tbuckley/cabot-search huggingface dataset:
MDB-88. DUAL TARGETING OF PROCESSIVE TRANSCRIPTION FOR MYC-DRIVEN CIRCUITRY IN MEDULLOBLASTOMA
Authors: Faye M Walker, Krishna Madhavan, Lays Martin Sobral, Sahiti Donthula, Ilango Balakrishnan, Dong Wang, Angela Pierce, Bethany Veo, Sana D Karam, Natalie J Serkova, Nicholas K Foreman, Sujatha Venkataraman, Rajeev Vibhakar, Nathan A Dahl
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The highest-risk medulloblastomas are driven by recurrent Myc amplifications (Myc-MB) and experience poorer outcomes despite intensive multimodal therapy. The Myc transcription factor defines core regulatory circuitry for these tumors and acts to broadly amplify downstream pro-survival transcriptional programs. Therapeutic targeting of Myc directly has proven elusive, but inhibiting transcriptional cofactors may present an indirect means of drugging the oncogenic transcriptional circuitry sustaining Myc-MB. METHODS Independent CRISPR-Cas9 screens were pooled to identify conserved dependencies in Myc-MB. We performed chromatin conformation capture (Hi-C) from primary patient Myc-MB samples to map enhancer-promoter interactions. We then treated in vitro and xenograft models with the dual CDK9/7 inhibitor zotiraciclib to evaluate effect on Myc-driven programs and tumor growth. RESULTS Eight CRISPR-Cas9 screens performed across three independent labs identify CDK9 as a conserved dependency in Myc-MB. Myc-MB cell lines are sensitive to CDK9 inhibition at low nanomolar concentrations, and these synergize with CDK7 inhibition. We find that treatment with the dual CDK9/7 inhibitor zotiraciclib depletes Myc binding and transcriptional activity at enhancer elements within the Myc topologically associated domain, largely abrogating transcriptional output from the Myc promoter. This leads to a decrease in Myc binding genome-wide with a concordant downregulation of hallmark Myc-driven transcriptional programs. Clinically relevant CDK9 inhibitors show variable efficacy in vivo, but CNS-penetrant agents achieved a significant prolongation in xenograft survival. CONCLUSIONS CDK9/7 catalytic activity represents a druggable vulnerability underpinning Myc-driven transcriptional programs. The development of CNS-penetrant CDK9/7 inhibitors may open new avenues for rational therapy in these high-risk medulloblastomas.
MDB-86. ISOTRETINOIN HAS NO EFFECT ON EVENT FREE SURVIVAL ACROSS HIGH-RISK MEDULLOBLASTOMA MOLECULAR SUBGROUPS WHEN ADDED TO MAINTENANCE CHEMOTHERAPY: A SECONDARY ANALYSIS OF THE CHILDREN’S ONCOLOGY GROUP ACNS0332 DATA
Authors: Scott I Raskin, Peter M K de Blank, Catherine A Billups, Yimei Li, James M Olson, Sarah E S Leary
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma has been redefined into four molecular subgroups (WNT, SHH, Group 3, and Group 4), with distinct prognoses and responses to treatment. The ACNS0332 trial investigated the impact of carboplatin and isotretinoin in high-risk medulloblastoma finding a differential effect of carboplatin by molecular subgroup. An interim futility analysis showed no benefit from isotretinoin, but did not evaluate results by molecular subgroup in the primary analysis. We performed a secondary analysis to examine whether the effect of isotretinoin on event-free survival (EFS) differed by molecular subgroup. METHODS Evaluable patients with known molecular subgroups were analyzed. Molecular subgroup analysis was conducted retrospectively in 231 patients at a central laboratory by methylation array. Kaplan-Meier survival analysis compared EFS (time from enrollment to disease progression or recurrence, second malignancy, death from any cause, or to date of last follow-up for patients without events). RESULTS Based on data from the 2014 interim analysis, 164 patients were eligible for secondary analyses. Group 3 (n=56, 34.1%) and Group 4 (n=75, 45.7%) were the most common groups. SHH (n=22, 13.4%) and WNT (n=11, 6.7%) groups were less common. There was no difference in isotretinoin (p=0.87) or carboplatin (p=0.49) randomization by subgroup. Race was well-balanced with expected differences in age (p=0.017) and sex (p=0.016) among molecular subgroups. Based on the interim analysis, there was no evidence of a difference in EFS by isotretinoin randomization (p=0.34; one-sided log-rank test stratified by carboplatin randomization). Based on secondary analysis data, there was no difference in EFS between patients receiving isotretinoin or no additional therapy in any molecular subgroup: Group 3 (p=0.68), Group 4 (p=0.55), SHH (p=0.68), WNT (p=1) based on two-sided log-rank tests. CONCLUSIONS Despite differential efficacy of carboplatin among molecular subgroups, no difference was found in EFS between patients receiving isotretinoin and those who did not, regardless of molecular subgroup.
