bluuebunny/crossref_metadata_2025 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

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

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

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

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

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

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

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

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

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

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.
PDTM-32. RESOLVING MEDULLOBLASTOMA CELLULAR ARCHITECTURE BY SINGLE-CELL GENOMICS
Authors: Bihannic Laure , Hovestadt Volker , Smith Kyle , Filbin Mariella , Shaw McKenzie , Baumgartner Alicia , DeWitt John , Groves Andrew , Mayr Lisa , Weisman Hannah , Richman Alyssa , Shore Marni , Goumnerova Liliana , Rosencrance Celeste , Carter Robert , Phoenix Timothy , Hadley Jennifer , Tong Yiai , Houston Jim , Ashmun Richard , DeCuypere Michael , Sharma Tanvi , Ligon Keith , Pomeroy Scott , Rivera Miguel , Rozenblatt-Rosen Orit , Rusert Jessica , Wechsler-Reya Robert , Li Xiao-Nan , Peyrl Andreas , Gojo Johannes , Kirchhofer Dominik , Lötsch Daniela , Czech Thomas , Dorfer Christian , Haberler Christine , Geyeregger Rene , Halfmann Angela , Gawad Charles , Easton John , Pfister Stefan , Regev Aviv , Gajjar Amar , Orr Brent , Slavc Irene , Robinson Giles , Bernstein Bradley , Suvà Mario , Northcott Paul
Published: November 2019

Medulloblastoma is a malignant childhood cerebellar tumor comprised of distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. We used single-cell transcriptomics to investigate intra- and inter-tumoral heterogeneity in twenty-five medulloblastomas spanning all molecular subgroups. WNT, SHH, and Group 3 tumors comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumors were exclusively comprised of differentiated neuronal-like neoplastic cells. SHH tumors closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumors exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, whose relative proportions distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide novel insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.
PDTM-39. CRACKING THE HISTONE CODE: REVEALING THERAPEUTIC EPIGENETIC TARGETS THROUGH HISTONE H3 TAIL ANALYSIS OF DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Li Daphne , Huang Tina , Camarillo Jeannie , Qi Jin , Weiss Hannah , Nazarian Javad , Thomas Paul , Saratsis Amanda
Published: November 2019

INTRODUCTION

Diffuse intrinsic pontine glioma (DIPG) is a highly morbid pediatric cancer. Up to 80% harbor a Histone H3K27M mutation, which alters wild type Histone H3 protein post-translational modifications (PTMs) and genomic enrichment patterns to impact chromatin structure and transcription regulation. We previously identified tumorigenic patterns of H3K27Ac/bromodomain co-enrichment in DIPG, and demonstrated pre-clinical efficacy of bromodomain inhibition (JQ1). Here, we employ a novel proteomics platform, developed at our institution, to further elucidate the impact of H3K7M mutation on glioma histone codes and response to bromodomain inhibition.

METHODS

Epiproteomic analysis was performed on pediatric glioma cell lines (H3K27 WT n=2, H3K27M n=2) to characterize 95 distinct Histone H3.3 and H3.1 N-terminal tail modification states. Cells were treated with JQ1 or DMSO, and collected at 0h, 24h, 48h. Histones were extracted from isolated nuclei, immunopurified, and analyzed by LC-MS/MS. Results were integrated with RNA-Seq and ChIP Seq results (H3K27M, H3K27Ac, H3K27me3, H3K4me1, H3K4me3) from the same DIPG cell lines. Pediatric glioma tissues (H3K27M WT n=3, H3K27M n= 9) were similarly analyzed to validate cell line results.

RESULTS

Cell PTM profiles cluster by H3 mutation status on unsupervised analysis. Relative H3 PTM abundance were compared across cell lines by tumor location, H3 mutation status, and in response to treatment. Significant differential genomic enrichment H3K27M and H3.3 WT proteins, H3K27Me3 and H3K27Ac were observed between mutant and wild type cell lines with epigenetic-targeted therapy, correlating with cell transcriptomes.

