tbuckley/cabot-search huggingface dataset:
LMIC-13. ENCOURAGING EXPERIENCE OF CONCURRENT CARBOPLATIN DURING CRANIOSPINAL IRRADIATION USING IMAGE GUIDED INTENSITY MODULATED PROTON BEAM (IMPT) IN HIGH-RISK EMBRYONAL TUMORS: FIRST REPORT FROM A LOW MIDDLE-INCOME COUNTRY
Authors: Vasudeva Bhat K, Ramya Uppuluri, Uday Krishna, Anindita Das, Ganapathy KC, Preethi S, Venkateswaran VS, Adithyan R, Sushma Patil, Rakesh Jalali
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Concurrent carboplatin during craniospinal irradiation (CSI) using photon radiotherapy in High risk (HR) embryonal tumors has been shown to improve the event free survival in select subgroup of patients. Experience of using concurrent carboplatin during CSI using proton therapy is limited. METHOD A retrospective audit was done in Children &amp;lt;18 years from January 2018 to December 2023 diagnosed with HR embryonal tumors who received image guided pencil beam intensity modulated proton beam therapy-based CSI (35Gy/21#) along with concurrent carboplatin 35mg/m2 at least for 15 fractions. The patient demographics, pathological diagnosis, treatment related toxicities and date of follow-up were recorded in predesigned proforma using electronic medical record. RESULTS Twenty children with HR embryonal tumors with median age at diagnosis 5 years (Range: 1-15 years) with M: F ratio of 3:1 were included in the study. Fifteen (75%) of the patients had HR medulloblastoma defined by spinal metastases or HR molecular subtype of which 5 patients had group 3 medulloblastoma (3- leptomeningeal disease at baseline, 2- MYC amplification) while rest had embryonal tumors (3-NOS, 1-Pinealoblastoma and 1-ETMR). Carboplatin was well tolerated, however 12 (60%) patients developed neutropenia requiring daily G-CSF for an average of 5 days. Average time to complete radiotherapy was 45 days with median interruption of 4 days (Range 1-7). Radiotherapy induced toxicities included Grade 3 skin toxicity in 6 (30%) and grade 2 weight loss in 3 (15%). At a median follow up of 14 months (Range: 4-58), the PFS was 80% in the whole cohort while in the Group 3 Medulloblastoma the PFS was only 20% which was statistically significant(p=0.004). CONCLUSIONS Carboplatin along with proton CSI is well tolerated in children with HR embryonal tumors without significant adversities. Experience is encouraging especially in non-group 3 medulloblastoma patients in our cohort of children with HR embryonal tumors.
ETMR-03. REPORT OF 9 CASES OF EMBRYONAL TUMORS OF THE CENTRAL NERVOUS SYSTEM WITH MULTILAYERED ROSETTES (ETMR)
Authors: Ruyu Ai, Juan Li, Mingyao Lai, Linbo Cai
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE Embryonal Tumors of the Central Nervous System with Multilayered Rosettes (ETMR) are rare, and there’s no standard treatment protocol. This article reports on the current treatment status and prognosis of ETMR in our hospital. METHODS We retrospectively collected patients with ETMR who received treatment in the Oncology Department of Guangdong sanjiu Brain Hospital from January 2017 to January 2021, analyzed their clinical data. RESULTS Among 31 cases of central nervous system embryonic tumors (excluding medulloblastoma and ATRT), 9 (29.03%) were ETMR. The median age at diagnosis was 3 years old (1-15), and the male to female ratio was 4:5. Among them, 5 cases were accompanied by C19MC gene variation. Tumor location:6 was in supratentorial, 1 in the pineal region, 1 in the pons, 1 in the cerebellopontine. Eight patients underwent surgical resection at the first diagnosis, with 6 cases of total resection, 1 case of partial resection, and 1 case of biopsy. One case was misdiagnosed as a germinoma in the pineal region at the initial. After recurrence, surgical resection was performed to confirm the pathology as ETMR. One case was misdiagnosed as glioblastoma during the first surgery. The initial treatment for 4 patients after surgery was radiotherapy combined with concurrent chemotherapy. Recurrence patterns: 2 cases were intracranial dissemination, 2 cases were local recurrence, 1 was spinal cord dissemination. One patient did not receive treatment after surgery and tumor recurrence 3 months later. Survival analysis: The median survival time was 20 months. The 1-year progression-free survival rate (PFS) and overall survival rate (OS) were 22% and 61%, and the 2-year overall survival rate (OS) was 31%. CONCLUSION ETMR has a low incidence and poor prognosis. It is easy to misdiagnose and NGS is necessary to assist diagnosis when needed. More effective treatment methods need to be explored.
