tbuckley/cabot-search huggingface dataset:
CP-06. PEDIATRIC CRANIOPHARYNGIOMA: SINGLE CENTER RETROSPECTIVE STUDY OF SURVIVAL, ENDOCRINOLOGIC, AND VISION OUTCOMES IN 90 PATIENTS
Authors: Rebecca Ronsley, Lydia T Tam, Olivia Do, Ralph P Ermoian, Sarah E S Leary, David Werny, Skyler Leonard, Manuel Ferreria, Jeffrey Ojemann, Richard G Ellenbogen, Amy Lee, Jacob Ruzevick
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Craniopharyngioma is histologically benign. However, due to its location, morbidity is high and may be impacted by therapeutic approach. METHODS A retrospective study of patients treated for craniopharyngioma at Seattle Children’s Hospital from 1996-2023 was performed. Surgical approach, extent of resection, subsequent surgery, radiation and medical therapies, and serial surveillance magnetic resonance imaging for progression were reviewed. Five-year overall survival (OS) and progression free survival (PFS) were calculated and morbidity including endocrine and vision dysfunction was described. RESULTS 90 patients were included of which 53(58.9%) were male. Median age at diagnosis was 8.70 (range 1.39-25.17) years. Surgical approach included endoscopic (N=24), craniotomy (N=64), and combined (N=2). Extent of resection was biopsy N=2, subtotal resection N=7, near total resection N=38, gross total resection N=30. Pathology was adamantinomatous subtype in all cases and 68 had a documented CTNNB1 alteration and 3 had a BRAF alteration in those with molecular analysis. 5-year OS was 96.1% (SE 0.13) and 5-year PFS was 51.9% (SE0.21), with median follow-up of 97 months. Transcranial compared to endoscopic endonasal approach was associated with increased risk of progression (62% vs 30%, OR 1.23). 34 patients were treated with radiation upfront (N=19) or at progression (N=15). 55% of patients at diagnosis and an additional 30% in follow up had pituitary hormone dysfunction. Hypothalamic obesity was documented in 31% of patients and varied by surgical approach. At presentation, ophthalmologic abnormalities included optic nerve edema (18%) and optic nerve pallor (24%) and 30% had abnormal visual acuity. Following initial surgery, 50% had improvement in visual acuity, 35% stable and 15% had worsened visual acuity. CONCLUSIONS Upfront surgical strategy may impact risk of disease recurrence; however, its relationship to long term morbidity is not clear. Further work to delineate therapeutic strategies and their relationship to morbidity in this patient population is needed.
PATH-03. FOXR2-OVEREXPRESSING CENTRAL NERVOUS SYSTEM (CNS) TUMORS EXHIBIT SUBSTANTIAL DIVERSITY ACROSS HISTOLOGICAL, MOLECULAR, AND CLINICAL DIMENSIONS
Authors: Emily Hanzlik, Alexa N Siskar, Mohammad K Eldomery, Soniya Pinto, Christopher L Tinkle, Qunyu Zhang, Maria F Cardenas, Sandeep K Dhanda, Xiaoyu Li, Giles W Robinson, David A Wheeler, Patrick R Blackburn, Jason Chiang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND FOXR2 activation is regarded as the pathognomonic molecular signature of CNS neuroblastoma. However, a comprehensive understanding of the landscape for CNS tumors exhibiting FOXR2 activation is lacking. METHODS Integrated histopathologic, molecular, and clinical data analysis of 36 FOXR2-overexpressing CNS tumors identified through screening of an institutional dataset. RESULTS FOXR2-overexpressing CNS tumors showed a broad anatomic distribution throughout the neuraxis. Of the 36 tumors, 17 (47.2%) were gliomas and 17 (47.2%) were embryonal tumors. The gliomas included 16 high-grade gliomas (eight histone H3 K27M-mutant diffuse midline gliomas, seven radiation-associated tumors, and one with MN1::PATZ1 fusion) and one pilocytic astrocytoma. The embryonal tumors included ten CNS neuroblastomas, six pineoblastomas, and