CONCLUSIONS

Histone H3 tail epiproteomic analysis reveals DIPG histone codes in situ, revealing the effects of bromodomain inhibition on the tumor epigenetic landscape and providing new insight to the mechanism of tumor formation and therapy response. Further investigation of the utility of these signatures as biomarkers for diagnosis and longitudinal monitoring of treatment response are therefore currently underway.
QOLP-13. IMPACT OF CANNABIS USE ON QUALITY OF LIFE IN PATIENTS WITH CENTRAL NERVOUS SYSTEM TUMORS
Authors: Rodriguez Almaraz Eduardo , Butowski Nicholas , Chang Susan , Ann Oberheim-Bush Nancy , Clarke Jennifer , Taylor Jennie , Buerki Robin , Berger Mitchel
Published: November 2019

BACKGROUND

Nearly 80,000 new cases of primary brain tumors are expected to be diagnosed this year, 32% of CNS tumors are malignant. Anecdotally, patients who report use of cannabis, frequently describe higher quality of life scores (QOL) in standardized instruments. However, the lack of available tools that allow systematic documentation of cannabis use results in a barrier to accurately assess efficacy, potential benefits and risks.

METHODS

We conducted a single center, observational study: patients with primary brain tumors answered a previously validated instrument to explore cannabis use. QOL was assessed using the instruments from the European Organisation for Research and Treatment of Cancer: QLQ-C30 and its complementary module BN-20 as well as the EuroQol instrument EQ-5D-5L. Eligible participants were identified as cannabis users or non-users, completing the instruments in a self-administered fashion.

RESULTS

To date, 51 patients who signed informed consent were enrolled and answered the questionnaires, mean age was 51 (SD 12.95) years, 34 were male, 30 were considered active cannabis users (66.6% males and 33.3% females). The mean global health score in the QLQ-C30 instrument was 68.4 (SD: 20.7) among cannabis users and 82.2 (SD: 17.5) among non-users. The mean difference in QOL scores between users and non-users was 13.8 (95%CI: 2.8, 24.8; p=0.01). In contrast the difference between cannabis users and non-users in QOL index in the EQ-5D-5L instrument was 0.13 (95% CI: 0.06, 0.2; p=0.001). Among cannabis users, patients perceive their symptoms as moderate before using cannabis and mild after using cannabis (p >0.001)

CONCLUSIONS

In our analysis, patients who use cannabis reported, on average, lower QOL scores. Potentially, sicker patients resort to cannabis to improve their symptoms and ultimately quality of life. The perception of patients is that cannabis usage improves overall quality of life. Findings provide support to perform prospective studies.
QOLP-14. CAREGIVER PERCEPTIONS OF END OF LIFE CARE IN PATIENTS WITH HIGH GRADE GLIOMA
Authors: Fortunato John , Schultz Lonni , Phillips Joel , Walbert Tobias
Published: November 2019

INTRODUCTION

Patients dying from high-grade gliomas (HGG) often suffer from a high symptom burden in the end-of-life (EoL) phase. Since patients with HGG typically do not follow up with providers in the EoL phase, information about quality of life and symptom management is sparse. Family caregivers are most informed about the patient’s symptoms and disease course. The aim of this study is to assess the quality of EoL care of HGG patients from the caregiver perspective.

METHODS

Caregivers participated in the Toolkit After-Death Bereaved Family Member Interview (TIME survey). This validated survey assesses EoL care by calculating “domain scores” (DS) in five different areas: 1) physical comfort and emotional support, 2) advance care planning, 3) focus on the individual, 4) attention to family, and 5) coordination of care. Caregivers also rated aspects of care using a 10 point Likert scale.

RESULTS

In a prospective study, 40 of 55 enrolled family caregivers completed the interview a median of 26 days after death. 68% of caregivers were female. DS indicate the quality of care. (0 = no opportunity to improve care, 1 = care was always sub-optimal). Caregivers perceived high satisfaction with information and decision-making (0.18), advance care planning (0.19), focus on the individual (0.16) and coordination of care (0.11). Attention to family (0.25) was not as well rated. Caregivers rated the overall care 8.90 ±1.36/10 on a 0–10 scale.

