bluuebunny/crossref_metadata_2025_split huggingface dataset:
DIPG-57. INITIAL AND EARLY METASTATIC SPREAD IN DIPG AND DIFFUSE MIDLINE GLIOMA, H3 K27-ALTERED - REPORT FROM THE EUROPEAN SOCIETY FOR PEDIATRIC ONCOLOGY (SIOPE) AND INTERNATIONAL DIPG/DMG REGISTRIES
Authors: Perwein Thomas , Gielen Gerrit H , Karremann Michael , Bison Brigitte , Damen-Korbijn Carin M , Baugh Joshua N , Hummel Trent R , Blank Courtney , Biassoni Veronica , Bellón Marina Caballero , Szychot Elwira , Papusha Lyudmila , Jones David T W , Sturm Dominik , Hoffmann Marion , Kullmann Silke , Steffen Laura S , Simon Thorsten , Friker Lea L , Pietsch Torsten , Seidel Clemens , Eyrich Matthias , El-Ayadi Moatasem , Nussbaumer Gunther , Massimino Maura , La Madrid Andres Morales , Bailey Simon , von Bueren André O , Benesch Martin , Veldhuijzen van Zanten Sophie E M , Hoffman Lindsey , Kramm Christof M 
Published: June 2024

Abstract

BACKGROUND
We aimed to assess frequency, patterns and potential prognostic impact of initial and early dissemination in pediatric patients with diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma, H3K27-altered (DMG).

METHODS
199 patients (age, 0-18 years) with DIPG/DMG and positive CSF cytology and/or metastases on MRI at diagnosis (Types 1-3) were identified within the SIOPE and International DIPG/DMG Registries. Data on metastatic first progression (PD) in DIPG/DMG (Type 4) were analyzed from the HIT-HGG-2007/2013 trials.

RESULTS
Dissemination at diagnosis was present in 5% of patients with DIPG/DMG (16.9% in non-pontine DMG). For all 199 patients with initially disseminated pontine (n=166) and non-pontine DMG (n=33), median overall survival (OS) was 10±0.5 months and progression-free survival (PFS) was 6.6±0.2 months. Tumor cells in the CSF without metastases on initial MRI (Type 1) were detected in 12 patients. Four patients had no primary tumor but primary extensive leptomeningeal dissemination resembling diffuse leptomeningeal glioneuronal tumor, molecularly confirmed as DMG, with aggressive course (Type 2). 183 DIPG/DMG patients were identified with primary tumor and metastases on MRI at diagnosis (Type 3). OS and PFS was superior in patients receiving additional treatment to radiotherapy (n=124), without significant differences between focal and craniospinal irradiation. Metastatic spread at first progression (Type 4) occurred in 32.1% (65.3% in non-pontine DMG) of 224 HIT-HGG patients with DMG and recorded PD. OS of patients with metastatic PD was inferior to local PD (median, 10.8±0.9 vs. 13.3±0.9 months, p=0.005), as was post-progression survival (median, 3.1±0.4 vs. 5.2±0.5 months, p=0.003).

CONCLUSIONS
We observed a propensity for early dissemination in (especially non-pontine) DMG. While additional treatment beyond radiotherapy seems beneficial, preventing dissemination at progression (e.g., by upfront CSI) may help to prolong survival of patients with DMG and possibly provide options for further therapy.
DIPG-60. OPERATIVE PERFORMANCE OF RAPNO DIPG CRITERIA FOR IMAGING REVIEW- A STUDY FROM THE INTERNATIONAL DIPG/DMG REGISTRY (IDIPGR)
Authors: Gorsi Hamza S , Guryildirim Melike , Kuwabara Michael , Dhatt Jovan , Hoffman Lindsey M , Cohen Kenneth J 
Published: June 2024

Abstract

BACKGROUND
The Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group for diffuse intrinsic pontine glioma (DIPG) recently published its recommendations. Response criteria incorporate radiologic findings, neurologic status, and use of concurrent steroids and antiangiogenic drugs to define response. To test the operative performance of the imaging component, we retrospectively applied RAPNO DIPG recommendations to a convenience sample of 46 patients enrolled in the International DIPG/DMG Registry(IDIPGR).

METHODS
MRIs were independently reviewed by 2 pediatric neuro-radiologists. These measurements were analyzed utilizing RAPNO DIPG imaging criteria to categorize the response as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). For PR evaluation, each MRI was compared to the baseline MRI, and for PD evaluation, each MRI was compared to the MRI with the smallest cross-sectional measurement. The response category for each MRI was compared between 2 neuro-radiologists and was classified as concordant if they agreed, minor discordant if one reported SD and the other reported PR or PD, and major discordant if one reported PR and the other reported PD.