one medulloblastoma. Two were difficult-to-classify high-grade neuroepithelial tumors. The gliomas and embryonal tumors demonstrated comparable FOXR2 expression based on normalized RNA-sequencing data. FOXR2-overexpressing gliomas, but not embryonal tumors, displayed diverse concomitant genetic alterations. The most common mechanisms of FOXR2 activation involved structural alterations leading to proximity effects, frequently incorporating non-canonical non-coding exons, followed by activation of the exon -3 promoter. Tumor location, histology, and concomitant alterations correlated with patient outcomes. While FOXR2-overexpressing gliomas were aggressive with a 5-year overall survival of 13.3%, FOXR2-overexpressing embryonal tumors showed a diverse prognosis. FOXR2-activated CNS neuroblastoma showed a 5-year overall survival of 100%. Pineoblastomas with FOXR2 activation in the PB-FOXR2 DNA methylation group showed a 3-year survival of 0% despite multimodal therapy. The one medulloblastoma patient in the cohort is alive at three years post-diagnosis. CONCLUSION FOXR2-overexpressing CNS tumors manifest significant histological, molecular, and clinical diversity and can occur as post-radiation tumors. Glioma histology and concomitant genetic alterations correlate with treatment resistance and inferior prognosis, while FOXR2-overexpressing embryonal tumors show more heterogeneous outcomes. Integrating histologic and molecular diagnostic approaches along with therapeutic interventions and clinical outcomes is imperative for accurate prognostication and optimal therapeutic decision-making.
DIPG-02. LIN28B EXPRESSION IN DIFFUSE MIDLINE GLIOMA
Authors: Truman Knowles, Shejuan An, Tina Huang, Jin Qi, Amanda Saratsis
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse midline glioma (DMG) is the most lethal of all childhood cancers. LIN28B is a RNA binding protein expressed in a variety of cancers, which suppresses the let-7 family of microRNAs, which in turn suppresses a plethora of oncogenes. However, the role of LIN28B in DMG has not yet been explored. Therefore, we sought to determine the pattern of expression and potential function of LIN28B in DMG using rare DMG cell lines. METHODS All studies were performed on DMG cell lines (n=6) and controls (normal human astrocytes n=1, human neural stem cells n=1). RNA-Seq was performed using single-read sequencing at 50bp on the Illumina NextSeq 500 Sequencing System. Cells were then treated with DMSO or the LIN28B inhibitor, LI71, and submitted to functional in vitro studies, as well as RNA-Seq and Western Blot analysis. Functional pathways analysis was subsequently performed on resulting gene expression values with Ingenuity Pathways Analysis (Qiagen). RESULTS Differential LIN28B expression was demonstrated across cell lines, with DMG cells expressing greater LIN28B gene and protein levels compared to controls. LIN28B inhibition with small molecule inhibitor LI71 resulted in decreased cell proliferation and migration, in vitro. A total of 946 differentially expressed genes were identified between treatment groups (FC&amp;gt;2 or &amp;lt;-2, p&amp;lt;0.05). Functional pathways analysis of differentially expressed genes implicated Cancer and Neurological Disease as the top disease processes, with Cellular Movement as the top molecular process in cell lines expressing LIN28B. Further, inactivation of Myc signaling was implicated in cells treated with LI71. CONCLUSIONS Our data demonstrates increased LIN28B expression in DMG cell lines compared with controls, with oncogenic effects on cell proliferation and migration. Further investigation of the LIN28B-let7 signaling axis is warranted in order to further explore LIN28B as a novel therapeutic target in DMG.
