tbuckley/cabot-search huggingface dataset:
NURS-21. EXPLORATION OF CORRELATIVE STUDIES IN EARLY PHASE TRIALS FOR PEDIATRIC AND YOUNG ADULT CENTRAL NERVOUS SYSTEM (CNS) TUMORS AND THE POTENTIAL TRANSLATION TO CLINICAL CARE
Authors: Ken Seidl, Courtney Baker Briamonte, Micah Higgins, Carly Hoffman, Susan Holtzlaw, Michele McHugh, Ashley Meyer, Kasey Rangan, Cindy Schmus, Marylynne Strachan, Kaaren Waters, Lanipua Yeh-Nayre, Cassie Kline, Michael Prados, Sabine Mueller, Shannon Raber
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Correlative studies are common in early phase clinical trials. In addition to primary aims establishing maximum tolerated dose or efficacy, supplementary information from biospecimens is frequently collected with patient consent. The Pediatric Neuro-Oncology Consortium (PNOC) has included several correlative studies with implications for understanding patterns in the development of tumors, response to treatment, and prognosis. A needs assessment survey of PNOC institutions by the Advanced Practice Provider and Investigational Nurse Committee (APPNIC) highlighted that nurses and advanced practice providers (APPs) desire further education regarding correlative studies. METHODS Blood, stool, cerebrospinal fluid (CSF) and hair strands are examples of correlative biospecimens incorporated in PNOC protocols. We will share a review of the literature and implications for practice. RESULTS Blood, drawn in conjunction with clinical labs, is commonly analyzed for circulating tumor DNA to conduct molecular profiling in blood compared to tissue, explore less invasive means of molecular evolution of tumor somatic mutations, and identify early markers of tumor response or resistance. Stool is collected to utilize the gut microbiome as a lens into treatment response in CNS tumors via the gut-brain axis. Stool samples are compared to normal controls and longitudinally within patients during treatment. CSF sampling provides less invasive disease monitoring, tumor molecular characterization, markers of tumor response or resistance, and drug pharmacokinetics. Hair sampling can be used to further quantify drug levels for pharmacokinetics and assess treatment compliance. The robustness of these correlative samples collected at various timepoints (diagnosis, pre-surgery and post-surgery, post-radiation and/or with recurrence) informs on prognosis, response to treatment; and ultimately, interventions to improve outcomes for pediatric and young adult CNS tumors. CONCLUSION Our assessment identified a need for APP and nursing-focused education on biospecimen collection to inform on emerging clinical and research advances while improving protocol compliance.
MDB-57. PROTEOMIC ANALYSIS REVEALS AMBRA1 AS A NEW CRL3REN/KCTD11 SUBSTRATE PROMOTING SONIC HEDGEHOG-DEPENDENT MEDULLOBLASTOMA
Authors: Irene Basili, Paola Infante, Marilisa Conenna, Flavia Bernardi, Veronique Marsaud, Gabriele Cancila, Francesca Bufalieri, Ludovica Lospinoso Severini, Hua Yu, Jacob Torrejon Diaz, Valentina Lo Re, Gennaro Adabbo, Daniele Guardavaccaro, Olivier Ayrault, Lucia Di Marcotullio
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Sonic Hedgehog (SHH) signaling pathway is fundamental for a proper embryonic development and its uncontrolled activation is responsible for various cancers. One the most relevant SHH-dependent tumors is medulloblastoma (MB), a highly heterogeneous brain malignancy that predominantly occurs in childhood. Understanding the complex networks that govern SHH aberrant activation represents a dramatic challenge for the development of efficient personalized therapies. Here, we identify a new role of the pro-autophagic protein AMBRA1 as interactor of REN/KCTD11 (here REN), the substrate-receptor subunit of the Cullin3-RING ubiquitin ligase complex (CRL3REN) and tumor suppressor lost in ~30% of human SHH-MBs. We show a novel mechanism of action of AMBRA1 in SHH-MB pathogenesis whereby its highly expression, due to loss of REN, drives the activation of GLI1, the final effector of SHH signaling. METHODS Proteomic analysis, co-immunoprecipitation, ubiquitylation and cycloheximide assays have been performed to demonstrate that AMBRA1 is a substrate of ubiquitylation of CRL3REN and to define AMBRA1 mechanism of action in SHH-MB tumorigenesis. Transcriptomic analysis, in vitro and in vivo proliferation assays have been carried out on murine and patient-derived xenograft (PDX) models to examine the effect of AMBRA1 modulation on SHH-MB growth. RESULTS We demonstrate that CRL3REN binds and induces polyubiquitylation and proteasome-mediated degradation of AMBRA1. Interestingly, we found that genetic depletion of AMBRA1 strongly reduces SHH-dependent MB growth both in vitro and in vivo, an effect associated with the decrease in the expression of GLI1 and other SHH target genes. We hypothesize that AMBRA1 could impact on the stability of GLI1 by counteracting the activity of E3 ubiquitin ligases regulating GLI proteins. Remarkably, transcriptomic analysis of SHH PDX upon AMBRA1 knockdown revealed an impairment of SHH activity and an upregulation of cerebellum differentiation. CONCLUSION Our findings identify AMBRA1 as a novel CRL3REN substrate and promising therapeutic target for SHH-dependent cancer.
