bluuebunny/crossref_metadata_2025_split huggingface dataset:
ATRT-02. MEK/ERK SIGNALLING DEPENDENCY IN ATYPICAL TERATOID RHABDOID TUMOURS
Authors: Shi Hui (Claire) , Sooraj Dhanya , Sun Claire , Daniel Paul , Bradshaw Gabrielle , Cain Jason , Firestein Ron 
Published: December 2020

Abstract
Atypical teratoid rhabdoid tumours (ATRTs) are high-grade malignant paediatric brain tumours with a less than one-year survival rate after diagnosis. Current treatment for ATRT, which includes high-intensive radiotherapy and chemotherapy, results in long-term side effects on ATRT patients. Hence, there is an urgent need to discover targeted therapies that could be used to treat patients with ATRT. As part of the Hudson Monash Paediatric Precision Medicine Program, we have collected 23 ATRT cell lines which we used to performed high-throughput small molecule and genetic (CRISPR) screening to identify new therapies and therapeutic targets. In parallel, we characterised the ATRT cell lines based on transcriptomic (RNA-seq) and epigenetic (methylation) signatures. An integrative multi-omic approach was then used to uncover discrete vulnerabilities in specific subsets of ATRT patients. Strikingly, these include a number of druggable dependencies, such as MEK, CDK, HDAC, and Topoisomerase, that offer a promise of rapid clinical translation. In our study, we focus on MEK dependency in a subtype of ATRT lines to further define the underlying mechanisms and biomarkers. While future studies validating the MEK/ERK signalling dependency in a wider cohort of patient models and in in vivo models are required, these data provide a framework for applying an integrative multi-omic approach in paediatric cancer precision medicine.
ATRT-03. IDENTIFICATION OF microRNA-BASED PROGNOSTIC BIOMARKERS AND CANDIDATE THERAPEUTIC AGENTS FOR ATYPICAL TERATOID/RHABDOID TUMOR
Authors: Zhang Yang , Xu Jianguo 
Published: December 2020

Abstract

BACKGROUND
MicroRNA (miRNA) has been found to be involved in development of many malignant pediatric brain tumors, including atypical teratoid/rhabdoid tumor (AT/RT) that is highly aggressive and carries a dismal prognosis. The current study investigated the potential value of miRNAs and pivotal genes associated with AT/RT using bioinformatics analysis, aiming to identify new prognostic biomarkers and candidate drugs for AT/RT patients.

METHODS
Differentially expressed miRNAs (DEMs) and genes (DEGs) between AT/RT and normal control samples were obtained from GEO database. The target genes of DEMs were predicted via TargetScanHuman7.2 and miRDB, and then intersected with DEGs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of overlapping genes were conducted, followed by construction of protein-protein interaction network. Hub genes were determined by Cytoscape software, and their prognostic values were evaluated using Kaplan-Meier analysis. Connectivity Map database was used to identify latent therapeutic agents.

RESULTS
A total of 11 DEMs (hsa-miR-1224-5p, hsa-miR-128-3p, hsa-miR-17-5p, hsa-miR-18b-5p, hsa-miR-29c-5p, hsa-miR-329-3p, hsa-miR-379-5p, hsa-miR-433-3p, hsa-miR-488-5p, hsa-miR-656-3p and hsa-miR-885-5p) were screened. By intersecting 3275 predicted target genes and 925 DEGs, we finally identified 226 overlapping genes that were enriched in pathways in cancer and MAPK signaling pathway. Four hub genes (GRIA2, NRXN1, SLC6A1 and SYT1) were significantly associated with the overall survival of AT/RT patients. Candidate drugs included histone deacetylase inhibitor (givinostat), DNA synthesis inhibitor (floxuridine), cyclin-dependent kinase inhibitor (purvalanol) and janus kinase inhibitor (lestaurtinib).

