bluuebunny/crossref_metadata_2025_split huggingface dataset:
GCT-29. MULTI-INSTITUTIONAL ANALYSIS OF PEDIATRIC RELAPSED/REFRACTORY CENTRAL NERVOUS SYSTEM GERMINOMAS
Authors: McGlynn Mary Claire , Abu-Arja Mohammad H , Zaghloul Mohamed Saad , Bertrand Kelsey , Gajjar Amar , Alias Hamidah , Cappellano Andrea , Graham Richard T , Baglivo Sofia Jares , Bhadri Vivek , Govender Dinisha , Dassi Natalia , Czogala Malgorzata , Ronsley Rebecca , Knowles Truman , Mueller Sabine , Dhall Girish , Nagabushan Sumanth , Abdelbaki Mohamed S 
Published: June 2024

Abstract

BACKGROUND
Relapsed central nervous system germinomas are rare with no universal agreement regarding management. We explored the prognostic factors that may impact the treatment of patients with relapsed CNS germinoma.

METHODS
We collected data on relapsed/progressive germinomas from nine large international sites. Data was summarized using descriptive statistics. Overall survival (OS) was evaluated using Kaplan-Meier and Fischer’s exact test to estimate odds ratios (OR) and 95% confidence intervals (CI).

RESULTS
Twenty-seven patients with relapsed (24) and progressive (3) germinomas were included (3.7% metastatic). Median age at diagnosis was 15.8 years (interquartile range (IQR): 11.9-18.5). Complete remission (CR) after initial treatment (chemotherapy 63.9% and radiotherapy 88.9%) was achieved in 15 patients (55.6%). The median time from diagnosis to relapse/progression was 20.0 months (range: 10.8-65.1 months) with 55.6% occurring within 24 months. Twenty-five patients (92.6%) underwent chemotherapy, 15 (55.6%) received high-dose chemotherapy with stem cell support (HDCx), and 16 received (59.3%) radiotherapy. At last follow-up, 86.6% of HDCx and 87.5% of radiotherapy recipients were alive. Median time to last follow-up was 41.8 months (IQR: 19.6-132.1). Fifteen children (55.6%) achieved CR after therapy and 21 (77.8%) were alive at last follow-up. Of patients receiving irradiation, 12.5% received whole ventricular irradiation, 81.3% craniospinal irradiation, and 6.3% focal irradiation. Chemotherapy at relapse was associated with improved 5-year OS (OR=1.32 95%CI: 1.06-1.64) Re-irradiation at relapse (OR=2.6, 95%CI: 0.36-19.2) and HDCx at relapse (OR=2.17, 95%CI: 0.30-15.71) did not reach statistically significant difference. CR after initial therapy (OR=1.25, 95%CI: 0.97-1.61) was not associated with improved 5-year OS, CR after relapse therapy was associated with increased 5-year OS (OR=3.50, 95%CI: 1.08-11.24)

CONCLUSIONS
Relapsed CNS germinomas are salvageable at relapse. This ongoing multi-institutional study will contribute to existing knowledge about relapsed/progressive CNS germinomas and inform prospective clinical trials to improve outcomes for children with relapsed/progressive disease.
HGG-06. MOLECULAR PATTERNS OF PEDIATRIC HIGH-GRADE GLIOMAS IN SOUTHEAST ASIA
Authors: Aw Sze Jet , Merchant Khurshid , Goh Jian Yuan , Mok Yingting , Tan Char Loo , Tan Enrica Ee Kar , Low Sharon Yin Yee , Chang Kenneth Tou En 
Published: June 2024

Abstract

BACKGROUND
Molecular characteristics of pediatric high-grade gliomas are largely based on cohorts derived from North America and Europe. In this study, we compare the molecular findings of a Southeast Asian cohort of pediatric high-grade gliomas with published data.

