tbuckley/cabot-search huggingface dataset:
Tumor Genomic Profiling Guides Patients with Metastatic Gastric Cancer to Targeted Treatment: The VIKTORY Umbrella Trial
Authors: Jeeyun Lee, Seung Tae Kim, Kyung Kim, Hyuk Lee, Iwanka Kozarewa, Peter G.S. Mortimer, Justin I. Odegaard, Elizabeth A. Harrington, Juyoung Lee, Taehyang Lee, Sung Yong Oh, Jung-Hun Kang, Jung Hoon Kim, Youjin Kim, Jun Ho Ji, Young Saing Kim, Kyoung Eun Lee, Jinchul Kim, Tae Sung Sohn, Ji Yeong An, Min-Gew Choi, Jun Ho Lee, Jae Moon Bae, Sung Kim, Jae J. Kim, Yang Won Min, Byung-Hoon Min, Nayoung K.D. Kim, Sally Luke, Young Hwa Kim, Jung Yong Hong, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, AmirAli Talasaz, Simon J. Hollingsworth, Kyoung-Mee Kim, Won Ki Kang
Journal: Cancer Discovery (2019)

Abstract The VIKTORY (targeted agent eValuation In gastric cancer basket KORea) trial was designed to classify patients with metastatic gastric cancer based on clinical sequencing and focused on eight different biomarker groups (RAS aberration, TP53 mutation, PIK3CA mutation/amplification, MET amplification, MET overexpression, all negative, TSC2 deficient, or RICTOR amplification) to assign patients to one of the 10 associated clinical trials in second-line (2L) treatment. Capivasertib (AKT inhibitor), savolitinib (MET inhibitor), selumetinib (MEK inhibitor), adavosertib (WEE1 inhibitor), and vistusertib (TORC inhibitor) were tested with or without chemotherapy. Seven hundred seventy-two patients with gastric cancer were enrolled, and sequencing was successfully achieved in 715 patients (92.6%). When molecular screening was linked to seamless immediate access to parallel matched trials, 14.7% of patients received biomarker-assigned drug treatment. The biomarker-assigned treatment cohort had encouraging response rates and survival when compared with conventional 2L chemotherapy. Circulating tumor (ctDNA) analysis demonstrated good correlation between high MET copy number by ctDNA and response to savolitinib. Significance: Prospective clinical sequencing revealed that baseline heterogeneity between tumor samples from different patients affected response to biomarker-selected therapies. VIKTORY is the first and largest platform study in gastric cancer and supports both the feasibility of tumor profiling and its clinical utility. This article is highlighted in the In This Issue feature, p. 1325
Stool donor qualification and collection from metastatic melanoma (MM) patients (pts) who have responded to checkpoint inhibitors (CPI) for manufacturing of fecal microbiota transplantation (FMT).
Authors: Elizabeth M. Burton, Isabella Claudia Glitza, Jennifer Mahoney, Jennifer Wortman, John Aunis, Kevin Litcofsky, David Cook, Lata Jayaraman, Ramy A. Ibrahim, Theresa LaVallee, Hussein Abdul-Hassan Tawbi, Jennifer A. Wargo
Journal: Journal of Clinical Oncology (2019)

