bluuebunny/crossref_metadata_2025_split huggingface dataset:
NCMP-14. EEG FEATURES THAT INDEPENDENTLY ASSOCIATE WITH HIGHER GRADE NEUROTOXICITY IN PATIENTS TREATED WITH CHIMERIC ANTIGEN RECEPTOR (CAR) T CELL THERAPY
Authors: Mao David , Kotchetkov Ivan , Reiner Anne , Panageas Katherine , Chen Xi , Avila Edward , Santomasso Bianca 
Published: November 2019

Abstract

RATIONALE
CAR T cell therapy has emerged as a promising treatment of refractory or relapsed leukemia and lymphoma. It is associated with severe side effects, such as immune effector cell-associated neurotoxicity syndrome (ICANS). Electroencephalography (EEG) is often performed in these patients as part of an evaluation of their altered mental status. We hypothesize certain EEG features are associated with high ICANS grade.

METHODS
Retrospective review of medical records was performed. From February 2010 through June 2016, 53 adults with relapsed B-cell acute lymphoblastic leukemia received 19-28z CAR T cells at MSKCC as part of a phase 1 trial. We identified patients from this group who were monitored with video EEG and recorded daily EEG features. A multivariable generalized estimating equation model was used to identify EEG findings that were independently associated with high ICANS grade (3 or 4). A Cox model was used to associate initial EEG findings with development of high ICANS grade.

RESULTS
There were 27 unique patients with a combined 109 days of video EEGs. In a multivariable model, lack of posterior dominant rhythm (PDR) (Odds Ratio (OR)=12.49, p< .0001) and discontinuity (OR=9.50, p=0.01) were independently statistically significantly associated with high ICANS grade and generalized sharps retained marginal statistical significance (OR=4.77, p=0.06). Presence of state changes, focal slowing, generalized slowing, and epileptic discharges did not have statistically significant association. No EEG findings on initial day of monitoring was statistically significantly associated with eventual development of high ICANS grade.

CONCLUSIONS
EEG discontinuity and lack of PDR were associated with high severity of neurotoxicity. There may be clinical utility in monitoring for specific features when assessing for development or resolution of ICANS, but additional prospective studies employing EEG in patients receiving CAR T cell therapy are necessary.
PDTM-04. EARLY DETECTION BY MRI OF MOUSE MODELS WITH DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Thomas Lincy , Towner Rheal , Gulej Rafal , Smith Nataliya , Zalles Michelle , Saunders Debra 
Published: November 2019

Abstract
Diffuse intrinsic pontine glioma (DIPG) is the most common brainstem tumor in childhood with a very devastating prognosis and no curative treatment options as of yet. Approximately 300 children in the U.S. are diagnosed with DIPG each year. Our project hopes to assess the effectiveness of OKlahoma Nitrone-007 (OKN-007) as a therapeutic agent for DIPG. This agent has shown promise in prior studies involving pediatric glioma mouse models by decreasing growth of blood vessels, which is essential for any tumor progression, and by decreasing temozolomide (TMZ) resistance when used as adjunct therapy in adult GBM. We have successfully created an in vivo DIPG model using post-mortem patient-derived neurospheres, harboring the H3 K27M mutation, injected into the pontine region of immunocompromised mouse (SCID) brainstems via a stereotaxic device. After surgical implantation, mice are imaged every week using a 7.0 Tesla 30-cm bore Bruker Biospec Magnetic Resonance Imaging (MRI) system to assess tumor growth and progression of disease. We describe to you the first pre-clinical DIPG mouse model that shows evidence of tumor growth as early as 42 days, as detected on T2-weighted MR images. Another characteristic feature is that the blood-brain barrier (BBB) is intact in this DIPG model, as assessed by contrast-enhanced MRI. Additional MRI methods, including diffusion-weighted imaging (DWI), and perfusion imaging (arterial spin labeling) are also evaluated. Prior pre-clinical DIPG mouse models only had tumor detection by MRI 78 days after implantation. Once the tumors are large enough for treatment (clinically relevant), we separate the mice into a control group (no treatment), OKN-007 treatment alone, as well as combination therapy with OKN-007 and TMZ. With the dismal prognosis and limited effective chemotherapy available for DIPG, there is significant room for continued research studies to help clinicians better understand and treat pediatric DIPG patients.
PDTM-10. USE OF A NOVEL, HAND-HELD, ELECTRONIC DNA ANALYSIS PLATFORM TO QUANTIFY MULTI-GENE MOLECULAR RESPONSE IN CSF OF PATIENTS WITH HIGH-GRADE GLIOMA
Authors: Bruzek Amy , Tunkle Leo , Babila Clarissa , Muruganand Ashwath , Stallard Stefanie , Thamilselvan Veena , Qin Tingting , Wolfe Ian , Mody Rajen , Robertson Patricia , Maher Cormac , Muraszko Karin , Garton Hugh , Koschmann Carl 
Published: November 2019

