tbuckley/cabot-search huggingface dataset:
Spatio-temporal distribution of lung cancer mortality rate in Peru: 2005-2014.
Authors: Claudio J. Flores, Junior S Torres-Roman, Luis Mas, Rossana Esther Ruiz Mendoza, Cesar Augusto Samanez, Alfredo Aguilar, Carlos Vallejos Sologuren
Journal: Journal of Clinical Oncology (2017)

e20081 Background: Lung cancer still remains as the principal death cause in many regions around the world. Its mortality varies according to the regions and study periods. In Peru it represents the sixth most frequent malignant neoplasm and the fourth cause of cancer related death. We reported the spatial autocorrelation and the temporal variation in lung cancer mortality rate in Peru. Methods: Data of lung cancer mortality in Peru between 2005-2014 was obtained from the Ministry of Health. Information on the number of inhabitants was obtained from National Institute of Statistics and Informatics. Age standardized mortality rate (ASMR) was calculated based on the 2011 world standard population. Spatial autocorrelation was determined according to Moran’s Index and the Local G Cluster Map to explore the cluster patterns between regions. Results: During the study period 16,839 deaths due to lung cancer were reported. The lung cancer mortality rate in Peru increased from an ASMR of 12.8 (95% CI: 11.9-13.7) by 100,000 persons in 2005 to 13.4 (95% CI: 12.5-14.3) in 2014. According to the quartiles, the ASMR was higher in the north, south and east, and lowest in others regions. The spatial distribution of the ASMR showed a significant spatial autocorrelation (Moran´s I: p = 0.025). Also, during the study period, the ASMR showed a significant increase and decrease in some regions and in others it was constant. Conclusions: In Peru, lung cancer mortality rate showed a spatial and temporal variation in different regions. The increase in mortality rate in some regions requires identification of risk factors in order to establish public measures to reduce the risk of lung cancer mortality.
Analysis of tumor mutation burden (TMB) in &gt;51,000 clinical cancer patients to identify novel non-coding <i>PMS2</i> promoter mutations associated with increased TMB.
Authors: Zachary Rockow Chalmers, Franklin W. Huang, Laurie M Gay, Siraj Mahamed Ali, Juliann Chmielecki, Jeffrey S. Ross, Vincent A. Miller, Shridar Ganesan, Phil Stephens, Levi A. Garraway, Garrett Michael Frampton
Journal: Journal of Clinical Oncology (2016)

9572 Background: Immunotherapies have emerged as approved treatments for melanoma and non-small cell lung cancer, and have shown promise in many other tumor types. Sensitivity to these checkpoint inhibitors is known to correlate with high TMB. Numerous somatic and germline defects can lead to high TMB, including alterations affecting the mismatch repair pathway, DNA polymerases, and cell cycle regulators. We present novel mutations in the promoter of PMS2 that are significantly associated with high TMB. Methods: Hybridization capture of 236 or 315 cancer-related genes and select introns from 19 or 28 genes commonly rearranged in cancer was performed on DNA extracted from > 51,000 clinical FFPE cancer specimens and sequenced to high, uniform coverage ( > 500x). TMB was assessed as the number of somatic coding point mutations per megabase of targeted territory. Results: TMB assessed via targeted sequencing of ~1.25Mb broadly recapitulates previous results of whole exome TMB analysis. Analysis of recurrent somatic mutations identified common mutations in the promoter of PMS2, a dimerization partner of MLH1 and integral to the DNA mismatch repair complex. Promoter mutations were found in 7.5% of melanoma specimens (n = 101/1,348) and 17% of cutaneous squamous cell carcinomas (cSCC) (n = 30/175). In both tumor types, PMS2 promoter mutations are the most significant (p < 1e-5, Mann–Whitney U test) genomic correlate of TMB. Within the melanoma population, median TMB of PMS2 promoter mutant tumors increased > 5-fold (9.5 to 53.3 mutations per Mb). PMS2 promoter mutant cSCC showed a 2-fold increase in TMB over wild type tumors (35.9 to 72.7 mutations per Mb). Conclusions: PMS2 promoter mutations extend the small set of known non-coding mutations thought to affect tumor development and highlight the power of large-scale genomic analysis to uncover novel disease mechanisms. Given recent evidence that TMB may be the most sensitive and specific predictor of immune checkpoint inhibitor efficacy in a variety of tumor types, further study of PMS2 promoter mutation as a biomarker for immunotherapy selection appears warranted.
