tbuckley/cabot-search huggingface dataset:
MDB-76. ONC201 INHIBITS THE CHARACTERISTICS OF CANCER STEM CELLS IN GROUP 3 MEDULLOBLASTOMA
Authors: Luana Abballe, Celeste Antonacci, Matteo Gianesello, Chiara Lago, Angela Mastronuzzi, Giuseppina Catanzaro, Angela Di Giannatale, Luca Tiberi, Franco Locatelli, Evelina Miele
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB), the most frequent childhood brain tumor, originates in the cerebellum. Despite treatment advances, recurrence affects 40%, with a mortality rate of 30%. Cancer stem cells drive tumor initiation, maintenance, and therapy resistance, in several tumors including MB (MBSC). In response to stress, stem cells activate mechanisms like the unfolded protein response (UPR) to maintain homeostasis and survive adverse conditions. The UPR restores endoplasmic reticulum balance, supporting cell function and survival. Recent studies have shown that the UPR plays an important role in tumorigenesis, however, its function in MBSC remains unknown. METHODS To understand the involvement of the UPR in stem cell maintenance, we have investigated the biological effects of its pharmacological inhibition on Group 3 (G3) MBSC. We selected three G3 MB cell lines (D283-Med, D341-Med and Med411), for in vitro studies. Cell line selection was based on their fidelity to the expected methylation class, corresponding to the subgroup of the parental tumors, and were grown in “stem-like” conditions as neurospheres. We evaluated drugs targeting the UPR stress program, identifying ONC201 as the most effective against MBSC. ONC201 is an imipridone compound that activates p53-independent apoptosis causing changes in gene expression similar to those caused by UPR. RESULTS Our findings revealed that ONC201 modulates protein synthesis via ATF4, a pivotal UPR molecule, with stronger induction observed in MB cells cultured under “stem-like” conditions. This ATF4 upregulation triggers the activation of pro-apoptotic programs. Additionaly, ONC201 was effective on reducing the stem-like features of MBSC, including self-renewal, stem cell markers expression, migration, and invasion potential. Notably, ONC201 demonstrates synergy with vincristine and methotrexate chemotherapy. CONCLUSIONS These results propose ONC201 as a promising agent for targeting G3 medulloblastoma by compromising the stem cell compartment. Further investigation is warranted to confirm its efficacy and potential clinical application.
LGG-11. UNDERSTANDING THE TRANSCRIPTIONAL HETEROGENEITY OF PEDIATRIC LOW-GRADE GLIOMAS AND ITS IMPLICATION FOR TUMOR PATHOPHYSIOLOGY
Authors: Michelle Boisvert, Ashwyn A Perera, John Jeang, Alexandra L Condurat, Jessica W Tsai, Dana Novikov, Jared Collins, Eric Morin, Jared Woods, Kevin Zhou, Madison Chacon, Jeromy DiGiacomo, Rushil Kumbhani, Dayle Wang, Michael D Taylor, Jordan R Hansford, Louise E A Ludlow, Nada Jabado, Keith L Ligon, Rameen Beroukhim, Pratiti Bandopadhayay, David T W Jones
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric low-grade gliomas (pLGGs) are the most frequent brain tumors in children and comprise a heterogeneous group of tumors with different locations, histologic subtypes, ages at presentation, and clinical behavior. Tumors frequently respond to treatment with chemotherapy or radiation therapy, but they can regrow after a period of quiescence, requiring further therapy. Thus, a deeper understanding of the molecular processes involved in these tumors is required to develop therapeutic strategies that are effective against their disease mechanisms. METHODS To better understand the cellular behaviors of this heterogenous group of tumors, we have employed single-cell and single-nuclei RNA sequencing technologies to analyze a large-scale dataset (&amp;gt;250,000 cells) of 55 pLGGs across many histological subtypes (pilocytic astrocytoma, pleomorphic xanthoastrocytoma, pilomyxoid astrocytoma, DNET, ganglioglioma, RGNT, diffuse astrocytoma, SEGA, glioneuronal, oligodendroglioma). RESULTS Analysis of this data identified a heterogenous population of cell types and cell states, detecting mature and progenitor-like astrocytes and oligodendrocytes, as well as cells exhibiting senescence or cycling programs. Moreover, we identify a significant immune infiltrate, comprised primarily of microglia. In addition to heterogeneity within pLGG tumors, heterogeneity between LGG subtypes represents another layer that stratifies pLGG biology. We performed a compositional analysis of the cell types present in these tumors and compared transcription signatures and gene expression programs across shared cellular populations of histologically and genetically distinct pLGGs. Finally, we used spatial transcriptomic data to investigate and annotate the cellular architecture of multiple pLGGs with BRAF mutations and draw comparisons to findings from our single-cell and single-nuclei transcriptomic analysis. CONCLUSIONS Our analysis of human pLGGs at the single-cell and single-nuclei resolution provides critical insight into the heterogenous biological activities that constitute these tumors.
