bluuebunny/crossref_metadata_2025_split huggingface dataset:
GCT-07. Central nervous system germ cell tumors of children in Slovakia from 2000 to 2020
Authors: Hederova Stanislava , Mocna Andrea , Bublakova Estera , Ballova Anna , Husakova Kristina , Stancokova Terezia , Deak Ladislav , Kolenova Alexandra 
Published: June 2022

Abstract
INTRODUCTION: Central nervous system germ cell tumors (CNS GCTs) are very heterogenous group of tumors, which are divided into two main subgroups - germinomas and non- germinomatous germ cell tumors (NGGCTs). NGGCTs consist of embryonal carcinomas, yolk sac tumors, choriocarcinomas, and teratomas - mature, immature, or with malignant transformation, as well as mixed types. CNS GCTs are rare tumors, accounting approximately for 4-5% of all brain tumors in children, with a peak of incidence between the ages of 10 and 15 years, affecting predominantly boys. METHODS: Retrospective study of a cohort of 34 patients, age 0-18 years old, with CNS germ cell tumors diagnosed and treated in one of three Slovak pediatric oncology centers over a 21-year period from 01/2000 to 12/2020. Treatment was done according to the SIOP strategy. RESULTS: Out of 34 patients 15 patients were treated in the largest center, in Bratislava and 19 patients in the remaining 2 centers. Germinomas occurred in 16 (47.1%) and non-germinomatous germ cell tumors in 18 (52.9%) patients, 7 of whom had teratomas. In our cohort, 24 patients (70.6%) survived with an average follow-up age of 8.5 years. Twenty two patients remain in the 1st remission of the disease, 2 patients got through after disease recurrence. Ten patients (29.4%) died, 9 patients due to disease progression and 1 patient due to treatment complications. CONCLUSION: The overall survival of children with CNS GCT is most dependent on the histologic subtype of the tumor. Overall survival in children with germinomas reaches 90% and with NGGCTs around 60-70%, depending on the extent of the disease. In our cohort, we have achieved 70.6% 5 year overall survival of patients.
HGG-06. Phase 2 Study of Veliparib and Local Irradiation, Followed by Maintenance Veliparib and Temozolomide, in Patients with Newly Diagnosed High-Grade Glioma without H3 K27M or BRAF Mutations: A Report from the Children's Oncology Group ACNS1721 Study
Authors: Karajannis Matthias , Onar-Thomas Arzu , Baxter Patricia , Butingan Nina , Fuller Christine , Gajjar Amar , Haque Sofia , Jabado Nada , Lin Tong , Lucas John , MacDonald Shannon , Matsushima Celeste , Patel Namrata , Pierson Christopher , Springer Linda , Stark Eileen , Souweidane Mark , Walsh Michael , Zaky Wafik , Fouladi Maryam , Cohen Kenneth 
Published: June 2022

Abstract
BACKGROUND: The outcome for pediatric patients with high-grade glioma (HGG) remains poor. Veliparib, a potent oral PARP1/2 inhibitor, enhances the activity of radiotherapy and DNA-damaging chemotherapy. Preclinical data indicates that veliparib crosses the blood-brain-barrier and enhances the efficacy of radiotherapy and temozolomide in IDH mutant and wild-type HGG models. ACNS1721 was a single-arm, non-randomized phase 2 clinical trial designed to determine whether treatment with veliparib and radiotherapy, followed by the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib and temozolomide, improves progression-free survival (PFS) in pediatric patients with newly diagnosed HGG without H3 K27M or BRAF mutations compared to patient level data from historical cohorts with closely matching clinical and molecular features. METHODS: Following surgical resection, newly diagnosed children with non-metastatic HGG were screened by rapid central pathology review and molecular testing. Eligible patients without somatic H3 K27M or BRAF mutations were enrolled on Stratum 1 (IDH wild-type) or Stratum 2 (IDH mutant). Protocol radiochemotherapy consisted of involved field radiotherapy with concurrent veliparib at 65 mg/m2 twice daily. Adjuvant chemotherapy consisted of up to 10 cycles of veliparib 25 mg/m2 twice daily and temozolomide 135 mg/m2 once daily for 5 days every 4 weeks. RESULTS: Both strata were closed to accrual for futility after planned interim analyses. Among the 23 eligible patients who enrolled on Stratum 1 and received protocol therapy, the 1-year progression-free survival (PFS) was 0.29 (SE = 0.09) and 1-year overall survival (OS) was 0.67 (SE = 0.10). Among the 14 eligible patients who enrolled on Stratum 2 and received protocol therapy, the 1-year PFS was 0.57 (SE = 0.15) and 1-year OS was 0.90 (SE = 0.09). CONCLUSION: Rapid central pathology review and molecular testing was feasible. The protocol therapy was well tolerated but failed to improve outcome compared to clinically and molecularly matched historical control cohorts.
HGG-14. Molecular characterization of unique biological subgroups among H3 wild type high-grade gliomas
Authors: Vanova Katerina , Krskova Lenka , Vicha Ales , Sumerauer David , Zamecnik Josef , Koblizek Miroslav , Libý Petr , Benes Vladimir , Malinova Bela , Zapotocky Michal 
Published: June 2022