RESULTS
A total of 276 paired MRIs were analyzed. Sixty-seven percent of the time, the analyzed response assessment was concordant. In 33% discordant reads, 26% were minor discordant, and 7% were major discordant. There were no CRs reported. Further analysis of minor discordant cases showed that 62% of these cases were within 10% of the boundary for PR or PD. The median difference between 2 neuro-radiologists’ long axis measurements was 2 mm (range 0-27mm) and short axis measurements was 2mm (range 0-29mm). These small differences in measurements account for all discordant response categories between 2 neuro-oncologists.

CONCLUSION
This study demonstrated that RAPNO DIPG imaging criteria can be successfully applied with high concordance between readers. When discordant, measurements were largely at the boundaries of response type.
DIPG-71. XPEDITE: A STUDY TO EXPEDITE DIPG AND DMG RESEARCH
Authors: Stuhlmiller Timothy J , Ward Lisa , Lewis Sarah , Cole Zachariah D , Chuyka Donald , Ginn Sarah , Federowicz Bryan , Shapiro Mark A 
Published: June 2024

Abstract

BACKGROUND
Diffuse midline glioma (DMG), particularly the subtype known as diffuse intrinsic pontine glioma (DIPG), poses a significant challenge due to its aggressive nature and low survival rates, especially in children. Despite ongoing research and clinical trials, the survival rate remains alarmingly low. The scarcity of cases and siloed nature of current registry efforts have hindered the establishment of a reliable natural disease history for benchmarking studies and led to the need for randomization in clinical trials.

METHODS
xPedite (NCT06140719) is a fully virtual, patient-driven, nationwide, real-time observational study to collect, annotate, standardize, and report the critical data elements of DMG and DIPG in a regulatory-compliant framework. Patients of any age can join via electronic consent, with recruitment supported by provider referrals and patient advocacy organizations DDRFA and My DIPG Navigator. Medical records are accessed from institutions, sequencing vendors, and health information networks. Notably, data elements are annotated comprehensively and longitudinally in a 21 CFR Part 11-compliant clinical database by xCures remote study staff, eliminating the need for data entry by treating site staff or physicians. Data collected include anti-cancer interventions, non-cancer medications, biomarker results, radiological endpoints, steroid use, vitals, demographics, raw DICOM images, and genomics. In addition to clinical data, patient- and caregiver-reported outcome questionnaires (PROs) and video assessments of mobility and neurological status are collected for clinician review. The objective of the study is to collect these clinical, imaging, biomarker, and assessment data in a manner suitable to provide to health authorities to reduce randomization in future trials. In a commitment to scientific understanding and collaborative research, the data collected through the xPedite study is openly available to academic, government, and non-profit researchers. As of January 2024, 182 patients were enrolled in xPedite. Real-time enrollment and data statistics are available at https://xcures.com/dmgdashboard/.
DIPG-83. RBPJ-SIX1 AS A TUMOR SUPPRESSOR AXIS IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Racanelli Anna , Shen Chen , Gadd Samantha L , Chizhik Mili , Setara Ruby , Ge Yi , Schüpper Alexander J , Puigdelloses Montserrat , Hambardzumyan Dolores , Tsankova Nadejda M , Becher Oren J 
Published: June 2024

Abstract

BACKGROUND
Diffuse intrinsic pontine glioma (DIPG) is a rare, incurable pediatric brain tumor that arises in the brainstem. Despite decades of clinical trials, no treatments have proven effective at prolonging survival for children with this disease. A deeper insight into the epigenetic and genetic changes driving DIPG are imperative for identifying therapeutic targets. A defining feature of DIPG is the histone H3 lysine to methionine mutation at residue 27 (H3K27M), which prevents H3K27 trimethylation. The H3.1K27M mutation, specifically, co-segregates with mutations in the Activin A receptor ACVR1. Tumor cells with both mutations have significantly higher levels of the transcripts and proteins that inhibit proneural gene expression in the NOTCH signaling pathway.

METHODS
We used the replication-competent avian sarcoma-leukosis virus long terminal repeat with splice acceptor/tumor virus A (RCAS/Tv-a) system to evaluate the role of various NOTCH signaling proteins in a genetically engineered mouse model of DIPG. We also performed RNA sequencing of specific NOTCH signaling protein knockout DIPG models.