RADT-07. CLINICAL RESULTS, ACUTE AND EARLY LATE TOXICITY AFTER PROTON RADIOTHERAPY FOR PEDIATRIC MEDULLOBLASTOMA, RETROSPECTIVE ANALYSIS
Authors: Barbora Ondrova, David Sumerauer, Michal Zapotocky, Stanislava Hederova, Filip Jadrijevic-Cvrlje, Zdenek Pavelka, Irena Vlahova, Michal Andrlik, Vladimir Vondracek, Lucie Landova
Journal: Neuro-Oncology (2024)

Abstract Craniospinal irradiation with boost to primary tumor site (and metastatic sites) is current radiotherapy standard for most patients diagnosed with medulloblastoma (MB). This treatment is effective, but survivors frequently develop long-term toxicity affecting the quality of life. Proton radiotherapy has the same efficacy compared to conventional photon-based techiques, but might achieve lower risk of toxicity. We retrospectivelly analyzed our cohort of patients irradiated for MB in our institution, using IMPT (intensity modulated proton therapy). Between May 2013 and December 2023 eighty patients (50 male, 30 female, median age at radiotherapy 8 years/range 3-17/) with primary or recurrent MB (not previously irradiated) were treated and included into analysis. 36 patients were treated for high-risk MB (mostly metastatic), 44 pts for SR disease. Neoadjuvant, concurrent and adjuvant systemic treatment was applied according to the protocol selected by the pediatric oncologist. All but one patients completed their treatment, acute toxicity including hematological was mild and lead to treatment interruption in seven cases. With a median of follow-up 39,6 months (range 3-119) 62 pts were in complete remission, 3 pts alive with disease, 14 died from disease progression and one died from complication (intracranial hemorrhage). We were able to identify two secondary malignancies potentially associated with IMPT (thyroid cancer, radiation induced high-grade glioma). Most common endocrinopathy observed in our patients was hypothyroidism and growth-hormon decifit. Due to lack of data, we were not able to analyze cognitive functions and quality of life. There was one case of severe brainstem necrosis with persistent neurological deficit, treated with corticosteroids and bevacizumab. Proton radiotherapy using IMPT for craniospinal irradiation in MB is feasible, treatment outcomes and toxicity are encouraging, although a longer follow-up is needed.
RADT-08. BASAL GANGLIA TOXICITY FOLLOWING PROTON THERAPY OF THE PINEAL REGION WITH BILATERAL ACTION-INDUCED MYOCLONUS
Authors: Michael H Soike, Emily Warren, Fabrício G Gonçalves, Agustin Cardenas, Mary E Littrell, Laura K Metrock, Elizabeth Alva, Marla Thompson, Emily Gantz, Brandon Rocque, Donna Murdaugh, Girish Dhall
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION We sought to evaluate the toxicity profile for children receiving 54Gy to the pineal region with a significant dose delivered to posterior thalamus and basal ganglia. METHODS We performed a retrospective review of patients treated at a single institution with intensity modulated proton therapy (IMPT) receiving 54Gy to the pineal region. Multiple beam angles were utilized for planning. Patient characteristics and dosimetric data were correlated with late-toxicity and imaging. RESULTS From 2021-2023, six children were treated, and at a median follow-up of 13 months [9-26], all patients remain disease-free. Three patients had non-germinomatous germ cell tumors, 1 low-grade glioma, 1 atypical teratoid rhabdoid tumor (ATRT), and 1 embryonal tumor with multilayered rosettes. Age range was 2.4 to 16.8 years. All patients received chemotherapy prior to IMPT. Neuropsychological evaluation indicated range of intellectual functioning (mean = 98.3 [83-118]). One patient, a 4-year-old female with ATRT, developed T2 changes within the globus pallidus and thalamus on 3 month follow-up. At 5 months, she developed bilateral action-induced myoclonus with corresponding enhancing lesions in the globus pallidus bilaterally. Neuropsychological evaluation at 5 months post-treatment indicated memory impairments. She was treated with dexamethasone without improvement. Between 912 months post-treatment, tremors improved with physical therapy and imaging showed near complete resolution of enhancement within globus pallidus. CONCLUSION One of six children developed grade 3 toxicity manifesting as bilateral action-induced myoclonus with imaging changes in the globus pallidus bilaterally following IMPT and exhibited related neuropsychological deficits. While brainstem toxicity from IMPT is well documented, globus pallidus toxicity is not well characterized. Given the contiguous neuronal tracts with the brainstem, it is logical to apply similar treatment planning techniques, i.e. minimizing hotspots within the globus pallidus and thalamic “core” structures, and being cognizant of LET/RBE effects for treatment involving the pineal region in young children.