DIPG-35. OVERCOMING THE BLOOD-BRAIN BARRIER CHALLENGE IN DIFFUSE MIDLINE GLIOMA
Authors: Maria Tsoli, Caitlin Ung, Dannielle H Upton, Pooja Venkat, Antonietta Salerno, Ruby Pandher, Chelsea Mayoh, Orazio Vittorio, David S Ziegler
Journal: Neuro-Oncology (2024)

Abstract Diffuse midline gliomas (DMGs) are aggressive paediatric brainstem tumours with no known cure. The development of effective treatments is greatly impeded by the failure of most anti-tumour agents to penetrate the blood-brain barrier (BBB). Our research, along with that of others, has revealed that the BBB remains intact in DMG. We employed DMG orthotopic models to explore potential region-specific variations in response to the therapeutic agent temsirolimus as well as confocal microscopy and single-cell RNA sequencing (scRNAseq) to elucidate the impact of DMGs on brain endothelial morphology and pathways governing BBB integrity. We first assessed the effectiveness of the mTOR inhibitor temsirolimus when administered in cortex-injected DMG models compared to brainstem-injected DMG. We found significantly increased survival rates, elevated temsirolimus levels, and reduced tumour cell proliferation in the cortex versus the brainstem. Confocal imaging analysis indicated no structural differences between DMG and Matrigel-injected animals. However, scRNAseq unveiled distinct transcriptomic changes: brainstem-injected DMG exhibited downregulation of genes related to inflammatory and apoptotic pathways, whereas cortex-injected DMG showed downregulation of interferon pathways. To overcome the tightened barrier in the brainstem, we explored three MCL1 inhibitors and SNGR-TNFa (targeting CD13) as potential blood-brain barrier modulators. These inhibitors significantly reduced transendothelial electrical resistance, increased tracer dye leakage in an in vitro DMG BBB model, and decreased the protein expression of claudin-5. Moreover, in vivo, we found that administration of a single dose of either SNGR-TNFa or the MCL1 inhibitor S63845 improved penetration of Texas-Red (3KDa) in DMG-engrafted animals, indicating the effective opening of the BBB. In summary, our study revealed that DMG directly affects BBB pathways in endothelial cells, tightening the barrier and reducing treatment efficacy. MCL1 inhibitors and SNGR-TNFa show promise in modulating the BBB and have the potential to enhance therapeutic activity.
