bluuebunny/crossref_metadata_2025_split huggingface dataset:
CMET-36. IMMUNOTHERAPY VERSUS STANDARD OF CARE IN MELANOMA BRAIN METASTASES WITH KNOWN BRAF STATUS
Authors: Barnett Addison , Sagar Soumya , Lauko Adam , (Auston) Wei Wei , Chao Samuel , Peereboom David , Stevens Glen , Angelov Lilyana , Yu Jennifer , Murphy Erin , Mohammadi Alireza , Suh John , Barnett Gene , Ahluwalia Manmeet 
Published: November 2019

Abstract

INTRO/OBJECTIVE
A mutation of the BRAF protein is seen in approximately 50% of melanoma patients. Immune checkpoint inhibitors (ICI) are standard therapy in melanoma patients independent of a patient’s BRAF status. The primary objective of this study is to investigate the impact of BRAF status in patients treated with ICI compared to non-ICI systemic therapy on overall survival (OS) in patients with melanoma brain metastasis (MBM).

METHODS
We reviewed 351 patients with MBM treated at our tertiary care center between 2000 and 2018. Of these, 144 had known BRAF status, 71 of which were BRAF mutant and 73 were BRAF wild-type. OS was calculated from the date of diagnosis of MBM to compare the efficacy of ICI to other systemic therapies. Many of these patients received multiple lines of treatment including targeted therapies at some point during their care. The log-rank test and Cox proportional hazard model was utilized to determine differences in OS.

RESULTS
Eighty-four percent of patients received local therapy that included either surgery, stereotactic radiosurgery, or whole brain radiation therapy. In BRAF wild-type patients, 40 received ICI and 33 underwent non-ICI systemic therapy with a median survival (5.6 vs 7.1 months) and 2-year survival (28% vs 32%), respectively (p=0.64). Of the BRAF mutant patients, 33 received ICI and 38 did not with a median survival (17.1 vs 9.0 months) and 2-year survival (36% and 19%), respectively (p=0.014). When controlling for age, KPS, ECM, and number of lesions, BRAF mutant MBM patients treated with ICI compared to non-ICI had an OS hazard ratio, HR=0.4 (95% CI=0.21 – 0.78, p=0.0069).

CONCLUSION
ICI therapy in BRAF mutant MBM patients results in improved OS compared to those with non-ICI systemic therapy. No such difference was observed in the BRAF wild-type cohort.
CMET-38. PREVALENCE AND SURVIVAL OUTCOMES OF UROTHELIAL CARCINOMA BRAIN METASTASES
Authors: Kavouridis Vasileios , Harary Maya , Smith Timothy , Braun David , Iorgulescu Bryan 
Published: November 2019

Abstract

BACKGROUND
Urothelial carcinoma is a common malignancy with ~79,000 new cases diagnosed annually. However, urothelial brain metastases (UBM) are encountered uncommonly. Herein we evaluate their national prevalence, predictors, and treatment outcomes in the contemporary era.

METHODS
The characteristics, management, and overall survival (OS) of UBM patients (2010–2015) were evaluated using the National Cancer Database, which comprises >70% of all newly diagnosed cancers in the U.S. OS was analyzed with Kaplan-Meier methods and log-rank tests. National outcomes were compared to our institutional cohort of UBMs.

RESULTS
Out of 208,600 patients diagnosed with urothelial carcinoma, 8.4% presented with stage IV disease--of these only 216 (1.2%) had BMs at the time of diagnosis. Patients presenting with bone, liver, or lung metastases were more likely to present with synchronous BMs. Brain involvement demonstrated significantly worse median OS (3.9mos, 95%CI: 3.1–4.9) than non-BM stage IV disease (10.9mos, 95%CI: 10.6–11.2, p< 0.001). Compared to non-BM stage IV disease, UBMs were more likely to have surgery for metastatic disease and receive radiotherapy (p< 0.001); but were less likely to have primary resection or chemotherapy. In multivariable analysis of stage IV urothelial cancer, BMs demonstrated significantly worse OS (HR 1.43, 95%CI: 1.20–1.72, p< 0.001). In our institutional data, 10 urothelial cancer patients developed BMs; of which 7 were male, median age and KPS at diagnosis were 64.9yo (IQR 56.4–72.0) and 85 (IQR 75–100). Four patients had synchronous metastases; the median number of BM lesions was 2 (IQR 1–2), with a median size of 2.6cm (IQR 1.6–3.3). All 10 underwent GTR, 3 also with SRS and 7 with WBRT, associated with a median OS of 16.5mos.