NURS-10. DEVELOPMENT OF A NATIONAL PAEDIATRIC NEURO-ONCOLOGY NURSES GROUP (UNITED KINGDOM)
Authors: Rachel McAndrew, Elizabeth Laughlin, Joanne Page, Helen Paisley, Angela Howat, Paul Coyle
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The purpose of developing this group is to provide neuro-oncology patients with a high standard of care from diagnosis, treatment and beyond that is research based and reflects individual needs. This forum allows nurses working within paediatric neuro-oncology to share knowledge, experience, collaborate on projects, benchmarking and research opportunities. This will allow paediatric neuro-oncology nurses to increase their expertise and to foster relationships and collaborate with the wider neuro-oncology field and multi-disciplinary team. METHODS Develop an affiliation with a national association or organization Develop links to ensure all neuro-oncology nurses within CCLG centres are aware of the group, have the opportunity to join, fostering collaboration and support. Develop awareness of the neuro-oncology nursing speciality Develop a mission statement, terms of reference, and rolling agenda Literature reviews to ensure group has similar operation in line with other national nurses’ groups. Developing accountability. RESULTS Developed database of national neuro oncology nurses with all CCLG UK and Ireland centres represented. Set frequency of meetings and agendas. Ensure it operates to the same standard as other nurses’ groups. Organised working groups for projects. Agreed role of chair. CONCLUSION These activities have continued the development of the group since it’s conception in 2015 providing more structure, continued support to its members and wider recognition of its work. A robust mission statement, terms of reference, organisation and structure will ensure continued provision of education and support to neuro-oncology nurses, recognition of the group to the wider neuro-oncology community and improve overall patient experience.
RADT-09. IMMUNE RESPONSE IN DIFFUSE MIDLINE GLIOMA (DMG) FOLLOWING FLASH OR CONVENTIONAL RADIATION
Authors: Hanna E Minns, Oscar Padilla, Hong-Jian Wei, Andrea Webster-Carrion, Matthew Gallitto, Luca Szalontay, Jovana Pavisic, Yuewen Tan, Naresh Deoli, Guy Garty, James H Garvin, Peter Canoll, Claire I Vanpouille-Box, Raul Rabadan, Cheng-Chia Wu, Robyn D Gartrell
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse Midline Glioma (DMG) is a fatal, unresectable, pediatric brain tumor with limited treatment options and a median survival of 9-15mths. As radiation therapy (RT) can only extend life by 3mths, novel RT techniques are needed, including ultra-high dose rate RT (FLASH). RT can stimulate immune responses in many cancers especially via type 1 interferon (IFN1) but the effect of RT on DMG is understudied as post treatment tissue is not readily available. METHODS We evaluated the effect of RT on immune response in an orthotopic syngeneic model of DMG, comparing FLASH, given at 90Gy/second, to conventional dose rate RT (CONV), given at 2Gy/min. We evaluated single-cell RNA sequencing (scRNA-seq) on CD45+ immune cells isolated from tumors 4 days post 15Gy FLASH or CONV RT and compared to unirradiated tumor (SHAM). We also performed flow cytometry on tumors at both day 4 and day 10 post-RT. RESULTS We find microglia (MG) are the most abundant immune cell type followed by non-resident myeloid cells including macrophages (MAC) and dendritic cells (DC). While there’s no significant difference in tumor growth or proportion of immune subtypes comparing FLASH, CONV and SHAM, we see similar IFN1 enrichment in MG comparing FLASH and CONV at day 4. Interestingly, at day 10 post-RT we observe higher IFN1 receptor (IFNAR1) by flow in MGs after CONV (p=0.016) and SHAM (p=0.040) compared to FLASH. At day 4 CONV shows higher IFN1 gene set enrichment in MACs and DCs compared to FLASH (both p&amp;lt;0.0001) as well as higher IFNAR1 in DCs comparing CONV to FLASH (p=0.0079), while day 10 post-RT shows equivalent IFNAR1 in MACs and DCs between dose rates. CONCLUSION Changes in DMG tumor immune microenvironment post-RT differ over time. Though both RT modalities increase IFN1, the timing of this response is dependent on both cell phenotype and dose.