METB-15. ROLE OF DNA METHYLATION PROFILING IN THE MANAGEMENT OF PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS: A SINGLE INSTITUTIONAL SERIES
Authors: Mariko Sato, Prachi Sharma, Pournima Navalkele, Jody Pathare, Zied Abdullae, Ken Aldape, John Crawford
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND DNA methylation profiling has now been integrated into the WHO classification of CNS tumors and serves as confirmatory means to diagnose CNS tumors in conjunction with genetic sequencing/microarray analysis. The practical impact on patient care in the retrospective and prospective settings is less known. METHODS Methylation analysis was performed on a cohort of previously and newly diagnosed children with CNS tumors at Children’s Hospital Orange County from 2022-2023. Data regarding histologic diagnosis, integrated molecular diagnosis, methylation classification, timing of result completion and functional impact of methylation results on patient diagnosis/management was evaluated. RESULTS Forty patients (21 boys, ages 5 weeks-17 years) with previously diagnosed (N=11) or newly diagnosed (N=21) CNS tumors were evaluated by methylation analysis at one or more institutions. The most common tumor types were diffuse type pediatric high-grade glioma (N=6) and ependymoma PFA (n=4). Methylation analysis revealed no match in two cases (ALK-EML4 fusion embryonal tumor and recurrent low grade glioneuronal tumor) and had insufficient DNA extraction in one patient with low grade glioneuronal spinal cord tumor. Among the 5 tumors with duplicate methylation analyses at two institutions, three Ependymoma PFA subgroups were concordant while two showed differing classifications (diffuse type pediatric high-grade glioma RTK1 subtype vs. non- classifiable and medulloblastoma group 4 vs. non-WNT, non-SHH). In patients with previously diagnosed CNS tumors, methylation either led to a change in classification or modification of diagnosis in 7 out of 11 patients. The average time from surgery to the receipt of methylation results for newly diagnosed patients was 24 days (range 4-90 days). CONCLUSION Methylation analysis was beneficial in both the previously diagnosed and newly diagnosed setting in patients with previously difficult to classify tumors following conventional molecular analysis. Changes in tumor classification or modifications in diagnosis were observed in the majority of patients.