CONCLUSIONS
Our results confirm the rarity of UBMs and suggest that BM screening may only be indicated in stage IV patients with neurological symptoms. Systemic therapies demonstrate improved OS in these patients.
CMET-40. IMPACT OF WHOLE BRAIN RADIOTHERAPY ON LEPTOMENINGEAL METASTASIS FROM NON-SMALL CELL LUNG CANCER
Authors: Wen Lei , Zhou Zhaoming , Zhen Junjie , Zhou Cheng , Lai Mingyao , Shan Changguo , Cai Linbo 
Published: November 2019

Abstract

BACKGROUND
Leptomeningeal metastasis (LM) is a detrimental complication of patients with non-small cell lung cancer (NSCLC) and its incidence has increased due to recent improvements in survival. The aim of this study was to assess the impact of whole brain radiotherapy (WBRT), chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) on survival.

METHODS
Seventy-four consecutive patients diagnosed with LM from NSCLC between 2009 and 2018 in Sanjiu Brain Hospital were retrospectively reviewed. Survival was assessed by Kaplan-Meier analyses.

RESULTS
The median age was 54.5 (range 30–76) years. LM were diagnosed by MRI (36/74), cytology (4/74), or both (34/74). Eighteen patients (24.3%) were diagnosed at the initial presentation of lung cancer. Forty-seven (63.5%) patients harboring EGFR positive mutation while other twenty-seven patients (36.5%) were EGFR wild type. The median overall survival from diagnosis of LM was 8.1 months (95% confidence interval: 5.2 to 11.0). Patients who received EGFR-TKIs after LM had longer survival than those who did not (10.5 vs. 4.4 months, p＜0.001). No significant differences in survival were seen between patients who were treated with WBRT and those without, whether in EGFR mutation positive patients (11.6 vs. 15.0 months, p=0.353), or in EGFR wild type ones (5.1 vs. 3.3 months, p=0.116). Similarly, intravenous chemotherapy after LM had no impact on overall survival (7.5 vs. 8.1 months, p=0.9).

CONCLUSION
Median overall survival was higher than historical experience in our retrospective analysis. Survival was not improved by WBRT or intravenous chemotherapy. EGFR-TKIs could prolong survival of patients with LM from NSCLC.
COMP-06. PROBING GLIOBLASTOMA AND ITS MICROENVIRONMENT USING SINGLE-NUCLEUS AND SINGLE-CELL SEQUENCING
Authors: Peng Sen , Rath Sanhita , Vuong Connor , Bollam Saumya , Eschbacher Jenny , Mehta Shwetal , Sanai Nader , Kim Seungchan , Berens Michael , Dhruv Harshil 
Published: November 2019

Abstract
Single-cell (scSeq) and single-nucleus sequencing (snSeq) are powerful tools to investigate cancer genomics at single cell resolution. Multiple studies have recently illuminated intratumoral heterogeneity in glioblastoma, however, the majority focused on molecular complexity of tumor cells, without taking into account unexplored host cell types that contribute to the microenvironment around tumor. To address the glioblastoma microenvironment composition and potential tumor-host interactions, we performed deep coverage sequencing of freshly resected primary GBM patient tissue without implementing any tumor enrichment strategies. The sequencing resulted in 902 cells and 1186 nuclei, respectively, passing quality control and with low mitochondrial gene percentage. We customized reference transcriptome by listing gene transcript loci as exons to take into account immature RNA, which greatly improved the alignment rate for single-nucleus data. We applied Cell Ranger pipelines (Version 3.0.2) and Seurat package (Version 2.3.1) and discovered 10 clusters in both scSEQ and snSEQ. Pathway analysis of each cluster signature in scSeq data along with known GBM microenvironment cell signatures revealed glioma tumor population along with surrounding microglia/macrophages, astrocytes, pericytes, oligodendrocytes, T cells and endothelial cells. The analysis of snSEQ was able to capture the majority of cell types from patient tissues (tumor and microenvironment cells), but interestingly presented different cell type composition in microenvironment cell types such as microglia/marcophages. Integrating single-cell and single-nucleus transcriptomic data using canonical correlation analysis facilitated a comparison of snSEQ and scSEQ, contrasting depiction for certain cell types (e.g. NKX6-2 gene in Oligodendrocytes). Differential analysis of pathways between tumor and microenvironment cells unveiled potentially rewired pathways such as double strand break repair pathway. Our results demonstrate the cellular diversity of brain tumor microenvironment and lay a foundation to further investigate the individual tumor and host cell transcriptomes that are influenced not only by their cell identity but also by their interaction with surrounding microenvironment.
COMP-09. A CANCER DRUG ATLAS ENABLES PREDICTION OF PARALLEL DRUG VULNERABILITIES OF GLIOBLASTOMA
Authors: Narayan Ravi , Molenaar Piet , Cornelissen Fleur , Wurdinger Tom , Koster Jan , Westerman Bart 
Published: November 2019

