bluuebunny/crossref_metadata_2025_split huggingface dataset:
ATRT-06. RESULTS OF MULTICENTER TRIAL CONCERNING THE TREATMENT OF CHILDREN WITH ATYPICAL TERATOID RHABDOID TUMORS OF THE CENTRAL NERVOUS SYSTEM UNDER 3 YEARS OLD
Authors: Olga Zheludkova , Liudmila Olkhova , Ludmilla Zubarovskaya , Julia Dinikina , Anna Smirnova , Yuri Kushel’ , Armenak Melikyan , Shavkat Kadyrov , Marina Ryzhova , Liudmila Shishkina , Alexey Kislyakov , Evgeniy Shultz , Svetlana Gorbatykh , Olga Polushkina , Eugenia Inyushkina , Natalia Yudina , Asmik Gevorgian , Liudmila Privalova , Liudmila Minkina , Artem Zaichikov , Ivan Fisyun , Daniil Sakun , Vyacheslav Mitrofanov , Sergey Kovalenko , Ekaterina Grishina , Nadezhda Pishchaeva , Nikolay Vorob’ev , Nadezhda Plakhotina , Natalia Popova , Dmitriy Pogorelov , Alexander Shapochnik , Andrey Korchunov 
Published: June 2021

Abstract

Objective
To evaluate the prognostic factors in children with AT/RT aged under 3 years. Patients and methods: The prognostic factors were analyzed in 106patients under 3 years who got treatment and follow-up from 2008 to 2020.There were 41children younger than 12 months and 65patients older than 12 months. The location of the tumor was infratentorial in 58 patients, supratentorial in 46, and spinal cord in 2. There were 54 boys and 52 girls. Among the patients,57 had stage M0,36 had stage М+ or a multifocal tumor, and 13 had stage Mx. All the patients had undergone surgical treatment: total tumor removal in 27, subtotal-33, partial-42, biopsy - 4;67patients had got chemoradiotherapy according to the ATRT-2006(IRS III) protocol; 15, MUV-ATRT protocol; 3, CWS protocol; 9, EU-RHAB protocol; 6, HIT-SKK protocol; and 6 according to individual treatment schemes.12 patients received HDC with AuHCR.

Results
47 are alive,1 was lost to follow-up, and 58 died:52 of progressive disease,6 of chemotherapy complications. The five-year PFS was 0.27; the five-year OS was 0.40. The PFS was significantly better in patients older than 12months old compared to patients under 12months: 0.33 and 0.17, respectively; p=0.0047. The PFS after total resection was higher than after subtotal resection, partial resection, and tumor biopsy: 0.51, 0.29, 0.09, and 0%, respectively (p=0.025).The PFS after radiotherapy was markedly higher compared to patients without radiotherapy: 0.63 and 0.0, respectively (р&lt;0.001). The tumor location, stage, and gender did not affect the PFS. The survival rate was statistically significantly higher among the patients who had got treatment according to the ATRT-2006 protocol compared to MUV-ATRT,EU-RHAB, individual therapeutic regimens, CWS, and HIT-SKK: 0.33, 0.26, 0.11, 0.30, and 0.0, respectively; p=0.0020. The PFS was higher among the patients who had got intraventricular/intrathecal chemotherapy; p=0.0002. HDC with AuHCR did not statistically affect the PFS; p=0.0546.In multivariate analysis, the PFS was influenced by the age, tumor location, extent of surgery, radiotherapy, regional chemotherapy, HDC with AuHCR.