TPS146 Background: There have been remarkable improvements in responses rates (RR) and outcomes for pts with MM with the use of single agent CPIs. However, only 35% of pts respond to therapy and less than 10% achieve a complete response (CR). Although CPIs are approved for advanced MM treatment, there is a critical need to identify predictors of response and improve outcomes for these pts, the majority of whom will die from their disease. In an analysis of stool from MM pts prior to receiving CPI (anti-PD1), MD Anderson reported the association of higher alpha diversity and a favorable “Type I” signature with improved RR and prolonged PFS. Subsequently, FMT in mice via oral gavage using stool from CR MM pts responding to anti-PD1 with a favorable microbiome signature and treated with CPI demonstrated improved RR compared to FMT with stool from non-responders. Although FMT has been studied and has shown efficacy in other diseases, clinical safety and utility in pts with MM requires investigation. We hypothesize that FMT from MM pts with CR to CPIs and a Type I signature will be tolerable and demonstrate favorable outcomes. Methods: To initiate the testing of this hypothesis, we designed a study to identify and screen pts with MM who have responded to anti-PD1 for FMT stool donation. Pts must be in CR from MM for 6 months on 2 consecutive scans. Screening procedures per standard practice of approved INDs for FMT include health history questionnaires, physical exam, confirmation of current disease status, infectious disease screening, and an evaluation of the stool sample to ensure Type I signature requirements. Notably, there have been specific modifications made to this protocol in donor eligibility criteria, as accepted by the FDA, to accommodate this unique patient population. Participants will donate stool for up to 4 weeks and may be considered for subsequent donation cycles after undergoing re-screening. Stool will be manufactured into capsule form and used in the clinical trial. This study is open and active at three sites, MD Anderson, MGH, and DFCI.
Optimized intratumoral delivery of a STING agonist results in improvements in local tumor immune activation.
Authors: Rahul Sheth, Nina Munoz, Crystal Dupuis, Malea Williams, Katherine Dixon, Kiersten Maldonado, Ravi Murthy, Alda Tam, Rony Avritscher
Journal: Journal of Clinical Oncology (2019)

38 Background: There has been a renaissance in the concept of promoting the immune-responsiveness of the tumor immune microenvironment via intratumoral (IT) delivery of immunostimulatory agents. As with any invasive intervention, though, outcomes following intratumoral drug delivery depend on procedural technique. We have previously shown that multi-sidehole needles (MSHNs) provide a 3-fold improvement in intratumoral drug delivery and retention relative to conventional end-hole needles (EHNs). The purpose of this study was to characterize how variations in drug delivery affect drug efficacy by evaluating immune activation following the IT delivery of a STING agonist using conventional end-hole needles (EHNs) versus multi-sidehole needles (MSHNs). Methods: Syngeneic McArdle RH-7777 (ATCC) hepatoma cells were implanted in the flank of Buffalo rats (n=20). Once tumors reached 15-20 mm in size, a STING agonist (50 ug ML RR-S2 CDA, Sigma Aldrich) vs saline (control) was injected under ultrasound visualization using either a 22G EHN or a 21G MSHN (ProFusion, Cook Regentec). Tumor tissue was harvested at 24 and 48 hours post-injection. Immune profiling was performed using flow cytometry and single cell RNA sequencing (scRNAseq). Results: There was a significant increase in tumor necrosis with MSHN injections compared to EHN or control injections (tumor viability 32%, 54%, and 82% at 48 hours, respectively). Gene expression profiling demonstrated a significant increase in interferon sensitive genes as well as STING-TBK1-IRF3 axis genes within dendritic cells with MSHN injections compared to EHN or control injections (Table). This signaling upregulation was greater at 24 hours than at 48 hours. MSHN injected tumors also exhibited fewer macrophages with immunosuppressive gene signatures and fewer T cells with exhaustion gene signatures relative to EHN or control tumors. Conclusions: Variations in IT delivery technique have a significant impact on subsequent immune activation following the injection of a STING agonist in an animal model of HCC. [Table: see text]
Abstract 12400: Association of Early Post-Discharge Visit After Heart Failure Admission and 30-Day Post-Discharge Outcomes
Authors: Nancy M Albert, Karen Distelhorst, James F Bena, Shannon L Morrison, Kelly Dion, Donna Walker, Renee Claussen, Hua-Li Tai
Journal: Circulation (2017)