LGG-59. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR; MOLECULAR IMPLICATIONS ON PROGNOSIS
Authors: Faryal Munir, Jiasen He, Lea M Stitzlein, Melissa Chen, Mary F McAleer, Susan McGovern, Arnold Paulino, Gregory K Friedman, David Sandberg, Wafik Zaky
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse leptomeningeal glioneuronal tumors (DLGNTs) are extremely rare tumors that were first described in the WHO Classification in 2016. While usually considered low-grade tumors, DLGNTs currently lack a standard of care as well as literature on molecular profiling and treatment responses. METHODS Retrospective review of pediatric DLGNTs seen at MD Anderson Cancer Center with Institutional Board Review approval. RESULTS Twelve patients with a histopathological and neuroradiological diagnosis of DLGNT were identified with a median age at diagnosis of 7.5 years (range 4 months – 21 years). Histologically, 10/12 (83%) tumors were low-grade while 2 were reported as high-grade. BRAF gene alterations were reported in 50% (6/12; 4 fusions and 2 mutations). Other reported genetic alterations were mutations [PTPN11 (n=2), PIK3CA (n=1), FGFR1 (n=1), ALK (n=1)], amplifications [NOTCH1 (n=1) and STK11(n=1)], and fusion [NTRK (n=1)]. Upfront, 9 patients received chemotherapy including temozolomide (n=5), carboplatin (n=4), and vincristine (n=4) or vinblastine (n=1). Nine patients (88%) received proton radiation, including 5 upfront and 4 upon progression. Targeted therapy [NTRK (n=1), BRAF (n=1) or MEK inhibitors (n=6)] was initiated upon progression in 8 patients, and at diagnosis in one. The median progression-free survival (PFS) in the group receiving upfront chemoradiation (n=3) is 57 months versus chemotherapy alone (n=6) of 30.5 months, and 26.7 months for radiotherapy alone (n=3). The PFS at 2 years and 5 years were 58.3% and 17% respectively; OS was 100% at both time intervals. BRAF genetic alterations and younger age trended toward a worse outcome, hence upfront targeted therapy may be warranted when radiation needs to be avoided. CONCLUSION In our experience, DLGNTs are more commonly low-grade with frequent BRAF gene alterations; upfront chemoradiation provided the longest PFS compared to chemotherapy or radiation alone. In the absence of established standard of care, our case series emphasizes the potential role of targeted therapy upfront for younger patients and progressive disease post-chemoradiation. Larger prospective, collaborative studies are greatly needed for DLGNTs.
CP-05. MAPK PATHWAY ACTIVATION, CLONAL EVOLUTION, INCLUDING RARE TP53 LOSS, AND THE IMMUNE ENVIRONMENT OF RECURRENT CRANIOPHARYNGIOMA
Authors: John R Apps, Mario Gonzalez-Meljem, Romain Guiho, Jessica C Pickles, Eric Prince, Edward Schwalbe, Nikhil Joshi, Thomas J Stone, Olumide Ogunbiyi, Jane Chalker, Akang Bassey, Georg Otto, Rosalind Davies, Debbie Hughes, Enrica Tan, Sebastian Brandner, Victoria Lee, Caroline Hayhurst, Cassie Kline, Sergi Castellano, Todd C Hankinson, Timo Deutschbein, Thomas S Jacques, Juan Pedro Martinez-Barbera
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Craniopharyngiomas are rare challenging tumours, with around 25% of cases recurring despite surgery and/or radiotherapy. Relatively little is known about the biology of recurrence and there is an urgent need to develop new therapies. Our previous studies have suggested preclinical efficacy of MEKinhition with trametinib in human and murine adamantinomatous craniopharyngoioma (ACP) tissue. At ISPNO2022 we reported methylation and expression profiling results from a cohort of relapsed craniopharyngioma, identifying acquisition of chromosomal abnormalities across recurrence, the persistent activation of MAPK pathway at recurrence, the presence of myeloid cells and a rare case of malignant transformation associated with TP53 loss. METHODS Here we present an update from this study through exploring additional datasets, preclinical drug testing, and genetic manipulation of genetic engineered mouse models of ACP RESULTS Exploration of whole genome sequencing data from 67 cases of ACP from Children’s Brain Tumour Network has confirmed the presence of chromosomal arm changes in 7 (10%) of cases, including at diagnosis, confirming that the genomic landscape of ACP is more complex than previously thought. To further explore the potential of MAPK pathway inhibiton we have demonstrated efficacy of a further two clinically available MEK inbhiibtors, Selumetinib and Binimetinib, in reducing proliferation and inducing cell death in ex vivo explants of murine ACP. To explore the role of TP53 loss in aggressive craniopharyngioma, we show that Trp53 loss in a murine ACP model results in very aggressive tumours and reduced mouse survival. Finally, we have further characterised the tumour immune infiltrate showing differences in the cellular composition between ACP and Papillary CP, and revealing a diverse phenotype of macrophages in ACP. CONCLUSIONS Together, this research provides further preclinical support for the ongoing evaluation of MAPK pathway inhibitors and immunomodulatory approaches in clinical trials in patients with craniopharyngioma.