Conclusions
The survival of patients with CNS AT/RT aged under 3years significantly depended on the patients’ age, extent of surgery, chemotherapy protocol, radiotherapy, and regional administration of chemotherapeutic drugs.
BIOL-06. MIR-1253 POTENTIATES CISPLATIN RESPONSE IN PEDIATRIC GROUP 3 MEDULLOBLASTOMA BY REGULATING FERROPTOSIS
Authors: Kanchan Ranjana , Khan Parvez , Perumal Naveenkumar , Atri Pranita , Venkata Ramakanth Chirravuri , Thapa Ishwor , Doss David , Nasser Mohd Wasim , Batra Surinder , Mahapatra Sidhartha 
Published: June 2021

Abstract
Medulloblastoma (MB), the most common malignant pediatric brain tumor and a leading cause of childhood mortality, is stratified into four primary subgroups, i.e. SHH (sonic hedgehog), WNT (wingless), and non-SHH/WNT groups 3 and 4, the latter representing high-risk MB. Haploinsufficiency of 17p13.3, which houses the tumor suppressor gene miR-1253, characterizes high-risk tumors. Despite improvements in targeted therapies, a limited proportion of these patients survive the disease. Capitalizing on the tumor suppressive properties of miRNAs as adjuncts to chemotherapy provides a promising alternative to current therapeutic strategies. In this study, we explored the potentiating effects of miR-1253 on cisplatin cytotoxicity in group 3 MB. First, in silico and in vitro analyses revealed an upregulation of ABCB7, a mitochondrial iron transporter and putative target of miR-1253, in MB cell lines and group 3 MB tumors. Overexpression of miR-1253 resulted in downregulation of ABCB7 and GPX4, a critical ferroptosis regulator, which consequently increased labile mitochondrial iron pool and, in turn, mitochondrial ROS (mtROS). Complementarily, we demonstrated, using CRISPR knockdown of ABCB7, ferroptosis induction with downregulation of GPx4 expression, liberation of free iron, mtROS generation and lipid peroxidation. Cisplatin is reported as an inducer of both apoptosis and ferroptosis-mediated cancer cell death. Therapeutically, the combination of miR-1253 and cisplatin led to an additive effect on cell viability, colony formation, apoptosis, and ROS generation. In turn, treatment with mtROS inhibitor (MnTBAP) and ferroptosis inhibitor (Ferrostatin) lead to partial recovery from the cytotoxic effects of this combination therapy. These studies identify an miR-1253-induced ferroptosis pathway targeting the ABCB7/GPX4/mtROS axis in group 3 MB. They further provide proof-of-concept in using miR-based therapeutics to augment treatment efficacy of current chemotherapeutics in the treatment of high-risk tumors.
BIOL-08. IGFBP2 PROMOTES TUMOR METASTASIS IN SHH MEDULLOBLASTOMA
Authors: Kunhiraman Haritha , Kenney Anna 
Published: June 2021

Abstract
Medulloblastoma (MB) is the most common pediatric brain malignancy. MB comprises 5 major subgroups known as WNT, SHH p53wt, SHH p53mut, Group 3 and Group 4. Among the four MB subgroups SHH group is the most dominant molecular subgroup in infants and adults. These tumors are proposed to arise from cerebellar granule neuron precursors (CGNPs), whose developmental expansion requires SHH signaling from the neighboring Purkinje neurons. Previous reports suggest that SHH group features a unique tumor microenvironment compared with other MB groups. Recently, we performed cytokine array analysis of culture media from different MB cell lines. Interestingly, our data showed increased levels of IGFBP2 produced by SHH MB cell lines compared to others. We confirmed these results using ELISA and Western blotting from 3 human SHH MB cell lines, and Smo/A1 mouse tumor cells. IGFBP2 is a member of IGFBP super family of proteins; it plays important roles in tumor cell proliferation, metastasis and drug resistance. We analyzed the role of IGFBP2 in SHH group medulloblastoma tumor growth and metastasis. IGFBP2 knock-down stable cell lines showed phenotypic changes including reduced cell proliferation, cell migration and colony size. Our preliminary in vitro data suggest IGFBP2 exerts it metastasis-promoting role in SHH MB by regulating the expression of EMT marker proteins such as N cadherin, slug etc. and matrix remodeling proteins like MMPs and TIMPs. We are currently performing functional studies in organotypic tumor slice cultures to validate these findings and establish IGFBP2 as a novel regulator of aggressive tumor growth and spread in SHH MB.
EMBR-03. PINEOBLASTOMA: A POOLED OUTCOME STUDY OF NORTH AMERICAN AND AUSTRALIAN THERAPEUTIC DATA
Authors: Hansford Jordan , Huang Jie , Dodgshun Andrew , Li Bryan , Hwang Eugene , Leary Sarah , Gajjar Amar , Von Hoff Katja , Endersby Raelene , Wells Olivia , Wray Alison , Kotecha Rishi , Raleigh David , Stoller Schuyler , Mueller Sabine , Schild Steven , Bandopadhayay Pratiti , Fouladi Maryam , Bouffet Eric , Huang Annie , Onar Arzu , Gottardo Nicholas 
Published: June 2021