Introduction: National heart failure (HF) guidelines recommend 7-14 day office appointments after hospitalization to reduce the risk of post-discharge morbidity/mortality. In Medicare beneficiaries...
Off-the-shelf virus specific T-cells for therapy of adenovirus disease in immunosuppressed patients.
Authors: Hind Rafei, Nobuhiko Imahashi, Rafet Basar, Pinaki Prosad Banerjee, May Daher, Christina Ganesh, Chitra Hosing, Indreshpal Kaur, Partow Kebriaei, Issa F. Khouri, Rohtesh Mehta, Yago Nieto, Amanda Leigh Olson, Muzaffar H. Qazilbash, Bryan P Spencer, Samer Srour, Elizabeth J. Shpall, Richard E. Champlin, David Marin, Katayoun Rezvani
Journal: Journal of Clinical Oncology (2019)

7008 Background: Adenovirus infection can cause significant morbidity and mortality in immunosuppressed patients. Cidofovir is commonly used, but its nephrotoxicity is concerning and efficacy limited. Another approach is to restore the anti-adenovirus immunity. Indeed, virus specific T-cells have been shown to be safe and effective in stem cell transplant recipients. Methods: Immunosuppressed pts with either adenovirus viremia or adenovirus-related end organ damage were enrolled. Most closely HLA-matched adenovirus cytotoxic T lymphocytes (CTLs) were generated by expanding donor derived T-cells with a peptide library derived from the hexon protein of adenovirus serotype 3 in the presence of IL-2 20 IU/ml, IL7 10 ng/ml, IL4 10 ng/ml. After receiving 2x10 5 /kg T cells, pts were monitored for response and adverse events. Results: Eight pts received adenovirus CTLs with one infusion. The Table summarizes their characteristics and responses. Seven pts had complete resolution of their symptoms (CR) and adenovirus becoming undetectable (ND). Those pts are alive to date. The remaining patient initially responded but then lost the response when started on high dose prednisolone for treatment of GVHD to which she eventually succumbed. Best response was achieved after a median time of 13 days [10-36]. No cytokine release syndrome occurred and we did not observe any side effect attributable to the CTLs. Conclusions: The use of off-the-shelf adenovirus CTLs is a feasible, safe, and effective approach to treat severe adenovirus infections in immunosuppressed pts. Clinical trial information: NCT03425526. [Table: see text]
Integrative analysis of vascular endothelial cell genomic features identifies AIDA as a coronary artery disease candidate gene
Authors: Simon Lalonde, Valérie-Anne Codina-Fauteux, Sébastian Méric de Bellefon, Francis Leblanc, Mélissa Beaudoin, Marie-Michelle Simon, Rola Dali, Tony Kwan, Ken Sin Lo, Tomi Pastinen, Guillaume Lettre
Journal: Genome biology (2019)

Genome-wide association studies (GWAS) have identified hundreds of loci associated with coronary artery disease (CAD) and blood pressure (BP) or hypertension. Many of these loci are not linked to traditional risk factors, nor do they include obvious candidate genes, complicating their functional characterization. We hypothesize that many GWAS loci associated with vascular diseases modulate endothelial functions. Endothelial cells play critical roles in regulating vascular homeostasis, such as roles in forming a selective barrier, inflammation, hemostasis, and vascular tone, and endothelial dysfunction is a hallmark of atherosclerosis and hypertension. To test this hypothesis, we generate an integrated map of gene expression, open chromatin region, and 3D interactions in resting and TNFα-treated human endothelial cells. We show that genetic variants associated with CAD and BP are enriched in open chromatin regions identified in endothelial cells. We identify physical loops by Hi-C and link open chromatin peaks that include CAD or BP SNPs with the promoters of genes expressed in endothelial cells. This analysis highlights 991 combinations of open chromatin regions and gene promoters that map to 38 CAD and 92 BP GWAS loci. We validate one CAD locus, by engineering a deletion of the TNFα-sensitive regulatory element using CRISPR/Cas9 and measure the effect on the expression of the novel CAD candidate gene AIDA. Our data support an important role played by genetic variants acting in the vascular endothelium to modulate inter-individual risk in CAD and hypertension.
Effects of Nutritional Supplements and Dietary Interventions on Cardiovascular Outcomes
Authors: Safi U. Khan, Muhammad U. Khan, Haris Riaz, Shahul Valavoor, Di Zhao, Lauren Vaughan, Victor Okunrintemi, Irbaz Bin Riaz, Muhammad Shahzeb Khan, Edo Kaluski, M. Hassan Murad, Michael J. Blaha, Eliseo Guallar, Erin D. Michos
Journal: Annals of Internal Medicine (2019)

