bluuebunny/crossref_metadata_2025_split huggingface dataset:
DIPG-25. MAPPING TUMOR MICROENVIRONMENT USING EMERGING TECHNOLOGIES FOR PEDIATRIC BRAIN CANCERS
Authors: Laternser Sandra , Petrovic Antonela , Eze Augustine , Dettwiler Susanne , Prutek Fabiola , Contini Paola Agata , Morinigo Denise , Bornhorst Miriam , Rushing Elisabeth Jane , McDonough Elizabeth , Surrette Christine , Ginty Fiona , Minnis Hanna , Gartrell Robyn , Müller Sabine , Packer Roger , Nazarian Javad 
Published: June 2023

Abstract
Diffuse midline glioma (DMG) is a fatal childhood brain cancer with a survival rate of less than one year from diagnosis. Pharmacological approaches as well as immunotherapy have failed to make a clinical impact. Incomplete understanding of the tumor microenvironment (TME) and tumor associated antigens have contributed to the observed poor prognosis. We hypothesize that characterization of the DMG TME will identify biology-informed targeted treatments. We thus obtained postmortem specimens from 70 patients diagnosed with brain cancers, including 50 DMGs, 20 other types and 10 non-CNS-cancer patients. Up to four anatomical brain locations were selected including the primary tumor, metastatic and adjacent healthy sites. Formalin-fixed-paraffin-embedded (FFPE) specimens were processed for constructing a tissue microarray (TMA). The TMA was stained for a number of markers (H&E, H3K27M, H3K27me3, KI67) and was scored by a neuropathologist. We then used a multiplexed immunofluorescence (MxIF) technology, Cell DIVE™, to iteratively probe 33 biomarkers on a single tissue slide, focusing on immune cell type profiling and activation, and histone mutation status. Analysis of biomarker density and spatial relationships are underway. The main expressed immune markers across all patients were CD163, CD68, and CD8. CD8, a cytotoxic T-cell biomarker, was highly detected in pons, cerebellum, thalamus and the frontal lobe (tumor and healthy) of DMG patients and varied according to clinical intervention, including ONC201 treatment. Furthermore, in comparison to other tumors, DMGs exhibited a higher expression of CD3, T- cell marker, and CD4, a T-helper cell biomarker. Analysis of Iba1, a microglial marker, confirmed a higher difference in microglial activation in primary tumor compared to metastatic and adjacent healthy tissue. In contrast, CD68 was significantly increased in metastatic sites. Analysis is still ongoing. We report establishment of the most comprehensive TMA for pediatric brain tumors, which provides insights into TME comparing critically important clinical variables.
DIPG-52. EXTRAPONTINE PROGRESSION WITH STABLE PONTINE DISEASE POST-RADIOTHERAPY IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) ON A CONNECT TRIAL: IMPLICATIONS FOR RADIATION TREATMENT VOLUMES
Authors: Lazow Margot , Palmer Joshua , Stanek Joseph , Baxter Patricia , Thomas Diana , Salloum Ralph , de Blank Peter , Mikael Leonie , Kumar Shiva Senthil , Leonard Jeffrey , Mardis Elaine , Drissi Rachid , Fouladi Maryam , Rodriguez Diana 
Published: June 2023