TCT-28 Repeat Chronic Total Occlusion Angioplasty Following an Unsuccessful CTO PCI Attempt: Predictors of Success and Association of Success with Angina Symptoms
Authors: Adam Salisbury, Taishi Hirai, Kensey Gosch, Ajay Jayant Kirtane, William Lombardi, William Nicholson, Jeffrey W. Moses, Dimitrios Karmpaliotis, J. Aaron Grantham
Journal: Journal of the American College of Cardiology (2018)
Abstract 17662: High-risk Carotid Atherosclerotic Lesions Identified by CT-angiogram Can Predict Acute Coronary Events
Authors: keenan adib, Andres Carmona Rubio, Roshan Karki, Narasa Madam, Gregory Gudleski, Umesh C Sharma
Journal: Circulation (2015)

Introduction: Computed Tomography Angiogram (CTA) is increasingly being utilized as an imaging tool for the characterization of atherosclerotic lesions of major arteries. Our recent ex vivo study has shown the presence of high-risk necrotic coronary lesions in the subjects who had suffered sudden cardiac death following acute stroke. Although stroke and myocardial infarction (MI) have shared risk factors and outcomes, there are no data available to predict the coronary events based on the high-risk features identified in the carotid arteries by non-invasive CTA of the neck vessels. Methods: We examined the carotid CTAs of 485 patients who had presented to our tertiary stroke center with symptoms suggestive of TIA or stroke. Using reformatted CT images, we first characterized the atherosclerotic plaques of the common, internal and external carotid arteries. We then examined the follow up events of these 485 patients for 12-months to evaluate the significance of newly identified carotid lesions for the subsequent development of acute coronary events (ACS). Carotid lesions were defined in terms of the degree of stenosis, calcifications (speckled or eccentric), presence of non-calcified plaques, positive remodeling, and presence of a Napkin-Ring Sign. Results: Our data analysis using Mann-Whitney U tests showed that presence of speckled carotid calcifications visualized by CTA was strongly associated with increased risk of obstructive coronary artery disease or ACS within 12-months (p&lt;0.001). Patients who had ACS within a year were more likely to have higher number of calcific speckles (10-speckles in ACS group vs 4-speckles in non-ACS group; P&lt;0.05) in their carotid arteries. Receiver-Operating Curve analysis showed that presence of more than four calcific speckles in the carotid arteries portends higher likelihood of developing ACS within 12-months (P&lt;0.05). Conclusions: This novel study shows that presence of speckled carotid calcifications in patients with symptoms of TIA or stroke can predict the higher risk of developing ACS within 12-months. In fact, Four or more speckles was the optimal cut-off point associated with the higher likelihood of developing ACS within 12-months.
Comparison of the c-MET gene amplification between primary tumor and metastatic lymph nodes in non-small cell lung cancer.