ATRT-11. IRS-III: LONG-TERM FOLLOW-UP SHOWS FAVORABLE OUTCOMES AND DURABLE RESPONSES FOR LOCALIZED ATYPICAL TERATOID RHABDOID TUMOR (ATRT)
Authors: Kavita Desai, Tom Rosenberg, Phoebe Power, Neevika Manoharan, Sumanth Nagabushan, Audrey Green-Murphy, David S Ziegler, Yimei Li, Michael J Fisher, Susan Chi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND IRS-III-based chemotherapy is a long-standing treatment approach for ATRT, which mostly affects infants under the age of 3. We provide long-term outcomes from three high-volume pediatric centers, including a subgroup of patients treated with “moderately-delayed” radiation therapy (RT). METHODS We performed a retrospective analysis of 60 patients treated between 1999-2021. Patients at Boston and Sydney Children’s Hospitals received per-protocol early chemoradiation during induction cycles 3-4, while patients at Children’s Hospital of Philadelphia received moderately-delayed RT with temozolomide post 6 induction cycles. Demographic, clinical and outcome data were collected. RESULTS Median age at diagnosis was 2.3 years (range:0.5-19.5) with median follow-up 2.7 years (range:0.1-15.5); however, 20/60 patients were followed &amp;gt; 5 years (median 10.4, range:5.1-15.5). Thirty-six patients (60%) underwent gross or near-total resection; 14 (23%) had metastatic disease. Seventeen (28%) did not receive RT due to progression, toxicity, or provider discretion; 27 (45%) received focal and 17 (28%) craniospinal RT. For the entire cohort, 5- and 10-year PFS were both 30% (95%CI: 19-42). OS were 38% (95%CI: 27-51) and 31% (95%CI: 19-43), respectively. For patients with localized disease, 5-year PFS and OS were 38% (95%CI: 24-52) and 45% (95%CI: 30-56), respectively. Patients with metastatic disease had 5-year PFS and OS of 0% and 19% (95%CI: 3-43), with no long-term survivors. In multivariate analysis, RT was a statistically significant prognostic factor. However, treatment field (focal vs. CSI), RT timing (early vs. moderately-delayed), patient age, resection extent, or metastatic status were not significant. CONCLUSIONS Our results suggest that IRS-III should remain a standard of care approach for localized ATRT, based on the favorable survival outcomes with the longest follow up of any published ATRT regimen to date. In addition, it highlights the importance of RT for localized disease and proposes it can be given after induction without compromising outcomes, reducing treatment-related toxicity.
MODL-08. PATIENT-DERIVED ORGANOIDS RECAPITULATE THE MOLECULAR LANDSCAPE OF PEDIATRIC BRAIN TUMORS
Authors: Bárbara Ferreira, Joana Peixoto, Anabela Ferro, Jorge Pinheiro, Roberto Silva, Josué Pereira, Joana Oliveira, Arnaud Cruz Da Paula, Paula Soares, Susana Nunes, Ana Paula Fernandes, Maria João Gil da Costa, Jorge Lima
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric brain tumors (PBT) are the leading cause of non-accidental death in pediatric age. These tumors are rare and lack adequate experimental models capable of accurately capturing their complex molecular landscape. METHODS AND RESULTS Our team has established specific protocols for the generation and expansion of ex-vivo patient-derived organoids (PDO) from fresh surgical material of a variety of PBT, within a clinically relevant timeframe. These include pilocytic astrocytomas, a pleomorphic xanthoastrocytoma, a rosette-forming glioneuronal tumor, a supratentorial ependymoma, diffuse high-grade gliomas, a medulloblastoma, an atypical teratoid rhabdoid tumor, and a meningioma. The PDO cultures were set within 7-15 days, with organoids reaching 200-800 μm in diameter. Immunofluorescence analysis using confocal high-content microscopy imaging revealed that PDO kept the protein markers typically found in the corresponding primary tumors. Likewise, at a genomic level, PDO recapitulated the molecular landscape of corresponding primary tumors, as denoted by the maintenance of NF1, PIK3CA, and FGFR1mutations (rosette-forming glioneuronal tumor), KIAA1549::BRAF fusions (pilocytic astrocytomas), ZFTA::RELA fusion(supratentorial ependymoma) or gene amplifications, such as KRAS, CDK4, MDM2, GLI1, PTPN11 and PI3KCA. Additionally, PDO exhibited minimal genetic drift after over one month in culture. In three PBT cases from a medulloblastoma, an atypical teratoid rhabdoid tumor, and a meningioma, where no molecular alterations were detected using a comprehensive NGS panel, we are running DNA methylation arrays and copy number variations. CONCLUSIONS Our results underscore the potential of PDO as a robust ex-vivo experimental model. The generated PDO cultures can be rapidly established and retain key molecular features of corresponding primary tumors. This preclinical model presents versatile applications, serving as a valuable molecular tool for precision medicine approaches in PBT patients, the study of PBT biology, and the acceleration of drug development processes within the context of PBT.