LMIC-06. WEB-BASED SURVEY RESULTS OF THE INTERNATIONAL PEDIATRIC NEURO-ONCOLOGY TUMOR BOARD AT WASHINGTON UNIVERSITY IN ST. LOUIS SCHOOL OF MEDICINE
Authors: Margaret Shatara, Abbey Rocco, Andrew Cluster, Nicole M Brossier, Amy E Armstrong, Angela C Hirbe, David H Gutmann, Mohamed S Abdelbaki
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The International Pediatric Neuro-Oncology Tumor Board at Washington University in St. Louis School of Medicine (WUSM) was established in January 2021 as a monthly multi-disciplinary collaboration to help guide the care of pediatric central nervous system (CNS) tumor patients worldwide. The quarterly integration of Neurofibromatosis (NF) meetings expanded the initiative in September 2021. This survey explores participant experiences and their satisfaction aiming to optimize this international collaboration. METHODS A cross-sectional survey was distributed via a web-based platform in September 2023 amongst the participating healthcare professionals. RESULTS Fifty-three respondents from 23 countries completed the survey. The majority identified as pediatric hematology-oncologists (59%), and 10% as neuro-oncologists. Ninety-eight percent attended at least one session over two years, and 71% actively engaged in the quarterly NF meetings. Sixty percent attended more than five meetings, and 29% engaged in over 10 meetings. Barriers to attendance were primarily attributed to time constraints (71%) and conflicting professional or personal experiences (27%), while only 7% cited technical limitations and lack of awareness. Ninety-one percent reported that the meetings provide valuable educational insights and knowledge, particularly addressing challenging pediatric neuro-oncology cases. Additionally, 95% acknowledged the tumor board meetings’ positive contribution to professional development. Consensus recommendations emerging from the tumor board were reported to align with institutional recommendations (71%), be clear and comprehensible (93%,) and led to improved outcomes (93%). Notably, meeting frequency, leader expertise, knowledge enhancement, and level of engagement had positive influence on the participants’ willingness to attend the meeting. CONCLUSION Healthcare professionals attending the WUSM International Pediatric Neuro-Oncology Tumor Board reported the effectiveness of this virtual meeting format, its impact on professional development, and the alignment of recommendations with diverse institutional needs. The study provides valuable insights to further enhance the program’s sustainability, international collaboration, and overall effectiveness in improving global pediatric neuro-oncology patient care.
DIPG-75. PHARMACOLOGICAL INHIBITION OF LSD1/KDM1A IN DIFFUSE MIDLINE GLIOMA MODELS AND IMPACT ON KINASE SIGNALING
Authors: Faith A Hernandez, Lea M Stitzlein, Deokhwa Nam, Jack Adams, Caitlin McCabe, Michelle Monje, Piotr Waranecki, Esther Hulleman, Oren Becher, Joya Chandra
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND High grade gliomas (HGGs) in both adults and children confer poor prognosis, with median survival rates under two years post-diagnosis. Diffuse midline gliomas (DMG) are a subset of HGG characterized by histone mutations, typically occurring in children. Genetic alterations in chromatin modifiers and receptor tyrosine kinases (RTKs) are seen in both adult and pediatric glioblastoma, however the interplay between these pathways requires further investigation to design therapeutic strategies. Our past work has evaluated KDM1A/ LSD1 (Lysine-Specific Demethylase 1) inhibition through gene silencing and small molecules; here we assessed crosstalk between LSD1 and kinase signaling networks to uncover potential compensatory resistance mechanisms using clinically relevant pharmacological inhibitors of LSD1. METHODS RNA-Seq and GSEA in high grade glioma cells bearing LSD1 knockdown were evaluated for kinase signaling pathway enrichment. A panel of DMG lines (SU-DIPGIV (MDM4, ACVR1), SU-DIPGVI (TP53), VUMC-DIPG10 (NF1, MYCN), and SU-DIPGXIII and DMG data sets were probed for LSD1 expression, activity and kinase expression and treated with pharmacological inhibitors of LSD1 in vitro and in vivo. RESULTS Pharmacological inhibition of LSD1 using clinically relevant agents revealed IC50s in the micromolar range across DMG lines. DMG lines varied with respect to LSD1 expression and baseline activation of ERK and AKT pathways. With LSD1 inhibition at subtoxic doses, increased phospho-ERK/ERK and phospho-AKT/AKT was noted in several DMG models and co-inhibition of these pathways suggests improved efficacy. CONCLUSIONS Our data reveals that LSD1 inhibition causes an increase in kinase signaling at subtoxic doses which may alter drug response. These results urge the assessment of combination treatments with kinase inhibitors and additional in vivo analysis, which are currently underway.
