tbuckley/cabot-search huggingface dataset:
Abstract 19569: Racial Differences in Clinical Outcomes and Resource Utilization Associated With Acute Myocardial Infarction Hospitalizations in the United States: A Population-wide Analysis From 2011-2012
Authors: Nilay Kumar, Rohan Khera, Neetika Garg
Journal: Circulation (2015)

Background and objectives: Racial-ethnic disparities in cardiovascular diseases are a major public health problem in the US. There are few recent data on racial differences in clinical outcomes and resource utilization associated with acute myocardial infarction (AMI) hospitalizations. Hypothesis: There are significant racial-ethnic differences in AMI hospitalization outcomes. Methods: We used the 2011-2012 Nationwide/National Inpatient Sample to identify primary AMI hospitalizations. Outcomes of interest included in-hospital mortality, utilization of PCI and thrombolysis, inflation adjusted charges and length of stay. Relevant ICD-9 codes were used. Racial-ethnic differences in outcomes were tested using logistic and linear regression models. Results: 228,302 AMI hospitalizations representing 1.1 million hospitalizations nationwide were included in the study. After adjusting for age, sex, HTN, DM, PCI, thrombolysis, socioeconomic status (SES) and APR-DRG mortality risk, Blacks had significantly lower (OR 0.88, 95% CI 0.81 - 0.94; &lt;0.001) and Native Americans significantly higher (OR 1.37, 1.03 - 1.81; p=0.03) case fatality compared to Whites (Model ROC=0.88, p&lt;0.001). Blacks were less likely (OR 0.76, 95% CI 0.72 - 0.80; p&lt;0.001) and other races more likely (OR 1.33, 95% CI 1.23 - 1.43; p&lt;0.001) to undergo PCI adjusted for SES. SES adjusted odds of thrombolysis were lower in Blacks (OR 0.80, 0.67 - 0.97; p&lt;0.001) and higher in Native Americans (OR 3.78, 1.42 - 10.07; p=0.01) compared to Whites. There were significant differences in charges and LOS across races. Conclusions: Blacks hospitalized for AMI are less likely and NA more likely to die in the hospital compared to Whites. Blacks are less likely to receive reperfusion therapy compared to Whites. Future studies should investigate the mechanism of the apparent protective effect of Black race on in-hospital mortality in AMI.
COMP-11. CHROMATIN RUN-ON AND SEQUENCING (ChRO-seq) PROVIDES RETROSPECTIVE MOLECULAR PROFILING AND TRANSCRIPTIONAL ACTIVITY OF BRAIN TUMOR SPECIMENS UNSUITABLE FOR CONVENTIONAL RNA SEQUENCING
Authors: Tinyi Chu, Edward Rice, Hans Salamanca, Zhong Wang, Sharon Longo, Jared Sweeney, Brendon Verhave, Alexa Bodman, Robert Corona, Mariano Viapiano, Lawrence Chin, Charles Danko
Journal: Neuro-Oncology (2018)

The human genome encodes a variety of poorly understood RNA species that play important roles in the etiology complex disease yet remain challenging to identify in clinical isolates. We recently developed chromatin run-on and sequencing (ChRO-seq), a novel technology that maps the location of RNA polymerase genome-wide using virtually any frozen tissue sample, including samples with degraded RNA that are intractable to conventional RNA-seq. Here we report an integrative analysis of ChRO-seq maps from 61 primary human glioblastoma (GBM) tumors with matching clinical data, obtained from a retrospective cohort of patients banked at SUNY Upstate Medical Center (Syracuse, NY) between 1987 and 2007 (characteristics: Male:Female ratio= 2:1; median age at diagnosis= 59 years; median KPS=80; median overall survival= 343 days). Using ChRO-seq we discovered the boundaries and expression levels of annotated and unknown genes, lincRNAs, and active distal enhancers. Surprisingly, active enhancers in primary GBMs closely resembled the patterns found in the normal human brain, suggesting that malignant GBM tissue remains similar to the cell of origin. Despite extensive overall similarity, approximately 12% of enhancers were unique to GBMs. These enhancers drive regulatory programs similar to those in the developing nervous system and are enriched for transcription factor binding sites that specify a stem-like cell fate. More importantly, we discovered a core group of immune-related transcription factors and their associated binding sites whose activity is highly predictive of clinical outcomes in primary GBMs (HR= 2.66; p = 3.8e-4). Finally, we used the characteristic signatures of cell-type-specific enhancer activation to deconvolve the proportion of immune cell types infiltrating each tumor. Our study uncovers new insights into the molecular etiology of GBM and introduces ChRO-seq as a useful approach to map regulatory programs contributing to complex and heterogeneous diseases.
ATIM-10. A PHASE I/II CLINICAL TRIAL OF AUTOLOGOUS CMV-SPECIFIC CYTOTOXIC T CELLS (CMV-TC) FOR GLIOBLASTOMA: DOSE ESCALATION AND CORRELATIVE RESULTS
Authors: Marta Penas-Prado, Shiao-Pei Weathers, Shouhao Zhou, Carlos Kamiya-Matsuoka, Barbara O’Brien, Monica Loghin, Rebecca Harrison, Be Lian Pei, Sandra Ictech, Kathy Hunter, W K Alfred Yung, John de Groot, Elizabeth J Shpall, Amy Heimberger, Katy Rezvani
Journal: Neuro-Oncology (2018)