This article has been corrected. The original version (PDF) is appended to this article as a Supplement. Background: The role of nutritional supplements and dietary interventions in preventing mortality and cardiovascular disease (CVD) outcomes is unclear. Purpose: To examine evidence about the effects of nutritional supplements and dietary interventions on mortality and cardiovascular outcomes in adults. Data Sources: PubMed, CINAHL, and the Cochrane Library from inception until March 2019; ClinicalTrials.gov (10 March 2019); journal Web sites; and reference lists. Study Selection: English-language, randomized controlled trials (RCTs) and meta-analyses of RCTs that assessed the effects of nutritional supplements or dietary interventions on all-cause mortality or cardiovascular outcomes, such as death, myocardial infarction, stroke, and coronary heart disease. Data Extraction: Two independent investigators abstracted data, assessed the quality of evidence, and rated the certainty of evidence. Data Synthesis: Nine systematic reviews and 4 new RCTs were selected that encompassed a total of 277 trials, 24 interventions, and 992 129 participants. A total of 105 meta-analyses were generated. Low-certainty evidence showed that omega-3 long-chain polyunsaturated fatty acid (LC-PUFA) was associated with reduced risk for myocardial infarction (RR, 0.92 [CI, 0.85 to 0.99]) and coronary heart disease (RR, 0.93 [CI, 0.89 to 0.98]). Folic acid was associated with lower risk for stroke (RR, 0.80 [CI, 0.67 to 0.96]; low certainty), whereas calcium plus vitamin D increased the risk for stroke (RR, 1.17 [CI, 1.05 to 1.30]; moderate certainty). Other nutritional supplements, such as vitamin B6, vitamin A, multivitamins, antioxidants, and iron and dietary interventions, such as reduced fat intake, had no significant effect on mortality or cardiovascular disease outcomes (very low– to moderate-certainty evidence). Limitations: Suboptimal quality and certainty of evidence. Conclusion: Use of omega-3 LC-PUFA and folate supplementation could reduce risk for some cardiovascular outcomes in adults. Combined calcium plus vitamin D might increase risk for stroke. Primary Funding Source: None.
Exercise-Based Rehabilitation for Heart Failure
Authors: Rod S. Taylor, Linda Long, Ify R. Mordi, Michael Tvilling Madsen, Edward J. Davies, Hasnain Dalal, Karen Rees, Sally J. Singh, Christian Gluud, Ann-Dorthe Zwisler
Journal: JACC Heart Failure (2019)