METHODS
We collated clinical, histopathological, and molecular data from pediatric high-grade gliomas diagnosed in our laboratory over the past 5 years. Molecular testing methods used included Illumina’s Childhood Cancer Panel (26 cases), FoundationOne’s CDx panel (2 cases), and Archer FUSIONPlex Pan Solid Tumour v2 panel (2 cases). 7 cases had no molecular data. 11 cases underwent additional DNA methylation analysis using Illumina’s Infinium MethylationEPIC v1.0 kit.

RESULTS
37 cases of pediatric high-grade gliomas from 34 patients were identified. Patient age ranged from 2 to 26 years (median 14 years). The male-female ratio was 1.1:1. Diffuse midline gliomas, H3K27-altered (DMG, H3K27-altered) constituted 51% of the cases (19/37), followed by diffuse pediatric-type high-grade gliomas, H3-wildtype and IDH-wildtype (32%; 12/37) and diffuse hemispheric gliomas H3G34-mutant (16%; 6/37). The commonest genes with pathogenic single nucleotide variants were TP53 (79%;22/28), followed by H3F3A (54%;15/28). The commonest amplified genes were MYCN and EGFR (both 4/28; 14%). Three gene fusions were detected, none of which arose from infants – 2 were found in diffuse pediatric-type high-grade gliomas, H3-wildtype and IDH-wildtype (CSTF3::ALK and PRCC::NTRK1 fusions), and one occurred in a DMG, H3K27-altered (ERC1::RET fusion). The most common methylation groups identified were DMG, H3K27-altered and diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, MYCN subtype (both 3/11; 27%).

CONCLUSIONS
Although small, our Southeast Asian cohort comprised a higher percentage of TP53-mutant high-grade gliomas amongst all pediatric high-grade gliomas as a group. The commonest amplified genes were MYCN and EGFR. We detected gene fusions in non-infant gliomas. These findings suggest geographical differences in the biology of pediatric high-grade gliomas.
HGG-07. INVESTIGATING THE ROLE OF SENESCENCE IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Chang Timothy H , Nassar Alexander , Kleinman Claudia , Bandopadhayay Pratiti 
Published: June 2024

Abstract
Cellular senescence has expanded well past the original definition of just proliferative exhaustion and tumor suppression. Today, senescence is considered a “Hallmark of Cancer” and the senescence-associated secretory phenotype (SASP) secretes molecules that can promote oncogenesis, angiogenesis, and an immunosuppressive tumor microenvironment (TME). Pediatric high-grade gliomas (pHGGs) are aggressive brain tumors with dismal outcomes and limited therapeutic options. Accumulating evidence suggests potential therapeutic vulnerabilities in targeting senescence in adult solid and brain tumors. Furthermore, senescent immune cells in the TME appear to play an important role in the initiation and progression in adult solid tumors. The role of senescence in pHGGs, however, has not been well described. Here, we show evidence of senescent glial and immune cells in pHGG tumors. Using patient-derived cell lines, we also investigate triggers of senescence and further characterize SASP in pHGGs. By understanding the role of senescence in gliomagenesis, we hope to open new approaches in treating pHGGs.
HGG-16. PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMA OF METHYLATION-BASED RTK2A AND RTK2B SUBCLASSES PRESENT DISTINCT RADIOLOGICAL AND HISTOMOLECULAR FEATURES
Authors: Tauziède-Espariat Arnault , Friker Lea L , Nussbaumer Gunther , Alice Métais , Antonelli Manila , Benesch Martin , Bison Brigitte , Dangouloff-Ros Volodia , Garrè Maria Luisa , Giangaspero Felice , Grabovska Yura , Grill Jacques , Jones David T W , Jones Chris , Karremann Michael , Kramm Christof M , Mackay Alan , La Madrid Andrés Morales , Perwein Thomas , Pietsch Torsten , Sumerauer David , van Vuurden Dannis , von Bueren André O , Warmuth-Metz Monika , Wesseling Pieter , Zamecnik Josef , Castel David , Gielen Gerrit H , Varlet Pascale 
Published: June 2024

Abstract

BACKGROUND
Diffuse pediatric-type high-grade gliomas (pedHGG), H3-wildtype and IDH-wildtype, encompass three main methylome-based subclasses: pedHGG-MYCN, -RTK1A/B/C, and -RTK2A/B. Since their first description in 2017, tumors of pedHGG-RTK2A/B have not been further characterized and their clinical significance is unknown.