Abstract

BACKGROUND
For midline tumors, surgical biopsy risks neurological injury. Non-invasive methods for diagnosis and surveillance are greatly needed. Tumors release DNA into cerebrospinal fluid (CSF-ctDNA), allowing for potential detection and serial monitoring of tumor-associated genetic mutations by CSF sampling. Current detection platforms are limited by their requirement for assay development for each mutation (digital droplet PCR), or cost and timeliness (Illumina sequencing). We hypothesized that direct, electronic analysis of CSF-ctDNA with a novel, hand-held platform (Oxford Nanopore MinION) could provide real-time, ultra-deep sequencing of patient-specific alterations in CSF-ctDNA.

METHODS
We established multiple clinical trials for pediatric high-grade glioma with required multi-time point (0, 2, and 6 month) correlate lumbar puncture (LP) at time of MRI, with accrual ongoing. We performed amplicon-based PCR on CSF-ctDNA for recurrent mutations and sequenced patient samples (tumor tissue n=8, tumor CSF n=60) and normal controls (tissue n=5, CSF n=24) using NanoPore technology. Variant allele fractions (VAF) were determined via MinKNOW, Guppy, MiniMap2, and Integrated Genome Browser.

RESULTS
Sensitivity was 79% and specificity 100% by NanoPore. Time from LP to results was 12 hours. A 17-year-old female presented with a biopsy-proven grade IV thalamic glioma with clonal mutations in H3F3A K27M, PIK3CA E545G, TP53 R158G, and TP53 R248Q. After failing standard treatment, she was enrolled in the ONC201 clinical trial and underwent serial LPs. MRI showed stable tumor at 2 months and 40% decrease at 6 months of treatment. H3K27M VAF increased from baseline at 2 months, but decreased to 1% at 6 months of treatment, results that were confirmed by ddPCR. PIK3CA E545G, TP53 R158G, and TP53 R248Q demonstrated the same decrease in VAF, with p-value of < 0.0001.

CONCLUSIONS
We demonstrate a rapid, reliable method to detect tumor mutations in CSF, and further show molecular remission of H3K27M glioma by CSF sampling.
PDTM-12. ADGRB3 IS EPIGENETICALLY SILENCED IN WNT-MEDULLOBLASTOMA AND ITS REACTIVATION HAS THERAPEUTIC BENEFITS
Authors: Bhattacharya Debanjan , Zhu Dan , Osuka Satoru , Kaluz Stefan , Devi Narra , Van Meir Erwin 
Published: November 2019

Abstract
Medulloblastoma (MB) are the most aggressive primary malignant brain tumors in children and are classified into four major molecular subgroups. WNT-MB is characterized by an activated WNT signature and has relatively better prognosis with treatment. However, young WNT-MB patients who survive after conventional treatment suffer from long-term irreversible neurocognitive and endocrine side effects leading to poor quality of life. ADGRB3 is a member of the ADGRB1-3 subfamily of adhesion GPCR transmembrane proteins, which are highly expressed in the cerebellum and hippocampal neurons. Our recent analysis of RNA-seq data from a published panel of MB tumor samples and RT-PCR experiments with tumor samples showed that ADGRB3 mRNA expression is selectively repressed in WNT-MB tumors compared to the other molecular subgroups and normal human cerebellum. We detected hypermethylation of the ADGRB3 promoter exclusively in WNT-MB samples. ChIP assays revealed enrichment of repressive methyl CpG binding MBD2 protein and trimethylated histone H3K9me3 in the ADGRB3 promoter region. We found that ATP dependent chromatin remodeler protein BRG-1 regulates ADGRB3 expression through epigenetic reprogramming at the gene promoter. Lentiviral reconstitution of ADGRB3 inhibited growth and WNT signaling in UW288-1, and PFSK-1 cells in culture. ADGRB3 reconstitution in UW288-1 MB cells causes a significant reduction in tumor growth and WNT target gene activation in orthotopic xenografts in nude mice. Furthermore, we found that ADGRB3 reactivation could be achieved using a blood brain barrier permeable MBD2 antagonist and an EZH2 inhibitor and this can significantly reduce cell growth and inhibit WNT signaling targets. Altogether, our findings define an epigenetic mechanism for ADGRB3 silencing in WNT-MB and demonstrated that reactivation of ADGRB3 can prevent WNT-MB tumor growth by suppressing WNT signaling. Our study supports translating epigenetic reactivation of ADGRB3 as a novel therapeutic intervention for children affected with WNT-MB.
PDTM-15. EMBRYONIC STEM CELL SIGNATURE DRIVES ATYPICAL TERATOID/RHABDOID TUMOR DEVELOPMENT IN HUMAN PLURIPOTENT STEM CELL-DERIVED TUMOR MODEL
Authors: Arakawa Yoshiki , Terada Yukinori , Mineharu Yohei , Miyamoto Susumu , Yamada Yasuhiro 
Published: November 2019