Abstract

Background
Pineoblastoma (PB) is a rare embryonal brain tumour most often diagnosed in young children. To date, no clinical trials have been conducted specific to pediatric PB. Collaborative studies performed over the past 30 years have included PB in studies accruing for other embryonal tumours, primarily medulloblastoma (MB), but also including the entity formerly known as CNS-PNET and atypical teratoid rhabdoid tumors. Each of these studies have included only a small number of children with PB, making clinical features difficult to interpret and determinants of outcome difficult to ascertain.

Patients and Methods
Published centrally reviewed series with sufficient treatment and outcome data from North American and Australian cases were pooled. To investigate associations between variables, Fisher’s exact and Wilcoxon-Mann-Whitney tests, and Spearman correlations were used as appropriate. Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models were used in survival analysis.

Results
We describe a 30-year review of the reported clinical features of PB and a pooled centrally reviewed, cohort analysis of cases (n=178) from the Children’s Oncology Group (COG) (n=82) groups and several published, centrally reviewed institutional series (n=96). We find young children &lt;3 years of age have a dramatically poorer outlook compared to older children (5-year OS 16.2% +/- 5.3% vs 67.3% +/- 5%) confirming new and novel approaches are needed in future clinical trials for this at risk group. Interestingly, male gender was predictive of worse outcome possibly suggestive of gender specific subgroup risks that needs validation in future studies. Assessment of radiation therapy is not possible as the vast majority of children under age three did not receive any form of radiation therapy.

Conclusion
Given the relative scarcity of this tumor and the emerging data on subgroups of pineoblastoma, prospective, collaborative international studies will be vital to improving the long-term survival of these patients.
EMBR-10. INOSITOL TREATMENT INHIBITS MEDULLOBLASTOMA THROUGH SUPPRESSION OF EPIGENETIC-DRIVEN METABOLIC ADAPTATION
Authors: Badodi Sara , Pomella Nicola , Zhang Xinyu , Morrison Gillian , Pollard Steve M , Bennett Christopher D , Clifford Steven C , Peet Andrew , Marino Silvia 
Published: June 2021

Abstract
Medulloblastoma (MB) is the most common paediatric malignant brain tumour and is classified into four distinct molecular subgroups (WNT, SHH, G3 and G4), each of them further subdivided into subtypes with different prognosis and responses to therapy. Deregulation of chromatin modifier genes plays an essential role in MB, particularly in the G4 subgroup, the least understood of all subgroups, despite being the most common and associated with poor prognosis. A BMI1High; CHD7Low molecular signature identifies patients with poor survival within this subgroup. We show that BMI1High; CHD7Low mediates a novel epigenetic regulation of inositol metabolism in both G4 MB cells and patients. These tumours display hyperactivation of the AKT/mTOR pathway which leads to energetic rewiring characterized by enhanced glycolytic capacity and reduced mitochondrial function. We demonstrate that inositol administration counteracts this metabolic alteration, impairs MB proliferation in vitro and significantly extends survival in an in vivo pre-clinical model. Moreover, inositol synergises with cisplatin, a chemotherapy agent currently used in MB treatment, enhancing its therapeutic effect in vivo. Importantly, cerebellar neural stem cells bearing the BMI1High; CHD7Low signature do not show metabolic adaptation and are thus resistant to inositol treatment, highlighting a fundamental difference between normal and neoplastic metabolism in the developing cerebellum. In summary, we have identified an actionable vulnerability in a pre-clinical setting modelling a molecularly defined group of MB patients, the translational value of which can now be explored in signature-matched clinical trials in MB.
EMBR-14. INFLUENCE OF MRI FEATURES ON THE SURVIVAL AND IMPACT ON INDIVIDUAL MOLECULAR SUBGROUPS: RESULT FROM 171 PATIENTS WITH MEDULLOBLASTOMA
Authors: Dasgupta Archya , Maitre Madan , Kalra Babusha , Chatterjee Abhishek , Krishnatry Rahul , Goda Jayant , Shirsat Neelam , Epari Sridhar , Sahay Ayusi , Janu Amit , Pungavkar Sona , Chinnaswamy Girish , Moiyadi Aliasgar , Shetty Prakash , Gupta Tejpal , Jalali Rakesh 
Published: June 2021