This study performed a contemporary systematic review and meta-analysis of exercise-based cardiac rehabilitation (ExCR) for heart failure (HF).There is an increasing call for trials of models of ExCR for patients with HF that provide alternatives to conventional center-based provision and recruitment of patients that reflect a broader HF population.The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, and PsycINFO databases were searched between January 2013 and January 2018. Randomized trials comparing patients undergoing ExCR to control patients not undergoing exercise were included. Study outcomes were pooled using meta-analysis. Metaregression examined potential effect modification according to ExCR program characteristics, and risk of bias, trial sequential analysis (TSA), and Grading of Recommendations Assessment Development and Evaluation (GRADE) were applied.Across 44 trials (n = 5,783; median follow-up of 6 months), compared with control subjects, ExCR did not reduce the risk of all-cause mortality (relative risk [RR]: 0.89; 95% confidence interval [CI]: 0.66 to 1.21; TSA-adjusted CI: 0.26 to 3.10) but did reduce all-cause hospitalization (RR: 0.70; 95% CI: 0.60 to 0.83; TSA-adjusted CI: 0.54 to 0.92) and HF-specific hospitalization (RR: 0.59; 95% CI: 0.42 to 0.84; TSA-adjusted CI: 0.14 for 2.46), and patients reported improved Minnesota Living with Heart Failure questionnaire overall scores (mean difference: -7.1; 95% CI: -10.5 to -3.7; TSA-adjusted CI: -13.2 to -1.0). No evidence of differential effects across different models of delivery, including center- versus home-based programs, were found.This review supports the beneficial effects of ExCR on patient outcomes. These benefits appear to be consistent across ExCR program characteristics. GRADE and TSA assessments indicated that further high-quality randomized trials are needed.
A Stepwise Approach to Identify the Clinical Role of 18F-FDG PET/CT in Patients With Suspicious Bone Metastasis From an Unknown Primary Site
Authors: Md. Sunny Anam Chowdhury, Subin Jeon, Hee-Seung Bom, Jung-Joon Min, Seong Young Kwon
Journal: Clinical Nuclear Medicine (2019)

Abstract In patients with suspicious bone metastasis, the clinical impact of PET/CT for differential diagnosis and primary lesion identification could differ according to 18 F-FDG uptake patterns. We report the findings in patients with suspicious bone metastasis who underwent PET/CT for the evaluation of the primary lesion site and were classified in a stepwise manner, first based on the multiplicity of positive bone uptake and then the presence of extraskeletal uptake.
Abstract 17939: iPSC Based Cardiac Model of a Patient With Autosomal Recessive Leigh Syndrome Exhibits Phenotypic Characteristics of This Disorder
Authors: Glen Lester Sequiera, Andrew Muranyi, Meenal Moudgil, Cheryl Rockman-Greenberg, Sanjiv Dhingra
Journal: Circulation (2017)

Background: Inborn mitochondrial disorders result in adverse energy production in many cell types, including cardiac cells, leading to abnormal cardiac function and cardiomyopathy. Given the variab...
Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial
Authors: Roy S Herbst, Hendrik-Tobias Arkenau, Rafael Santana-Davila, Emiliano Calvo, Luis Paz-Ares, Philippe A Cassier, Johanna Bendell, Nicolas Penel, Matthew G Krebs, Juan Martin-Liberal, Nicolas Isambert, Andres Soriano, Martin Wermke, Jennifer Cultrera, Ling Gao, Ryan C Widau, Gu Mi, Jin Jin, David Ferry, Charles S Fuchs, Daniel P Petrylak, Ian Chau
Journal: The Lancet Oncology (2019)
Barriers for compliance to breast, colorectal, and cervical screening cancer test among Hispanics patients.
Authors: Yelitza Ruiz, Elba Betancourt, Christine Miranda, Robert F. Hunter
Journal: Journal of Clinical Oncology (2013)