Abstract

BACKGROUND
Atypical teratoid/rhabdoid tumor (AT/RT), which harbors SMARCB1 mutation and exhibits a characteristic histology of rhabdoid cells, has a poor prognosis because of the lack of effective treatment.

METHODS
To investigate the pathogenesis of AT/RT, we establish human SMARCB1-deficient pluripotent stem cells (hPSCs).

RESULTS
Although neural progenitors have been suggested as being a cell-of-origin of AT/RT, SMARCB1-deficient hPSC-derived neural progenitor-like cells (NPLCs) give rise to mostly medulloblastoma-like tumors when transplanted into the mouse brain. In contrast, transplantation of SMARCB1-deficient hPSCs cause AT/RT-like tumor containing a large number of typical rhabdoid cells. hPSC-derived tumors exhibit activation of embryonic stem cell-like gene expression signature (ESC-like signature) compare with NPLC-derived tumors. Forced activation of ESC-like signature by expression of reprogramming factors confers rhabdoid histology in SMARCB1-deficient NPLC-derived tumors. Activation of ESC-like signature is associated with poor survival. Consistently, the activation of ESC-like signature is found in clinical specimens of AT/RT. Finally, we perform CRISPR/Cas9 knockout screening to inhibit activation of ESC-like signature in AT/RT. Our effort identifies candidate genes including RAD21 that encodes a key component within the cohesin complex. Notably, chemical inhibition of HDAC8 that indirectly targets the function of cohesin with simultaneous inhibition of EZH2 efficiently suppresses the activation of ESC-like signature and inhibits the growth of AT/RT cells both in vitro and in vivo.

CONCLUSION
SMARCB1-deficient hPSCs offer the first human model for AT/RT, which uncovers the unappreciated role of the activated ESC-like signature in worse prognosis and unique histology. We propose that ESC-like signature could be a crucial therapeutic target for AT/RT.
PDTM-16. PEDIATRIC HIGH GRADE GLIOMA RESOURCES FROM THE CHILDREN’S BRAIN TUMOR TISSUE CONSORTIUM (CBTTC) AND PEDIATRIC BRAIN TUMOR ATLAS (PBTA)
Authors: Ijaz Heba , Koptyra Mateusz , Gaonkar Krutika , Lynne Rokita Jo , Baubet Valerie , Tauhid Lamiya , Zhu Yuankun , Brown Miguel , Lopez Gonzalo , Zhang Bo , Diskin Sharon , Vaksman Zalman , Mason Jennifer , Appert Elizabeth , Lilly Jena , Lulla Rishi , De Raedt Thomas , Heath Allison , Felmeister Alex , Raman Pichai , Nazarian Javad , Santi Mariarita , Storm Phillip , Resnick Adam , Waanders Angela , Cole Kristina 
Published: November 2019

Abstract

BACKGROUND
Pediatric high grade glioma (pHGG) remains a fatal disease. Access to richly annotated biospecimens and patient derived tumor models will accelerate pHGG research and support translation of research discoveries. This work describes the pediatric high grade glioma set of the Children’s Brain Tumor Tissue Consortium (CBTTC) from the first release of the Pediatric Brain Tumor Atlas (PBTA).

METHODS
pHGG tumors with associated clinical data and imaging were prospectively collected through the CBTTC and analyzed as the Pediatric Brain Tumor Atlas (PBTA) with processed genomic data deposited into PedcBioPortal for broad access and visualization. Matched tumor was cultured to create high grade glioma cell lines analyzed by targeted and WGS and RNA-seq. A tissue microarray (TMA) of primary pHGG tumors was also created.