METHODS
A not yet published cases series on pedHGG with a gliomatosis cerebri (GC) growth pattern showed an increased incidence of pedHGG-RTK2A/B (n=18/40). We assembled a cohort of 14 additional methylation-based pedHGG-RTK2A/B tumors and pooled them with the GC tumors providing centrally reviewed radiological, histological, and molecular characterization.

RESULTS
Our cohort of 32 pedHGG-RTK2A/B tumors consisted of 25 RTK2A (78%) and seven RTK2B (22%) cases. The median age was 11.6 years (4-17) with an overall survival of 15.9 months (interquartile range 12.1-25.8). Of the additional unselected cases with available imaging (10 of 14), seven showed a GC phenotype at diagnosis or follow-up. In addition, pedHGG-RTK2B tumors exhibited bithalamic involvement (6/7, 86%). Histopathology confirmed a diffuse glial neoplasm in all cases with prominent angiocentric features in both subclasses. Most tumors (24/29, 83%) diffusely expressed EGFR, notably with a focal perivascular enhancement. Cells of pedHGG-RTK2A lacked Olig2 expression, whereas 43% (3/7) of pedHGG-RTK2B expressed Olig2. Loss of ATRX expression occurred in four pedHGG-RTK2B samples (57%). In sequencing analyses (RTK2A: n=18, RTK2B: n=5), EGFR alterations (n=15/23, 65%; predominantly point mutations) were commonly found in both subclasses. Mutations in BCOR (n=14/18, 78%), SETD2 (n=7/18, 39%), and TERT promoter (n=6/18, 33%) occurred exclusively in pedHGG-RTK2A tumors, while pedHGG-RTK2B tumors were enriched for TP53 mutations (4/5, 80%).

CONCLUSIONS
In conclusion, genotype-phenotype correlations in a multicenter series of pedHGG-RTK2A/B tumors revealed a highly diffuse-infiltrating tumor frequently exhibiting a GC phenotype. The two subclasses share particular histomolecular features (EGFR alterations, angiocentric pattern), whereas they differ in specific characteristics (pedHGG-RTK2A: Olig2 negativity, BCOR and SETD2 mutations; pedHGG-RTK2B: ATRX and TP53 alterations).
HGG-18. ONC201 COMBINED WITH THE ONCOLYTIC ADENOVIRUS DELTA-24-RGD AS A NEW THERAPEUTIC REGIME FOR PEDIATRIC HIGH-GRADE AND DIFFUSE MIDLINE GLIOMAS
Authors: de la Nava Daniel , Ausejo-Mauleon Iker , Nazarian Javad , Mueller Sabine , Allen Joshua E , Koschmann Carl , Venneti Sriram , Dun Matthew D , Gomez-Manzano Candelaria , Fueyo Juan , Patiño-Garcia Ana , Alonso Marta M 
Published: June 2024

Abstract

BACKGROUND
Pediatric high-grade (pHGGs) and diffuse midline gliomas (DMGs) patients have the worst survival rates in childhood cancer. The oncolytic adenovirus Delta-24-RGD and the imipridone ONC201 are two of the most promising therapeutic agents in the field, having demonstrated safety and effectiveness in clinical trials. Therefore, we evaluated whether the Delta-24-RGD/ONC201 combination could increase the therapeutic benefit in pHGGs and DMGs.

