilocytic astrocytoma) and high-grade (e.g. medulloblastoma) tumours. Even though overall survival rates of paediatric brain tumours have substantially increased, survivors face neuropsychological impairments impacting behaviour, cognition, language and motor skills. Post-treatment outcomes are associated with structural changes within the brain, but it is unclear if observed microstructural damage is caused exclusively by radiotherapy or if there is earlier damage from the tumour and related effects. Diffusion MRI is a non-invasive technique that can be used to better understand white matter microstructure by quantifying water diffusion in the brain. Diffusion tensor imaging (DTI) can be used to assess white matter damage. METHODS In this work, we used DTI to understand white matter microstructure in 8 posterior fossa tumour patients prior to surgery. We compared individual patients to age- and sex-matched healthy controls in a one-against-many approach. RESULTS We demonstrate the presence of supratentorial white matter abnormalities prior to treatment in 3 patients. Before treatment, all patients are found to have significantly enlarged lateral ventricles relative to total brain volume (p&amp;lt;0.05). Patients with ventricle volumes &amp;gt;4% relative to brain volume correspond to significant changes in DTI parameters found in pre-treatment images, suggesting that hydrocephalus impacts white matter microstructure before surgery. Observed white matter changes are complex and patient-dependent, patients demonstrate compression (increased fractional anisotropy; FA) or diffuse oedema and damage (decreased FA). These white matter abnormalities persist over time, which could lead to cumulative damage, for example when adjuvant treatment involves radiotherapy. CONCLUSIONS To improve patient outcomes, pre-treatment imaging could be considered during individual treatment planning and risk evaluation to avoid further injury to white matter. Pre-treatment white matter abnormalities may have a bearing on neurocognitive patient outcomes, which will be the focus of future work.
HGG-31. GENOMIC CORRELATIONS WITH HEMORRHAGE RISK IN PEDIATRIC PATIENTS WITH DIFFUSE HEMISPHERIC GLIOMA
Authors: Nikhil Joshi, Sina Bagheri, Ezra Beaubien, Kyra Harvey, Olivia McManus, Cullen Wilson, Sreehita Hajeebu, Deepak Mishra, Ali Nabavizadeh, Peter Madsen, Jessica Foster
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric diffuse hemispheric glioma (DHG) is a histone-mutated (H3.3G34R/V) high-grade glioma with poor prognosis. Clinical observation and previous reports have identified that a subset of patients present with tumor-associated hemorrhage. Here, we present our findings from radiological review of these patients and determine genomic risk factors predictive for hemorrhage risk in this cohort. METHODS Data was abstracted through the Children’s Brain Tumor Network (CBTN) and EGAS00001004301. Transcriptomic and genomic analyses were completed in R 4.3.1 using edgeR, msigdbr, and xCell. Presence of blood products was determined on preoperative MRI by a board certified pediatric neuroradiologist. RESULTS 48 samples were available across cohorts with transcriptomic or genomic data. 10 samples (21%) had pre-operative imaging and transcriptomic data available. Initial analysis determined that 6 samples (60%) had acute/chronic hemorrhage based on radiological review. Samples with hemorrhage had increased levels of VEGFA (LFC: 3.45, p=2E-07) and CA9 (LFC: 5.97, p=8E-05) expression on the transcriptomic level suggesting that patients with high expression of these markers (AngioHi) had increased risk of hemorrhage compared to patients with low expression of these markers (AngioLo). AngioHi patients had notably higher levels of IL8 (LFC: 3.56, p=0.01) and increased macrophage populations. Genomic information was available for 15 samples (31%, 7 AngioHi, 8 AngioLo). PTEN alterations (n=4, 57%), FBXW7 alterations (n= 2, 29%), or PDGFRa driver alterations (n= 3, 43%) were found in the AngioHi cohort while none of these alterations were identified in the AngioLo cohort. Notably, at least one of these mutations was seen in all cases in the AngioHi cohort. CONCLUSIONS These findings identify potential mutational alterations predictive for tumor-associated hemorrhage in pediatric DHG. Current work is being completed to further characterize how these mutations impact vascular remodeling for patients with DHG and may offer targeted therapeutic opportunities.
CNSC-03. LINKING CELL FATE DETERMINATION IN THE EMBRYONIC FOREBRAIN TO PEDIATRIC HIGH-GRADE GLIOMA
Authors: Liam M Furst, Enola M Roussel, Ryan F Leung, Ankita M George, Ron Firestein, Maree C Faux, David D Eisenstat
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric high-grade gliomas are treatment resistant, usually fatal cancers encompassing diffuse midline glioma, K27-altered (DMG), and diffuse hemispheric glioma, G34R/V (DHG). Most patients harbour canonical and non-canonical mutations in histone variants H3.1 and H3.3, leading to global epigenetic dysregulation and stalled differentiation states as oligodendroglial progenitor cells (OPC) in DMG and GABAergic interneuron precursors in DHG. DLX2 is a homeobox transcription factor that directly represses OPC cell fate and promotes GABAergic interneuron cell fate and migration during early neurogenesis. Methods &amp; Results Our lab has shown DLX2 promoter occupancy of Gad1/Gad2, and early (Olig2, Nkx2.2) and late (Myt1, Plp1) genes required for OPC differentiation in vivo. Co-expression of DLX2 with these target sequences reduces reporter gene expression in vitro, and the Dlx1/Dlx2 double knockout (DKO) mouse showed increases in Olig2, Nkx2.2, and Plp-1 expression in vivo. Transient over-expression of a Dlx2-GFP construct into murine DMG cells resulted in significant increased expression of Gad1/2 isoforms and decreased Olig2 and Nkx2.2, global restoration of H3K27me3 and loss of H3K27 acetylation, as well as a reduction in migration, invasion, and colony formation in vitro. To validate in human pHGG, we first probed an RNA-seq database containing 62 patient-derived pHGG cell lines which demonstrated an inverse correlation between DLX2 expression and OLIG1/2. Cell fate changes in DHG cell lines were evaluated by knockout of DLX2 using CRISPR/Cas9. Concurrently, OLIG1/2-expressing DMG cell lines underwent stable transfection of a DLX2-mCherry overexpression construct in conjunction with a SOX2-BFP overexpression construct, confirmed by qPCR and immunoblot. Analysis of histone H3 marks, K27M, and OPC signature genes will be compared to OPC genes from Dlx1/Dlx2 DKO mouse ganglionic eminences. CONCLUSIONS Manipulation of DLX2 in pHGG provides a model system for assessing the contribution of a homeobox factor to cell fate decisions regulating differentiation and tumorigenicity.