MDB-83. OUTCOMES OF INFANTS AND YOUNG CHILDREN WITH NEWLY DIAGNOSED SHH MEDULLOBLASTOMA TREATED ON THE NEXT CONSORTIUM “HEAD START” 4 PROTOCOL
Authors: Girish Dhall, Joseph Stanek, Megan Blue, Parth Patel, Diana Thomas, CHristopher Pierson, Benita Tamrazi, Kris Mahadeo, Jessica Fleming, Erica Bell, Katherine MIller, Olivia Grischow, Thomas Liszkay, Scott Owen, Caroline Hastings, Karen Tsui, Claire Mazewski, Gregory Friedman, Christopher Moertel, Derek Hanson, Carl Koschman, Guy Brock, Shahab Asgharzadeh, Arnab Chakravarti, Kenneth Wong, Marvin Nelson, Daniel Boue, Jaclyn Biegel, Elaine Mardis, Jonathan Finlay
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Infants and young children with SHH medulloblastoma were demonstrated to have a favorable outcome on “Head Start (HS)” III clinical trial utilizing five cycles of induction followed by one myeloablative high-dose chemotherapy (HDCT) cycle. We present the results of “Head Start” 4 (HS-4) trial where SHH subgroup patients received either three or five cycles of induction based on response followed by one HDCT cycle (similar to HS III). METHODS Eligibility included children &amp;lt;6 years of age at diagnosis of localized medulloblastoma and &amp;lt;10 years for patients with disseminated disease. Eligible patients with SHH medulloblastoma were considered “low-risk” and non-randomly assigned to receive three cycles (five cycles if &amp;lt;complete response) of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, etoposide, and high-dose methotrexate) followed by consolidation with single HDCT cycle (thiotepa, carboplatin, etoposide) and autologous hematopoietic stem-cell rescue. RESULTS Thirty-nine children with SHH medulloblastoma were enrolled on HS-4 with median age of 2.18 years (range: 0.28-6.88 years). Median follow-up for this cohort is 41 months (range: 18-67 months). Patients with localized SHH medulloblastoma (n=28) had significantly better 3-year event-free (EFS) compared to disseminated patients (n=11): 96.4% (95% CI: 90-100%) and 36.4% (95% CI: 16.6-79.5%), respectively (p&amp;lt;0.0001); however, there was no significant difference in 3-year overall survival (OS) between the two groups: 100% and 90.0% (95% CI: 73.2-100%), respectively (p=0.10). The estimated 3-year EFS for localized SHH subtype 1 and 2 patients was 100% and 95%, respectively (p=0.63). None of trial patients received irradiation prior to progression. All patients, except for four, underwent three cycles of induction. Germline variants were detected in 27% of patients tested (8/30). CONCLUSION We report excellent results for young children with localized SHH medulloblastoma when treated with only three cycles (reduced) of induction and single HDCT cycle on HS-4 trial without irradiation. Molecular data will be presented.
MDB-32. PRDM6 PROMOTES MEDULLOBLASTOMA FORMATION IN NEUROEPITHELIAL STEM CELLS AND IS A CHROMATIN REPRESSOR BY BINDING TO HISTONE H3 LYSINE 27 TRIMETHYLATION MARKS
Authors: Christin Schmidt, Sarah Cohen, Brian L Gudenas, Sarah Husain, Annika Carlson, Samantha Westelman, Linyu Wang, Joanna J Phillips, Paul A Northcott, William A Weiss, Bjoern Schwer
Journal: Neuro-Oncology (2024)

Abstract A substantial fraction of Group 4 MBs are characterized by enhancer hijacking through tandem duplication of SNCAIP, resulting in high expression of PRDM6, a putative transcriptional repressor and histone methyltransferase. PRDM6 is a poorly characterized member of the PRDF1 and RIZ1 homology domain-containing (PRDM) family of transcription factors. Here, we investigated the function of PRDM6 in human hindbrain neuroepithelial stem cells and its potential role as a driver of Group 4 medulloblastoma. We report that human PRDM6 localizes predominantly to the nucleus, where it causes widespread repression of chromatin accessibility and complex alterations of gene expression patterns. Genome-wide mapping of PRDM6 binding reveals that PRDM6 binds to chromatin regions marked by histone H3 lysine 27 trimethylation that are located within, or proximal to, genes. Moreover, we show that PRDM6 expression in neuroepithelial stem cells promotes medulloblastoma. Surprisingly, medulloblastomas derived from PRDM6-expressing neuroepithelial stem cells match human Group 3, but not Group 4, medulloblastoma. We conclude that PRDM6 expression has oncogenic potential but is insufficient to drive Group 4 medulloblastoma from neuroepithelial stem cells. We propose that both PRDM6 and additional factors, such as specific cell-of-origin features, are required for Group 4 medulloblastoma. Given the lack of PRDM6 expression in normal tissues and its oncogenic potential shown here, we suggest that PRDM6 inhibition may have therapeutic value in PRDM6-expressing medulloblastomas.