Abstract

Background
To investigate the influence of different MRI features on survival in patients with medulloblastoma.

Methods
A total of 171 patients were included in the study, including 131 pediatric and 40 adults (&gt; 18 years). A set of 16 pre-defined semantic MRI features was analyzed using T1W (pre and post-contrast), T2W, and diffusion-weighted imaging (additional sequences as available). Patients with a definitive event (recurrence) or a minimum follow up of 12 months (in case of no recurrence) were included in the current analysis. All patients were treated and followed up according to standard institutional practice. Log-rank test was used for univariate analysis (UVA) and Cox regression for multivariate analysis (MVA).

Results
The molecular subgroups were as follows: WNT-27 children, 7 adults; SHH-31 children, 29 adults; group 3–32 children, 3 adults; and group 4–41 children, 1 adult. The median follow up was 45 months (range 1 to 137 months). For all the patients, on UVA the recurrence-free survival (RFS) was significantly (p&lt;0.05) influenced by location-vertical, brainstem involvement, contrast uptake area, contrast heterogeneity, necrosis, and calcification. Similar factors (T2W homogeneity instead of area of contrast) impacted overall survival (OS). On MVA, location-vertical, brainstem involvement, and calcification were significant features for both RFS and OS. Tumor location-vertical was the only feature influencing RFS and OS within the SHH subgroup. For group 3 tumors, contrast uptake area (RFS and OS) and calcification (RFS alone) had a significant influence (MVA). Within group 4, contrast pattern (RFS) and T2W homogeneity (RFS and OS) were significant factors on UVA, none on MVA.

Conclusion
Several MRI features can be linked with survival in patients with medulloblastoma, with a specific impact on individual molecular subgroups. Considering the entire population, non-central location on the vertical aspect, tumors away from brainstem, calcification are risk factors associated with inferior outcomes.
EMBR-23. KIF11 DEPENDENCY ON P53 MUTATIONAL STATUS IN MEDULLOBLASTOMA
Authors: Huang Shiying , Karthik Sekar , Lin Qi , Du YuChen , Lau Ching C , Adekunle Adesina , Su Jack M F , Major Angela , Elghetany M Tarek , Hui Kam-Man , Li Xiaonan , Teo Wan-Yee 
Published: June 2021

Abstract

Introduction
KIF11, a mitotic kinesin, is a component responsible for assembly and maintenance of mitotic spindle during mitosis. Tumor cells can upregulate KIF11. Inhibition of KIF11 results monopolar spindle formation, resulting in monoastral mitosis in cells. This activates the spindle assembly checkpoint, cells are arrested and prevented from entering cell cycle, resulting in cell death via apoptosis or necrosis, cell division with aneuploidy or mitotic slippage without division into tetraploid G1 phase.

Methods
We hypothesized that the effect of KIF11 inhibition on medulloblastoma (MB) is dependent of its p53 mutational status.