Abstract
INTRODUCTION: Paediatric high-grade gliomas (HGG) are characterised by the aggressive biological behaviour with dismal prognosis of long-term survival 10-15%. Current molecular-biological diagnostic approaches allow for more precise characterization and determination of new unique subgroups of HGG. Our aim was to identify novel and rare HGG subgroups within our institution cohort. PATIENTS AND METHODS: Our reference centre patients′ cohort consisted of 97 clinically annotated patients with HGG diagnosed between 2000 and 2021. Sanger sequencing was used for screening of the most common HGG-related oncogenic drivers; furthermore we employed whole genome methylation array (Illumina Infinium MethylationEPIC BeadChip) and for selected samples RNA sequencing and expression profiling. RESULTS: Based on H3 status and previous radiotherapy we separated our HGG cases into the RIG, H3mut and H3wt groups. In contrast to H3mut(n=35) and RIG(n=11) that were uniformly fatal, H3wt group contained a proportion of long-term survivors. In the H3wt group we found patients carrying driver mutations in IDH1/2 (n=2) and BRAFV600E (7). Five young patients (under 3) consisted of 3 infant hemispheric gliomas (with NTRK and ROS1 fusions), one gliomatosis cerebri and one brainstem anaplastic astrocytoma with MYB/QKI fusion. We also identified a rare EWSR1-PATZ1 gene fusion in one patient. Importantly, long-term survivors recruited from these subgroups. On the contrary, four cases of MYCN GBM with poor prognosis presented in various locations: one disseminated, one gliomatosis cerebri and two with hemispheric tumour. We identified one patient with “hypermutated” glioblastoma and used targeted therapy with Nivolumab. In three samples of our patients with thalamic glioblastomas, we detected “loss of H3K27-trimethylation” caused by EZHIP overexpression. These tumours proved to be very aggressive with early metastatic recurrence and dismal prognosis. SUMMARY: Detailed characterization of H3 wild-type HGG is very important for further understanding of their biological behaviour, diagnostics, prognostication and identification of therapeutic targets.
HGG-15. Generation of a novel mouse model for brain tumors of the DNA methylation class “GBM MYCN”
Authors: Schoof Melanie , Godbole Shweta , Walter Carolin , Dottermusch Matthias , Albert Thomas , Ballast Annika , Göbel Carolin , Neyazi Sina , Holdhof Dörthe , Kresbach Catena , Blattner-Johnson Mirjam , Modemann Franziska , Afflerbach Ann-Kristin , Eckhardt Alicia , Struve Nina , Jones David , Kerl Kornelius , Neumann Julia E , Schüller Ulrich 
Published: June 2022

Abstract
Multiple recent publications have described a highly aggressive subgroup of pediatric glioblastoma, which is clearly separable from other pediatric and adult glioblastoma based on its DNA methylation profile (GBM MYCN). These tumors almost exclusively occur in children and have a median overall survival of only 14 months. Many tumors in this group are driven by MYCN amplifications and harbor TP53 mutations. Otherwise, information about these tumors are still sparse and treatment is ineffective and causes severe side effects in many cases. In order to further investigate the biology and treatment options of these tumors, preclinical models are urgently needed. Here, we describe the generation of hGFAP-cre::TP53Fl/Fl::lsl-MYCN mice, which carry a loss of TP53 and show aberrant MYCN expression in neural precursors of the central nervous system. These animals develop large forebrain tumors within the first 80 days of life with 100 % penetrance. These tumors resemble human GBM MYCN tumors by histology, global gene expression, and DNA methylation. In order to understand the developmental biology and intratumoral heterogeneity, we employed single cell RNA sequencing (scRNAseq) to the murine tumors with first results indicating a resemblance of tumor cells to committed oligodendrocyte precursors. We further show that both murine and human tumor cells are sensitive to AURKA inhibition in vitro, suggesting a potential new therapeutic option for improved patient care. We believe that further characterization and utilization of the model will pave the way to improved treatment strategies for patients with these highly aggressive tumors.
HGG-18. Long-term efficacy and safety of larotrectinib in paediatric patients with tropomyosin receptor kinase (TRK) fusion-positive primary central nervous system (CNS) tumours
Authors: Nysom Karsten , Doz François , Geoerger Birgit , Øra Ingrid , Perreault Sebastien , Norenberg Ricarda , Fellous Marc , De La Cuesta Esther , Laetsch Theodore W , van Tilburg Cornelis M 
Published: June 2022