Abstract
Radiotherapy remains the only treatment modality proven to prolong survival and alleviate symptom burden for patients with DIPG. Upfront focal photon radiation to 54 Gy with 1-1.5cm margins is standard. Subventricular, leptomeningeal, and/or spinal dissemination is observed in up to 50% of cases at autopsy, with activation of metastasis-related pathways (eg, epithelial-mesenchymal transition) in a subset of tumors. Given potential for metastatic spread and critical implications for radiation field volumes, we analyzed the frequency of extrapontine disease progression with pontine tumor stability within a prospective cohort with standardized longitudinal imaging. In a CONNECT consortium-sponsored phase Ib trial with a radiosensitizing agent administered concurrently with focal radiation and adjuvantly, among 10 patients with DIPG who experienced progressive disease with available serial imaging, four (40%) had evidence of disease extension and/or non-contiguous dissemination with stable pontine tumor size at a median of 9 months (range: 5-15 months) from diagnosis. Specifically, extrapontine progression was observed in the spinal cord (n=3), cerebellum (n=2), basal ganglia (n=1), temporal lobe (n=1) and/or leptomeninges and ependymal surfaces (n=1), without radiographic pontine disease progression. Five of the remaining six patients (who came off treatment due to pontine progression) subsequently had radiographic evidence of extrapontine extension (cerebellar, spinal, thalamic, supratentorial). Comprehensive molecular profiling is underway on biopsy or autopsy specimens for three patients, focusing on metastasis pathways. In summary, within a small prospective cohort with longitudinal imaging, we observed extrapontine progression despite local pontine disease control following focal radiotherapy in 40% of patients with DIPG at a median of 9 months after diagnosis. Further research will be essential to identify biological predictors of dissemination and corroborate findings in a larger cohort, but results suggest at least a subset of patients with DIPG may benefit from larger radiation volume expansion into contiguous structures and white matter tracts.
EPEN-05. TRANSCRIPTIONAL FACTOR-DIRECTED EPIGENETIC REGULATION IN CANCER NEUROSCIENCE OF ZFTA-RELA EPENDYMOMA
Authors: Chen Hsiao-Chi , McDonald Malcolm , Varadharajan Srinidhi , Sardar Debosmita , Mack Stephen C , Deneen Benjamin 
Published: June 2023

Abstract
ZFTA-RELA (ZRFUS) ependymoma is a pediatric brain tumor with dismal 10-year progression free survival rates. Prior studies revealed low somatic mutation load in pediatric ependymoma compared to adult glioma, suggesting that developmental mechanisms play a key role during disease development. Using human tissues and mouse tumors generated from our autochthonous in utero electroporation (IUE) model, we identified a cohort of developmental transcription factors (TFs) linked to ZRFUS by investigating histone serotonylation changes with other epigenetic datasets. We further performed in vivo barcode-screening and identified the ETS variant transcription factor 5 (ETV5) is sufficient and required for disease progression. To further reveal the disease mechanism driven by ETV5, we applied transcriptomic, epigenetic, and proteomic analyses, and found ETV5 suppresses neuropeptide Y (NPY) expression in mouse ZRFUS tumors by binding with epigenetic modulator, chromobox 3 (CBX3). We further found NPY overexpression delays tumor progression and suppressed tumor-driven neuronal activity in mice. This study suggests developmental TF can shape tumor-promoting microenvironment during disease progression through epigenetic regulation.
EPEN-13. PATTERN OF RELAPSE IN POSTERIOR FOSSA EPENDYMOMA GROUP A
Authors: Bajin Inci Yaman , Zapotocky Michal , Bartels Ute , Tabori Uri , Huang Annie , Tsang Derek , Laperierre Normand , Dirks Peter , Laughlin Suzanne , Bouffet Eric , Ramaswamy Vijay 
Published: June 2023

Abstract

PURPOSE/OBJECTIVE
Posterior fossa ependymoma group A (PF-EPN-A) is a poor prognostic ependymoma subgroup, predominantly seen in infants and young children. Among all ependymomas, most of the recurrences are seen in patients with the PF-EPN-A subgroup. Despite advances in neurosurgery and postoperative adjuvant therapy, management of these tumors remains challenging, and recurrence occurs in over 50% of cases. In this study, we aimed to evaluate the pattern of relapse in PF-EPN-A.

MATERIALS AND METHODS
The clinical features, treatment strategies and relapse patterns of patients diagnosed and treated with PF-EPN-A at the Hospital for Sick Children, Toronto have been evaluated retrospectively.