QOL-08. THE LONG-TERM UTILITY OF METHYLPHENIDATE FOR THE PRESERVATION OF INTELLECTUAL DEVELOPMENT IN CHILDHOOD SURVIVORS OF BRAIN TUMOUR
Authors: Alexander J Hagan, Sarah J Verity
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Enduring neurocognitive late effects are a common consequence of childhood brain tumour survivorship. Conceptual modelling of intelligence suggests initial deficits to processing speed and attention lead to the subsequent plateauing of intellectual and academic development. The utility of methylphenidate in improving attentional and processing speed deficits within the early phase of recovery has been previously reported. The longer-term contribution of methylphenidate in preserving intellectual ability through ameliorating these early deficits is yet to be evaluated. METHODS Twenty-nine childhood survivors were matched retrospectively with a no-treatment synthetic control. Intellectual assessments were conducted prior to starting methylphenidate and a minimum of 12 months thereafter. For the no-treatment control group, intellectual data were collected retrospectively from archival records, employing a similar assessment period. Linear Mixed Models were used to assess the influence of methylphenidate on intellectual trajectories between groups and fatigue scores over time. RESULTS Methylphenidate was associated with raw score improvements across all intellectual indices compared to no-treatment controls. Linear Mixed Modelling reported a borderline significant improvement in Processing Speed (t = 1.98, p =.05) for the methylphenidate group. In comparison, a borderline significant (p =.05) within-group decrease in Working Memory scores was reported for the no-treatment group. There was a significant within-group decrease in pooled PedsQL MFS scores between assessments for the treatment group (t = -4.01, p &amp;lt;.01), with the most notable decrease observed in Sleep/Rest Fatigue (t = -10.17, p &amp;lt;.01). CONCLUSIONS Methylphenidate may pose a valuable long-term rehabilitative strategy in preserving Processing Speed in childhood survivors of brain tumour. Whilst our sample size is small, there is tentative evidence for the utility of methylphenidate in alleviating fatigue experienced by childhood survivors.
QOL-06. RECURRENCE PATTERNS AND SURVEILLANCE IMAGING IN PEDIATRIC BRAIN TUMOR SURVIVORS
Authors: Chantel Cacciotti, Alicia Lenzen, Chelsea Self, Natasha Pillay-Smiley
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Surveillance magnetic resonance imaging (MRI) is routinely used to detect recurrence in pediatric central nervous system (CNS) tumors. Frequency of neuroimaging varies with no standardized approach. METHODS A single institution retrospective cohort study evaluated frequency and pattern of recurrences. Pediatric patients (birth to age 21 years) diagnosed with a primary CNS tumor between 1988 and 2011 treated at Lurie Children’s Hospital were included. RESULTS This study included 476 patients; the majority diagnosed with a low-grade glioma (LGG) (n=138; 29%), high grade glioma (HGG) (n=77; 16%), ependymoma (n=70; 15%) or medulloblastoma (n=61; 13%). LGG, HGG and ependymoma patients more commonly had multiply recurrent disease (p=0.08), with ependymoma patients demonstrating ≥2 relapses in 47% of cases. Recurrent disease was identified by imaging more often than clinical symptoms (65% vs 32%; p=&amp;lt;0.01). Treatment at relapse included surgical managment more often than non-surgical approach (59% vs. 41%; p=0.0016) in patients, leading to pathology confirmation of recurrence. Mean time to first relapse for the entire cohort was 2.5 years (range 1 day-24.8 years). Patients diagnosed with meningioma demonstrated the longest mean time to first relapse (74.7 months) whereas those with Atypical Teratoid Rhabdoid Tumor and Choroid plexus carcinoma tended to have the shortest time to relapse (8.9 months and 9 months, respectively). Overall, 22 patients sustained first relapse &amp;gt;10 years from initial diagnosis, including those diagnosed with LGG, medulloblastoma, pineoblastoma, craniopharyngioma, GCT, and meningioma. CONCLUSION With a higher percentage of tumor recurrence/progression seen on neuroimaging before development of symptoms, surveillance imaging is necessary in routine follow up of pediatric CNS tumor survivors. While the study is limited since we did not look at overall survival, earlier detection of recurrence would lead to earlier initiation of treatment and implementation of salvage treatment regimens which can impact survival and quality of life.