RESULTS
Knocking out Hairy of Enhancer Split-1 (Hes-1) in combination with H3K27M and ACVR1 mutations did not significantly reduce survival compared to control. However, knocking out Recombination Signal Binding Protein for Immunoglobulin kappa J region (RBPjk)—a transcriptional regulator upstream of Hes-1—did significantly reduce survival compared to wild-type RBPjk expression. RNA sequencing of RBPjk knockout tumors revealed that Sine Oculis-related Homeobox 1 (Six1) was the most top most differentially expressed gene. To assess whether Six1 downregulation drives DIPG tumorigenesis in RBPjk knockout tumors, we overexpressed Six1 in a murine model of DIPG with H3.3K27M and p53 loss. Six1 overexpression did not significantly prolong survival or decrease tumor grade but trended toward significance. However, Six1 overexpression significantly increased tumor cell proliferation.

CONCLUSIONS
These results indicate that Six1 could function as a potential tumor suppressor in DIPG, necessitating further exploration.
DIPG-86. INVESTIGATING THE TUMOR ENVIRONMENT AND SIGNALING DEPENDENCIES DRIVING DIFFUSE MIDLINE GLIOMA TUMOR INITIATION, PROGRESSION, AND RESISTANCE: A COMPREHENSIVE APPROACH LEVERAGING BULK MULTIOMICS DECONVOLUTION AND SINGLE-CELL OMICS VALIDATION
Authors: Patel Palak , Ryall Scott , Kukreja Bharti , Turinski Andrei , Siddaway Robert , Brudno Michael , Ramani Arun , Pajovic Sanja , Kalish Brian , Hawkins Cynthia 
Published: June 2024

Abstract

BACKGROUND
Diffuse Midline Glioma (DMG) is a incurable tumor affecting children. Recent genomic investigations have identified a recurrent H3K27M mutation which induces global alterations in histone methylation patterns and DNA methylation. These epigenetic modifications hint at pivotal roles in DMG pathogenesis, yet effective therapeutic strategies remain elusive, with median survival rates stagnant at approximately one year. This shortfall stems from two main factors: 1) Inadequate multiomics studies hindering our understanding of DMG evolution and tumor progression, and 2) Limited comprehension of the tumor microenvironment in DMG.

METHODS
To elucidate DMG’s clonal evolution, we adopted a comprehensive multi-region sampling approach, acquiring 33 specimens from seven patients. Whole-exome and transcriptome sequencing, alongside DNA methylation profiling, were performed. Additionally, we generated one of the most extensive single-cell multiomics datasets (&gt;300,000 cells from 21 additional samples), with a focus on pre- and post-treatment, and dissemination effects in DMG.

RESULTS
Our analysis delineated a tumor-promoting microenvironment characterized by hypoxia and pro-inflammatory conditions, nurturing genomic alterations and specialized biological processes such as proliferation and epithelial-mesenchymal transition. Notably, a majority of immune cells exhibited M1-like polarization, bolstering pro-inflammatory programs within the tumor milieu. Subclones within the DMG cohort demonstrated dissemination potential, often exhibiting up-regulation of NOTCH, P53, and WNT beta-catenin signaling pathways. These findings suggest that DMG clones harboring dissemination capabilities outside the pons acquire additional phenotypic features, possibly mediated by epigenetic or transcriptional alterations, contributing to enhanced migratory and aggressive behaviors.

CONCLUSIONS
Our study unveils the parallel evolution of DMG at genetic, epigenetic, and transcriptional levels, unveiling novel subclonal phenotypes governing tumor behavior. Crucially, we identify critical environmental shifts such as hypoxia and inflammatory changes, coupled with specialized signaling programs, driving dissemination and resistance phenotypes. These insights may pave the way for generating accurate genetically mouse models and targeted therapeutic interventions to combat this challenging malignancy.
DIPG-88. TARGETING THE ANTIOXIDANT RESPONSE ELEMENT AXIS SENSITIZES DIFFUSE MIDLINE GLIOMA CELLS TO ONC201
Authors: Jackson Evangeline R , Duchatel Ryan J , Fish Cameron J , Persson Mika L , Staudt Dilana E , Findlay Izac J , Dun Matthew D 
Published: June 2024

Abstract

BACKGROUND
Diffuse midline glioma (DMG) is a universally fatal CNS tumor, with a median overall survival of &lt;12-months. Recent studies, including our own, have identified overexpression of the mitochondrial protease ClpP in DMG patient samples. ClpP plays a pivotal role in regulating energy production. Brain-penetrant ClpP agonists, including ONC201, ONC206, and TR107, induce non-specific degradation of the mitochondrial electron transport chain. However, there is considerable variability in the response of DMG cell lines to these therapies, with only about half reaching IC50. Notably, TP53-mutant cell lines exhibit reduced sensitivity.