CONCLUSIONS

Caregivers reported a high overall satisfaction with EoL care provided, though attention to family could be improved. While previous research suggests the importance of good physician communication in allowing patients to die with dignity, more focus should be on the caregiver in the EoL phase to improve end of life care, caregiver burnout and bereavement.
QOLP-19. A NEW MODEL OF CARE FOR PATIENTS WITH CENTRAL NERVOUS SYSTEM CANCERS
Authors: Nevel Kathryn , Konig Franchesca , Elizabeth Davis Mary , Skakodub Anna , Sibilla Maryann , Harrison Mabel , Rawlins-Peters Gayle , Jean-Charles Dominique , Zankowsky Anastasia , Gilman Jody , Kelly Brian , Reiner Anne , Zavolas Stephanie , Goldman Hannah , Diamond Eli , Carver Alan , Ruppert Lisa , DeAngelis Lisa , Pentsova Elena
Published: November 2019

Patients (pts) with primary or metastatic central nervous system (CNS) cancers often have multiple physical, psychosocial, and spiritual needs. Neurological impairments can transform relationship dynamics with caregivers. These issues are difficult to address within a single outpatient oncology clinic. The Neurological Multidisciplinary Care Clinic (MdCC) at Memorial Sloan Kettering Cancer Center was a pilot study from 08/2017 to 04/2019 to foster a new model of care for complex pts with CNS cancers to identify and address their needs. The MdCC team: a neurologist, nurse, physiatrist (RM), physical therapist, social worker (SW), case manager (CM), dietitian (RD), and chaplain saw each pt/caregiver during a 3-hour visit. Since 11/2017 participants completed validated surveys on unmet needs, financial strain, and home equipment prior to their visit and satisfaction surveys afterward. Descriptive statistics were used to analyze results. Seventy-eight pts were seen: 39 were female, median age 59. Of these 78 pts, 65 had primary CNS cancers; predominantly glioblastoma (52%) and high-grade glioma (29%). Over 60% had never seen a SW, CM, RD, or physiatrist prior to MdCC. Seventy-six pts (97%) received symptom management recommendations. Prognosis/coping with cancer was discussed with 72 (92%) which increased signed health care proxy forms by 17% and DNR orders by 6% at time or within a month post MdCC. New/updated physical therapy was ordered for 48 pts (61%), orthotics for 8 (10%), and new equipment for 12 (15%). 25 pts (32%) continued following with physiatrists. Forty-eight pts completed a satisfaction survey; of these, 96% were highly satisfied, and would recommend MdCC to others. Pts’/caregivers’ unmet needs were effectively identified and addressed in this new model, The presence of these providers at time of MdCC allows for real time assessment of pts’/caregivers’, their support system, multidisciplinary team collaboration, planning, coordination of community services and implementation of a safe patient centered plan of care.
QOLP-30. CLINICAL PREDICTIVE MODEL FOR THE DEVELOPMENT OF VENOUS THROMBOEMBOLISM IN GLIOBLASTOMA
Authors: Yust-Katz Shlomit , Donthireddy Vijaya , Mandel Jacob , Abunafeesa Hussna , Patil Neha , Yadav Dhiraj , Jabbour-Aida Hiba , Wu Jimin , Yuan Ying , Tsavachidis Spiridon , Walbert Tobias , Bondy Melissa , Armstrong Terri
Published: November 2019

INTRODUCTION

The risk of venous thromboembolism (VTE) remains high for patients with glioblastoma (GBM) throughout the disease trajectory. Our previous work demonstrated the Khorana scale lacks specificity in this population. We therefore constructed, and attempted to validate a predictive model specific for the development of VTE during adjuvant chemotherapy in glioblastoma patients.

METHODS

A prior study of GBM patients treated at MD Anderson (MDACC) during the years 2005–2011 found from a multivariate analysis that male sex, BMI ≥ 35, KPS ≤ 80, and steroid therapy were significantly associated with the development of VTE. A predictive model from the MDACC cohort was created using these risk factors, and we attempted to validate the model in an independent cohort of GBM patients treated at Henry Ford from 2010–2015.