OTHR-13. A RETROSPECTIVE ANALYSIS OF A CLINICO-PATHOLOGICAL DATA ON CHILDHOOD AND ADOLESCENT MENINGIOMA- A SINGLE CENTRE EXPERIENCE
Authors: Tanveer Ahmed Shaikh, Shireena Yasin, Darren Hargrave, Enrica Tan, Elwira Szychot
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Meningiomas in young patients remain poorly understood in terms of their origin, outcomes, and best treatment approaches. Current knowledge is limited to small studies and applying adult data, making dedicated research crucial for better understanding and management of these tumours. METHOD We reviewed meningioma cases (1990-2023) from our database, analysing demographics, tumour details, treatment, and outcomes. Neuroimaging and records confirmed tumour location and resection extent. Pathology was reviewed for alignment with WHO 2016 classification. RESULTS At GOSH, 60 patients with meningioma were treated over 33 years. Ages ranged from infants (142 days) to young adults (21 years) of which 51.7% were males. The commonest tumour location was at the skull base (31.6%), followed by the convexity (23.3%). Notably, 6.6% were previously exposed to therapeutic irradiation, and 20% were diagnosed with neurofibromatosis type 2 (NF-2) while 3 others had suspected mosaic NF-2. Among 55 cases with slides available for histopathology review, 26 (46.42%) were WHO grade-I, while 25 (44.64%) WHO grade-II and 4 (7%) WHO grade-III which had a 50% fatality rate. Complete surgical removal offered the best outcome, with only 3 out of 29 patients (10%) experiencing relapse as compared to 11 out of 17 (64.7%) in those who underwent incomplete resection alone. However, radiotherapy after incomplete surgery showed promise, with all 8 patients remaining relapse-free. Unfortunately, the single patient with a very aggressive tumour type (rhabdoid histology) progressed even after complete removal and irradiation. CONCLUSION In children and teens with meningioma, extent of initial surgical resection is considered the strongest independent prognostic factor, but radiotherapy after incomplete removal can improve relapse-free survival. Careful monitoring is crucial for those with partial resections, high-grade tumours, or NF2. Molecular data may bring light in the future on how the unique characteristics of paediatric meningiomas impact clinical status, management approach and survival.
LGG-10. RECOMBINANT HUMAN ENDOSTATIN IN COMBINATION WITH CHEMOTHERAPY FOR PEDIATRIC LOW-GRADE GLIOMAS
Authors: Jun-ping Zhang, Jing-jing Ge, Ya-jing Liu
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric low-grade gliomas (pLGGs) entail highly effective treatment regimens. In this study, we aimed to examine the efficacy and safety of recombinant human endostatin (rh-ES) combined with chemotherapy for pLGGs. METHODS We collected the clinical data of pLGG patients treated with carboplatin and vincristine (CV) plus rh-ES in the Department of Neuro-oncology, Sanbo Brain Hospital Capital Medical University, Beijing, China, from July 2015 to October 2019 and retrospectively analyzed the effectiveness and safety of this regimen. RESULTS A total of 41 eligible patients were enrolled. Median age at diagnosis was 4 years. Median follow-up lasted for 22.7 months (range 8-73.4 months). Six patients achieved complete response, 7 attained partial response, 4 had minor response, the disease was stable in 3 cases, and in 1 the condition progressed. The objective response rate was 90.2% and complete response rate was 14.6%. The median time to response was 4.1 months. The duration of response was 28.1 months. The progression rate within 6 months of treatment completion was 6.9%. 5-year rates were 74% for progression-free survival and 92% for overall survival. The main toxicities included myelosuppression and carboplatin allergy. No serious rh-ES-related toxicities were observed. CONCLUSIONS Rh-ES in combination with CV in pLGG patients was effective and safe and could achieve rapid and lasting responses.