e12544 Background: Hispanics are less likely to undergo colorectal cancer and cervical cancer screening tests than non-Hispanic population. We address the barriers for compliance in a Hispanic community. Methods: A descriptive study was performed with 194 patients between 21 to 85 y/o, while they attended routine medical encounters at a private and a government sponsored clinics. Compliance and barriers for non compliance for mammography (MAMMO), occult blood testing (FOBT), colonoscopy (COLO) and cervical smears (Pap) were studied. Univariate and bivariate tests were used. Results: Females (62.9%) had a mean age of 53.4 ±15.0; had a high school diploma or higher degree (80.5%), unemployed (52.15), had private health insurance (68.0%), and practiced routine medical checkups (79.9%). Gender differences for patients undergoing FOBT and COLO were found only in patients older than 50 y/o. Females were more likely than males to undergo COLO (62.3% vs. 42.2%; p&lt;0.05) whereas males are more likely than females to had a FOBT (66.7% vs. 56.5%; p&gt;0.05). Differences between employed and unemployed patients undergoing FOBT were seen (48.4% vs. 65.1%; p=0.105) and COLO (38.7% vs. 60.2%; p=0.040). Seventy four percent of women between 40 to 65 y/o had a Pap and 85% had a MAMMO. Predominant reasons for avoiding MAMMO and Pap were fear (20%; p&lt;0.05 and 6%; p&gt;0.05), uncomfortable sensation (13%; p&lt;0.05 and 19%; p&lt;0.05), lack of time (67%; p&lt;0.0001 and 56%; p&lt;0.0001). Reasons for avoiding FOBT and COLO were not recommended by physician (42%; p&lt;0.05 and 52%; p&gt;0.05) and lack of knowledge (16%; p&lt;0.05 and 17%; p&lt;0.05). Conclusions: Occupational status in women (p&lt;0.05) was found as a barrier for compliance with screening MAMMO, while it was also a barrier for COLO in both men and female over the age of 50. (p&lt;0.05) Educational level in men and women was not associated with non compliance with FOBT or COLO in patients older than 50 y/o. Having a private health insurance is a predictor of compliance with MAMMO (71.3%), FOBT (78.3%), COLO (80.6%), and Pap (68.6%). Several physician and patient related factors were identified as barriers for compliance. Study was supported by NIH grant #'s 8U54MD007587 &amp; 8G12MD007583.
Should patients with extrapulmonary small cell carcinoma receive prophylactic cranial irradiation? An Irish experience.
Authors: Jarushka Naidoo, Sandra Deady, Harry Comber, Paula Calvert
Journal: Journal of Clinical Oncology (2012)

2609 Background: Extrapulmonary small cell carcinoma (EPSCC) is a rare disease. Management is based on small cell lung carcinoma, and experience of disease biology on single institution studies. Prophylactic cranial irradiation (PCI) is not routinely administered in EPSCC. This study investigates the role of PCI in EPSCC, by analyzing the incidence, treatment and survival of patients with brain metastases in a national cohort. Secondary aims were to investigate disease biology and epidemiology. Methods: An audit was undertaken of patients diagnosed with primary EPSCC from the National Cancer Registry of Ireland, between 1995-2007. The number of patients who developed brain metastases, received cranial radiotherapy, and their survival data, were documented. Patient and disease characteristics, treatment, and survival data stratified by stage and primary site, were tabulated. Results: 280 patients were found. 141 (50.4%) patients were male, and 139 (49.6%) were female. 186 (66.4%) patients had extensive stage disease, 65 (23.2%) had limited stage disease, and in 29 (10.3%) patients the stage was not known. 17 patients (5.4%) developed brain metastases, 11 of which (64.7%) received cranial irradiation. These patients had a median progression-free survival (PFS) of 5.2 months, and a median overall survival (OS) of 10.2 months. The commonest primary sites were the oesophagus (n=43, 15.4%), cervix uteri (n=17, 6.0%), bladder (n=13, 4.6%) and prostate (n=10, 3.6%). There were 315 events of distant metastasis, and 21 local recurrence events. The commonest metastatic sites were the liver, 110 (34.9%), lymph nodes 58 (20.7%), lung 38 (12.1%), and bone 36 (12.8%). The median PFS and OS for limited stage EPSCC was 8.8 months and 14.9 months, and 1.5 months and 2.3 months for extensive stage EPSCC. Conclusions: Brain metastases were uncommon in this cohort (5.4%), and patients lived longer, suggesting a low rate of mortality from brain metastases. PCI is thus probably not warranted in EPSCC. Prospective data are necessary to support PCI in EPSCC. This is one of the largest datasets on EPSCC, providing insights into disease biology.