RESULTS
Seventy-five patients were diagnosed with PF-EPN-A at the Hospital for Sick Children, Toronto from 01 June 1996 to 01 June 2022. All patients were treated with surgery +/- focal radiation +/- chemotherapy after diagnosis. Out of 75 patients, 38 (50.6%) had recurrent disease. Twenty-three patients (60.5%) had a local relapse while 15 patients (40.5) experienced a distant relapse. Out of 23 patients who had a local relapse, only 8 patients (34%) developed a local relapse after a gross total resection (GTR). Other 15 patients developed a local relapse after either subtotal (STR) or near total resection (nTR). Out of 15 patients who experienced a distant relapse, 10 patients (66%) developed a distant relapse after GTR. Time to relapse was mean 32 months (11-132 months) after GTR and 24 months (1-98 months) after STR /nTR.

CONCLUSIONS
The modern management approach (more aggressive resection and early conformal radiotherapy) changed the relapse pattern and the classical dogma that “nearly all relapses in ependymoma are local’’ in modern series. This study supported the importance of GTR in the management of PF-EPN-A and also demonstrated that PF-EPN-A tends to recur more on distant sites rather than locally when the initial surgical intervention is a GTR.
METB-03. THE DISTINCT GENOMICS OF HIGH-GRADE INFANT GLIOMAS AMONG PEDIATRIC GLIOMAS HARBORING RECEPTOR TYROSINE KINASE FUSIONS
Authors: de Biagi-Junior Carlos A O , Eder Sebastian K , LaBelle Jenna , Filbin Mariella G 
Published: June 2023

Abstract
Gliomas account for about 60% of pediatric brain tumors, about half of which are classified as high-grade. Recent studies have shown that infants with high-grade gliomas (HGG) harboring receptor tyrosine kinase (RTK) fusions have a more favorable prognosis than pediatric HGG patients. The molecular mechanisms for this favorable, but from the histology divergent clinical outcome, are yet unknown. We analyzed n=18 brain tumor samples (n=7 infant, n=11 pediatric) of patients with low-grade glioma (LGGs) or HGG presenting with RTK fusions using single-cell RNA sequencing. Considering the different fusion genes (ALK n=6, NTRK n=8, and MET n=4), age groups, and glioma grades, we evaluated the metaprograms of tumor cells and their proportions using non-negative matrix factorization. Preliminary results show similar metaprograms comparing infant and pediatric LGG. Cells detected as MES-like did not occur in LGG but were found in several HGG samples. However, in HGG, the MES-like cells show different expression patterns for infant and pediatric samples. In addition, compared with pediatric HGG, infant HGG has a higher proportion of programs that are predominantly present in LGG, such as AC-like and NPC-like. These initial findings serve as a starting point for cell type-specific transcription factor regulatory networks and are an important step toward understanding the underlying biology of this distinct pediatric brain tumor entity.
RARE-04. DEVELOPMENT OF A PLATFORM TO PROFILE MICRORNA IN CEREBROSPINAL FLUID FROM PATIENTS WITH INTRACRANIAL GERM CELL TUMORS
Authors: Gell Joanna , Therieault Jody , Ng Patrick , Lau Ching 
Published: June 2023

Abstract

BACKGROUND
Current diagnosis of intracranial germ cell tumors (iGCTs) utilizes alpha fetoprotein (AFP) and chorionic gonadotropin (β-HCG) as biomarkers in the blood or cerebrospinal fluid (CSF). Two thirds of iGCTs are marker negative and AFP/HCG are not specific to iGCTs. Thus, there is a need to develop other biomarkers to improve the diagnosis of iGCT. Two microRNA (miRNA) clusters, miR-371-373 and miR-302/367 have previously been identified as biomarkers for extracranial GCTs and preliminary data from our lab and others confirmed their potential utility in iGCTs. However, the optimal way to profile miRNAs in CSF is not fully established. Two commonly used methods are real-time polymerase chain reaction (qPCR) or droplet digital polymerase chain reaction (ddPCR).