Results
Our findings on Hoechst staining demonstrated a small molecule inhibitor of KIF11 which induced apoptosis in p53-wildtype MB cells at 48h (p&lt;0.0001), was able to trigger mitotic catastrophe (p = 0.0010) in p53-mutant MB cells at 24h and subsequent necrosis (p=0.0039) at 48h. KIF11 inhibitor exerted anti-proliferative effects on five MB cell lines at nanomolar concentration range, independent of its p53 mutational status. Cells treated with KIF11 inhibitor were arrested in G2/M phase. Apoptosis was observed on Annexin V flow cytometry 24h after treatment, followed by necrosis after 48h in p53-wildtype cells. In contrast, treated p53-mutant cells underwent necrosis at 24h. Differences in cell death mechanisms upon KIF11 inhibition was confirmed on immunoblotting by upregulated p53 expression and presence of cleaved-PARP and DNA-damage marker in p53-wildtype cells, indicative of apoptosis. While inhibition of KIF11 and increased p53 expression were observed only after 48h, cleaved-PARP expression was detected as early as 24h in p53-wildtype, suggesting KIF11-independent, cleaved-PARP-mediated cell death at 24h. In contrast, treated p53-mutant cells showed decreased p53 expression and absence of cleaved-PARP and DNA-damage marker after 24h.

Conclusions
Our results suggest that when mitotic arrest is induced, p53-mutant MB cells undergo mitotic catastrophe and necrosis while p53-wildtype MB cells predominantly undergo apoptosis.
EMBR-27. NEOPLASTIC AND IMMUNE SINGLE CELL TRANSCRIPTOMICS DEFINE SUBGROUP-SPECIFIC INTRA-TUMORAL HETEROGENEITY OF CHILDHOOD MEDULLOBLASTOMA
Authors: Donson Andrew , Riemondy Kent , Venkataraman Sujatha , Willard Nicholas , Nellan Anandani , Sanford Bridget , Griesinger Andrea , Amani Vladimir , Mitra Siddhartha , Hankinson Todd , Handler Michael , Sill Martin , Ocasio Jennifer , Weir Seth , Malawsky Daniel , Gershon Timothy , Garancher Alexandra , Wechsler-Reya Robert , Hesselberg Jay , Foreman Nicholas , Vibhakar Rajeev 
Published: June 2021

Abstract
Medulloblastoma (MB) is a heterogeneous disease in which neoplastic cells and associated immune cells contribute to disease progression. To better understand cellular heterogeneity in MB we used single-cell RNA sequencing, immunohistochemistry and deconvolution of transcriptomic data to profile neoplastic and immune populations in childhood MB samples and MB genetically engineered mouse models (GEMM). Neoplastic cells clustered primarily according to individual sample of origin which is in part due to the effect of chromosomal copy number gains and losses. Harmony alignment of single cell transcriptomic data revealed novel MB subgroup/subtype-associated subpopulations that recapitulate neurodevelopmental processes and are associated with clinical outcomes. This includes photoreceptor-like cells and glutamatergic lineage unipolar brush cells in both GP3 and GP4 subgroups of MB, and a SHH subgroup nodule-associated neuronally-differentiated cell subpopulation. We definitively chart the spectrum of MB immune cell infiltrates, which reveals unexpected degree of myeloid cell diversity. Myeloid subpopulations include subgroup/subtype-associated developmentally-related neuron-pruning as well as antigen presenting myeloid cells. Human MB cellular diversity is recapitulated in subgroup-specific MB GEMM, supporting the fidelity of these models. These findings provide a clearer understanding of both the neoplastic and immune cell heterogeneity in MB and how these impact subgroup/subtype classification and clinical outcome.
EMBR-31. DEVELOPMENT OF INJECTABLE POLYSACCHARIDE HYDROGEL TO ENHANCE DRUG PENETRATION IN PEDIATRIC BRAIN TUMORS
Authors: Patel Jenny , Barker Elizabeth 
Published: June 2021