CP-04. UNVEILING THE MYSTERIES OF PEDIATRIC ADAMANTINOMATOUS CRANIOPHARYNGIOMA - INSIGHTS FROM DIAGNOSIS TO ADVANCED THERAPEUTICS
Authors: Margaret Shatara, Mohamed S Abdelbaki
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Adamantinomatous Craniopharyngiomas (ACPs) are rare tumors arising from the remnants of the craniopharyngeal duct epithelium. Their diagnosis poses unique challenges, often resulting in delayed identification due to their slow growth and nonspecific symptoms. Additionally, the prolonged overall survival (OS) is overshadowed by a substantial recurrence rate and late consequences, posing significant challenges, and impairing the patient’s quality of life (QoL). Recent advancements in understanding ACP’s genomic, transcriptomic, and proteomic aspects underscore the need for innovative treatments to mitigate these long-term consequences. METHODS We conducted an in-depth literature review, focusing on large clinical trials and major publications in ACP to provide a comprehensive perspective on the challenges in the diagnosis, treatment, and molecular aspects of pediatric ACP. RESULTS ACP’s clinical presentation involves increased intracranial pressure, endocrine abnormalities, and visual impairments. Despite their low-grade classification, ACPs exhibit aggressive clinical behavior, often invading or adhering to adjacent tissues, particularly critical neurovascular structures. Imaging techniques, including CT and MRI with a focus on hypothalamic involvement, play a crucial role in diagnosis, pre-operative evaluation, and surgical planning. Multidisciplinary approaches are essential for developing tailored treatment strategies. Neurosurgical management and radiotherapy, particularly proton therapy, are the primary therapeutic modalities. The molecular landscape reveals intricate and complex mechanisms and include the upregulation of the Wingless (WNT) signaling pathway driven by CTNNB1 mutations, along with involvement of inflammatory, programmed cell death, and the MAPK/ERK pathways. Ongoing trials exploring targeted therapies may play a pivotal role in refining treatment strategies and improving outcomes. CONCLUSIONS Navigating the complexities of ACP requires a multidisciplinary approach. Advances in diagnostics, surgical strategies, and targeted therapies, informed by molecular insights, offer promising avenues for improving outcomes and QoL. Ongoing collaborative efforts and participation in clinical trials are vital for refining treatment strategies and advancing the understanding of this challenging condition.