Cytomegalovirus (CMV) antigens are present in > 90% of GBMs but not in normal brain. CMV-TC in GBM tumor tissue have their effector function suppressed. Highly functional CMV pp65 specific T cells can be expanded in vitro from peripheral blood (PB) of GBM patients. Autologous polyclonal CD8+ and CD4+ CMV-TC from patients with recurrent GBM were expanded ex vivo under GMP-compliant conditions and administered after 3 weeks of lymphodepleting dose-dense temozolomide (ddTMZ, 100 mg/m2); 4 dose levels (5 x 106 cells to 1 x 108 cells), 3 + 3 design. Treatment was repeated q 6 weeks; total of 4 cycles. Eligibility: ≥18 years of age, KPS ≥60, CMV sero+, on ≤ 2 mg of dexamethasone daily, any number of relapses. Imaging response evaluated by MRI q 6 weeks. In vivo persistence and expansion of adoptively-infused CMV-TC determined by dextramer staining and multiparameter flow cytometry in serially-sampled PB. 34 patients screened, 18 underwent leukapheresis, 15 completed cycle 1. Median age 56 (27–69), median KPS 90; 11 were at 1st, 3 at 2nd and 1 at 3rd relapse. MGMT methylated in 6, unmethylated in 3, indeterminate/unknown in 6. IDH status wildtype in 10, mutated in 3, unknown in 2. No dose limiting toxicities (DLTs) observed. Complete radiographic response observed in 1 patient, partial response in 2, stable disease in 6, and progressive disease in 6. Repeated infusions of CMV-TC were associated with significant increase in circulating CMV+ CD8+ T-cells, but cytokine production (CD107a, TNFα, IFNγ, IL2) was suppressed (dose level 4 analysis ongoing). Adoptive infusion of CMV-TC after lymphodepleting therapy with ddTMZ was well tolerated with no DLTs; 1 x 10e8 confirmed as safe dose. Effector function in PB was suppressed. Correlative studies of CMV-specific T cell effector function in tumor microenvironment will be assessed in window-of-opportunity expansion cohort.
PATH-57. MOLECULAR DETERMINANTS OF RECURRENCE AND MALIGNANT TRANSFORMATION IN DIFFUSE LOW GRADE GLIOMA
Authors: Ko-Ting Chen, Ian Chang, Tai-Wei Erich Wu
Journal: Neuro-Oncology (2018)

Tumor recurrence and malignant transformation (MT) are the main contributing factors of poor prognosis in treating diffuse infiltrative low grade gliomas (LGG). In the current study, we conducted an integrated approach – transcriptomic analysis and in-depth clinical and molecular information to find susceptible genes associated with MT. MATERIALS AND From 2004 to 2015, a total of 56 newly diagnosed World Health Organization (WHO) grade II LGG tumor samples were collected during surgical resection. All tissues were subjected to whole exome sequencing (WES) as well as transcriptome profiling by RNA sequencing (RNA-Seq) analysis. Twenty-eight (50%) patients had disease recurrence with a median RFS of 47.6 months. Among 18 of the 28 (64.3%) re-operated patients had MT with a median malignant transformation-free survival (MTFS) of 82.3 months. After adjusting all clinical factors in multivariate Cox proportional hazard model, male gender was the only clinical risk factors of poorer RFS with an adjusted hazard ratio (AHR) of 3.695 (95% CI: 1.353–10.093, p=0.0108); larger tumor volume (AHR:5.422, 95% CI: 1.549–18.977, p=0.0082) was the only risk factor of shorter MTFS. Of the top 50 expressed variant genes, we identified 15 genes that could cluster the 56 samples differentially into two categories: over-expression (n=26) and under-expression (n=30). A further comparison of clinical characteristics between under-expression group and over-expression group revealed a significantly shorter RFS (39.6 vs. 82.6 months, p=0.0201) and shorter MTFS (59.1 months, p=0.0239). Tumor locations in the paraventricular zone (PVZ) were significantly higher in the under-expression group (p=0.0466). CONCLUSIONS: Among molecular parameters, we found that down-regulation of a 15-gene signature was significantly correlated with tumor infiltrated to PVZ and with both shorter RFS and MTFS. Further examination of this prognostic gene signature reveals a functional connection to core neuronal processes, such as neurotransmission and calcium signaling.
ACTR-70. INCREASING SURVIVAL IN BIOPSY-ONLY GBM PATIENTS
Authors: John Gainer, Harry Cook
Journal: Neuro-Oncology (2018)