CONCLUSION
In summary, this study systematically analyzed AT/RT-related miRNAs and pivotal genes to provide novel prognostic biomarkers and potential therapeutic agents.
ATRT-14. MACROPHAGE-TUMOR CELL INTERACTION PROMOTES ATRT PROGRESSION AND CHEMORESISTANCE
Authors: Melcher Viktoria , Graf Monika , Interlandi Marta , Moreno Natalia , de Faria Flavia W , Kim Su Na , Kastrati Dennis , Korbanka Sonja , Alfert Amelie , Gerß Joachim , zu Hörste Gerd Meyer , Hartmann Wolfgang , Frühwald Michael C , Dugas Martin , Schüller Ulrich , Hasselblatt Martin , Albert Thomas K , Kerl Kornelius 
Published: December 2020

Abstract
Atypical teratoid/rhabdoid tumors (ATRT) are pediatric brain neoplasms that are known for their heterogeneity concerning pathophysiology and outcome. The three genetically rather uniform but epigenetically distinct molecular subgroups of ATRT alone do not sufficiently explain the clinical heterogeneity. Therefore, we examined the tumor microenvironment (TME) in the context of tumor diversity. By using multiplex-immunofluorescent staining and single-cell RNA sequencing (scRNA-seq) we unveiled the pan-macrophage marker CD68 as a subgroup-independent negative prognostic marker for survival of ATRT patients. ScRNA-seq analysis of murine ATRT-SHH, ATRT-MYC and extracranial RT (eRT) provide a delineation of the TME, which is predominantly infiltrated by myeloid cells: more specifically a microglia-enriched niche in ATRT-SHH and a bone marrow-derived macrophage infiltration in ATRT-MYC and eRT. Exploring the cell-cell communication of tumor cells with tumor-associated immune cells, we found that Cd68+ tumor-associated macrophages (TAMs) are central to intercellular communication with tumor cells. Moreover, we uncovered distinct tumor phenotypes in murine ATRT-MYC that share genetic traits with TAMs. These intermediary cells considerably increase the intratumoral heterogeneity of ATRT-MYC tumors. In vitro co-culture experiments recapitulated the capability of ATRT-MYC cells to interchange cell material with macrophages extensively, in contrast to ATRT-SHH cells. We found that microglia are less involved in the exchange of information with ATRT cells and that direct contact is a prerequisite for incorporation. A relapse xenograft model implied that intermediary cells are involved in the acquisition of chemotherapy resistance. We show evidence that TAM-tumor cell interaction is one mechanism of chemotherapy resistance and relapse in ATRT.
ATRT-18. SHH-SUBTYPE ATYPICAL TERATOID/RHABDOID TUMORS ARE SELECTIVELY SENSITIVE TO GEMCITABINE TREATMENT
Authors: Metselaar Dennis , Meel Michaël Hananja , Goulding Joshua , Waranecki Piotr , de Gooijer Mark , Breur Marjolein , van Zanten Sophie Veldhuizen , Bugiani Marianna , Wesseling Pieter , Kaspers Gertjan , Hulleman Esther 
Published: December 2020

Abstract
Atypical Teratoid Rhabdoid Tumors (ATRT) are highly malignant embryonal tumors of the central nervous system with a dismal prognosis. ATRT can be divided into three molecular subgroups of which the Sonic Hedgehog (SHH) subgroup is most prevalent. In this study, we developed and validated a novel patient-derived ATRT model, which we used along a panel of other primary ATRT models for large scale drug discovery assays. We found that ATRTs are selectively sensitive to the nucleoside analogue gemcitabine, with SHH-subtype ATRTs being the most sensitive subgroup. Gene expression profiles and protein analysis indicated that gemcitabine treatment causes degradation of Sirtuin 1 (SIRT1), which causes ATRT specific cell-death through NF-kB and p53 activation. Furthermore, we found that this gemcitabine induced loss of SIRT1 results in a nucleus-to-cytoplasm shift of the SHH signaling activator Gli, explaining the additional gemcitabine sensitivity in SHH-subtype ATRT. Treatment of SHH-subgroup ATRT xenograft-bearing mice resulted in a &gt;40% increase in median survival (p&lt;0.01, log-rank test) and long-term survivors in two independent models. To prepare translation of our findings to the clinic, we investigated potential gemcitabine induced resistance mechanisms by conducting kinome-wide CRISPR/Cas9 knockout screens in primary ATRT cells. Through these experiments we found that low-dose gemcitabine treatment combined with inhibition of protein kinase C zeta (PKCζ) prevents regrowth of resistant ATRT subclones. Together, these findings show that ATRT are highly sensitive to gemcitabine treatment; and as such we suggest that gemcitabine may be rapidly incorporated into future treatment regimens for SHH-ATRT.
ATRT-24. CELL SURFACE PROTEOME ANALYSIS OF ATRT IDENTIFIES TARGETS FOR IMMUNOTHERAPY
Authors: Cole Allison , Hoffmeyer Eric , Zanini Marco , Vibhakar Rajeev , Nellan Anandani , Ayrault Olivier , Mitra Siddhartha 
Published: December 2020