GCT-25. THE IMPACT OF RESIDUAL DISEASE ON THE OUTCOMES OF CENTRAL NERVOUS SYSTEM GERMINOMAS – A MULTICENTER INSTITUTION EXPERIENCE
Authors: Jimin Shin, Anne Cochrane, Andrea Ogle, Ashley Meyer, Nicole M Brossier, Margaret Shatara, Andrew Cluster, Truman Knowles, Sabine Mueller, Małgorzata Czogała, Evan Cantor, Mohamed S Abdelbaki
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Germinomas make up about two-thirds of central nervous system (CNS) germ cell tumors and are highly radio-sensitive with excellent survival rate of more than 90%. Current standard of care involves the combination of chemotherapy with reduced-dose radiotherapy. Typically, patients with residual disease receive a higher dose of radiotherapy. However, recent clinical trials showed that there were no differences in the outcomes between those who had complete response (CR) versus partial response (PR) to initial chemotherapy. Hence, we aimed to assess the outcomes of germinoma patients based on the responses to both chemotherapy and radiotherapy. METHODS A multicenter retrospective chart review of patients with germinoma from four large academic institutions was conducted. RESULTS Data from 41 germinoma patients treated between 2011 and 2022 were analyzed. Thirty-two patients had stable disease (SD)(2), PR(28), or CR(2) to chemotherapy. At the end of radiotherapy, 12 had CR, 5 had PR, and 13 had SD. All patients were alive at the time of review, with a median duration of survival from diagnosis of 78.85 months (range 3.90-278.67). One patient experienced radiographic progression following chemotherapy with SD noted following radiotherapy. CONCLUSION Relapses are extremely rare in patients who have residual disease at the end of therapy for germinoma. Future prospective clinical trials are needed to test the possibility of treating germinoma patients who have residual disease with a dose of radiotherapy comparable to that used in patients who achieve complete response.
GCT-24. ISOLATED PITUITARY STALK THICKENING
Authors: Julie Bennett, Liana Nobre, Eric Bouffet, Bryan Maguire, Afsaneh Amirabadi, Cynthia Hawkins, Oussama Abla, Jonathan Wasserman, Birgit Ertl-Wagner, Ute Bartels
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Few studies have examined predictive factors and outcome of isolated pituitary stalk thickening (iPST) in children. We aim to describe our institutional cohort to determine predictors of future proliferative disease. METHODS A search of the radiology, endocrinology and neuro-oncology databases was performed to identify patients with iPST diagnosed between January 2000 and June 2019. Clinical data was collected along with detailed radiology review of MRIs in a blinded fashion. RESULTS Forty-seven patients were identified, with 40 meeting criteria for inclusion. Median age of baseline MRI was 9.6 years (range 0.9-17.5). Twenty-five (63%) were female. Median follow up time was 5.2 years (range 0.3-18.6). Indication for MRI was symptoms of diabetes insipidus (DI) in 29 patients followed by concerns for anterior endocrine disturbance (6), headache (1) or visual impairment (1). Thirty-four (85%) subjects had pituitary dysfunction, including 31 with DI however DI was not predictive of future development of proliferative disease (69% with presumed hypophysitis vs 93% with proliferative disease, p=0.12). Fourteen (35%) patients developed proliferative disease, with germinoma (8), Langerhans cell histiocytosis (5) and lymphoma (1) at median of 1.3 years (range 0.3-4.0), 2.2 years (range 0.3-9.4) and 1.1 years after initial MRI respectively. Lumbar puncture was performed in 24 patients with elevated white blood cell count (&amp;gt;5 x 106/L) found in 6 (75%) patients with germinoma, 1 (100%) patient with lymphoma, 0 patients with LCH and 3 of 11 (27%) patients with presumed hypophysitis (p=0.015). Thickening of the entire stalk at time of diagnosis and radiographic progression were more likely to be seen in those that developed proliferative disease. CONCLUSION In this cohort 35% of children with PST were eventually diagnosed with a proliferative disease. Importantly, central DI was not associated with risk of proliferative disease. Several radiographic features and elevated CSF WBC were predictive of this outcome.