LGG-17. NATURAL HISTORY AND MANAGEMENT OF INCIDENTALLY DISCOVERED BRAIN LESIONS SUSPECT FOR NEOPLASM IN CHILDREN
Authors: Celine C A Delhez, Karina J Kersbergen, Antoinette Y N Schouten – van Meeteren, Janneke C van den Bergen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The rise in neuroimaging has resulted in an increase of incidentally discovered brain lesions suspect for a neoplasm (‘incidentaloma’) in children. With the experience in our national hospital, we aim to diversify and broaden the knowledge on the management and natural history of pediatric incidentaloma. METHODS A retrospective analysis of all incidentaloma patients in the Princess Maxima Center for Pediatric Oncology from June 2018 until March 2023. RESULTS Our research population consists of 23 patients (10M/13F) with an incidentaloma. The lesions were mostly located in the cerebellum (21.7%), thalamus and ventricle (both 17%) and cerebral hemisphere (13%) The average age at diagnosis was 7.9 years (range 0-15 years) and the mean duration of follow-up was 4.6 years (range 0-11 years). The initial management was clinical and radiological follow-up in seventeen (74%), resection in five (22%) and biopsy in one patient (4%). Pathological examination performed in the six neurosurgical patients revealed low grade gliomas (LGGs) in three patients, medulloblastoma in one and plexus papilloma in one patient respectively. The pathological analysis of the patient with biopsy only was indecisive. One patient became symptomatic with clear tumor growth on imaging after 6.8 years of follow-up. Biopsy showed a H3K27M mutant diffuse midline glioma. She died 8.1 years after initial diagnosis. In 11 other patients radiographic changes (mostly tumor progression) were observed with a median of 23 months after diagnosis (range 3-70 months). Two of these underwent complete resection of an LGG. CONCLUSIONS For most incidentalomas, clinical and radiological follow-up is sufficient. As late disease progression can occur as seen in our patient who became symptomatic after 7 years, this follow-up should be long-term. Future studies should focus on identifying (radiological) prognostic factors for tumor progression, so follow-up of incidentaloma can be more personalized.
NFS-19. ATYPICAL PRESENTATION OF GLIOMAS IN ADOLESCENTS WITH NEUROFIBROMATOSIS TYPE 1 (NF1): A CASE SERIES
Authors: Abbey Rocco, Mary Beck, Michele McHugh, Ashley Lampe, Ashley Meyer, Andrea Ogle, Andrew Cluster, Margaret Shatara, Mohamed S Abdelbaki, Nicole M Brossier
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Patients with NF1 are at risk for developing gliomas, usually low-grade in childhood but may be high-grade in adults. In children, the most common sites of disease are the optic pathway and brainstem; tumors in these regions often arise in young children and display histological features characteristic of pilocytic astrocytoma (PA) when biopsied. Typical MRI findings include T2 hyperintense, T1 hypointense lesions with minimal contrast enhancement and no diffusion restriction. Due to the well-established pattern of low-grade tumor formation in children with NF1, as well as the surgically challenging areas in which these tumors develop, low-grade glioma (LGG) therapy is often initiated without histologic confirmation of the diagnosis in classic cases. In cases with atypical disease location, older age at presentation or imaging appearance, a biopsy may be considered to exclude higher-grade lesions. METHODS Retrospective chart review, case series RESULTS Four adolescent patients with NF1 presented with atypical suspected gliomas. All four patients underwent surgical biopsy/resection. Case 1 was a left temporal lesion in the previous radiation field for optic pathway glioma; biopsy confirmed LGG with MAP2K1 mutation and increased focal proliferation index (28%), but methylation did not match with any established classification. The patient progressed through multiple rounds of therapy and succumbed to her tumor. Case 2 was a left occipital lesion; biopsy confirmed PA with CDKN2A deletion. The tumor displayed rapid regrowth, but subsequently stabilized. Case 3 was a right frontal lesion; confirmed PA. The tumor demonstrated some regrowth but then stabilized. Case 4 was a basal ganglia lesion; confirmed PA. The patient has demonstrated stable MRI findings and has not required further intervention. CONCLUSIONS Biopsy yielded helpful prognostic information (additional mutations, proliferation rate) in half of these atypical cases. Biopsy should be carefully considered for NF1 patients with atypical presentation or a history of radiation.