Abstract
INTRODUCTION: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various tumours. Larotrectinib, a highly selective TRK inhibitor, demonstrated an objective response rate (ORR) of 75% across 206 evaluable patients with various non-primary CNS cancers (Hong et al, ASCO 2021). We report long-term data on larotrectinib-treated paediatric patients with TRK fusion-positive primary CNS tumours. METHODS: Patients aged &lt;18 years with TRK fusion-positive primary CNS tumours enrolled in two clinical trials (NCT02637687, NCT02576431) were included. Larotrectinib was administered at 100 mg/m2 (maximum: 100 mg) twice-daily. Response was investigator-assessed per RECIST v1.1 and RANO. RESULTS: As of July 2021, 28 patients with TRK fusion-positive primary CNS tumours were enrolled, including 14 high-grade and eight low-grade gliomas. Median age at enrolment was 7.0 years (range 1.0–17.0). Twenty-three patients (82%) received prior systemic therapy and 12 (43%) received prior radiotherapy. The ORR was 39% (95% confidence interval [CI] 22–59): three complete responses, eight partial responses, 15 stable disease and two progressive disease. The 24-week disease control rate was 82% (95% CI 63–94). Median duration of response (DoR) was not reached; median follow-up was 25.6 months. Median progression-free survival was 21.9 months (95% CI 9.2–not estimable). Median overall survival (OS) was not reached; median follow-up was 27.6 months. DoR and OS 24-month rates were 53% and 71%, respectively. Treatment duration ranged from 1.0 to 39.0+ months. Treatment-related adverse events (TRAEs) were mostly Grade 1–2. Grade 3–4 events occurred in three patients (increased gamma-glutamyltransferase, hyperglycaemia, hypernatraemia, hyponatraemia and neutropaenia). No patients discontinued treatment due to TRAEs. Fourteen patients progressed on treatment; four continued treatment post-progression for ≥4 weeks. CONCLUSION: Larotrectinib demonstrated high disease control rate, durable responses and a manageable safety profile. These results support testing for NTRK gene fusions in paediatric patients with primary CNS tumours.
HGG-19. Co-occurrences of a high-grade glioma with cavernous malformations and pathogenic variants inPDCD10 andSMARCA4
Authors: Glanz Hannah , Damodharan Sudarshawn , Smith-Simmer Kelcy , Bradley Kristin , Rebsamen Susan , Casey Kristin , Iskandar Bermans , Helgager Jeffrey , Puccetti Diane 
Published: June 2022