METHODS
CSF samples were obtained from biorepositories at Connecticut Children’s and through the Children’s Brain Tumor Network. Cell culture media from an embryonal carcinoma cell line was used as positive control. MicroRNA was extracted from 50uL of CSF, reverse transcribed into cDNA and pre-amplified. Samples were then diluted 1:5 for qPCR and 1:10 or 1:50 for ddPCR.

RESULTS
We profiled the CSF from 6 germinomas and 4 non-germinomatous, including two mature teratomas. Additionally, we profiled CSF from two non-iGCT brain tumors and two leukemia patients, as non-iGCT controls. For qPCR, raw CT values were evaluated with CT &lt;35 considered detectable. Both platforms, qPCR and ddPCR were able to detect miR-371-373 and miR-302/367 in malignant iGCTs, including marker negative germinomas. miR-302/367 cluster showed varying expression in non-iGCT samples.

CONCLUSIONS
We were able to use low input (50uL) of CSF to identify markers of malignant iGCT, the microRNA clusters miR-371-373 and miR-302/367. Both platforms were able to identify the microRNAs. More samples will need to be profiled to evaluate which platform ddPCR or qPCR is best to move forward towards a clinically validated platform.
OUTC-08. IMPLEMENTING SOCIAL DETERMINANT OF HEALTH DATA COLLECTION FOR PEDIATRIC, ADOLESCENT AND YOUNG ADULT NEURO-ONCOLOGY PATIENTS IN THE CLINICAL TRIAL CONSORTIA SETTING: PROGRESS AND CHALLENGES
Authors: Puthenpura Vidya , Bona Kira , Cooney Tab , Coven Scott , Davidson Tom , Fouladi Maryam , Kline Cassie , Leary Sarah , Mueller Sabine , Green Adam , Marks Asher 
Published: June 2023

Abstract
Adverse social determinants of health (SDoH) are associated with decreased survival and increased long-term complications amongst pediatric and adolescent and young adult (AYA) neuro-oncology patients. These outcome disparities are in part due to inferior access to clinical trials and comprehensive, multidisciplinary care. SDoH including food insecurity, housing instability, inability to pay for utilities, and personal safety issues have been shown to negatively impact therapy adherence and exacerbate survival disparities. As such, efforts to improve health equity must include evaluating and addressing SDoH at diagnosis. Existing literature has been limited by a reliance on proxy measures of adverse SDOH such as neighborhood or census area-level socioeconomic status data, which poorly reflect individual circumstances. There is a complex interplay between neighborhood and personal socioeconomic status that has not been extensively studied and is poorly understood. In addition, socioeconomic status is only one component of SDoH. No validated tool currently exists to assess SDoH amongst pediatric and AYA cancer patients. It is imperative that multicenter clinical trials collect SDoH data to inform both trial design and interpretation of results. These data will be important to understanding and identifying patterns in tumor and toxicity incidence, as well as understanding the burden on families in adhering to trial therapies. Based on our previous work, we will present the importance of incorporating SDoH data collection within the clinical trial consortia setting. In addition, we will review the development of a comprehensive SDoH questionnaire and discuss facilitators and barriers to the incorporation of SDoH questionnaires into multicenter clinical trials and offer solutions based on our experience.
HGG-01. INFANT-TYPE HEMISPHERIC GLIOMA: NEW MOLECULAR ALTERATIONS AND PRECISION-MEDICINE TREATMENT
Authors: Hu Wanming , Yuan Li , Zeng Jing 
Published: June 2023

Abstract

Introduction
Infant-type hemispheric glioma, harboring alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET, is a new subtype of Pediatric-type diffuse high-grade gliomas in the 2021 WHO classification of CNS tumors. It has important clinical therapeutic value with specialized therapeutic drugs. Here, we presented 3 cases of infant-type hemispheric glioma. Patient1 with EML4-ALK fusion which often appeared in lung cancer, the other 2 patients have new molecular alterations which has not been reported before (Patient2 has both NTRK1-TP53/TP53-NTRK1 fusions and p53 protein showed characteristic cytoplasm positive; Patient3 presented a brand-new ALK-QKI fusion combined with ALK mutation and focal SMARCB1 deletion. All these 3 cases received corresponding targeted therapy and have a good recovery and normal neurologic function till now.