Abstract
Improving unacceptable low response rates and reducing acute and long-term morbidities remain significant challenges in pediatric neuro-oncology. Chemotherapy is an effective primary or adjuvant treatment for pediatric disease, but current administration approaches hinder the pharmacological activity exerted by chemotherapy treatments. Barriers in the route of drug administration and in the tumor microenvironment limit anticancer drugs from penetrating tissue efficiently and reaching all cancer cells. Strategies have been proposed to overcome these barriers with hope of leading to sustained and elongated drug exposure in solid tumors. However, few methods have been explored to design drug delivery systems to circumvent these barriers with potential to enhance drug penetration and reduce adverse systemic side effects in treating pediatric brain tumors. In this study, we validate an injectable polysaccharide hydrogel capable of releasing drugs locally at tumor site, sustaining drug concentration, and eliciting tumor response. We synthesized a hydrogel with dimethyl sulfoxide (DMSO) incorporating amylopectin, a polysaccharide found in starch, loaded with doxorubicin. We determined the structure of doxorubicin is not altered when released from the hydrogel through characterization of drug-loaded and unloaded hydrogels, suggesting drug is encapsulated in the hydrogel network and is able to maintain structure to induce mechanism of action. We tested sustained release of drug and therapeutic efficacy in vitro with DAOY, a medulloblastoma cell line. Our approach demonstrates that local drug delivery presents potential to enhance drug penetration in pediatric brain tumors by sustaining drug concentration at tumor site for an extended period of time. Local drug delivery systems have been investigated for decades but few have been investigated for treatment of pediatric brain tumors. For researchers, physicians, and clinicians, this research can lead to a greater effort to improve current outcomes of conventional drug treatment and provide an opportunity to address current challenges in pediatric oncology.
EPEN-05. MUTATIONAL ANALYSIS OF THE C11ORF95 DOMAIN AND SINGLE-CELL RNA-SEQ PROFILE OF A MOUSE MODEL OF SUPRATENTORIAL EPENDYMOMA
Authors: Truong Kevin , He James , Birdsall Gavin , Randazzo Ericka , Dunnack Jesse , LoTurco Joseph 
Published: June 2021

Abstract
We used a recently developed mouse model to better understand the cellular and molecular determinants of tumors driven by the oncogenic fusion protein C11orf95-RELA. Our approach makes use of in utero electroporation and a binary transposase system to introduce human C11orf95-RELA sequence, wild type and mutant forms, into neural progenitors. We used single cell RNA-seq to profile the cellular constituents within the resulting tumors in mice. We find that approximately 70% of the cells in the tumors do not express the oncogene C11orf95-RELA and these non-oncogene expressing cells are a combination of different non-tumor cell cell-types, including significant numbers of T-cells, and macrophages. The C11orf95-RELA expressing tumor cells have a unique transcriptomic profile that includes both astrocytic and neural progenitor marker genes, and is distinct from glioblastoma transcriptomic profiles. Since C11orf95-RELA is believed to function through a combination of both activation of NF-κB response genes by constitutive activation of RELA, and genes not activated by NF-κB, we assessed the expression of NF-κB response genes across the populations of cells in the tumor. Interestingly, when tumor cells highly expressing C11orf95-RELA were analyzed further, the subclusters identified were distinguished by upregulation of non-NF-kB pathways involved in cell proliferation, cell fate determination, and immune activation. We hypothesized that the C11orf95 domain may function to bring RELA transcriptional activation to inappropriate non-NF-κB targets, and we therefore performed a point mutation analysis of the C11orf95 domain. We found that mutations in either of the cysteines or histidines that make up a possible zinc finger domain in C11orf95 eliminate the ability of the fusion to induce tumors. In cell lines, these loss-of-function point mutants still trafficked to nuclei, and activated NF-κB pathways. We are currently using RNAseq and CRISPR loss-of function to identify genes downstream of C11orf95-RELA that are required for tumorigenesis.