HGG-49. INTERNEURONS THAT BITE: A CELLULAR DELIVERY SYSTEM FOR PEDIATRIC HIGH-GRADE GLIOMA
Authors: Stephanie N Brosius, William Manley, Kyra Harvey, Jamie Galanaugh, Kay Labella, Angela Liou, Stewart Anderson, Thomas De Raedt
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND High-grade gliomas (HGG) represent the leading cause of cancer-related mortality in children due to a lack of curative therapies. Challenges of cellular therapies in brain tumors include the lack of unique tumor antigens, downregulation of targeted antigens, and immune suppressive tumor microenvironment. To circumvent these obstacles, we devised a cellular delivery system using post-mitotic migratory cortical inhibitory interneuron precursors (MCIPs) to deliver therapeutic payloads in an antigen-independent manner. Notably, HGGs secrete the same chemoattractants stimulating long-distance MCIP migration as during normal fetal development, leading to the hypothesis that MCIPs would preferentially migrate to HGG cells. METHODS MCIP to HGG cell migration was assessed in vitro using transwell migration assays, and in vivo via stereotactic injection of MCIP and glioma xenografts in nude mice. As proof of principle, MCIPs were equipped with an EGFR or CD19 control bispecific T-cell engager (BiTE) which activates T-cells upon their linkage to the tumor cells resulting in glioma elimination. Equipped MCIPs were co-cultured with HGG cells and CD8 T-cells at an effector to target ratio of 4:1. Results were validated in vivo via xenografts of HGG, MCIPs, and either a single dose of CD8 T-cells or repeated T-cell dosing via intraventricular cannula. Survival was evaluated via Kaplan-Meier curves. RESULTS MCIPs migrated preferentially to the majority of HGG cell lines in vitro and in vivo. This migration was mediated, at least in part, via CXCR4 ligands. MCIPs secreting an EGFR-BiTE potently killed HGG cells in vitro versus CD19-BiTE controls. Furthermore, nude mice xenografted with HGG and EGFR-expressing MCIPs experienced prolonged survival versus controls. CONCLUSION These data suggest that MCIPs form a viable cellular delivery system and can be equipped with various agents targeting HGG. Modified MCIPs could be differentiated from induced pluripotent stem cells and injected into the resection cavity margins to eliminate residual cells.
MDB-61. STARVING TUMORS OF POLYAMINES: A NOVEL APPROACH IN TREATING AGGRESSIVE PEDIATRIC MEDULLOBLASTOMA
Authors: Aaminah Khan, Anjana Gopalakrishnan, Jie Liu, Mark R Burns, Maria Tsoli, David S Ziegler
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Polyamines, essential intracellular polycations, govern fundamental cell processes and drive oncogenesis. Our research unveiled the dependency of pediatric Diffuse Midline Gliomas (DMG) on the polyamine pathway (Khan et al.,2021). Disruption of this pathway with the synthesis inhibitor DFMO, and the transport inhibitor AMXT1501, potently inhibited DMG tumors, yielding unprecedented survival in-vivo. We hypothesized that dual polyamine pathway targeting could similarly suppress growth in other aggressive pediatric brain tumors. METHODS/RESULTS We analyzed the expression of polyamine pathway regulators in high-risk pediatric brain cancers ZERO precision medicine platform and found elevated expression in medulloblastoma. ODC1, a polyamine synthesis driver, was found to have significant correlation in high-grade gliomas with four key functional tumor states—stemness, cell cycle, hypoxia, and angiogenesis. Medulloblastoma cells were sensitive to treatment with DFMO but showed a compensatory increase in polyamine transporter expression. Conversely, treatment with AMXT1501 increased ODC1 expression. Dual targeting of the polyamine pathway potently and synergistically inhibited cell proliferation and clonogenic potential in Group-3 medulloblastoma cells. Flow cytometric analysis of Annexin V-stained cells showed that treatment with DFMO and AMXT1501 in combination led to induction of apoptosis. Critically, dual polyamine inhibition potently sensitized medulloblastoma cells to the topoisomerase-I inhibitor, SN-38, leading to complete eradication of medulloblastoma cell proliferation and colony formation at nanomolar chemotherapeutic concentrations, with the effect most pronounced in Group-3 medulloblastoma. In triple combination-treated cells, over-representation analysis revealed heightened mitotic DNA damage, macroautophagy, and apoptosis, coupled with diminished neuron/synapse development, glycosylation, and cellular signaling pathways. We are currently testing this treatment strategy in aggressive orthotopic medulloblastoma models. CONCLUSION These findings suggest targeting the polyamine pathway as a promising strategy to sensitize aggressive pediatric medulloblastoma tumors to chemotherapy. DFMO/AMXT1501 is in Phase I evaluation for adults (NCT05500508) and advancing to a Phase I/II trial for children through the CONNECT consortium.