Authors: Mei-yu Fang, Chun-wei Xu, Wen-xian Wang, Mei-juan Wu, Wu Zhuang, Gen Lin, Xiao-hui Chen, You-cai Zhu, Xing-hui Liao, Kai-qi Du, Yun-jian Huang, Hai-peng Xu, Yan-ping Chen, Gang Chen, Tangfeng Lv, Yong Song
Journal: Journal of Clinical Oncology (2017)

e23138 Background: Activation of c-MET lead to a wide range of biological activities. MET has recently been identified as a novel promising target in NSCLC, some c-MET inhibitors have been developed. The primary aim of this study was to evaluate the c-MET amplification status in advanced NSCLC and compare the consistency of c-MET amplification analyses in metastatic lymph nodes and tumor tissue.Methods: Real-time fluorescent quantitative polymerase chain reaction was used to test the tumor tissues in 368 patients of NSCLCs and 178 paired metastatic lymph nodes samples and compared the amplifications consistency inmetastatic lymph nodesand tissue samples, and analyzed the correlation between c-MET gene amplification and clinical characteristics of patients. Another 5 cases of normal lung tissue were taken as negative control.Results: The c-MET gene amplification rate was 8.97%(33/368) in tumor tissues . Of the178 paired cases, c-MET gene amplification was positive in 7.95%(15/178) cancerous tissuesand18.54%(33/178) in metastatic lymph nodes; Of these patients,13 were positive in the two kinds of samples. 20 cases in the paired group were detected positive c-MET in metastatic lymph nodes but was negative in cancerous tissues; 2 cases in the paired group were detected positive c-MET gene amplification in cancerous tissues but was negative in metastatic lymph nodes,there were statistically significant differences between the two samples (χ 2 = 45.536, P &lt; 0.001). c-MET gene amplification was detected more in metastatic lymph nodes than the primary cancerous tissue. Consistency was evaluated by consistency test(Kappa = 0.482, P &lt; 0.001).When lymph nodes were used as surrogate samples of primary cancerous tissues, sensitivity was86.67%, the specificity was 87.69%.Conclusions: More c-MET gene amplification positive were detected in metastatic lymph nodes compare with the primary cancerous tissue. c-MET gene amplification detected in lymph node metastases could screen more patients suitable for TKI therapy. Lymph node Metastasis can predict the c-MET gene amplification of primary tumor, and guide the clinical use of gene targeted drugs.
Abstract P325: Emergency Department Visit Rates for Influenza-like Illness Can be Used to Predict Seasonal Cardiovascular Disease Mortality Rates Among Older Adults
Authors: Jennifer Nguyen, Wan Yang, Kazuhiko Ito, Thomas Matte, Jeffrey L Shaman, Patrick L Kinney
Journal: Circulation (2016)

Introduction: In temperate regions, cardiovascular deaths and influenza epidemics peak with regularity during the winter months. Hypothesis: We assessed the hypothesis that population increases in seasonal influenza infections are associated with a rise in mortality due to cardiovascular causes, and that influenza incidence can be used to predict cardiovascular mortality rates during the influenza season. Methods: We used time series regression models, adjusted for season and time trend, to quantify the temporal association between influenza incidence and cardiovascular mortality during the influenza season in New York City. Mortality data on date of death, age, and underlying cause of death were obtained from the New York City Office of Vital Statistics. Daily mortality counts from 2006 to 2012 were aggregated for all cardiovascular causes (International Classification of Diseases, Revision 10 (ICD-10) codes I00-I99), ischemic heart disease (ICD-10 codes I20-I25), and myocardial infarction (ICD-10 code I21). Influenza incidence was represented using four different measures: emergency department visits for influenza-like illness, grouped by age ≥ 0 and age ≥ 65 years, and these same measures scaled by laboratory surveillance data for viral types/sub-types. The 2009 H1N1 pandemic period was excluded from temporal analyses and reserved for out-of-sample prediction. Results: There were 73,384 cardiovascular deaths among adults age ≥ 65 years during the influenza seasons between 2006 and 2012, excluding the 2009 H1N1 pandemic period. Interquartile range increases of the four indicators of influenza incidence in the previous 21 days were associated with increases in cardiovascular mortality of between 2.3% (95% confidence interval (CI): 0.7%, 3.9%) and 6.3% (95% CI: 3.6%, 8.9%), and increases in ischemic heart disease mortality of between 2.4% (95% CI: 1.1%, 3.7%) and 7.0% (95% CI: 4.1%, 10.0%). Associations were most acute and strongest for myocardial infarction mortality, with interquartile range increases for the four influenza indicators during the previous 14 days associated with mortality increases between 5.9% (95% CI: 2.7%, 9.2%) and 12.8% (95% CI: 5.1%, 20.6%). Out-of-sample prediction of cardiovascular mortality among adults age ≥ 65 years during the 2009-2010 influenza season yielded average estimates with 94.4% accuracy. Conclusions: Emergency department visits for influenza-like illness are associated with and predictive of cardiovascular disease mortality in New York City. Retrospective estimation of influenza-attributable cardiovascular mortality burden, combined with accurate and reliable influenza forecasts, could predict the timing and burden of seasonal increases in cardiovascular mortality.