It is generally expected that survival from GBM is correlated to the extent of resection. That is, patients having only a biopsy don’t live as long as those having partial or complete resections. Fifteen years ago, 2-year survival of biopsy-only patients was 5%. In 2005, Stupp et al. added temozolomide (TM Z) to radiation therapy and also established a follow-up TMZ chemotherapy regimen. This increased 2-year survival of unresected GBM patients from 4.6% to 10.4 % (Stupp et al., 2009). Lately, due to the still-low survival rate, biopsy-only patients are often excluded from GBM clinical trials. It is known that hypoxic tumors are resistant to radiation therapy (Sheehan et al., 2010). Thus, Diffusion Pharmaceuticals Inc. added trans sodium crocetinate (TSC) to temozolomide-radiation therapy, but not to the chemotherapy in a Phase 2 clinical trial (Gainer, et al., 2017). TSC stimulates re-oxygenation of hypoxic tumors (Sheehan, et al, 2009, 2011). It acts systemically to re-oxygenate hypoxic tissue but has no effect on normal cells. When combined with temozolomide and radiation, TSC resulted in a 2-year survival of biopsy-only patients of 40%, in effect quadrupling the 2005 Stoop results. TSC is being currently studied in a Phase 3 GBM trial involving solely biopsy-only patients. In this trial, TSC is added to both the radiotherapy and chemotherapy sessions, preceding the dosing of TMZ. This trial is called INTACT (NCT03393000) and is currently enrolling patients.
CADD-21. PROTEASOME INHIBITION IS A TARGETED THERAPY FOR PTEN-DEFICIENT GLIOBLASTOMAS
Authors: Jorge Benitez, Darren Finlay, Jianhui Ma, Tomoyuki Koga, Kristiina Vuori, Frank Furnari
Journal: Neuro-Oncology (2018)

One of the most common genetic alterations in glioblastoma (30–40%) occurs in the PTEN (phosphatase and tensin homolog) tumor suppressor gene, where loss of function has been mechanistically linked to increased tumor cell invasion, and to a lack of radio- and chemo-therapy response. To identify new drug compounds that target PTEN-deficient brain tumors we performed a high throughput drug screen using patient-derived GBM spheres and found that PTEN-deficient samples were highly sensitive to proteasome inhibition. We confirmed this sensitivity in GBM spheres and iNPCs (inducible Neuronal Progenitor Cells) by genetically over-expressing or deleting PTEN, where PTEN over-expression decreased and PTEN-deletion increased sensitivity to the drug, respectively. Additionally, proteasome inhibition specifically suppressed tumor growth in mice of orthotopically engrafted human glioblastoma samples. Mechanistically, we determined that PTEN-deficient cells are more sensitive to proteasome inhibition due to an increase in protein synthesis rate and loss of autophagy activity associated with activation of the PI3K/mTOR pathway. This study reveals that proteasome inhibition is a targeted-therapeutic strategy for PTEN-deficient brain cancer.
ATIM-40. HIGH RATE OF OBJECTIVE ANTI-TUMOR RESPONSE IN 9 PATIENTS WITH GLIOBLASTOMA AFTER VIRO-IMMUNOTHERAPY WITH ONCOLYTIC PARVOVIRUS H-1 IN COMBINATION WITH BEVACICUMAB AND PD-1 CHECKPOINT BLOCKADE
Authors: Karsten Geletneky, Andreas Bartsch, Christian Weiss, Helga Bernhard, Antonio Marchini, Jean Rommelaere
Journal: Neuro-Oncology (2018)