RESULTS

To develop the model 315 patients from the MDACC cohort were randomly divided into two parts: training (75% of data) used for model building, and validation (25% of data) used for model validation. Using the predictive model, the MDACC validation cohort found 80% sensitivity and 80% specificity. We then validated the model in the Henry Ford cohort of 190 GBM patients of which 50 developed a VTE. In the external validation set, the predictive model was found to have a sensitivity = 78% and specificity = 49.3% (Fisher test p-value = 0.0008).

CONCLUSIONS

Our predictive model for the development of VTE during adjuvant chemotherapy in GBM patients retained high sensitivity in an external data set, however high specificity was lost. While the specificity in our model was higher than in previous studies examining the Khorona scale in GBM patients, further refinement to improve the models reliability to correctly identify people who will not later develop a VTE may be helpful.
QOLP-31. ASSESSING THE IMPACT OF GLIOBLASTOMA ON WORK PRODUCTIVITY IN PATIENTS AND THEIR CAREGIVERS
Authors: Armstrong Terri , Puduvalli Vinay , Walbert Tobias , Peters Katherine , Loughan Ashlee , Ahluwalia Manmeet , Province Warren Paula , Cachia David , Taylor Jennie , O Blakeley Jaishri , Ganguli Arijit , Khandelwal Nikhil , Kamalakar Rajesh , Noe Les , Kumthekar Priya
Published: November 2019

Information is limited on the impact of glioblastoma (GBM) on patient employment and caregiver time commitments. This observational multisite study evaluated the impact of GBM on patients’ employment and on caregivers’ ability to work and perform daily activities. A total of 180 adults diagnosed with GBM and their caregivers were stratified across 4 groups representing specific stages in the disease course: Group 1=newly diagnosed; 2=postradiation; 3=stable disease; 4=recurrence. We assessed the impact of GBM on employment status and self-reported cognitive function in patients (EORTC QLQ-C30) and in caregivers (Work Productivity and Activity Impairment Questionnaire). Prior to diagnosis, 64% of all patients (74% < 65 years old) were employed, while only 22% (26% for those < 65 years old) were employed after diagnosis. Though not reaching significance, newly diagnosed patients and those with stable disease reported higher mean cognitive function scores (72.0 and 71.9) than other groups (61.1 and 61.3; P=0.227). At study enrollment, 56% of all caregivers were employed, while 41% had left their jobs to care for their patients. The impact on caregiver work productivity varied with a higher percentage of caregivers of newly diagnosed patients and those with recurrent disease missing work (45% and 24%, respectively) and experiencing work impairment (54% and 36%, respectively) than the other groups (P< 0.05). Forty-one percent of caregivers of newly diagnosed patients to 25% of patients with stable disease reported impairment of daily activities. GBM had a significant impact on patient and caregiver employment from the time of diagnosis. High cognitive burden among patients might have impacted their employment. Overall work and activity impairment for caregivers was evident in all groups with a notable impact at the time of first diagnosis and recurrence of disease. Future studies will explore the impact of these findings in a longitudinal cohort.
RDNA-12. THE FANCONI ANAEMIA (FA) PATHWAY AND GLIOBLASTOMA: A NEW FOUNDATION FOR DNA DAMAGE RESPONSE TARGETED COMBINATIONS
Authors: Rominiyi Ola , Myers Katie , Gomez-Roman Natividad , Lad Nikita , Dar Dawoud , Jellinek David , Chalmers Anthony , Carroll Thomas , Chen Beining , Al-Tamimi Yahia , Collis Spencer
Published: November 2019