Selection of the recommended phase 2 dose (RP2D) for M7824 (MSB0011359C), a bifunctional fusion protein targeting TGF-β and PD-L1.
Authors: Yulia Vugmeyster, Justin Wilkins, Eleanor Harrison-Moench, Wanping Geng, Andre Koenig, Liang Cao, James L. Gulley, Isabelle Dussault, Akash Khandelwal
Journal: Journal of Clinical Oncology (2018)

2566 Background: The transforming growth factor β (TGF-β) pathway plays an important role in tumor immune escape and may enhance the response to PD-L1 monoclonal antibodies (mAb). M7824 is an innovative first-in-class bifunctional fusion protein composed of a human IgG1 mAb against PD-L1 fused with 2 extracellular domains of TGF-β receptor II (a TGF-β "trap") and has shown promising antitumor activity and manageable safety in phase 1 trials, including as 2L treatment for NSCLC. Methods: A population PK model for M7824 was developed based on serum concentration data from 350 pts from 2 clinical trials of M7824 in multiple solid tumor types. Simulations were performed using the model to explore exposure variability for various dosing regimens. Exposure-response analysis was performed for 500 and 1200 mg biweekly (q2w) 2L NSCLC cohorts (combined) using logistic regression for the investigator-assessed overall response rate (ORR) and Kaplan-Meier analyses for progression-free survival (PFS). Results: Simulations of AUC and Cmin showed that variability in exposure was slightly higher for weight-based dosing compared with flat dosing, supporting the use of a flat-dose approach for M7824. Preliminary univariate analyses relating M7824 exposure (AUC and Cmin after a single dose) to ORR in 500 and 1200 mg 2L NSCLC cohorts did not show a conclusive relationship. However, there was a trend for pts in the lowest exposure quartile (Q1, comprised of pts in 500 mg cohort only) to have a lower ORR (10% for AUC Q1; 5% for Cmin Q1) than those in the higher exposure quartiles (25-30% and 20-40% ORR for AUC and Cmin Q2-Q4, respectively). Results of Kaplan-Meier analysis of PFS by exposure quartiles were in line with the exposure-ORR analyses, supporting 1200 mg q2w as the RP2D. At the Cmin associated with the RP2D, nearly complete target occupancy for PD-L1 (PBMC) and TGF-β trapping (plasma) was achieved. Moreover, these Cmin values were associated with 95% tumor-growth inhibition in mouse models. Conclusions: Based on the integrated analysis and modeling data available to date, a flat dose of 1200 mg q2w is the RP2D for M7824.
Clinical activity, safety and tolerability of ASN002, a dual SYK/JAK inhibitor, in patients non-Hodgkin lymphoma (NHL) and solid tumors.