Methods
Immunohistochemistry. Fluorescent in situ hybridization. Whole-transcriptome sequencing.

Results
Case 1: 8 months, male, right semiovale center occupation.

HISTOPATHOLOGY
High-grade neuroepithelial neoplasm. IHC: GFAP (only few cells+), Olig2(-), S100(+), CD56(+), Syn(-), NSE(focal+), NeuN(-), CD34(-), INI-1(+), Ki67(10%+). Characteristic Molecular Information: EML4-ALK fusion. Follow-up: 15 months, alive. Case 2: 3 years, female, insular lobe occupation.

HISTOPATHOLOGY
Gliosarcoma. IHC: GFAP(partly+), Olig2(partly+), Vimentin(+), P53(cytoplasm+), pan-TRK(+), Ki67(25%+). Reticular fiber staining showed biphasic tissue pattern with reticulin-rich sarcomatous and reticulin-free gliomatous elements. Characteristic Molecular Information: NTRK1-TP53 and TP53-NRTK1 fusion. Follow-up: 27 months, alive. Case 3: 3 years, male, left parietal occipital lobe occupation.

HISTOPATHOLOGY
GBM and AT/RT. IHC: GFAP(partly+), Olig2(partly+), INI-1(partly-), BRG1(+), SYN(-), CD34(-), BRAF(-), S100(-), CK(-), H3K27M(-), IDH1(-), P53(40%+), ATRX(+), pan-TRK(-), ALK(+), Ki67(30%+). Characteristic Molecular Information: ALK mutation, ALK-QKI fusion, RAD51C mutation and focal SMARCB1(INI-1) deletion. Follow-up: 14 months, alive. Conclusion: Infant-type hemispheric glioma is a special kind of glioma, which is particularly suitable for precision-medicine treatment approaches. Their overall survival is good compared with other three pHGG subtype.
HGG-08. COMBINATORIAL ACTIVITY OF CDK4/6-INHIBITORS AND TRAMETINIB IN PEDIATRIC HIGH-GRADE GLIOMA WITH BRAFV600E MUTATION AND HOMOZYGOUS CDKN2A DELETION
Authors: Mayr Lisa , Mager Leah , Gabler Lisa , Madlener Sibylle , Berger Julia , Kirchhofer Dominik , Lämmerer Anna , Bruckner Katharina , Lötsch Daniela , Berger Walter , Gojo Johannes 
Published: June 2023