Treatment resistance in glioblastoma is underpinned by highly interconnected DNA damage response (DDR) processes. The FA-pathway is a fundamental DDR process required for the resolution of replication fork impeding lesions, and we have previously shown that it is inactive in normal brain, but is re-activated in glioblastoma, providing a cancer-specific target for combination DDR therapies. Here, we find that elevated FA-pathway gene expression in gliomas is associated with poor survival (-17.1% 5-year OS, p< 0.0001, n=329–REMBRANT). Furthermore, patient-derived glioblastoma stem cell (GSC) populations, which drive therapeutic resistance, display high FA-pathway expression relative to paired bulk tumour cell populations (mean 2.3-fold higher across genes, p=0.0073). We further show that inhibition of a single DDR process (FA-pathway, PARP, ATR or ATM) increases the susceptibility of glioblastoma cell lines and patient-derived GSCs to current adjuvant therapy. Importantly, clinically approved PARP inhibitor (PARPi) monotherapy stimulates robust FANCD2 mono-ubiquitination, supporting a role of FA-pathway activation in response to current DDR-targeted therapy. In clinically-relevant 3D GSC models, simultaneous inhibition of the FA-pathway (FAPi) and PARP or ATR enhanced temozolomide sensitisation compared to a single DDR inhibitor (DDRi). Furthermore, combined FAPi+PARPi consistently conferred radiosensitisation whilst combined FAPi+ATRi led to a profoundly radiosensitising effect; e.g. sensitizer enhancement ratio (SER0.37) of 3.23 (3.03–3.49, 95% CI). Furthermore, comparison of α/β ratio enhancement suggests dual-DDRi strategies fundamentally alter the response of GSCs, whilst single cell gel electrophoresis & immunofluorescence studies suggest FA-pathway based DDRi combinations profoundly delay the resolution of IR-induced DNA strand breaks at 6 hours post-treatment, with increased persistent DNA double strand breaks at 24 hours. In conclusion, simultaneously targeting the FA-pathway and interconnected DDR processes represents an appealing therapeutic strategy. Additionally, constitutive lack of FA pathway function in some tumours, could serve as a novel predictive biomarker for patient response to PARPi and ATRi currently in clinical trials.
RDNA-14. RADIATION-INDUCED miR-4516 CONTRIBUTES TO RADIO-RESISTANCE AND PROMOTES AGGRESSIVE PHENOTYPE IN GLIOBLASTOMA
Authors: Sebastian Ebin , Cui Tiantian , Hlavin Bell Erica , McElroy Joseph , Johnson Benjamin , Manchanda Gulati Pooja , Geurts Marjolein , Paixao Becker Aline , Fleming Jessica , Jaharul Haque S , Robe Pierre , Chakravarti Arnab
Published: November 2019

BACKGROUND

Glioblastoma is the most aggressive brain tumor with poor prognosis despite the best available treatment. MicroRNAs (miRNAs) are emerging as promising, novel prognostic biomarkers and therapeutic targets in glioblastoma. In a previous study, we demonstrated that miR-4516 predicts poor prognosis and functions as an oncogene in glioblastoma. Aim of the current study is to examine the role miR-4516 in radiation resistance and identify downstream targets contributing to this phenotype

METHODS

Radiosensitization was evaluated by cell viability and clonogenic assays. Cell apoptosis was evaluated using flow cytometry and immunoblotting. Potential targets of miR-4516 were identified using bioinformatic analysis (Targetscan and miRDB) and confirmed by luciferase reporter assays. Results were validated using immunoblotting. miR-4516 expression in glioblastoma cell lines after radiation treatment was quantified by qRT-PCR.

RESULTS

Expression of miR-4516 was increased up to 15 fold following radiation treatment, peaking at around 15min-60 min in primary and established glioblastoma cell lines including GBM 08-387, GBM 30 and U87-MG. Furthermore, inhibition of miR-4516 sensitized GBM 08-387, GBM30 and U87-MG cells to radiation in comparison to control groups as determined by cell viability and clonogenic assays. Further, miR-4516 inhibition induced apoptosis in these cell lines following radiation treatment. While conducting mechanistic studies, we found that the tumor-promoting function of miR-4516 was, in part, mediated by inhibition of p21 and PTPN14, two direct targets of miR-4516

CONCLUSION

Our data suggest that radiation induces the expression of miR-4516 in glioblastoma cell lines. This miRNA plays a critical role in radio-resistance and promotes aggressive phenotypes in glioblastoma and therefore, functional analyses of its target pathways may uncover novel therapeutically vulnerable target(s) in glioblastoma. FUNDING: R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01(NCI), Brain Tumor Funders Collaborative Grant, and OSU-CCC (all to AC). The Ton and Patricia Bohnenn Fund for Neuro_Oncology Research (to PR).
RTHP-03. FRAME-BASED AND MASKED STEREOTACTIC RADIOSURGERY: A PATIENT EXPERIENCE COMPARISON WITH THE GAMMA KNIFE ICON
Authors: Dawley Troy , Rana Zaker , Goenka Anuj , Schulder Michael
Published: November 2019

INTRODUCTION

Patients undergoing stereotactic radiosurgery (SRS) for intracranial pathology have two treatment options: frame-based (FB) versus masked (MB). There is sparse information on a patient’s experience between the two types and to what extent a patient’s diagnosis will predict their SRS experience.