Abstract
INTRODUCTION: The co-occurrence of multiple disease processes can make for more challenging diagnoses. Here we report an unusual case of a patient found to have an IDH1-mutant high-grade glioma along with multiple cerebral cavernous malformations and pathogenic germline variants in PDCD10 and SMARCA4. CASE DESCRIPTION: A 17-year-old female presented with left arm paresthesia and weakness along with persistent headaches within the frontal and occipital regions that progressed in intensity to include nausea and emesis. A fast sequence magnetic resonance imaging (MRI) of her head was obtained that revealed the presence of multiple bilateral cystic lesions suspicious for cavernomas, with the most notable lesion in the right parietal lobe. Ophthalmology consultation revealed grade III papilledema bilaterally. A full brain MRI with and without contrast was obtained and demonstrated a right anterior parietal lobe lesion with associated mass effect, as well as multiple bilateral supratentorial and left cerebellar cavernous malformations. The patient underwent tumor debulking of her dominant lesion. Pathology revealed an IDH1-mutant diffuse astrocytoma, WHO grade III. Tumor genetic testing was done and identified a SMARCA4 and two TP53 variants. Germline genetic testing was then pursued which revealed a PDCD10 pathogenic variant consistent with familial cerebral cavernous malformation syndrome and a likely pathogenic variant in SMARCA4. Treatment of her high-grade-glioma included radiation therapy followed by maintenance oral temozolomide. DISCUSSION: This case illustrates the unusual co-occurrences of a high-grade glioma with familial cavernous malformation syndrome and germline pathogenic variants in PDCD10 and SMARCA4. Our patient continues to do well clinically, but because of her risk of developing small cell carcinoma of the ovary she has elected to undergo a prophylactic bilateral salpingo-oophorectomy. Recognition of abnormal genetic results is critical in the setting of multiple disease processes and can play a crucial role in the on-going care for a patient.
HGG-20. PRMT5 promotes the formation and growth of pediatric high-grade glioma by maintaining tumor stem cell populations
Authors: DeSisto John , Knox Aaron , Balakrishnan Ilango , Chatwin Hannah , Coleman Philip , Venkataraman Sujatha , Vibhakar Rajeev , Green Adam 
Published: June 2022

Abstract
BACKGROUND: Pediatric high-grade gliomas (PHGG) are aggressive, undifferentiated CNS tumors comprising two broad subtypes: diffuse midline glioma with H3K27M mutations (DMG) and cortical high-grade glioma (H3K27-wild-type (wt) PHGG). During normal development, PRMT5 promotes stem cell self-renewal through methylation of arginine residues in histone tails. We hypothesized that PRMT5 controls self-renewal essential to the proliferation of PHGG tumor initiating cells (TICs). METHODS: We identified PRMT5 as potentially oncogenic in PHGG through a screen of 4,139 shRNAs targeting 406 genes with epigenetic activity. To elucidate PRMT5’s activity, we used lentiviral shRNA delivery to knock down (KD) PRMT5 expression in four DMG and one H3K27-wt PHGG cell lines. We performed in vitro growth, cell cycle, apoptosis, limiting dilution and bulk RNA-Seq assays to determine the phenotypic effects of PRMT5 KD. To identify PRMT5’s gene targets, we performed cleavage under targets & release using nuclease (CUT&RUN) followed by qPCR and are currently performing CUT&RUN-Seq. We orthotopically implanted PRMT5 KD PHGG cells into mice and tracked survival, tumor growth and tumor histological characteristics. RESULTS: In vitro, PRMT5 KD reduced cell growth (p&lt;0.001), slowed cell cycle progression and increased apoptosis. PRMT KD also slowed neurosphere formation, demonstrating reduced self-renewal (p&lt;7E-9). Geneset expression analysis showed PRMT5 KD reduced expression of self-renewal genes and increased expression of differentiation genes (FDR&lt;0.0001). In vivo, PRMT5 KD reduced tumor growth, as monitored by bioluminescence and MRI, and aggressiveness, based on Ki-67 staining (p&lt;0.05), leading to increased survival (p&lt;0.001). CUT&RUN-qPCR results showed PRMT5 KD led to decreased expression and H3K4me3 promoter occupancy at PAX3, and decreased expression and increased H3K27me3 occupancy at S100A6. PAX3 and S100A6 are oncogenes that preserve TIC self-renewal. CONCLUSION. In vitro experiments show that PRMT5 KD epigenetically reduces TIC self-renewal. In vitro and in vivo, PRMT5 KD reduced PHGG tumor cell growth and aggressiveness.
HGG-43. Abrogation of exosome biogenesis significantly affects cell motility in heterogenous sub-populations of paediatric-type diffuse high-grade glioma
Authors: Pericoli Giulia , Galardi Angela , Petrilli Lucia Lisa , Paolini Alessandro , Mortera Stefano Levi , Pepe Gerardo , Palma Alessandro , de Billy Emmanuel , Ferretti Roberta , Colletti Marta , Giorda Ezio , Burford Anna , Mackay Alan , Pascucci Luisa , Peinado Hector , Jones Chris , Citterich Manuela Helmer , Putignani Lorenza , Carai Andrea , Mastronuzzi Angela , Masotti Andrea , Locatelli Franco , Giannatale Angela Di , Vinci Maria 
Published: June 2022