Abstract
Atypical teratoid rhabdoid tumor (ATRT) is a rare and fast-growing childhood tumor of the brain and spinal cord. While the recent advances in DNA and RNA sequencing have given deep insights into the biology of cancer, about 90% of ATRTs harbor a single deletion which leads to uncontrolled tumor growth. The lack of targetable genetic abnormalities in ATRT makes it a tough target for therapy and hence radical new approaches are required to develop a treatment. In many cases, the gene expression profile alone DOES NOT represent the presence of the gene product on the surface and cannot detect post-translational modifications such as the addition of sugars which are essential for the interaction of surface proteins with the tumor microenvironment. The ability to escape from surveillance by the immune system is regarded as one of the essential hallmarks of cancer cells. Here we carried out a comprehensive unbiased large-scale surface receptor profiling using high throughput multicolor flow cytometry on surgically resected ATRT patient samples, primary ATRT cell lines, and patient-derived xenograft models. By multiplexing primary samples with antibodies for CD31, CD45, CD11b, CCR2, Cx3cr1, and CD4, and CD8 we eliminated endothelial and immune cells from analysis while also identifying immune populations within the tumor. We identified increased surface expression of CD44, CD146, CD59, CD151, and CD276. These were validated in our screening of primary tumor samples. A combination of CAR-T cell and function-blocking monoclonal antibody approaches have been tested to verify the proof of principle of this approach.
ATRT-27. COST-EFFECTIVE ASSAYS TO SUBGROUP ATRT IN THE DAILY ROUTINE
Authors: Lobon-Iglesias María-Jesús , Tauziede-Espariat Arnault , Andrianteranagna Mamy , Han Zhiyan , Masliah-Planchon Julien , Bourdeaut Franck 
Published: December 2020

Abstract
Three atypical teratoid rhabdoid tumors (ATRT) molecular subgroups with different bio-clinical characteristics have been reported (TYR, SHH and MYC). Molecular subgrouping relies on either methylation profiling (reference methods), or expression profiling. However, the cost-effectiveness of such pangenomic screening is questionable. This work aims to study the reliability of alternative techniques for subgroup classification in the daily routine. Illumina EPIC-arrays were performed on 46 samples. Among those cases, expression profiling were analysed by RNAseq (n=30). We designed a 26-gene panel to assess expression profiling using the Nanostring technology; this was applied to 35 tumors. Immunohistochemistry (IHC) was used for 20 samples; it relied on the expression of MITF, TYR, OTX2 and MYC. We first assessed the concordance between DNA methylation and RNAseq based profilings; then, between RNAseq and Nanostring and, finally, between methylation profiling and Nanostring or IHC, the two rapidest and cheapest tools. The concordance between the two expression-based profiling was 19/21. EPIC-arrays and RNAseq or Nanostring were concordant in 26/30 and 30/35 samples, respectively. The concordance was perfect for methylation-defined MYC subtype. Finally, 17/20 tumor samples were classified in the same subgroup by EPIC-arrays and IHC; the 3/20 misclassified tumors were SHH by methylation but consistently MYC by IHC, Nanostring and RNAseq. There was 90–100% of concordance for TYR subgroup (all techniques). We have designed a gene panel-based expression signature that shows promising concordance with RNAseq and methylation profiling. Nanostring assay and IHC well predict ATRT subgroup classification for MYC and TYR subclass, but less so for methylation-defined SHH ones.
ATRT-28. SINGLE NUCLEI SEQUENCING REVEALS THE DIFFERENT PHENOTYPIC COMPOSITION OF THE ATRT SUBGROUPS
Authors: Johann Pascal , Büllesbach Annette , Ernst Kati , Okonechnikov Konstantin , Jones David T W , Pfister Stefan M , Hasselblatt Martin , Kool Marcel 
Published: December 2020