METB-13. GERMLINE GENETIC TESTING IN CHILDREN WITH CNS TUMORS; FIRST-EVER EXPERIENCE FROM JORDAN
Authors: Shrouq Amer, Mayada Abu Shanap, Nisreen Amayiri
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND It is expected that 10-15% of children with CNS tumors have an underlying cancer predisposition syndrome (CPS). This has important implications on treatment, cancer screening and family counseling. There is no published data on this genetic risk from Jordan. METHODS We retrospectively reviewed the medical charts of the Jordanian children &amp;lt;18 years old at the time of diagnosis with CNS tumors, and were treated at King Hussein Cancer Center/Jordan between January 2021 and December 2023. We reviewed their clinical characteristics and tumor diagnoses, then applied the updated Jongmans’ criteria and MIPOGG criteria and linked that with their germline genetic testing result if performed. RESULTS We identified 198 children (53% males); median age at diagnosis was 7years (range, 0-18 years). Consanguinity was found in 30% of families, and 35% had first/second degree relatives with cancer. Most common diagnoses were LGG (41%), HGG (22%) and medulloblastoma (14%). Most tumors were non-metastatic (90%) at initial diagnosis. Fifty-five percent of patients fulfilled the updated Jongmans’ criteria and 36% the MIPOGG criteria, however germline genetic testing was only performed for 34 patients (17%). Pathogenic germline variants were found in 15 patients (44%); 6 LGG (NF1 (3), TSC2, PTPN11, MUTYH), 4 medulloblastoma (SDHB, TP53, BRCA2, CHEK2), 4 HGG (MSH6 (3), TP53), and one had pathogenic NF2 gene. The presence of CPS affected the management received: children with NF1 were treated without tumor biopsy, the child with TSC2 received everolimus, and 3 children with MSH6 received checkpoint inhibitors instead of temozolomide. The underlying CPS also predicted prognosis e.g. rapid clinical deterioration in the TP53-mutated-SHH-medulloblastoma. Partial screening was provided to children with NF1, TSC, NF2, TP53 and BMMRD mutations. CONCLUSIONS High proportion of our patients fulfilled the criteria for referral to genetic clinic, but less than half were referred. Increasing awareness of these criteria is important. Identification of CPS impacted treatment and prognosis, yet families’ perceptions and attitudes toward these CPS need to be captured.
NURS-18. GERMINOMA PATIENTS – MORE PRONE TO PSYCHIATRIC DISORDERS, ALLERGIES, AND WEIGHT PROBLEMS? AN INSTITUTIONAL REVIEW
Authors: Tara McKeown, Foo Jen Chun, Amanda Li, Jordann Dutton, Rachel Rowe, Cynthia Hawkins, Laura Janzen, Ute Bartels
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Germinoma are the most frequent type of intracranial germ cell tumour. Within nursing clinical practice an increased prevalence of psychiatric manifestations, allergies, and weight gain throughout treatment and into survivorship within the germinoma population has been observed. There is only limited literature about these problems available. METHODS A retrospective review of clinical presentation, psychiatric co-morbidity, therapeutic course, and follow-up of 27 Germinoma patients (6.2-17 years) diagnosed and treated at a tertiary care center from 2008-2021 was performed. In addition, the presence and occurrence of allergies and weight changes throughout their therapy was reviewed. RESULTS Nearly half of the Germinoma patients (n=11) (suprasellar, pineal, basal ganglia) were diagnosed with pre-existing psychiatric co-morbidity (anxiety, depression, mood disorder and eating disorder) as per DSM-5 criteria, more commonly verified after their brain tumour diagnosis and persistent beyond treatment. Three of 27 (11%) patients indicated allergies (medication, food) at diagnosis. Seventeen of the 27 (63%) patients presented with allergies throughout their therapy (medication, tape, cleaning products, blood products). Six (35%) of those patients developed anaphylactic reaction to Etoposide and/or blood products. Eight of the patients (suprasellar &amp; pineal) were found to have a significant weight gain throughout their treatment and two (pineal &amp; suprasellar) were found to have significant weight loss, the rest of the cohort remained stable. The impact of tumour location (suprasellar, pineal) on the specific problems is ongoing. CONCLUSION The findings of this retrospective review could guide clinical practice. The potential higher incidence of psychiatric disorders should prompt practitioners to upfront screening and throughout therapy to ensure adequate support. Allergy prevalence in pediatrics is variable but an allergy occurrence of 35% is elevated in comparison to the general population and therefore increased awareness of allergies within this population is important for the bedside nurse. Lastly, early involvement of dieticians to aid in weight management seems crucial.