RESULTS
The pHGG set includes 87 collection events (73 patients, 60% at diagnosis, median age of 9 yrs, 55% female, 46% hemispheric). Operative reports, pathology reports and histology images are available for nearly all cases. Pre- and post-operative MRI images and reports are also available for a subset. Tumor WGS/RNAseq is available for 70 subjects. Analysis of somatic mutations and copy number alterations of known glioma genes were of expected distribution (36% H3.3, 47% TP53, 24% ATRX and 7% BRAFV600E variants). In our panel of pHGG, six patients (8 tumors) harbored germline mismatch repair mutations with tumor hyper-mutation. A pHGG TMA (n=77), includes 36 patient tumors with matched sequencing. At least one established glioma cell line was generated from 23 patients (32%). Unique reagents include those derived from a H3.3 G34R glioma and from tumors with mismatch repair deficiency.

CONCLUSION
The CBTTC and PBTA have created an openly available integrated resource of over 2,000 tumors, including a rich set of pHGG primary tumors, corresponding cell lines and archival fixed tissue to advance translational research for pHGG.
PDTM-22. A C19MC-LIN28A-MYCN ONCOGENIC CIRCUIT DRIVEN BY HIJACKED SUPER-ENHANCERS IS A DISTINCT THERAPEUTIC VULNERABILITY IN ETMRS – A LETHAL BRAIN TUMOR
Authors: Mumal Iqra , Sin-Chan Patrick , Suwal Tannu , Singh Irtisha , Li Xiao-Nan , Lin Charles , Rich Jeremy , Mack Stephen , Huang Annie 
Published: November 2019

Abstract
Embryonal tumors with multi-layered rosettes (ETMR) are aggressive brain cancers with characteristic C19MC oncomiR amplification and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a potent C19MC-LIN28A-MYCN circuitry driven by multiple regulatory loops and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. C19MC and LIN28A targets respectively converge on critical cell cycle tumor suppressors and neo-embryonic DNMT3A/B isoforms. We identify a MYCN driven, core transcriptional network, conserved in early neural stem cells, that is potently abrogated by treatment with bromodomain inhibitor JQ1, leading to ETMR cell death. Our collective data suggest C19MC oncomiRs drive a malignant primitive cell state in ETMRs via entrapment of an early neural lineage network, which represents a critical therapeutic vulnerability for this recalcitrant disease.
PDTM-24. PINEOBLASTOMA SEGREGATES INTO MOLECULAR SUBTYPES WITH DISTINCT CLINICOPATHOLOGIC FEATURES: REPORT FROM THE RARE BRAIN TUMOUR CONSORTIUM
Authors: Li Bryan , Vasiljevic Alexandre , Dufour Christelle , Ho Ben , Hwang Eugene , Gururangan Sridharan , Hansford Jordan , Laquerriere Annie , Delisle Marie-Bernadette , Fangusaro Jason , Forest Fabien , Sumihito Nobusawa , Toledano Helen , Birks Diane , Fan Xing , Fouladi Maryam , Gajjar Amar , Gauchotte Guillaume , Hoffman Lindsey , Jones Chris , Loussouarn Delphine , Mokhtari Karima , Pomeroy Scott , Rousseau Audrey , Somers Gino , Taylor Michael , Ziegler David S , Lu Mei , Hawkins Cynthia , Grundy Richard , Jouvet Anne , Bouffet Eric , Ashley Hill D , Huang Annie 
Published: November 2019

Abstract

BACKGROUND
Pineoblastoma (PB) is a rare but aggressive pediatric brain tumour arising from the pineal gland. Overall survival rates are estimated at 50–70%, with younger patients (< 5 years old) faring much worse (15–40%) despite intensive treatment regimens. Although germline RB1 and DICER1 alterations have been reported in a small proportion of PB, the clinical significance of such alterations and the biology of sporadic cases remains unknown.

METHODS
We collected tumor tissue from 93 PB cases diagnosed at their referring centres. We undertook global DNA methylation profiling and performed multiple orthogonal consensus clustering analyses to elucidate PB subgroups. Chromosomal copy number alterations were determined using Conumee and GISTIC2, and whole exome or targeted sequencing was completed. Clinical data was analyzed with correlative statistical methods and outcomes were measured by Kaplan-Meier survival estimates.

RESULTS
PB comprise five epigenetic groups, designated 1, 2, 3, 4A, and 4B. Deleterious, mutually exclusive alterations affecting miRNA biogenesis pathway members (DICER1, DROSHA, and DGCR8) were observed in 12/21 group 1 and 11/11 group 2 samples. Group 4A was characterized by recurrent RB1 loss and gain of the oncogenic miR-17/92, and group 4B by recurrent gain or amplification of MYC. These groups also exhibit distinct clinical features. PB groups 1–3 arose in older children (median ages 5.2–14.0 years) and had intermediate to excellent outcome (5-year OS of 71.9–100%). Group 4A and 4B were restricted to much younger children (median age 1.3–1.4 years) and had dismal prognoses (5-year OS 37.5% and 28.6%, respectively).