Combination therapy is an emerging concept to improve the clinical effects of oncolytic virus based anti-cancer strategies. In a phase I/IIa trial (ParvOryx01) the oncolytic H-1 parvovirus (H-1PV) induced markers of immune activation in patients with recurrent glioblastoma. The goal of this investigation was to enhanced H-1PV efficiency by combination treatment with immune modulators, namely bevacicumab and checkpoint blockade. 9 patients (age 29 to 69 years) with primary (n=2) or recurrent (n=7) glioblastoma were treated in a compassionate use (CU) program with a combination of H-1PV followed by bevacicumab and PD-1 blockade. 7 of the patients received both intratumoral and intravenous injection of H-1PV and 2 patients only intravenous virus treatment. GMP-grade H-1 virus and medication was provided by Oryx GmbH&Co KG, Baldham, Germany) on a humanitarian basis. MRI was analyzed by an independent neuroradiologist to determine objective tumor response rate (ORR) applying RANO criteria. Objective tumor response was observed in 7 of 9 patients (78%). Two patients showed complete responses (22%), 5 patients had partial remissions (56%) with tumor reduction between 49% up to 94% and 2 patients progressive disease (22%). Interestingly, both patients with progressive disease showed local anti-tumor responses where virus was injected but developed new lesions. The treatment was well tolerated and lead to clinical improvement in all symptomatic patients (n=5). CONCLUSION: H-1PV based viro-immunotherapy lead to ORR in 78% of glioblastoma patients. This is a much higher response rate than reported for treatment with either bevacizumab or checkpoint blockade and it supports further systematic clinical development of this novel concept for malignant glioma therapy.
INNV-41. MY STORI -- A SYMPTOM TRACKING AND REPORTING INSTRUMENT MOBILE APPLICATION FOR CENTRAL NERVOUS SYSTEM CANCER PATIENTS
Authors: Xinyi Li, Elizabeth Vera, Mark Gilbert, Orieta Celiku, Terri Armstrong
Journal: Neuro-Oncology (2018)

Managing symptom burden and its impact on the quality of life is an integral part of central nervous system (CNS) cancer patient care. However, keeping track of symptoms and their management is typically done through ad hoc means. Furthermore, reporting is often limited to completing survey instruments as part of the patient follow-up. While general-purpose mobile apps that track medical symptoms exist, they are not geared toward managing and recording the experience of patients with cancer. Cancer-specific apps are emerging but may not cover the entire range of symptoms in patients with CNS cancers. We used two open source frameworks introduced by Apple to enable development of iOS operating system apps for medical research and personal care -- ResearchKit and CareKit -- to develop a mobile app framework for the CNS cancer context. Existing validated symptom reporting instruments, qualitative interviews, and evidence-based symptom management tools were used in the framework. We developed the My STORI mobile app to center on the experience of brain and spine cancer patients: patients and their family members can assess daily symptoms and impact and record any actions that were taken to mitigate them. Summaries of how these measures have evolved over time can be displayed in a series of plots and compiled into reports shareable with the care team. The app is based on research instruments that reflect the knowledge accumulated through years of clinical research in neuro-oncology. Mobile applications have the potential to promote self care, facilitate symptom management, as well as facilitate intuitive, frequent, and convenient collection of invaluable clinical-outcome research data. The My STORI app is an innovation in patient care inspired and guided by years of outcomes research, and tells an important aspect of the story of brain and spine cancer patients.
Abstract #4584: Exploration of the mechanisms of PHY906 in reducing the intestinal toxicity caused by irinotecan
Authors: Wing Lam, Scott Bussom, Fulan Guan, Zaoli Jiang, Shwu-Huey Liu, YungChi Cheng
Journal: Cancer Research (2009)

PHY906 is a standardized four-herb traditional Chinese formulation that has been used for over 1700 years in the treatment of gastrointestinal ailments and is currently in anticancer clinical trials in the US as an adjuvant to chemotherapy. Preliminary clinical results indicated PHY906 could decrease G.I. toxicity triggered by irinotecan for treating colon cancer. In a murine colon-38 allograft model, PHY906 (500 mg bid days 0-3) alone, does not significantly inhibit tumor growth. However, the combination of PHY906 and irinotecan (360mg/kg, day 1) had higher anti-tumor activity in comparison to irinotecan alone. Additionally, PHY906 decreased weight loss caused by irinotecan. The impact of PHY906 on the intestinal toxicity caused by irinotecan at day 2 and day 4 were studied. Adding PHY906 to irinotecan treatment, a) reduced irinotecan induced degenerative changes throughout different regions of the intestine on day 4 but not on day 2, b) reduced irinotecan induced DNA damage and apoptosis of intestinal cells on day 4, c) promoted the re-growth of crypt cells which could be partially attributed to the wnt3a-potentiation activity of the aglycone component(s) of PHY906 on day 4, d) inhibited TNF-\#945; induced NF-kB activity, e) decreased the infiltration of neutrophils in intestinal crypt areas and decreased pro-inflammatory cytokine levels. In summary, our studies suggest that PHY906 reduces intestinal damage caused by irinotecan through the inhibition of inflammation and enhancement of intestinal repair by promoting intestinal progenitor cell proliferation.  This work is supported by a supplement grant: CA-63477 from NCI, USA    Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4584.
Abstract 13197: Hyperhomocysteinemia Enhances Fibrinogen-beta Amyloid-Collagen Complex Formation Causing Loss of Short Memory in Mice
Authors: Nino Muradashvili, Reeta Tyagi, Suresh C Tyagi, David Lominadze
Journal: Circulation (2013)