DIPG-70. NQO1 AS A RESISTANCE DRIVER AND THERAPEUTIC TARGET IN DMG
Authors: Leslie E Lupien, Eric Morin, Daren F Zhang, Dana R Novikov, Madison S Chacon, Nicholas Khuu, Hasmik Keshishian, Olivia Seidel, Steven A Carr, Amy Goodale, Nicole S Persky, David E Root, Margaret Cusick, Keith L Ligon, Rameen Beroukhim, Timothy M Phoenix, Veronica Rendo, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2024)

Abstract p53 pathway reactivation through pharmacologic inhibition of negative regulators was identified as a promising therapeutic strategy for TP53 wild-type (WT) high-grade gliomas, including Diffuse Midline Gliomas (DMGs). Despite widespread theoretical promise, the therapeutic efficacy of MDM2 inhibitors and PPM1D inhibitors as single agents have each been limited by issues, including sub-lethal effects on cancer cells and innate or emerging resistance leading to tumor progression. We carried out a genome-scale CRISPR activating (CRISPRa) screen to identify genes that, when overexpressed, confer resistance to p53 reactivation therapies. NAD(P)H quinone dehydrogenase 1 (NQO1) emerged as a top hit and was confirmed through secondary CRISPRa screens and low-throughput validations as driving a resistance phenotype in TP53 WT DMGs. Our subsequent work has aimed to elucidate the mechanisms through which NQO1 mediates the effects of p53 reactivation therapies, and assess the feasibility and impact of exploiting NQO1 in combination therapies towards a cure.
DIPG-32. NEOANTIGEN HEAT SHOCK PROTEIN VACCINE, RHSC-DIPGVAX, IS ASSOCIATED WITH INCREASED VACCINE-INDUCED B CELLS AND BCR/TCR REPERTOIRE DIVERSITY IN PEDIATRIC PATIENTS WITH DIFFUSE MIDLINE GLIOMAS
Authors: Lauren K Boland, Si Wang, Slim Fourati, Suzi DeLay, Tzu-Yi Chia, Leah Billingham, Joshua Katz, Chao Wei, Yuheng Geng, Patrick Sipila, Aru Narendran, Susan Chi, Mariko Sato, Caty Lee-Chang, Jason M Miska, Ashley S Plant-Fox
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse midline gliomas (DMG/DIPG) remain a devastating class of tumors with limited treatment options. Cancer vaccines educate the immune system to tumor neoantigens to facilitate immune-mediated tumor destruction. DMGs have high-frequency, co-occurring neoantigens and are therefore a relevant target for activation of anti-tumor immunity via vaccine. To this end, we have initiated a clinical trial (NCT04943848) to determine if a neoantigen peptide-based vaccine with recombinant human heat-shock constitutive protein 70 and QS-21 adjuvant can promote anti-tumor immunity against DMG/DIPG. NCT04943848 is ongoing and now enrolling subsequent arms with rHSC-DIPGVax plus checkpoint blockade. METHODS Whole blood was collected before the first vaccine cycle (C1D1). Vaccine doses were administered every 2 weeks and blood was collected prior to the third or fifth vaccine cycle (C3D1 &amp; C5D1). Peripheral blood mononuclear cells (PBMCs) were isolated and stored at -160°C. PBMCs from each patient, pre- and post-vaccine, were stained with human T-cell, myeloid, and B-cell antibody panels before spectral flow cytometry, single-cell RNA sequencing, and genomic DNA isolation for T- and B-cell receptor (TCR/BCR) sequencing. Spectral flow cytometry data was analyzed via FlowJo v10. TCR/BCR sequencing was processed via MiXCR and Immunarch. RESULTS Following vaccination, there were higher percentages of two mature CD20+CD19+IgM+ B cell populations, including a 4-1BBL+CD86+ population previously shown to induce robust CD8+ T-cell activation in adults with glioblastoma. Interestingly, given the recent discovery of TIM3’s importance in DIPG, we also identified TIM3-expressing CD4+ and CD8+ T cell populations. Finally, TCR/BCR sequencing demonstrated increased receptor repertoire diversity after vaccination, which is indicative of the vaccine shaping adaptive immunity. CONCLUSIONS Peripheral immune populations and TCR/BCR sequences change during vaccination with rHSC-DIPGVax. Ongoing analyses will determine the specificity of the patient immune response to vaccine antigens and correlate changes in immune populations to clinical course.