METHODS/RESULTS
Further analysis using quantitative proteomics of TP53-mutant DMG cell lines exhibited hallmark activation of ClpP, increased mitochondrial stress and dysfunction. Importantly, ClpP agonism increased the activity of the transcription factor NRF2, driving expression of NQO1 (p=0.0017). NQO1 is a cytoprotective enzyme, promoting redox balance and cell survival. This highlights a potential adaptive response to ClpP agonist therapy in DMG cells. Analysis of DMG patient samples through publicly available RNA sequencing data identified ubiquitously high NRF2 expression compared to other pediatric CNS tumors. This led us to hypothesize that a clinically relevant, selective NQO1 inhibitor could elicit a strong response to ClpP agonism. Therefore, we examined ARQ761, a CNS-active therapy that disrupts NQO1 leading to the formation of an unstable hydroquinone, causing oxidative DNA damage and apoptosis. When ARQ761 was used concurrently with a ClpP agonist, the combination showed additive effects, average Bliss Score of 9.91 (n=4). Interestingly, administering ARQ761 24 h after ClpP agonist exposure combined synergistically, average Bliss Score of 15.87 (n=4). This synergy was further potentiated using ARQ761 48 h after ClpP agonism, when NQO1 expression peaked, resulting in an average Bliss Score of 20.30 (n=4).

CONCLUSIONS
This study has unveiled an intrinsic antioxidant defense mechanism in DMG, which facilitates evasion from treatments inducing oxidative stress. This defense mechanism appears particularly robust in cell lines harboring TP53-mutations, which are also known to exhibit resistance to radiotherapy.
DIPG-92. IMMUNE ACTIVATION STUDIES WITH THE NEOANTIGEN-BASED PEPTIDE VACCINE RHSC-DIPGVAX DEMONSTRATE ANTIBODY-MEDIATED RESPONSES AND EPITOPE SPREADING IN PEDIATRIC PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPG)
Authors: Sipila Patrick , Boland Lauren , Miska Jason M , Chi Susan N , Sato Mariko , Plant-Fox Ashley S , Narendran Aru 
Published: June 2024

Abstract

BACKGROUND
Approximately 80% of DIPGs carry gain-of-function lysine-to-methionine (K27M) mutations in histone H3 proteins that frequently co-occur with other protein aberrations, including p53, ACVR1, and PDGFRA. Because the DIPG microenvironment has few infiltrating immune cells, resolution of negative regulatory mechanisms through checkpoint blockade may be necessary to promote vaccine-induced anti-tumor responses. Accordingly, rHSC-DIPGVax is a neoantigen-based peptide vaccine combined with checkpoint inhibitors currently under investigation in clinical trial, NCT04943848. The vaccine contains 16 neoantigen peptides, QS-21 adjuvant, and recombinant heat shock protein, Hsc70. In this study, we investigate vaccine-induced antibody-mediated immunity and the phenomenon of epitope spreading, an extension of the immune response to secondary epitopes not directly targeted by the therapy, thus promoting distinct, individualized responses.

METHODS
rHSC-DIPGVax is administered every two weeks to patients with DIPG and blood is collected pre-treatment and prior to each dose. To investigate vaccine-induced immunoreactivity to neoantigens targeted by rHSC-DIPGVax, DIPG lysates resolved by two-dimensional gel electrophoresis are immunoblotted with pre- and post-vaccine patient plasma containing antibodies against vaccine antigens. Proteins are immunoprecipitated (IP) from DIPG lysates, followed by mass spectrometry (MS) identification and validation.

RESULTS
In eight subjects to date, vaccination with rHSC-DIPGVax consistently induces IgM and IgG antibodies against proteins directly targeted by the vaccine, including strong immunoreactivity to ACVR1. Furthermore, antibodies against several secondary proteins are also detected in post-vaccination plasma. Immunoblotting and IP-MS analysis identified several distinct candidates of epitope spreading, including the tumor antigens CEP290, DNAH3, HRNR, KDM6B, LAMA5, and TRPA1.

CONCLUSIONS
rHSC-DIPGVax induces antibody-mediated tumor-specific responses to DIPG neoantigens, including direct vaccine targets and secondary targets via intra- and inter-molecular epitope spreading. We also present an experimental protocol to investigate vaccine-induced immune activation. Our ongoing studies aim to validate epitope spreading candidates and determine the important biological correlates between antibody responses and clinical outcomes.
DEI-01. CLINICAL AND SOCIOECONOMIC FACTORS ASSOCIATED WITH PARTICIPATION IN POST-MORTEM TISSUE DONATION IN PEDIATRIC BRAIN TUMORS: A RETROSPECTIVE CHART REVIEW
Authors: Boland Lauren K , Kabat Judith M , Williams Melissa , Lenzen Alicia , Plant-Fox Ashley S , Wadhwani Nitin , Waanders Angela J 
Published: June 2024

Abstract

BACKGROUND
The gift of post-mortem tissue donation is a critical resource in the discovery and interrogation of pathobiological mechanisms of pediatric brain tumors. Broad generalizability of research findings requires a representative population to participate in pre-clinical studies. As a “Center of Excellence” within the Gift from a Child initiative, our institution has a well-established post-mortem tissue donation program funded by the Swifty Foundation. Our primary objective was to determine if clinical and socioeconomic differences exist between patients that participated in and those that declined research-based autopsy.