It is known that high level of homocysteine (Hcy), called hyperhomocysteinemia (HHcy) is associated with vascular dementia, seizure, stroke, and Alzheimer disease (AD). Although a strong associatio...
Effects of Statins on Coronary Atherosclerotic Plaques
Authors: Sang-Eun Lee, Hyuk-Jae Chang, Ji Min Sung, Hyung-Bok Park, Ran Heo, Asim Rizvi, Fay Y. Lin, Amit Kumar, Martin Hadamitzky, Yong Jin Kim, Edoardo Conte, Daniele Andreini, Gianluca Pontone, Matthew J. Budoff, Ilan Gottlieb, Byoung Kwon Lee, Eun Ju Chun, Filippo Cademartiri, Erica Maffei, Hugo Marques, Jonathon A. Leipsic, Sanghoon Shin, Jung Hyun Choi, Kavitha Chinnaiyan, Gilbert Raff, Renu Virmani, Habib Samady, Peter H. Stone, Daniel S. Berman, Jagat Narula, Leslee J. Shaw, Jeroen J. Bax, James K. Min
Journal: JACC. Cardiovascular imaging (2018)
Near‐Infrared‐Triggered Release of Ca<sup>2+</sup> Ions for Potential Application in Combination Cancer Therapy
Authors: Qiaoshan Chen, Da Huo, Haoyan Cheng, Zhiheng Lyu, Chunlei Zhu, Baohong Guan, Younan Xia
Journal: Advanced Healthcare Materials (2018)

Abstract Calcium ion (Ca 2+ ), an abundant species in the body, is a potential therapeutic ion with manageable side effects. However, the delivery of such a highly charged species represents a great challenge. Here, a nanosystem based on Au nanocages (AuNCs) and a phase‐change material (PCM) for delivering calcium chloride (CaCl 2 ) into cancer cells and thereby triggering cell death upon near‐infrared (NIR) irradiation is demonstrated. In the absence of NIR irradiation, the nanosystem, denoted CaCl 2 ‐PCM‐AuNC, shows negligible cytotoxicity because the Ca 2+ ions are fully encapsulated in a solid matrix. Upon NIR irradiation, the Ca 2+ ions are swiftly released due to the melting of PCM matrix in response to photothermal heating. The sudden increase in intracellular Ca 2+ causes disruption to the mitochondrial Ca 2+ homeostasis and thus the loss of mitochondrial membrane potential, subsequently resulting in cell apoptosis. This nanosystem provides a new method for cancer treatment by tightly managing the intracellular concentration of a physiologically essential element.
Treatment‐free remission with first‐ and second‐generation tyrosine kinase inhibitors
Authors: Jorge Cortes, Delphine Rea, Jeffrey H. Lipton
Journal: American Journal of Hematology (2018)

Abstract Chronic myeloid leukemia (CML) has become a chronic disease, for which the chronic phase is manageable with tyrosine kinase inhibitor (TKI) therapy. Patients with optimal responses to TKIs have achieved long‐term survival, and treatment‐free remission (TFR) has since become an additional treatment goal in CML. In this review, we discuss important factors to consider prior to stopping treatment. In addition, published and presented data with the first‐generation TKI imatinib, as well as current clinical trials evaluating TFR with the second‐generation TKIs dasatinib and nilotinib, are examined. Results obtained outside of clinical trials have been included as well. Because successful TKI discontinuation depends upon accurate BCR‐ABL1 monitoring, emerging technologies are also discussed. Clinical data obtained to date indicate that for many patients who achieve deep molecular response (DMR) on TKI therapy, TFR is a safe treatment goal, and, if the response is lost, patients can expect to regain their responses immediately upon reinitiation of TKI. It is also clear that there remains much room for improvement to make TFR a successful reality for most patients. Data from ongoing trials should help refine decisions as to which patients are the best candidates to attempt TKI discontinuation with safe monitoring in place.