CP-01. FATIGUE IN PATIENTS WITH HYPOTHALAMIC SYNDROME – A CROSS-SECTIONAL ANALYSIS IN THE GERMAN CHILDHOOD-ONSET CRANIOPHARYNGIOMA COHORT
Authors: Julia Beckhaus, Jale Özyurt, Aylin Mehren, Carsten Friedrich, Hermann L Müller
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Patients with tumors of the sellar region are at risk of developing hypothalamic syndrome. Survivors experience fatigue and excessive daytime sleepiness even years after tumor treatment. The aim of this cross-sectional study was to determine the severity of fatigue in patients with and without hypothalamic syndrome. METHODS Patients diagnosed with CP or pilocytic astrocytoma were recruited from the KRANIOPHARYNGEOM 2000/2007/Registry 2019 studies and included in this analysis. Eligibility criteria were regular participation in outpatient after-care, one completed Multidimensional Fatigue Inventory-20 (MFI-20) questionnaire and complete medical records on criteria for hypothalamic syndrome. With univariable and multivariable linear regression, the relation of hypothalamic syndrome and levels of fatigue symptoms (MFI-20 sum score) were assessed. MFI-20 scores were compared to sex- and age-matched reference values from a German normative population using paired t-test. RESULTS Data on 46 patients, with a median age of 20 years, was available for this analysis of which 28 (61%) patients presented with hypothalamic syndrome. After adjustment for age and sex, patients with hypothalamic syndrome reported higher scores in the physical (= 3.61 [95% CI: 1.38–5.85]), mental (= 2.80 [95% CI: 0.28–5.32]) and sum MFI-20 (= 12.02 [95% CI: 2.93–21.10]) domain than patients without hypothalamic syndrome. Compared to reference values from a general German population, all patients reported higher mean scores in each fatigue domain. Regardless of the level of daytime sleepiness in patients with hypothalamic syndrome, the reported fatigue scores were high. Daytime sleepiness did not correlate with fatigue. CONCLUSIONS Fatigue symptoms are present in patients with CP. However, patients with hypothalamic syndrome are more affected in mental, physical and overall fatigue. It is crucial in clinical practice, to distinguish between sleep disorders and fatigue and to target patients with hypothalamic syndrome.
EPEN-18. MULTI-OMICS APPROACH REVEALED A TIGHT BLOOD-BRAIN BARRIER IN EPENDYMOMA
Authors: Julia K Sundheimer, Julia Benzel, Aniello Federico, Maximilian Knoll, Cornelia Gansert, Britta Statz, Sophia Scheuermann, Christian Seitz, Marcel Kool, Stefan M Pfister, Kendra K Maaß, Kristian W Pajtler
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND A major challenge in the treatment of brain tumors is the limited penetration of many drugs through the blood-brain barrier (BBB). BBB characteristics include endothelial cells connected by tight junction proteins (e.g. Claudin5, ZO1, occludin) and the expression of efflux transporters (e.g. P-gp) with the physiological role to limit the accumulation of potentially toxic substances in brain tissue. Our study aims to enhance our understanding of the BBB composition across different molecular groups of ependymoma (EPN) with the goal of leveraging this knowledge to improve therapeutic strategies against these tumors. METHODS We applied a multi-omics approach integrating single-nuclear RNA sequencing and ultra-high content imaging to unravel BBB composition at both transcriptomic and proteomic levels. Patient-derived xenograft (PDX) models were utilized to explore differences in BBB penetration between tumor and healthy brain tissue following drug treatments. RESULTS Expression of tight junction and transporter proteins revealed strong dependencies specific to molecular groups, but were independent of the corresponding brain regions. Human tissue of ST-EPN-ZFTA exhibited highest expression of claudin5, while both ST-EPN-ZFTA and PF-EPN-A represented upregulation of occludin and ZO1 in comparison to healthy tissue. These findings on claudin5 and ZO1 were further confirmed in PDX models. Single-cell data analysis from patients localized the expression of relevant BBB factors to tumor-associated endothelial cells. Treatment of PDX models with drugs revealed disparities in drug penetration between EPN tumors and healthy brain regions. Notably, for most drugs BBB penetration was lower in ST-EPN-ZFTA tumors than healthy brain region. CONCLUSIONS Molecular BBB specifics may contribute to drug resistance of aggressive EPN particularly in ST-EPN-ZFTA tumors, which presented high tight junction expressions and lower drug penetration. This resource aims to improve BBB penetration prediction in EPN, to identify combination therapies targeting BBB components and to select innovative drug delivery approaches.