Authors: Drew W. Rasco, Timothy J. O'Rourke, Andy I. Chen, Michael Wang, Anthony W. Tolcher, Niranjan Sathyanarayana Rao, Louis J. Denis, Sanjeeva Reddy, Stefan K. Barta
Journal: Journal of Clinical Oncology (2017)

7545 Background: ASN002 is a novel, potent inhibitor of Spleen Tyrosine Kinase (SYK) and Janus Kinases (JAK). Pre-clinical studies indicate that ASN002 has low nM IC50s against SYK and JAK, decreases proliferation in ibrutinib-resistant cell lines, and suppresses tumor growth in rodent xenograft models of NHL and other hematologic malignancies. Methods: This Phase 1/2 clinical trial in patients with solid tumors and hematologic malignancies evaluates escalating ASN002 oral doses of 10, 20, 30, 40, 50 and’ 75 mg BID and 80 and 120 mg QD mg (NCT02440685). Phase 1 allows patients with solid tumors or hematologic malignancies; Phase 2 allows only patients with diffuse large B-Cell lymphoma (DLBCL), follicular lymphoma (FL) or mantle cell lymphoma (MCL). Endpoints include safety, tolerability, pharmacokinetics, serum markers of inflammation, and response using RECIST or Lugano Classification System. Results: Twenty-eight patients have enrolled in the DLT phase at doses of 10 mg – 75 mg BID and at 80 mg QD. All patients had multiple prior lines of treatment (range: 2 – 8). ASN002 was well tolerated. No dose limiting adverse events have been reported at these dose levels. Most drug-related adverse events were Gr 1/2 (e.g. headache, fatigue). Steady-state systemic exposure was high (C max , AUC (0-12h) and T 1/2 at 40 mg BID were 0.7 µM, 6.3 µM.h and 18 h, respectively). High systemic exposure was also observed at 80 mg QD. Robust reduction of CRP, IL-18, MIP1β, VCAM-1, TNFR2 was observed at all doses. Stable disease (RECIST, 9+ months) in a patient with primary peritoneal cancer, about 50% reduction in target lesions at 3 months in a FL patient (Lugano, 6 prior lines) and stable disease and reduction of pruritus in a peripheral T-Cell lymphoma patient after 2 months (Lugano, 2 prior lines) of treatment were observed. ASN002 treatment continues in both lymphoma patients. Accrual of patients continues. Conclusions: ASN002 was safe and well tolerated. Encouraging preliminary evidence of efficacy in NHL patients was observed. MTD has not been reached and dose escalation continues. Updated and detailed results will be presented. Clinical trial information: NCT02440685.
Abstract 15593: Major Differences in the Use of Protocols for Dispatcher Assisted Cardiopulmonary Resuscitation - an Observational Study
Authors: Katrine Bjørnshave, Stinne E Rasmussen, Mette A Nebsbjerg, Lise Q Krogh, Kristian Krogh, Jonas A Povlsen, Bo Løfgren
Journal: Circulation (2016)

Introduction: Dispatcher assisted cardiopulmonary resuscitation (DA-CPR) increases rate of bystander CPR. DA-CPR is recommended by resuscitation councils globally and it has been shown that the gen...
TCT-463 Instability of Coronary Flow Velocity and Basal Microvascular Resistance does not Affect Reproducibility of iFR Post- PCI.
Authors: Muhammad Aetesam-ur-Rahman, Tian Zhao, Joel Giblett, Denise Braganza, Sarah Clarke, Martin Bennett, Nick West, Stephen Hoole
Journal: Journal of the American College of Cardiology (2018)
Carfilzomib and cardiac events in a single institution non-Caucasian cohort.