METHODS
A battery of human pHGG, DMG, and murine DMG cell lines was used for the study. Viral replication was assessed by hexon titration. Characterization of combination response was assessed by MTS, RNAseq, Seahorse, and immunofluorescence. In vivo experiments were performed to assess the efficacy of the proposed combination. The tumor microenvironment infiltration was evaluated by flow cytometry.

RESULTS
ONC201 cotreatment with Delta-24-RGD did not affect the virus replication capability in vitro. Cytotoxicity studies showed that cotreatment was either synergistic or additive. Importantly, cells treated with the combination maintain the mitochondrial damage caused by ONC201, showed a significant reduction of IGF1/IGF1R and PDGF pathways, and increased nuclear DNA damage. Remarkably, Delta-24-RGD/ONC201 treatment in human pHGG and DMG xenograft-bearing mice showed a safe toxicity profile and a significant increase in the median overall survival compared to each agent alone. Combination treatment in murine DMG models revealed a reshaping of the tumor microenvironment towards a proinflammatory phenotype. We observed an increase in both lymphoid and myeloid lineage in the combined treatment versus either single treatment. Interestingly, Delta-24-RGD/ONC201 produces a higher activation in CD8+ T cells, higher activation and proliferation in CD4+ T cells, and less immunosuppressed regulatory T cells.

CONCLUSIONS
Our data supports that the Delta-24-RGD/ONC201 combination improved the efficacy compared to each agent alone by potentiating nuclear DNA damage and improving the antitumor (immune) response. Altogether, our results reveal the potential of this combination for future clinical trials.
HGG-29. INTEGRATED MOLECULAR PROFILING OF &gt;2000 PAEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMA TUMOURS AND &gt;100 PATIENT-DERIVED MODELS
Authors: Mackay Alan , Grabovska Yura , Carvalho Diana , Burford Anna , Pereira Rita , Temelso Sara , Sejdiu Drenusha , Crampsie Shauna , Molinari Valeria , Rogers Rebecca , Kessler Ketty , Bjerke Lynn , Bridges Les , Reisz Zita , Al-Sarraj Safa , Singh Navneet , Stapleton Simon , Bleil Cristina , Hittite Samantha , Debian Bassel , Cockle Julia , Carceller Fernando , Clarke Matthew , Jones Chris 
Published: June 2024

Abstract

BACKGROUND
Paediatric-type diffuse high-grade glioma (PDHGG) is recognised in the WHO2021 CNS Tumour Classification as biologically distinct from ‘adult-types’, and comprises four major categories based on distinct biology and clinical presentation, though sub-types within these are less well-defined.

METHODS
Published and unpublished genome/exome/targeted sequencing from n=1593 cases were integrated with n=2027 cases with methylation array profiling, with an overlap of n=761. These were supplemented with varying availability of bulk/single-cell RNAseq, ChIP-seq and ATAC-seq, and analysed alongside data from ~100 patient-derived models representing 16 PDHGG sub-types.

RESULTS
Around half of cases were diffuse midline glioma with H3K27 alterations (DMG-H3K27), which can be split into sub-types based upon either the specific histone alteration (DMG-H3.3K27M/-H3.1K27M/-EZHIP) or co-segregating pathway activating mutations (DMG-EGFR/-MAPK/-ACVR1). These showed distinct copy number, transcriptomic and epigenetic signatures depending on the anatomical location, replicated in ~50 models established as 2D/3D cultures and CDX/PDX. By contrast, diffuse hemispheric glioma with H3G34 mutations (DHG-H3G34) presented a homogenous genomic landscape (TP53/ATRX/PDGFRA) but with a higher degree of transcriptional diversity in both tumours and models. In high-grade glioma, H3/IDH-wild-type (HGG-WT) samples, receptor tyrosine kinase (RTK) subtypes are split by the presence or absence of co-segregating mutations (BCOR/SETD2/NF1) and copy number changes. Across methylation-based subtypes, genetic drivers are associated with distinct phenotypes or drug responses independent of location. EGFR mutations are largely confined to the highly infiltrative pedHGG_RTK2 hemispheric (enriched in gliomatosis cerebri) and DMG-EGFR (bithalamic glioma) subtypes, whilst PDGFRAmutations span DMG-H3.3K27M, DHG-H3G34, and pedHGG-RTK1, and exhibit a differential drug response to targeted therapies depending on the nature of the alteration. Hypermutant tumours are split between pedHGG-RTK1A and the emerging ‘HGG-E’ subtype.