IMG-09. A DEEP LEARNING-BASED APPROACH FOR BRAIN TISSUE EXTRACTION USING MULTI- AND SINGLE-PARAMETRIC MRI IN PEDIATRICS
Authors: Deep B Gandhi, Anurag Gottipati, Wenxin Tu, Ariana Familiar, Shuvanjan Haldar, Neda Khalili, Paarth Jain, Karthik Viswanathan, Phillip B Storm, Adam C Resnick, Jeffrey B Ware, Arastoo Vossough, Ali Nabavizadeh, Anahita Fathi Kazerooni
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Skull-stripping, the process of extracting brain tissue from MR images, is an important step for tumor segmentation and downstream imaging-based analytics such as AI-powered radiomic feature extraction. Existing skull-stripping models, designed for pediatric or adult patients, show limitations in accurately segmenting tumors in sellar/suprasellar regions. This limitation hinders their reliable application across different histologies of pediatric brain tumors. We propose a deep learning approach for fully automated skull-stripping, compatible with both single- or multi-parametric MRI sequences. METHODS We developed 3D nnU-Net models trained on preprocessed MRI sequences (including pre- and post-contrast T1w, T2w, and FLAIR) from 336 patients with brain tumors across multiple tumor histologies such as low-grade, high-grade and brainstem gliomas, medulloblastoma, ependymoma, etc., aged between 3 months and 20 years (median age, 8.5 years). The training utilized manually generated brain masks, including the sellar/suprasellar region, from 153 patients and employed 5-fold cross-validation to split the data into inner training-validation sets. The models were then tested on a withheld set of 183 subjects. Additionally, we trained a single-parametric model on individual images, resulting in 612 training and 732 testing cases. Model performance was evaluated using the Dice similarity metric for segmenting both the entire brain and slices specifically containing the sella turcica. RESULTS The multi-parametric and single-parametric models achieved mean±sd Dice scores of 0.981±0.008 (median=0.983) and 0.979±0.009 (median=0.981), respectively. For the sellar/suprasellar slices, the scores were 0.983±0.009 (median=0.986) and 0.981±0.012 (median=0.984), respectively. These results indicate a high precision in segmenting not only the entire brain volume, but also the sellar/suprasellar region. CONCLUSION Our proposed deep learning-based skull-stripping approach, leveraging both multi-parametric and single-parametric MRI inputs, demonstrates excellent accuracy. These models, made publicly available, have potential for improving auto-processing pipelines in pediatric brain tumors.
GCT-23. LONG-TERM FOLLOW-UP AND SURVIVALS OF PATIENTS WITH LOCALIZED CENTRAL NERVOUS SYSTEM NON-GERMINOMATOUS GERM CELL TUMORS (NGGCT) ENROLLED ON ACNS1123: A CHILDREN’S ONCOLOGY GROUP (COG) STUDY
Authors: Girish Dhall, Yu Wang, Arzu Onar-Thomas, Dennis Shaw, Shannon MacDonald, Erin Murphy, Soumen Khatua, Ute Bartels, Jason Fangusaro
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND ACNS1123 was a Phase 2 study to determine whether irradiation could be safely reduced without impacting survival in a subgroup of NGGCT patients. METHODS Patients with localized disease who achieved a complete (CR) or partial response (PR) to induction chemotherapy were eligible to receive reduced dose/volume of irradiation to 30.6Gy whole ventricular field with 54Gy tumor-bed boost. RESULTS 107 eligible NGGCT patients were accrued. The median age of patients at enrollment was 11 years (3.7-21.6). Eighty patients (75%) were male. Location was pineal in 58 (55%), suprasellar in 37 (35%), ventricles in 6 (6%), and bifocal in 6 patients (6%). Sixty-six (61.7%) patients achieved a CR/PR post-induction and were eligible and evaluable for the primary objective and received reduced dose and volume of irradiation. Eight patients progressed; 6 had a distant spinal relapse (outside the irradiation field) and 2 had a local plus distant relapse. As of December 31, 2023, the median follow-up time for eligible and evaluable patients was 5.6 years (0.9-7.9) from enrollment. Except for an unrelated death due to SARS-CoV-2 at 5.5 years from enrollment, there were no grade 3 or higher adverse events at the 60-month follow-up timepoint and no disease progressions beyond 2 years. The 5-year progression-free and overall survival for all eligible and evaluable patients are 87.9% (95% CI:79%-94.8%) and 92.4% (95% CI:82.8%- 96.8%), respectively. CONCLUSION Although the study was closed prematurely due to the concern of increased spinal relapse, the current data suggest that most patients with localized NGGCT and a CR/PR to chemotherapy will survive long-term, and, in fact, have similar survival (PFS and OS) to patients enrolled on ACNS0122 who received full dose craniospinal irradiation. The key to future biologic studies and clinical trials is identifying at diagnosis those patients at high risk for relapse.