Abstract
Personalized cancer treatments using synergistic combinations of drugs is attractive but proves to be highly challenging. The combinatorial nature of such problems results in an enormous parameter space that cannot be resolved by empirical research, i.e. testing all combinations for all molecularly defined tumors. In addition, effective drug synergy is hard to predict. Here we present an approach to map data of drug-response encyclopedias and represent these as a drug atlas. This atlas consists of a framework of chemotherapeutic responses that represents a drug vulnerability landscape of cancer. Based on data from the literature we found that many synergistic drug combinations show distinct inter therapy responses and drug sensitivities. We confirmed this by performing a drug combination screen against glioblastoma where we used 270 combination experiments. From the identified dual therapies we were able to predict and validate a triple drug synergy which was validated in vivo. This new and generalizable strategy opens the door to unforeseen personalized multidrug combination approaches.
COMP-11. SINGLE CELL MASS CYTOMETRY SIGNALING PROFILES AND A NOVEL COMPUTATIONAL TOOL IDENTIFY HIGH RISK GLIOBLASTOMA CELLS
Authors: Leelatian Nalin , Sinnaeve Justine , Mistry Akshitkumar , Barone Sierra , Diggins Kirsten , Greenplate Allison , Bartkowiak Todd , Roe Caroline , Weaver Kyle , Thompson Reid , Chambless Lola , Mobley Bret , Irish Jonathan , Ihrie Rebecca 
Published: November 2019

Abstract
In glioblastoma, changes in signaling, gene sequence, copy number, or transcript expression can define patient subgroups, but these subgroups are not yet associated with differential outcome for most patients with high-risk, IDH wild-type disease. Single cell interrogation of phospho-protein signaling has successfully revealed novel cell types associated with patient outcomes in blood cancers, suggesting that a comparable approach could be used in brain tumors. The goal of this study was to combine a single cell phospho-protein profiling approach with novel, automated computational analysis to identify abnormal glioblastoma cells that stratify patient clinical risk. Effective tissue dissociation strategies and validated antibody panels were created for mass cytometry analyses of resected glioblastoma tissue. These panels simultaneously measured 45 determinants of neural and glioma cell identity, including transcription factors, phospho-proteins, and surface receptors. 28 glioblastoma tumors were stained and analyzed using traditional gating, existing computational tools, and a new risk assessment population identification algorithm (RAPID, https://www.biorxiv.org/content/10.1101/632208v3). RAPID revealed two malignant cell types closely associated with differential patient outcomes. Glioblastoma negative prognostic (GNP) cells were associated with poor survival and defined by phospho-protein signaling in cells with aberrant neural developmental phenotypes. Glioblastoma positive prognostic (GPP) cells were associated with better progression free survival and defined by increased immunogenic signaling. A Cox proportional-hazards regression model was created to assess the influence of GNP and GPP cells on OS and PFS as continuous variables while accounting for other well-known clinical predictors. Each 1% increase of GNP cells was associated with an 7% increase in annual mortality rate (HR=1.07 [95% CI 1.03–1.12], p=0.001). Tumors containing GNP cells also significantly lacked CD45+ immune cell infiltration (Pearson r=-0.8). The signaling events that define these clinically significant glioblastoma cells represent a useful molecular classification, may indicate responsiveness to immunotherapy, and are themselves important targets of opportunity for new therapeutic approaches.
COMP-13. EARLY TUMOR VOLUME EVOLUTION ADAPTIVELY PREDICTS PATIENT-SPECIFIC RESPONSE AND PROGRESSION RISK TO RADIOTHERAPY, PEMBROLIZUMAB, AND BEVACIZUMAB IN RECURRENT HIGH-GRADE GLIOMA IN A PHASE I TRIAL
Authors: Glazar Daniel , Brady Rene , Howard Rachel , Grass Daniel , Arrington John , Yu Michael , Raghunand Natarajan , Sahebjam Solmaz , Enderling Heiko 
Published: November 2019

Abstract

PURPOSE/OBJECTIVES
We set out to predict response and progression risk in recurrent high-grade glioma patients treated with hypofractionated stereotactic radiation plus pembrolizumab and bevacizumab (NCT02313272). At present RANO criteria define progression as 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement (either at baseline or best response) or significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids. To this extent, a predictive model is needed to adaptively learn and forecast individual response to therapy. We evaluate if early tumor volume evolution can train a mathematical model to predict subsequent response to therapy.