Abstract
Paediatric-type diffuse High-Grade Gliomas (PDHGG) are highly heterogenous tumours comprised of distinct cell sub-populations co-existing within the same tumour mass. We have shown that primary patient-derived sub-clones, as well as optical-barcoded sub-clones, function as an interconnected network conferring an aggressive phenotype. Here, we explored the role of exosomes in mediating PDHGG inter-clonal communication. A comprehensive characterization of 7 optical-barcoded single cell-derived clones obtained from two patient-derived cell lines (one DMGH3K27-altered and one diffuse high-grade paediatric-type glioma H3WT), confirmed extensive genomic and phenotypic heterogeneity. Live single-cell tracking in 3D migration and invasion assays demonstrated the key role of the inter-clonal crosstalk in driving a more aggressive phenotype. To determine the exosome role in this crosstalk, we first characterised them in terms of size, marker expression and cargo. Moreover, we demonstrated that exosomes were actively internalized by the sub-clones. Exosomal proteomic analysis showed differential protein contents implicated in the regulation of biological processes such as focal adhesion and extracellular matrix organization. The analysis of exosomal miRNome did not show differentially expressed miRNAs between sub-clones, however, specific and distinct exosomal miRNAs were found uniquely expressed by each sub-clone. The abrogation of the exosome biogenesis by GW4869 phospholipase inhibitor did not affect sub-clones viability, but significantly inhibited their motility, when cultured individually and more prominently in co-culture condition. Analysis of the exo-miRNAs uniquely expressed by the sub-clones highlighted a set of target genes regulating cell motility/invasion/migration. These target genes were differentially expressed when sub-clones were co-cultured compared to mono-culture. Moreover, the expression levels of these genes (e.g. CD44, PTRZ, GLI3, NTRK2) were significantly modulated upon GW4869 treatments. In conclusion, our study highlights the importance of the exosomes in the inter-clonal communication and suggests that interfering with the exosome biogenesis may be a valuable strategy to inhibit cell motility in PDHGG.
HGG-50. Specific sensitivity of pediatric high-grade glioma with ATRX inactivation to PARP inhibitor combinations
Authors: Laemmerer Anna , Kirchhofer Dominik , Madlener Sibylle , Loetsch-Gojo Daniela , Jaunecker Carola N , Gabler Lisa , Mayr Lisa , Stepien Natalia , Baumgartner Alicia , Dieckmann Karin , Pfister Stefan M , Kool Marcel , Krausert Sonja , Gopisetty Apurva , Jäger Natalie , Peyrl Andreas , Azizi Amedeo A , Berger Walter , Gojo Johannes 
Published: June 2022

Abstract
Pediatric high-grade gliomas (pHGG) account for approximately 12% of pediatric brain tumors. Despite advances in molecular diagnosis and identification of discrete molecular subtypes, pHGG are the leading cause of cancer-related death in children. Thus, current research focuses on identifying novel therapeutic targets. Sequencing analyses across pediatric cancer types identified DNA repair perturbations as potentially targetable events in certain types of pediatric brain tumors. Herein, we investigated the potential of PARP inhibitors (PARPi), impeding the central role of PARP in DNA damage repair, in pHGG. We screened a patient-derived primary pHGG cell line panel (n=7) for their sensitivity towards 6 different PARPi (niraparib, olaparib, pamiparib, rucaparib, talazoparib, veliparib) using cell viability assays. Basal expression of DNA repair related proteins was assessed by immunoblot, and propidium iodide-based flow cytometry was used for cell cycle analysis. All pHGG were resistant towards single compound PARP inhibition. Interestingly, two H3F3A-G34R mutant pHGG models harboring inactivating ATRX mutations were characterized by elevated basal levels of pH2AX, suggesting increased stress resulting from DNA damage. Consequently, simultaneous targeting of PARP and other components of DNA repair in the respective models showed strong synergistic effects on cell viability, which was not observed to a comparable extent in other models such as BRAFV600E/TERT promotor mutant pHGG. Combination of talazoparib and irinotecan resulted in S-phase arrest. Within a precision oncology approach, we treated a 11-year-old child suffering from H3F3A-G34R mutant pHGG with ATRX mutation, that progressed during radiation, with niraparib and topotecan. The patient achieved partial remission and disease stabilization for 1 year. Taken together, PARPi combinations show potential for the treatment of pHGG with ATRX mutations. Currently, all cell models are characterized for DNA repair signatures by DNA sequencing. Further, in depth characterization of DNA damage responses upon concomitant PARP and topoisomerase inhibition in ATRX-mutated pHGG are ongoing.