Abstract
Atypical teratoid/rhabdoid tumors (ATRT) represents a genomically homogeneous disease characterized by loss of SMARCB1 protein in the vast majority of cases. In recent years, it has become clear that these tumors display a high degree of intertumoral heterogeneity with three molecularly distinct subgroups. However, the degree of intratumoral heterogeneity and the information on cellular subpopulations currently remains largely an unchartered territory. To explore the transcriptomic composition of ATRTs, we performed single nuclei RNA sequencing for 16 ATRTs representing all three molecular subgroups (5 ATRT-TYR, 7 ATRT-SHH, 4 ATRT-MYC). By performing tSNE cluster analyses of all the single cell data (~50.000 cells have been sequenced), we were able to gain unprecedented insights into the phenotypic composition of ATRTs and unravelled substantial differences between the three subgroups. Integrating transcriptomic information from non-neoplastic brain cells and the data derived from single nuclei sequencing, we found an OPC like gene signature in ATRT-SHH. In contrast, ATRT-TYR subpopulations overexpressed more markers of neuronal stem cells suggesting a larger fraction of undifferentiated cells in this subgroup. We also identified a subpopulation of cells with a clear overexpression of cell cycle associated genes (CDK4, CDKN3), predominantly present in ATRT-MYC samples, a finding which may harbour important consequences for a targeted therapy with e.g. CDK inhibitors. In summary, our analyses reveal different cellular compartments in ATRT and provide important insights into the cellular differentiation of the three ATRT-subgroups. Further analyses to achieve a specific mapping of ATRT to its physiological cell of origin are currently being pursued.
ATRT-33. ENABLING RAPID CLASSIFICATION OF ATRT WITH NANOSTRING NCOUNTER PLATFORM
Authors: Ho Ben , Arnoldo Anthony , Zhong Yvonne , Lu Mei , Torchia Jonathon , Yao Fupan , Hawkins Cynthia , Huang Annie 
Published: December 2020

Abstract
In recent years, using gene expression and methylation array platform, multiple research groups have reported the presence of at least three major Atypical Teratoid Rhabdoid Tumor (ATRT) subtypes that exhibit distinct epigenetic, transcriptomic and clinical features. Yet, utilizing ATRT subtypes in a clinical setting remains challenging due to a lack of suitable biological markers, limited sample quantities and relatively high cost of current assays. To address this gap between research and clinical practice, we have designed an assay that utilizes a custom 35 signature genes panel for the NanoString nCounter System and have created a flexible machine learning classifier package for ATRT tumour subtyping. We have analyzed 71 ATRT primary tumours with matching gene expression data using the 35 genes panel. 60% of the data was used for models training (10 repeats of 10-fold cross validation with subgroup balanced sample splitting) resulting in overall 94.6% training accuracy. The remaining 40% of the samples were used for model validation and the assay was able to achieve 92–100% accuracy with no subgroup bias. To demonstrate the flexibility of the workflow, we have tested it against other transcriptome-based methods such as gene expression array and RNASeq. We have also demonstrated its use in samples that were not classifiable by methylation-based method. We are presenting here a rapid and accurate ATRT subtyping assay for clinical usage that is compatible with archived ATRT tissues.
COVD-04. CHARACTERISTICS OF SARS-COV-2 IN 64 CHILDREN WITH CNS TUMORS: A REPORT FROM THE SIOP/ST. JUDE CHILDREN’S RESEARCH HOSPITAL (SJCRH) GLOBAL COVID-19 CHILDHOOD CANCER REGISTRY
Authors: Moreira Daniel , Bouffet Eric , Bhakta Nickhill , Chantada Guillermo , Chen Yichen , Faughnan Lane , Vedaraju Yuvanesh , Avula Maghana , Homsi Maysam , Naidu Paula , Pappas Andrew , Ranadive Radhikesh , Santana Victor , Sullivan Michael , Baroni Lorena , Caniza Miguela , Devidas Meenakshi , Pritchard-Jones Kathy , Rodriguez-Galindo Carlos , Mukkada Sheena 
Published: December 2020

Abstract

BACKGROUND
The GCCCR is a collaboration between SIOP and SJCRH to describe the natural history of SARS-CoV-2 in children with cancer across the world.