MATERIALS/METHODS
We develop a mathematical model that describes patient-uniform tumor growth rate and initial pembrolizumab and bevacizumab responses, and patient-specific treatment response dynamics. A total of 154 radiology scans were delineated to derive longitudinal tumor volumes of 26 patients. In a leave-one-out study, patient-uniform model parameters are derived and then applied to the left-out patient to adaptively learn treatment response dynamics to forecast tumor volume evolution and progression risk. Model prediction performance is evaluated based on classification accuracy, including sensitivity and specificity.

RESULTS
Patient-uniform glioma growth rate and initial treatment response rates are estimated to achieve acceptable fits to the longitudinal data of all untrained patients with R2 = 0.81 [0.75, 0.89]. Response dynamics are predicted with high accuracy (0.78 [0.76, 0.79]), with positive and negative predictive values of 0.90 [0.86, 0.92] and 0.81 [0.78, 0.86], and sensitivity and specificity of 0.71 [0.69, 0.73] and 0.88 [0.83, 0.91] respectively.

CONCLUSIONS
Two patient-specific parameters in a mathematical model can be adaptively learned from early tumor volume evolution to predict subsequent response to therapy and progression risk for individual patients. Future validation is required in an independent dataset and prospective evaluation in another clinical trial.
COMP-15. MOLECULAR AND CLONAL EVOLUTION IN RECURRENT METASTATIC GLIOSARCOMA
Authors: Anderson Kevin , Tan Aaron , Parkinson Jonathon , Back Michael , Kastela Marina , Newey Allison , Brewer Janice , Wheeler Helen , Hudson Amanda , Amin Samirkumar , Johnson Kevin C , Barthel Floris , Verhaak Roel , Khasraw Mustafa 
Published: November 2019

Abstract
Gliosarcoma, a World Health Organization grade IV glioma, is a rare variant of glioblastoma (GBM) that contains distinct glial and mesenchymal components. Histologically, the glial component matches criteria for glioblastoma, and both components share genetic alterations common to GBM. Though GBM are known to strongly infiltrate surrounding tissue, extracranial metastases are rare, and the underlying mechanisms are still poorly understood. We present a rare case of a 37-year-old woman who was initially diagnosed with IDH wild-type gliosarcoma in the frontal lobe and later developed two local recurrences and extracranial metastases to the vertebral and pelvic bones. In order to understand the clonal relationships between four tumor instances and the origin of metastasis, we performed whole genome sequencing of the intracranial tumors and the tumor located in the right iliac bone. We compared mutational and copy number profiles and inferred tumor clonal phylogeny. The tumors harbored shared GBM alterations including TP53, NF1, and RB1 mutations and CDKN2A deletion. Comparisons of the metastatic to intracranial tumors highlighted a high similarity in molecular profiles, but contrasting evidence regarding the origin of the metastasis. The metastasis was most similar to the second recurrence with respect to mutational signatures, reflected in the activity of signatures associated with defective DNA mismatch repair not observed in the primary or first recurrent tumor. The metastasis was most similar to the first recurrence with respect to copy number profile; both samples displayed widespread amplifications indicative of whole genome doubling. Results of subclonal reconstruction suggested that the second recurrent and metastatic tumors originated from more than one clone and developed subclone-specific driver mutations. The branching phylogeny and copy number profiles suggest the metastasis was largely derived from the first recurrence. This is the first analysis of clonal evolution of extracranial metastasis in gliosarcoma and highlights alterations driving aggressive GBM progression.
DDIS-07. IDENTIFICATION OF DRUGGABLE MOLECULAR TARGETS IN MENINGIOMA
Authors: Tran Anh , Zhang Lyndsee , Sahm Felix , Scholtens Denise , Horbinski Craig 
Published: November 2019

Abstract

BACKGROUND
Meningioma is the most common primary intracranial tumor, with nearly 30,000 new cases in the US every year. Many meningiomas invade the brain, recur, and become radioresistant, causing severe disability and lethality. Prior work by Sahm et al. showed that meningiomas have consistent patterns of global CpG methylation, and that those patterns are better at prognostic stratification than traditional WHO grading (Lancet Oncol. 2017 May;18(5):682–694). In this study, we hypothesized that specific methylation events could provide further insights as to the signaling pathways driving more aggressive behavior, and identify druggable targets.