Abstract
BRAFV600E mutations occur in 10-15% and homozygous CDKN2A deletions in approximately 40% of adolescent and pediatric high-grad glioma (HGG) and is associated with significantly decreased overall survival. Moreover, a subset of pHGG is defined by combined BRAFV600E mutation and concomitant CDKN2A homozygous deletion. Standard therapy has remained unchanged and consists of maximal safe resection and focal radiotherapy still resulting in poor overall survival. Therefore, new therapeutic approaches to increase patient survival are of utmost importance. Targeted therapy of BRAFV600E mutant HGG has emerged as effective treatment but remains challenging due to therapy resistance. CDK4/6 inhibitors represent a promising target in CDKN2A altered HGG. However, palbociclib demonstrated only low efficacy in HGG patients. Therefore, combination approaches may be more effective, and we investigated CDK4/6-inhibitors alone and in combination with trametinib in HGG cell models with BRAFV600E mutation and homozygous CDKN2A deletion.
Efficacy of CDK4/6-inhibitor monotherapy and combinatorial approach with trametinib was assessed by short- and long-term viability assays in four patient-derived HGG cell models with homozygous CDKN2A deletion and BRAFV600E mutation. Furthermore, effects of CDK4/6 inhibitor therapy alone or in combination with trametinib on downstream signaling pathways (MAPK, PI3K) were analyzed with Western blots.
Abemaciclib showed the highest activity in all cell models with IC50-values ranging from 0,5 – 2µM. Combined treatment approaches with trametinib showed synergistic effects across all cell models. Long-term viability assays revealed distinct sensitivity in the nanomolar range for CDK4/6-inhibitors and combined treatment with trametinib in all cell models. Exposure to abemaciclib and trametinib significantly decreased pRB, pERK, pS6, and pAKT protein expression levels when compared to monotherapy alone.
Summarizing, combined treatment with CDK4/6-inhibitors and trametinib showed promising therapeutic effects on HGG models with homozygous CDKN2A deletion and BRAFV600E mutation. Currently, effects on cell cycle distribution and downstream molecular mechanisms are investigated to identify potential predictive biomarkers.
HGG-17. SINGLE-CELL AND SPATIAL ANALYSES DECIPHER THE UNIQUE INVASIVE GROWTH PATTERN OF GLIOMATOSIS CEREBRI
Authors: Crampsie Shauna , Liu Ilon , Petrilli Lucia Lisa , Mackay Alan , Spinozzi Giulio , Grabovska Yura , Hack Olivia A , Kessler Ketty , Temelso Sara , Carvalho Diana Martins , Burford Anna , Sejdiu Drenusha , Molinari Valeria , Shaw McKenzie L , Mire Hafsa M , Pericoli Giulia , Cerimele Alfredo , Barry Clémentine , Cocito Carolina , Debily Marie-Anne , Kergrohen Thomas , Ajlil Yassine , Beccaria Kévin , Varlet Pascale , Tauziède-Espariat Arnault , Mastronuzzi Angela , Carai Andrea , Giovannoni Isabella , Rossi Sabrina , Miele Evelina , Grill Jacques , Jacques Thomas S , Greenfield Jeffery P , Castel David , Vinci Maria , Filbin Mariella G , Jones Chris 
Published: June 2023

Abstract
Gliomatosis cerebri (GC) is a rare, lethal glioma that is radiologically diagnosed and characterised by its diffuse infiltration throughout the cerebral lobes of the brain. It is no longer recognised as a separate entity by the WHO classification, but its growth pattern and invasive phenotype differ from other types of glioma. In order to understand what underlies this unique presentation, we sought to unravel these complex tumours in children through single cell and spatial approaches. 26 paediatric cases (1.3-19 years, median=11.3) were collected for DNA methylation, whole exome sequencing and single cell RNA-sequencing. Of these, 16 cases were used for Imaging Mass Cytometry (IMC). 5 patient-derived cell lines were used to model migration and invasion in vitro, whereby we have also been able to explore gene expression differences associated with the invading cells by RNAseq. We analyzed the transcriptional landscape of all 26 GC patients at single-cell resolution, and identified shared tumor cellular programs of glial and neuronal lineage. We observed notable heterogeneity of neuronal lineage tumor cells that were composed of different states, such as metabolic active and synaptogenic states. We described tumor cell states associated with higher invasivity, as corroborated from integrated analysis with our in vitro invasion-associated gene expression profiles. Next, we stratified all tumors by their DNA methylation profiles, and defined 16 archetypal GC cases, for which we show specific transcriptional features. Furthermore, we analyzed multiple regions of interest within FFPE patient tissue sections by IMC and demonstrate spatial patterns in the interaction between the tumour and normal brain tissue interface, and inter-regional heterogeneity for stem, invasive and proliferative markers. Together, we dissect the characteristic invasive phenotype of GC at multiple molecular, spatial and functional layers, thereby providing the basis for modelling and therapeutic avenues much needed for this lethal disease.