CONCLUSIONS
PB divides into five groups with distinct genetic and clinical profiles. These findings will have important implications for precise patient stratification and form the foundation for preclinical studies of biology-informed therapies.
PDTM-25. STUDY OF ONC201 IN PRE-CLINICAL MODELS OF DIPG
Authors: Sharma Ajay , Lai Yanlai , Kennis Bridget , Sridharan Sreepradha , Dobson Tara , Swaminathan Jyothishmathi , Khatua Soumen , Sandberg David , Allen Joshua , Tarapore Rohinton , Gopalakrishnan Vidya , Zaky Wafik 
Published: November 2019

Abstract
Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain tumor that occur in the pons and brainstem and have a peak onset of age between 6–9 years of age. Radiation is currently used as standard of care. Chemotherapy has shown no improvements in survival. Here, we report our study of ONC201, a first-in-class anticancer small molecule developed by Oncoceutics, Inc., against DIPG cells in vitro and in mouse orthotopic models. ONC201 was discovered in a screen as a p53-independent inducer of the pro-apoptotic cytokine TRAIL. It is known to directly and selectively inhibit dopamine receptor D2 (DRD2), a member of the G protein-coupled receptor (GPCR) family. MTT assays to determine the sensitivity of DIPG cells to ONC201 revealed a slight but not significantly different response to the drug based on their expression of wild type (WT) histone H3 or histone H3K27M mutant protein, with IC50 values in the range of 3-8mM. Decrease in cell growth was associated with a decrease in AKT and ERK phosphorylation and an increase in TRAIL expression. In vivo, intraperitoneal administration of ONC201 to mice bearing pontine DIPG tumors, once every week for 6 weeks, caused a significant reduction in tumor burden relative to untreated controls as measured by bioluminescence assays. However, stoppage of treatment resulted in tumor regrowth within 6 weeks, suggesting the existence of a population that were not eliminated by the current schedule of ONC210. Single cell proteomic analyses-based comparison of untreated and ONC201-treated DIPG cells showed an expected global reduction in pro-survival signals such as phosphorylated AKT and ERK. Molecules with potential to predict susceptibility of cells to ONC201 were also revealed, and are being confirmed by transcriptome analyses. Results of a chemical screen to target ONC201-refractory tumor cells will be discussed.
PDTM-29. STRUCTURE FUNCTION AND CELL TYPE DETERMINANTS OF C11orf95-RELA DRIVEN TUMORS IN MICE
Authors: Dunnack Jesse , Randazzo Ericka , Caines Jahmique , He Jame , LoTurco Joseph 
Published: November 2019

Abstract
We used a new mouse model to better understand the cellular and molecular determinants of tumors driven by the C11orf95-RELA fusion. Our approach makes use of in utero electroporation and a binary transposase system to introduce human C11orf95-RELA sequence, wild type and mutant, into neural progenitors, and drive expression of the fusion in different glial and neuronal progenitor cell types. Our results indicate that truncations or point mutations in C11orf95 sequence which interfere with nuclear localization result in a complete loss of tumor-inducing activity. The mutations include truncations of the first 60 amino acids, internal truncations that delete possible mono and bipartite nuclear localization signals, and point mutations of two cysteines and histidines that make up a possible zinc finger domain in C11orf95. Interestingly, all of the mutations that block tumorigenesis also block signal independent nuclear localization of the wild type fusion, without blocking induction of NFKB response genes. We further found that over-expression of the NFKB1 subunit P50 which lacks a transcriptional activation domain significantly inhibits tumor formation by the fusion. In addition, we find that driving expression of the wild type fusion in glial progenitor types using promoters for either astrocytes or oligodendrocytes results in the formation of tumors with transcriptomes displaying significant similarities to human supratentorial ependymoma (ST-EPN), but with distinct patterns depending upon the glial progenitor promoter utilized. In contrast, promoters driving expression selectively in neuron restricted progenitors do not result in the formation of ST-EPN. Together our results reveal three new features of C11orf95-RELA driven tumorigenesis: i) multiple sequences within the C11orf95 domain are required for oncogenic driver activity of the fusion, ii) the P50 subunit of NFKB1 can inhibit fusion induced tumorigenesis, and iii) neuron-restricted precursors are less competent than glia-restricted precursors to form tumors induced by C11orf95-RELA.