METHODS
We performed a single-institution retrospective chart review of pediatric patients with central nervous system (CNS) malignancies who died from their disease between 1/1/2021 and 12/31/2022. Individual clinical, demographic, and socioeconomic data were assessed. Population-level data were estimated using Zip Code Tabulation Areas. Descriptive statistics were used to compare categorical data.

RESULTS
Among 26 patients who died secondary to disease in the study timeframe, 23 (88%) were approached and 8/23 (35%) consented to participation. In the consented group (C) vs. declined group (D), there was a higher percentage of White, Non-Hispanic/Latino patients by self-reported race (C: 88% vs. D: 55%) and no patients who identified as Asian or Hispanic/Latino (C: 0% & 0% vs. D: 13% & 27%). Of all patients approached, 2 required interpreters (9%) and both families declined participation. The rate of private insurance was higher in the consented group (C: 75% vs D: 47%) compared to Medicaid as primary insurance in the declined group (C: 13% vs D: 53%).

CONCLUSIONS
Patients from racial and ethnic minorities are underrepresented in tissue donation programs. Future research should aim to understand and improve identified disparities to ensure advancements benefit all children with CNS malignancies. One area we plan to address is improved communication with non-English speaking families by educating interpreter services prior to discussion.
DEI-02. DIRECT PATIENT OUTREACH IN PEDIATRIC NEURO-ONCOLOGY TO IMPROVE ACCESS TO GENOMIC PROFILING – THE MAKE-AN-IMPACT PROGRAM
Authors: Sait Sameer Farouk , O’Donohue Tara , Hill Katherine , Stockfish Emily , Giantini-Larsen Alexandra , Alano Tina , Bale Tejus , Rosenblum Marc , Benhamida Jamal , Dunkel Ira , Berger Michael , Arcila Maria E , Ladanyi Marc , Miller Alexandra , Chakravarty Debyani , Solit David , Shukla Neerav , Karajannis Matthias 
Published: June 2024

Abstract

BACKGROUND
Genomic profiling and precision medicine have revolutionized cancer care but are not accessible to all due to high costs, insurance issues, limited access to testing facilities or qualified personnel. We established a program providing free clinical genomic testing worldwide (Make-An-IMPACT) and report findings from the pediatric CNS tumor cohort.

METHODS
Following a referral from: (1) a physician, (2) a disease-specific advocacy group, or (3) submission of contact information through program website, patients were enrolled on an IRB-approved protocol (NCT01775072). CSF cell free DNA (cfDNA) and matched normal samples were analyzed using MSK-IMPACTTM, a New York State Department of Health authorized hybridization capture-based next-generation panel DNA sequencing clinical assay. If a driver mutation wasn’t reported, raw genomic data was reviewed. OncoKBTM was used to determine the level of evidence supporting the clinical actionability of genomic aberrations.

RESULTS
24 patients (median age 7.5; range 0.1-20 years) were enrolled; 9 (38%) from 5 non-US countries and 6 (25%) from non-NYC US sites. African American and Hispanics constituted 8% and 13% of the cohort. Potentially actionable alterations were identified in 4/24 (17%) cases; 2/24 (8%) subsequently received matched therapy. In unbiopsied or non-diagnostic cases, a disease defining alteration was identified in 8/15 (53.3%). BRAF-KIAA1549 fusions were identified in 2/3 DLGNT patients and 1p loss in all 3. Both patients with BRAF fused DLGNT started targeted therapy with Trametinib, one of whom achieved a durable treatment response for 2.5 years. 3/8 patients with unbiopsied brainstem lesions had a H3.3K27M mutation, while 2 had non-H3.3K27M mutations detected (1 SMARCB1 deletion, 1 IDHR172G mutation) leading to treatment regimen changes.

CONCLUSIONS
This study captured a broad range of pediatric CNS malignancies with a diverse patient representation across geographic regions. CSF cfDNA profiling provided important diagnostic and therapeutic information reported in real time to patients and local physicians.