CONCLUSIONS
These data aim to catalogue the diversity of PDHGG subtypes in order to identify biologically rational targets, and credential patient-derived models which can be exploited for mechanistic/preclinical studies.
HGG-41. COMBINATORIAL BH3-MIMETIC STRATEGY FOR OVERCOMING RADIORESISTANCE IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Madhavan Krishna , Donthula Sahiti , Walker Faye M , Sobral Lays Martin , Balakrishnan Ilango , Pierce Angela , Karam Sana D , Serkova Natalie J , Venkataraman Sujatha , Dahl Nathan A 
Published: June 2024

Abstract

BACKGROUND
High-grade gliomas (HGGs) are a leading cause of cancer-associated death in children. Radiation therapy (RT) continues to be the only standard-of-care treatment across HGG subtypes, but disease frequently recurs following only a transient response. We have recently identified that HGGs utilize the pro-survival BCL-2 family of proteins to evade cell death after radiation, and we demonstrated that effective inhibition of BCL-2 with the CNS-penetrant drug venetoclax could be utilized to disrupt this resistance and augment radiation-induced cell killing. While this treatment significantly prolonged survival in orthotopic mouse models of pediatric HGG, tumors invariably developed resistance to single-agent venetoclax and recurred.

METHODS
We profiled tumors from venetoclax-resistant animals for alternate BCL-2 family binding. We then assessed susceptibility to MCL1 inhibition in venetoclax-treated or treatment naïve culture models. Synergy was tested in vitro, and mitochondrial ROS production and induction of apoptosis was assessed using the MCL1-specific agent S63845. Finally, venetoclax and S63845 were tested in combination following fractionated radiotherapy in orthotopic models of DIPG.

RESULTS
MCL1 is an acquired dependency following treatment with RT + venetoclax. S63845 synergizes with venetoclax following RT to drive mitochondrial ROS production and apoptosis. The combination of venetoclax and S63845 significantly prolongs survival in xenograft models of DIPG.

CONCLUSIONS
Combinatorial targeting with BH3 mimetics augments radiation-induced cell killing and may open new therapeutic avenues for pediatric HGG.
HGG-43. DIFFUSE PEDIATRIC HIGH GRADE GLIOMA SUCCESSFULLY TREATED WITH MULTIMODAL THERAPY
Authors: Agarwal Vibhuti , Nagasubramanian Ramamoorthy , Maxwell Rochelle , Douglas-Lindsay Dorothea , Mercado Catherine , Hayes Laura , Chandra Tushar 
Published: June 2024

Abstract

BACKGROUND
Pediatric high grade glioma (HGG) have a dismal prognosis despite aggressive treatment. In this report, we discuss a patient with HGG successfully treated with combination of resection, radiotherapy, chemotherapy, and biologic therapy.