IMG-10. IMAGING SUBTYPES OF PEDIATRIC LOW-GRADE GLIOMA ARE ASSOCIATED WITH DISTINCT MOLECULAR CHARACTERISTICS
Authors: Anahita Fathi Kazerooni, Adam Kraya, Komal S Rathi, Meen Chul Kim, Varun Kesherwani, Arastoo Vossough, Ariana Familiar, Nastaran Khalili, Phillip B Storm, Jeffrey B Ware, Yuanquan Song, Jessica Foster, Sabine Mueller, Michael J Fisher, Adam C Resnick, Ali Nabavizadeh
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric low-grade gliomas (pLGGs) have diverse molecular subtypes with distinct prognoses, necessitating personalized treatments. We aimed to determine whether radiomic features of pLGGs co-segregate with molecular subtypes, establishing a proof-of-concept that distinct molecular aberrations could manifest in differentiable imaging features. METHODS Leveraging radiomic, genomic, and transcriptomic data from 201 pLGG patients from the Children’s Brain Tumor Network (CBTN), we identified imaging-based pLGG subtypes through their radiophenotypes. This involved investigating the association of imaging subtypes with 2021 WHO pLGG classifications and profiling transcriptional characteristics distinguishing pLGG clusters. We used principal component analysis and K-Means clustering on 881 radiomic features and incorporated clinical variables (age, sex, tumor location), and derived three imaging subtypes. RESULTS BRAF V600E mutations were mainly found in subtype 3, while BRAF::KIAA1549 fusion in subtype 1. To ascertain transcriptome pathways most closely associated with imaging-based subtypes, we applied a supervised machine learning model with elastic net logistic regression using a one-versus-rest strategy for each imaging cluster, considering the top 100 most variable pathways, identified through gene set enrichment and gene co-expression network analyses, molecular subtype, tumor location, age, sex, and race. The predictive accuracy (area under the receiver operating characteristic curve) of the model was 0.86 | 0.72 for imaging subtype 1, 0.93 | 0.71 for subtype 2, and 0.91 | 0.64 for subtype 3 in the training | testing sets. Notably, each imaging subtype exhibited distinct molecular mechanisms; subtype 1 showed up-regulation of oxidative phosphorylation, PDGFRB, and interleukin 4, 10, and 13 signaling, while subtype 3 was linked to histone acetylation and DNA methylation pathways, relating to BRAF V600E pLGGs. CONCLUSIONS Our radiogenomics study suggests that intrinsic molecular characteristics of tumors drive distinct imaging subgroups of pLGG, providing a basis for future multi-modal investigations that may better define progression and targetability of the disease.
MDB-82. TRANSFUSION-RELATED IRON OVERLOAD MIMICKING METASTATIC DISEASE IN A PEDIATRIC PATIENT WITH MEDULLOBLASTOMA ON A RADIATION-DELAYING CHEMOTHERAPY REGIMEN
Authors: Nicholas Pytel, Hannah Glanz
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Transfusion-related iron overload (TRIO) is a known complication of administering numerous packed red blood cell (pRBC) transfusions in pediatric oncology patients undergoing myelosuppressive therapy. Infant medulloblastoma regimens attempt to avoid or delay radiation and its adverse effects in this population, with intensive myelosuppressive chemotherapy. We report a case of TRIO first suspected as hepatic metastatic disease at time of CNS recurrence in a young patient with medulloblastoma after completion of a high-dose chemotherapy protocol. METHODS Case Report RESULTS A five-year-old male presented with four months of headaches, dizziness, imbalance, and emesis. MRI revealed a posterior fossa mass with near total resection of the mass confirming classic medulloblastoma, non-WNT, non-SHH. The patient received five cycles of induction chemotherapy. This was followed by a single cycle of high-dose chemotherapy (HDCSCR) with autologous stem cell rescue. During therapy, he received 26 pRBC transfusions to correct severe anemia. CNS recurrence occurred 19 months after therapy. Abdominal imaging revealed enlarging hepatic lesions concerning for metastases. Ferritin was 1,268 ng/mL (normal: 7-142 ng/mL) and MRI of liver revealed severe iron load with LIC of 11 mg Fe/g dry weight (dw) (normal: 0.4-2.2 mg Fe/g dw). Ultimately, hepatic lesions were thought to be non-cancerous, and he proceeded with craniospinal irradiation. He was diagnosed with TRIO. He underwent phlebotomy for 33 months with ferritin and MRI liver LIC within normal limits. CONCLUSION This case illustrates an occurrence of TRIO presenting as hepatic lesions concerning for metastatic disease during CNS recurrence in a patient who underwent an infant medulloblastoma regimen with HDCSCR. Our patient required phlebotomy for nearly 3 years to return ferritin and LIC to normal limits. Further investigation on the prevalence of TRIO in medulloblastoma survivors treated with radiation delaying/sparing protocols is necessary to improve outcomes and avoid end organ damage due to iron overload.