METHODS

A retrospective analysis of patients who completed a questionnaire of their experience after SRS using the Gamma Knife Icon was completed.

RESULTS

Fifty-eight patients completed the questionnaire, 60% were FB and 40% MB. The average age was 63.3 + 15.3 years, 40% were male. Of the patients treated with a FB technique, 51% didn’t find SRS to be uncomfortable. Comparatively, 91% of MB patients didn’t find SRS to be uncomfortable. Patients who underwent FB treatment rated their pain of frame placement on a visual analog scale (VAS) 1–3, 24%, VAS 4–6, 46%, VAS 7–10, 30%. Eight patients answered that they didn’t tolerate the procedure as expected, most of which were treated using a FB method (87%). Compared to previous surgery or SRS, five patients found their experience of SRS wasn’t tolerable, while 93% of patients would consider repeat SRS. All patients treated felt adequately informed about the procedure. The patient experience of discomfort during SRS and their evaluation of pain during frame placement between patients treated for benign versus malignant lesions (discomfort: 59% vs. 22%, respectively and median VAS pain: 6 + 2.67, 4.5 + 1.99, respectively) determined a benign diagnosis had more discomfort during SRS compared to a malignant diagnosis. Pain during frame placement was similar for both diagnoses.

CONCLUSION

Patients experienced frame-based SRS as more uncomfortable than mask-based treatment. Benign pathologies appeared to have more discomfort compared to malignant pathologies. All patients of both techniques felt adequately informed about their procedure.
RTHP-06. IMPACT OF THE AMERICAN TAX PAYER RELIEF ACT ON STEREOTACTIC RADIOSURGERY UTILIZATION IN THE UNITED STATES
Authors: McClelland III Shearwood , Degnin Catherine , Chen Yiyi , Watson Gordon , Jaboin Jerry
Published: November 2019

INTRODUCTION

For brain metastases, single-fraction stereotactic radiosurgery (SRS) spares appropriately chosen patients from the invasiveness of operative intervention and the permanent cognitive morbidity of whole brain radiation. SRS is delivered predominantly via two modalities: Gamma Knife, and linear accelerator (LINAC). The implementation of the American Tax Payer Relief Act (ATRA) in 2013 represented the first time limitations specifically targeting SRS reimbursement were introduced into federal law. The subsequent impact of the ATRA on SRS utilization in the United States (US) has yet to be examined.

METHODS

The National Cancer Data Base (NCDB) from 2010–2016 identified brain metastases patients from non-small cell lung cancer (NSCLC) throughout the US having undergone SRS. Utilization between GKRS and LINAC was assessed before (2010–2012) versus after (2013–2016) ATRA implementation. Utilization was adjusted for several variables, including patient demographics and healthcare system characteristics.

RESULTS

From 2012 to 2013, there was a substantial decrease of LINAC SRS in favor of GKRS overall (37% to 28%) and individually in both academic and non-academic centers. Over the three-year span immediately preceding ATRA implementation, 65.8% received GKRS and the remaining 34.2% receiving LINAC. In the four years immediately following ATRA implementation 68.0% received GKRS compared with 32% receiving LINAC; these differences were not statistically significant.

CONCLUSIONS

ATRA implementation in 2013 caused an initial spike in Gamma Knife SRS utilization, followed by a steady decline, similar to rates prior to implementation. These findings are indicative that the ATRA provision mandating Medicare reduction of outpatient payment rates for Gamma Knife to be equivalent with those of LINAC SRS had a significant short-term impact on the radiosurgical treatment of metastatic brain disease throughout the US. Such findings should serve as a reminder of the importance and impact of public policy on treatment modality utilization by physicians and hospitals.