ATRT-03. PRIMARY DIFFUSE LEPTOMENINGEAL ATYPICAL TERATOID/RHABDOID TUMOR (ATRT) OF CHILDHOOD DEMONSTRATING UNEXPECTED IMPROVEMENT UPON CESSATION OF CONVENTIONAL THERAPY FOR PRESUMED PROGRESSION; A MOLECULARLY CHARACTERIZED CASE REPORT
Authors: Stavros Stivaros, Laura Parkes, Rania Bedir, Edmund Cheesman, Dipak Ram, Lydia Leung, Annie Huang, John-Paul Kilday
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (ATRTs) are malignant tumors of the central nervous system, typically presenting in the posterior fossa of very young children. Prognosis remains poor despite current therapy, while tumorigenesis implicates both genomic and epigenetic dysregulation. Primary diffuse leptomeningeal disease (PDL ATRT), without a defined intraparenchymal lesion, is an extremely rare ATRT variant with only seven cases reported. None of these preceding cases had undergone molecular characterization. We compared our case, who demonstrated an atypical clinical and radiological trajectory, against these seven cases. CASE PRESENTATION We describe a PDL ATRT, with hitherto novel molecular and imaging characteristics, in a pediatric patient who subsequently demonstrated radiological and clinical recovery from radiologically diagnosed metastatic relapse in the absence of conventional ATRT salvage treatment. Our case is the first to utilize Magnetic Resonance Imaging Arterial Spin Labelling perfusion imaging to suggest an underlying malignancy as the responsible etiology for this patient’s complex presentation, and the first to use methylation profiling to establish a tumor molecular subgroup for a PDL ATRT patient (identifying a MYC-subgroup in this case). CONCLUSIONS For this reported case of pediatric MYC-subgroup PDL ATRT, MR perfusional imaging aided in establishing the diagnosis and predicting potential relapse as part of a multi-parametric imaging assessment. We administered upfront intensive multimodal therapy, including high-dose CSRT to the patient, resulting in the longest overall survival for any patient reported with this extremely challenging ATRT variant. His unanticipated clinical and radiological improvement following a subsequent radiological diagnosis of tumor relapse highlights the importance of confirming recurrence by tissue extraction where feasible, but suggests that further evaluation of histone deacetylase inhibition as a potential future therapy in ATRT is warranted.