METHODS
We analyzed the Illumina 450k CpG methylation profiles of 493 meningiomas that were published in Lancet Oncology, searching for associations between methylation at individual CpG sites and progression-free survival (PFS). Pathway enrichment analyses were performed using gProfiler and Reactome for genes closest to significant CpG sites, followed by screening for candidate drugs targeting the pathways that were linked with malignant behavior using the ReactomeFIViz Cytoscape Plugin.

RESULTS
Our analyses revealed 981 genes in which methylation of mapped CpG sites was consistently associated with either shorter PFS (positive hazard ratios (HRs)) or longer PFS (negative HRs) at FDR-adjusted p< 0.05. Methylation of genes encoding proteins involved in G-protein coupled receptor (GPCR) signaling pathways, especially G-alpha (s) and olfactory signaling pathways, showed pronounced association with PFS. We identified 134 anticancer drugs that target the GPCR pathway, including docetaxel and raloxifene hydrochloride, which specifically target G alpha (s) subcomponents. Both are FDA-approved, but no published data exist on their use in meningiomas.

CONCLUSIONS
This project is advancing our understanding of the molecular pathways driving aggressive behavior in meningioma, and is identifying existing drugs that can be repurposed to treat this tumor.
DDIS-20. IMIPRIDONE STRUCTURE ACTIVITY RELATIONSHIP UNCOVERS ONC206 AS THE NEXT BITOPIC DRD2 ANTAGONIST FOR ONCOLOGY WITH DIFFERENTIATED RECEPTOR PHARMACOLOGY
Authors: Prabhu Varun , Cuoco Caroline , Jung Jinkyu , Rahman Kawakibi Abed , Willette Blair , Day Marilyn , Anantharaman Lakshmi , Charter Neil , Rucker Joseph , Doranz Benjamin , Oster Wolfgang , Stogniew Martin , Gilbert Mark , Benjamin Free R , Sibley David , Allen Joshua 
Published: November 2019

Abstract
ONC201 is the first bitopic antagonist of dopamine receptor D2 (DRD2) in oncology clinical trials, which have shown that the small molecule is well tolerated and induces durable tumor regressions in H3 K27M-mutant glioma patients. ONC201 possesses a unique tri-heterocyclic core structure that prompted a medicinal chemistry exploration following its successful clinical translation. Chemical derivatization of the ONC201 pharmacophore from an angular to a linear isomer ablated DRD2 antagonist activity and anti-cancer activity, indicating the core structure integrity is critical. A series of analogs that share the same core structure, called imipridones, were profiled for modulation of β-arrestin recruitment to GPCRs and anti-cancer efficacy. The profiled imipridones exhibited a heterogeneous spectrum of GPCR agonist/antagonist activity that was exclusive to Class A GPCRs. The addition of electron withdrawing groups to one of two peripheral benzyl rings enhanced the potency of GPCR engagement and anti-cancer effects, while derivatization of the other benzyl ring was inactivating. Among the GPCR hits identified, maximal variance in imipridone GPCR antagonism was identified for DRD2/DRD3. ONC206 emerged as the most selective and potent antagonist for DRD2/DRD3 with a Ki of ~320nM for DRD2 with complete specificity across human GPCRs and complete DRD2 antagonism. Schild analyses of ONC206 in cAMP and β-Arrestin recruitment assays revealed hallmarks of non-competitive DRD2 antagonism, unlike antipsychotics but similar to ONC201. Shotgun mutagenesis across DRD2 identified 7 residues critical for ONC206-mediated antagonism at orthosteric and allosteric sites. Six residues were critical for ONC201 and ONC206, however the impact varied between the two compounds and one allosteric residue was exclusive to ONC206. Structural mapping revealed that some ONC206-critical allosteric residue interactions are located at the interface of TM-IV and –V that mediates the DRD2 homodimer interface. Thus, ONC206 is a bitopic DRD2 antagonist that may be poised to address oncogenic DRD2 monomers or dimers.