METHODS
The GCCCR is a deidentified registry of patients &lt;19 years of age with cancer or recipients of a hematopoietic stem cell transplant and laboratory-confirmed SARS-CoV-2 infection. Demographic data, cancer diagnosis, cancer-directed therapy, and clinical characteristics of SARS-CoV-2 infection were collected. Outcomes were collected at 30-days and 60-days post infection.

RESULTS
As of August 10th 2020, the GCCCR included 730 cases from 35 countries, including 64 children with CNS tumors (8.8%) from 17 countries. The most frequent diagnoses were embryonal tumors (31.2%) and low-grade glioma (17.2%). Thirty-nine (60.9%) children were asymptomatic from infection, while 19 (29.7%) patients required hospital admission and 2 (6.3%) transferred to the intensive care unit. There was a significant association between infection severity and ANC &lt;500 (p=0.04). At the time of infection, 44 (68.8%) patients were undergoing cancer-directed therapy. Thirty-two cases have follow-up data. No modification in cancer-directed therapy occurred in 11 (34.4%) patients, while chemotherapy was modified in 6 (18.8%), radiotherapy delayed in 2 (6.3%), and surgery postponed in 1 (3.1%). No patients died from SARS-CoV-2 infection, although 2 died from non-COVID-19 related causes.

CONCLUSION
The frequency and severity of COVID infection among children with CNS tumors appears to be proportionally lower compared to other children with cancer. Although this is the largest cohort of patients reported to date, additional insight is needed, including the effects of treatment modifications on outcomes.
DDEL-01. ENHANCING DRUG DELIVERY WITH MRgFUS FOR DIFFUSE INTRINSIC PONTINE GLIOMA MODEL
Authors: Ishida Joji , Alli Saira , Bondoc Andrew , Golbourn Brian , Sabha Nesrin , Mikloska Kristina , Srikanthan Dilakshan , Luck Amanda , Smith Christian , Hynynen Kullervo , Rutka James 
Published: December 2020

Abstract
Diffuse intrinsic pontine glioma (DIPG) is a surgically unresectable and devasting tumor in children. To date, there have been no effective chemotherapeutics despite a myriad of clinical trials. The intact blood-brain barrier (BBB) in part is responsible for the limited clinical response to chemotherapy. MRI guided focused ultrasound (MRgFUS) is a promising non-invasive tissue ablative method for CNS tumors. Moreover, MRgFUS allows for the temporary disruption of BBB. Our first objective was to determine the feasibility and safety of temporary BBB disruption within the brainstem using MRgFUS following intravenous (IV) administration of microbubbles in vivo. Our second objective was to select effective chemotherapeutics against DIPG cell lines, and to examine their therapeutic effects with MRgFUS in a mouse model of DIPG which exhibits an intact BBB. The non-invasive opening of the BBB was determined in the brainstem of normal rodents using physiological monitoring and histological analysis. Doxorubicin was selected from a drug screen consisting of conventional chemotherapeutics using SU-DIPG4 and SU-DIPG17 cell lines. We established SU-DIPG17 xenografts which demonstrated diffusely infiltrative tumor growth similar to human DIPG. By LC-MS/MS analysis, MRgFUS led to a 4-fold increase in doxorubicin concentrations within the brainstem tumors following IV administration when compared to IV administration alone, We demonstrated feasibility and safety of MRgFUS in the rodent brainstem and have shown that MRgFUS increases doxorubicin uptake in the brainstem of a rodent model of DIPG. These preclinical data will be helpful in designing clinical trials of BBB disruption using MRgFUS for DIPG in children.
DDEL-02. DECREASED TOXICITY OF CONVENTIONAL DOSE CHEMOTHERAPY UTILIZING BODY WEIGHT INSTEAD OF BODY SURFACE AREA FOR DOSING IN YOUNG CHILDREN &lt;6 YEARS OLD ENROLLED ON THE “HEAD START” 4 CLINICAL TRIAL
Authors: Dhall Girish , Khatib Ziad , Maher Ossama , Blue Megan , Harmon Myeshia , Patel Parth , Finlay Jonathan 
Published: December 2020