TRLS-04. EARLY INSIGHTS FROM PNOC027: PERSONALIZED TREATMENT APPROACHES BASED ON REAL-TIME DRUG SCREENING AND GENOMIC TESTING IN PEDIATRIC AND ADOLESCENT PATIENTS WITH RECURRENT MEDULLOBLASTOMA
Authors: Margaret Shatara, Megan R Paul, Janel R Long-Boyle, Ashley Meyer, Shannon Raber, Lanipua Yeh-Nayre, Aimee Jalkanen, Lindsay B Kilburn, Roger J Packer, Jennifer D Elster, Alyssa T Reddy, Carl Koschmann, Adam Kraya, Adam C Resnick, Michael Prados, Cassie Kline, Sabine Mueller, Robert J Wechsler-Reya, Joshua B Rubin
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND PNOC027, a clinical trial conducted by the Pediatric Neuro-Oncology Consortium (PNOC), explores a precision medicine strategy with up to four FDA-approved agents integrating real-time drug screening with whole exome DNA and RNA sequencing to guide personalized treatment approaches for children and young adults with relapsed medulloblastoma. METHODS Freshly isolated tumor cells from patients undergo high-throughput drug screening, evaluating responses to 232 clinically available compounds over 72 hours. In vitro drug responses are integrated with tumor genomic and transcriptomic data to predict drug combinations for each patient. Drugs are prioritized based on blood-brain barrier permeability, patient age, prior treatments, and other co-morbidities. Correlative studies include the collection of blood to assess circulating tumor DNA (ctDNA) before surgery and during treatment. Health-related quality of life (HRQOL) assessments will also be collected during therapy. RESULTS To date, nine patients have been enrolled. Eight of these have successfully completed real time drug screening with a median turnaround of 7 days from sample receipt. One patient was excluded due to ineligible (non-medulloblastoma) pathology after enrollment. Seven of these had whole exome sequencing, and six had RNA sequencing. Tumor board recommendations were rendered within 21 business days from the date of surgery. Among the diverse drug classes evaluated, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, anthracyclines, DNA crosslinkers, and kinase inhibitors showed the most robust in vitro responses. Six patients received the recommended regimens, experiencing tolerable (grade 1/2) toxicities. Two patients succumbed to disease prior to therapy initiation, three exhibited disease progression while on therapy, and three remain on therapy. CONCLUSION PNOC027 demonstrates preliminary feasibility of real-time drug screening combined with DNA/RNA sequencing to inform targeted therapy selection in clinically relevant timeframes and with potential for disease response.
BIOM-05. THE GUT-MICROBIOTA COMPOSITION IN PEDIATRIC BRAIN TUMORS: AN EMERGING CRUCIAL PLAYER
Authors: Chiara Dossena, Luca Bergamaschi, Federico Rossignoli, Armando G Licata, Matilde Oriani, Manuela Marra, Maria Carollo, Maura Massimino, Loris De Cecco
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Central nervous system (CNS) tumors represent the main cause of cancer-related deaths in children diagnosed at 0–14 years. It has been demonstrated that the bidirectional interaction between gut microbiota and brain, called microbiota-gut-brain axis, has a key role in pathophysiological processes, mediating proliferation of brain tumor cells. The aim of this study was to determine whether the gut microbiota composition of pediatric patients affected by CNS tumors has peculiarities. METHODS We included 42 pediatric patients from the clinical study NET-2019-12371188 that were divided in two groups: i) 12 affected by SNC tumors (group 1); ii) 30 affected by other tumor types (group 2), non related to CNS. From their stool samples, microbial DNA was extracted, 16S DNA libraries were generated and sequenced on IONS5xl (ThermoFisher). From the resulting operational taxonomic unit (OTU) tables, the composition of gut-microbiota was analyzed. RESULTS To determine the richness of gut microbiota in terms of different taxa, alpha diversity analysis was performed. We applied the number of observed features as data matrix and it was lower in group 1 compared to group 2 (p-value= 0.003); on the other side, the homogeneity of taxonomic groups was determined by Pielou’s evenness index, that was higher in group 1 (p-value=0.018), compared to group 2. Beta-diversity measured with unweighted UniFrac metrics revealed that the taxonomic and phylogenetics composition of gut microbiota is different between group 1 and 2 (p-value= 0.03). Finally, linear discriminant analysis effect size (LEfSe) revealed an increase of genus from RF32 order in group 1, while in group 2 genus Blautia ad genus from Coriobacteriaceaea family increased. CONCLUSIONS In conclusion, gut microbiota has a peculiar composition in pediatric patients affected by CNS tumors.