Authors: Ankit Mangla, Koosha Paydary, Jiaxiang Liu, Chimezie Mbachi, Romy Jose Thekkekara, Nikki Agarwal, Thomas E. Lad
Journal: Journal of Clinical Oncology (2018)

e20039 Background: Carfilzomib (Ky) is an irreversible proteasome inhibitor. Phase III trials, ASPIRE and ENDEAVOR reported cardiovascular adverse events (CvAE) associated with Ky. We performed this study to identify the factors associated with CvAE in a non-Caucasian cohort of patients diagnosed with multiple myeloma (MM). Methods: Patients diagnosed with MM at Cook County Hospital between January 2012 and December 2017 were retrospectively evaluated. Patients treated with Ky were included in the study. Data was analyzed using Fischer’s Exact test and two tailed p-value was obtained. Results: A total of 18 patients were included in the study, out of which 50% were men, with a median age of 56.5 years. Twelve (66.7%) patients were African-American, 4 (22.2%) were Hispanic, and 2 (11.2%) were Asian. Cardiovascular (CVS) risk factors included prior cardiotoxic chemotherapy (22.3%), smoking history (44.4%), hypertension (55.6%), diabetes (16.7%), chronic kidney disease (27.8%) and coronary artery disease (22.3%) were noted. EKG abnormalities, prior to starting Ky were noted in 12 (67%) patients, left ventricular hypertrophy (LVH) being the most common finding, seen in 5 patients (27.8%). An echocardiogram (Echo) was done in 5 patients (27.8%) prior to starting Ky and showed an ejection fraction (EF) less than 50% in 2 patients (11.2%). In 10 patients (55.6%), Ky was used as second line therapy. Three patients (16.7%) patients developed CvAE, where 2 patients developed hypertensive crises (HTNC) (after 1st and 2nd cycle) and 1 patient developed heart failure with reduced EF (HFrEF) (after 3rd cycle) which led to treatment discontinuation in all 3 patients. One patient with HTNC received 20/56 mg/m2 dose and the other 2 patients received 20/27mg/m2 dose. Only LVH (p-0.0123) and ≤ 3 cycles of Ky (p-0.0123) were significantly associated with CvAE. Conclusions: Our study shows that if CvAE occurs secondary to Ky, then it would generally occur early in the treatment course in non-Caucasians. This finding is in congruence with results of Phase III ASPIRE study. In our cohort, LVH in EKG was also associated with CvAE. Our results suggest that, in a non-Caucasian cohort of patients a closer monitoring of CVS function is required at the time of initiation of Ky.
Molecular profiling of advanced pancreatic cancer (PC) patients from a phase I/II study using circulating tumor DNA.
Authors: Daniel V.T. Catenacci, Emma Green, Michael Epstein, Greg Jones, Clive D. Morris, Emily O'Day, S Lomnicki, Melissa Maranto, Theodore G. Karrison, Hedy L. Kindler
Journal: Journal of Clinical Oncology (2017)

4124 Background: PC has a poor prognosis with a 5-year survival of 9%. Targeted therapies have yet to demonstrate improved outcomes in this disease. Circulating tumour DNA (ctDNA) may be used as a non-invasive method for the detection and quantification of genomic abnormalities. We performed a retrospective-prospective study to assess molecular alterations in the ctDNA of advanced PC patients. Methods: Plasma samples were banked from patients enrolled in the previously reported Phase Ib/II trial of gemcitabine with placebo or vismodegib (NCT01064622; Catenacci et al JCO 2015). Eligible patients had unresectable PC and no prior therapy for metastatic disease. Patient samples ( &lt; 3ml) collected pre-treatment and at regular intervals and stored for ~6-8 years were analyzed using InVision (enhanced tagged-amplicon sequencing) for “hotspot” regions of 34 genes, including KRAS (exons 2 and 3), and select full gene coverage. Results: Of 113 patients enrolled in the trial, a cohort of 72 patients were included in this study. Baseline plasma ctDNA profiling detected any genomic event in 88% of patients (SNV/indels found at range of 0.07%-23% allele fraction (AF) with 20% detected at &lt; 0.5% AF). Patients had between 1-5 mutations (median, 2): KRAS mutations were detected in 80% of patients tested, of which 86% had concurrent KRAS/TP53 mutation(s) and 16% with concurrent KRAS/TP53/CDK2NA. Of note, 2 cases presented with IDH1 point mutations (R132C, R132H). An ERBB2 amplification and a FGFR2 amplification were detected in 2 individuals. An update on the analyses will include serial ctDNA testing during treatment and correlation with outcomes. Conclusions: ctDNA analysis of this cohort of banked PC plasma samples described the landscape of genomic aberrations at baseline and over time, including rare but potentially important actionable events including ERBB2 and FGFR2 amplifications and IDH1 mutation. We demonstrate a sensitive method for re-analysing trial outcomes, despite limiting plasma volume and time lapse since samples were collected.