Abstract
Metabolism of drugs in infants and young children is significantly different from older individuals due to differences in distribution, protein-binding capacity, hepatic metabolism and renal excretion. To be consistent with Children’s Oncology Group (COG) guidelines, body surface area (BSA) was used to dose chemotherapeutics in children &gt;3 years old enrolled on “Head Start” 4 clinical trial (HS 4). Four of 30 patients enrolled on HS 4 developed sinusoidal obstruction syndrome (SOS) while receiving induction chemotherapy with cisplatin, etoposide, vincristine, cyclophosphamide and high-dose methotrexate using BSA for dosing (mg/m2). Patients #1 and #2 were both 2-years old at diagnosis, received and tolerated the first two cycles with mg/kg dosing uneventfully, then turned 3-years old and received cycle #3 with mg/m2 dosing as per protocol guidelines, and developed SOS. Patient #3 was 3-years old at diagnosis, received induction chemotherapy with mg/m2 dosing, and developed SOS during the very first cycle. Patient #4 was 4-years old at diagnosis and received all 3 induction cycles with mg/m2 dosing, developed serious nephrotoxicity during cycle #1 followed by SOS during cycle #3. The HS 4 trial was amended and reopened after external, independent Data Safety Monitoring Board review to dose all chemotherapy drugs in children &lt;6 years old with mg/kg dosing instead of BSA. None of 75 patients enrolled since the amendment developed SOS during induction. These data suggest using caution while dosing young children &lt;6 years of age with intensive induction chemotherapy by BSA.
DDEL-03. LONG-TERM INTRAVENTRICULAR THERAPY ALTERNATING ETOPOSIDE AND LIPOSOMAL CYTARABINE: EXPERIENCE IN 75 CHILDREN AND ADOLESCENTS WITH MALIGNANT BRAIN TUMORS
Authors: Stepien Natalia , Peyrl Andreas , Azizi Amedeo , Gojo Johannes , Mayr Lisa , Reisinger Dominik , Haberler Christine , Czech Thomas , Slavc Irene 
Published: December 2020

Abstract

BACKGROUND
Malignant brain tumors of childhood carry a high risk for leptomeningeal dissemination and tumor cells floating in the CSF are often not amenable to systemic and/or antiangiogenic chemotherapy. We report on our experience with an intraventricular therapy consisting of alternating cycles of liposomal cytarabine and etoposide.

PATIENTS AND METHODS
Between 2004 and 2017, 75 patients aged 0.6 to 22 years (median 11) with various malignant brain tumors received intraventricular etoposide 0.25mg (&lt;1year) - 0.5mg on five consecutive days alternating with liposomal cytarabine at a dose of 25mg (&lt;3 years) - 50mg via an Ommaya reservoir.

RESULTS
5533 doses of etoposide (5–277/patient, median 141) corresponding to 1–56 five-day-cycles/patient alternating with 534 doses of liposomal cytarabine (1–21/patient, median 11) were administered. Treatment was given over a period of 1 – 146 months (median 73.5). Toxicities did occur but were infrequent and mostly mild. Since all patients received some sort of concurrent anti-cancer therapy, the efficacy of intrathecal therapy cannot be assessed independently. However, 29/75 patients are still alive, and none of the patients had tumor cells in the CSF at their last evaluation.

CONCLUSION
In conclusion, alternating intraventricular liposomal cytarabine and etoposide produced responses and proved to be an important adjunct for patients receiving drugs with a low penetrance into the CSF. Since production of liposomal cytarabine was discontinued in 2017 it remains to be determined whether substitution of the slow release formulation by aqueous cytarabine on days 1, 4, 8, and 11 may produce similar results.