RESULTS
An 8-year-old male presented with intermittent headaches, vomiting and fatigue. Imaging demonstrated four solid/cystic enhancing intra-axial lesions within the left cerebral hemisphere- two within the left frontotemporal region, one in the superior parietal region, and one in the temporal lobe, all with perilesional edema and resultant subfalcine herniation with midline shift. The patient underwent subtotal resection of the frontotemporal and parietal lesions. Histopathology was consistent with glioblastoma. Whole exome sequencing revealed alterations in TP53, ATRX, PTEN, TSC2 as well as subclonal mutation in NF1. The tumor was unable to be further classified by DNA methylation. However histopathologic and molecular findings support the diagnosis of diffuse pediatric-high grade glioma, H3-wildtype and IDH-wildtype. The patient received adjuvant 59.4 Gy focal proton therapy with concurrent temozolomide and maintenance chemotherapy with temozolomide and lomustine for 6 cycles. End of therapy imaging demonstrated complete resolution of all sites of disease. Due to high likelihood of recurrence, the patient was subsequently started on targeted therapy with everolimus and ribociclib which continue to be well tolerated without dose adjustments. The patient remains stable and without recurrence 2.5 years since diagnosis, and 15 months since initiation of biologic therapy. Additionally, the patient underwent testing for cancer predisposition which revealed presence of TP53 heterozygous mutation consistent with Li-Fraumeni syndrome. The patient remains without other malignancies on surveillance imaging per LFS guidelines.

CONCLUSION
Our case report illustrates the value of both chemotherapy and biologic therapy in treatment of HGG. In addition to this, it emphasizes the importance of germline testing for cancer predisposition in patients with high grade tumors.
HGG-48. THE BLOOD-BASED TELOMERIC DNA C-CIRCLE ASSAY CAN DETECT ALTERNATIVE LENGTHENING OF TELOMERES (ALT) IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Lehman Tenley E , Deal Jenna L , Lee Jihyun , Foster Jessica B , Koptyra Mateusz P , Burrow Trevor A , Koneru Balakrishna , Cole Kristina A , Reynolds C Patrick 
Published: June 2024

Abstract

BACKGROUND
High-grade gliomas (HGG) comprise ~10% of pediatric brain tumors; 40% of pediatric HGG use the alternative lengthening of telomeres (ALT) mechanism to maintain replicative immortality. ALT cancers share a unique biology providing potential therapeutic targets. Extrachromosomal telomere DNA repeats, termed C-circles, can be detected by a unique PCR assay, providing a sensitive and specific biomarker for ALT cancers. C-circles have been detected in ALT tumors and serum of ALT patients. We have adapted the C-circle assay (CCA) to provide a sensitive and specific assay with cfDNA in patient plasma. Here we determined if cfDNA in plasma can be used to detect patients with ALT-positive HGG.

METHODS
Frozen plasma samples were collected in Streck tubes at time of surgery prior to resection from patients with HGG. DNA was extracted and quantified. Isothermal rolling C-circle amplification and real-time telomere PCR was performed followed by analysis. The C-circle positive neuroblastoma cell line, CHLA-90, and C-circle negative neuroblastoma cell line, CHLA-20, served as the positive and negative controls respectively. CCA values in plasma of 2 and above indicate positivity for C-circles.

RESULTS
Plasma samples were analyzed by CCA from three pediatric patients whose brain tumors were previously biopsied and identified as ATRX mutation positive. ATRX mutation indicates ALT however, not all ALT cancers have ATRX mutations. All plasma samples were above the 2.0 cutoff at 3.37, 3.13, and 4.59 and thus classified as C-circle positive.

CONCLUSIONS
This preliminary cohort shows that the CCA has potential for identifying ALT pediatric brain tumors using cfDNA from plasma. As novel therapies effective against ALT HGG are developed, the plasma CCA may allow accelerated initiation of neoadjuvant therapy to shrink tumor prior to surgical resection and lessen or prevent the need for tumor biopsy. Expansion of the initial test cohort is underway. Supported by NCI UO1 CA63988.
HGG-49. INTERNEURONS THAT BITE: A CELLULAR DELIVERY SYSTEM FOR PEDIATRIC HIGH-GRADE GLIOMA
Authors: Brosius Stephanie N , Manley William , Harvey Kyra , Galanaugh Jamie , Labella Kay , Liou Angela , Anderson Stewart , De Raedt Thomas 
Published: June 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.