tbuckley/cabot-search huggingface dataset:
Abstract 173: Cardiogenic Shock in Cardiac Arrest No Longer a Contraindication for Therapeutic Hypothermia
Authors: Kalie Y Kebed, Scott W Sharkey, Barbara T Unger, David S Feldman, Robert S Schwartz, Anil K Poulose, M Nicholas Burke, Michael R Mooney
Journal: Circulation (2011)

Introduction: Therapeutic hypothermia (TH) is neuroprotective and increases survival in cardiac arrest patients. Cardiac arrest is often seen in the setting of acute myocardial infarction (MI), and cardiogenic shock is a known poor prognostic factor. Methods: “Cool It” is a comprehensive TH protocol integrated into a regional STEMI network. From Feb 2006 to July 2010, 192 consecutive cardiac arrest patients who remained unresponsive following return of spontaneous circulation were enrolled in the Cool It protocol, regardless of initial rhythm or hemodynamic status. We hypothesize patients in cardiogenic shock secondary to MI treated with primary PCI will have greater survival and neurologic outcome than those without concurrent MI. Results: Of the 192 patients, 77 (40.1%) were in cardiogenic shock. Survival with favorable neurologic outcome (CPC 1 or 2) was poorer in cardiogenic shock patients than non-cardiogenic shock patients, 34/77 (44.2%) vs. 60/115 (52.2%) p=0.28, but not statistically significantly. Of those in cardiogenic shock, 32 (41.6%) had ST elevation on EKG, and a total of 42 (54.6%) were found to have an acute occlusion by angiography. Culprit arteries were: LAD n=19 (45.2%), RCA n=14 (33.3%), CMX n=5 (11.9%), L main n=4 (9.5%), and 39/42 (92.9%) and were successfully reperfused and stented. For patients with cardiogenic shock, survival with favorable neurologic outcome (CPC 1 or 2) was greater in patients with concurrent MI than without MI, 21/42 (50.0%) vs. 9/35 (25.7%) p=0.03. Cardiogenic shock with LAD lesions had the greatest favorable neurologic survival compared to other lesions, 13/19 (68.4%) vs. 8/23 (34.8%) p=0.03. Non-LAD lesion cardiogenic shock had no statistically significant survival or neurologic benefit over cardiogenic shock without concurrent MI, 8/23 (34.8%) vs. 9/35 (25.7%) p=0.46. Conclusion: TH should be the standard of care for unresponsive cardiac arrest patients in cardiogenic shock. Patients with cardiogenic shock and concurrent LAD STEMI have improved survival and neurologic outcomes than those cardiogenic shock patients without concurrent STEMI. Cardiogenic shock should no longer be considered a contraindication to TH, especially with concurrent STEMI.
Quality-adjusted life years assessment using cabozantinib for patients with advanced hepatocellular carcinoma (aHCC) in the CELESTIAL trial.
Authors: Ghassan K. Abou-Alfa, Patrick Mollon, Tim Meyer, Ann-Lii Cheng, Anthony B. El-Khoueiry, Robin Kate Kelley, Ari David Baron, Fawzi Benzaghou, Velichka Valerieva Valcheva, Saswati Hazra, Milan Mangeshkar, Nicholas Freemantle
Journal: Journal of Clinical Oncology (2019)

207 Background: In patients previously treated for aHCC, cabozantinib (cabo) led to longer overall survival and progression-free survival vs placebo (pbo) in the randomized, phase 3 CELESTIAL trial (NCT01908426; N = 707). CELESTIAL was stopped early for benefit at the second interim analysis. This post hoc analysis estimated the incremental quality-adjusted life years (QALYs) accrued in CELESTIAL. Methods: Health utility was elicited at each study visit using the EQ-5D-5L quality of life questionnaire. (completed by 82–100% of patients overall). UK crosswalk tariffs were applied for health states. Cumulative QALYs by patient were calculated by linear interpolation; for patients who were censored (31% of patients; including 9% within 100 days of randomization), the last observed utility value was carried forward to study end. The difference in restricted mean QALYs was calculated using generalized linear models, accounting for baseline utility, and with 0.06–0.08 QALYs considered the minimal important difference. Results: At day 50 after randomization (acute treatment phase), cabo was associated with a small reduction in mean total QALYs vs pbo (difference −0.003; 95% CI −0.005 to −0.002; p ≤ 0.001; n = 601 [cabo, n = 389; pbo, n = 212]). At day 100, there was a numerical benefit in mean total QALYs for cabo (difference +0.007; 95% CI −0.001 to 0.015; p = 0.103; n = 627 [cabo, n = 410; pbo, n = 217]), and at day 150 the difference was +0.032 QALYs (95% CI 0.017 to 0.047; p ≤ 0.001; n = 629 [cabo, n = 412; pbo, n = 217]) in favor of cabo. Over the entire follow-up, patients randomized to cabo accrued a mean of +0.092 (95% CI 0.016 to 0.169; p = 0.018; n = 700 [cabo, n = 465; pbo, n = 235]) additional QALYs compared with those receiving pbo. Using alternative Devlin weights for health states, the mean accrued QALYs with cabo was +0.115 vs pbo (95% CI 0.032 to 0.198; p = 0.007). Conclusions: Cabo was associated with an initial, small reduction in health utility. However, with continued treatment, health utility increased and at the end of the study there was a clinically and statistically significant benefit in mean QALYs in favor of cabo. Clinical trial information: NCT01908426.
Abstract P3-07-01: Towards a therapeutically relevant subtyping scheme for triple-negative breast cancer (TNBC), profiling results from A Randomized, TNBC Enrolling trial to confirm Molecular profiling Improves Survival (ARTEMIS)
Authors: S Seth, L Huo, G Rauch, R Lau, M Gilcrease, B Adrada, H Piwnica-Worms, WF Symmans, G Draetta, AP Futreal, S Moulder, JT Chang
Journal: Cancer Research (2019)

Abstract Triple-negative breast cancer is a highly diverse group of cancers, with poor prognosis, and currently, there are no targeted drugs available in the clinic. In TNBC around 50% percent of the patients respond to chemotherapy, while, the other 50% percent relapse with poor prognosis. There is a need to understand better the targetable mechanisms driving TNBC via integrative analysis of gene-expression, copy-number, and mutational data. Samples from 220 triple-negative breast cancer (TNBC) pts treated with NACT were prioritized for transcriptomic and genomic profiling. Non-negative matrix factorization was used on array-based profiling to identify six robust (ARTEMIS) subtypes. Comparing ARTEMIS subtypes with Vanderbilt subtypes, revealed significant overlap with 4/6 clusters while identifying two new clusters. Logistic regression on ssGSEA scores vs. subtypes revealed several pathways, selectively enriched specific subtypes. CL1/IM (Immune subtype), was enriched in INFg and INFa, while CL2 (MYC/mTOR), showed enrichment of several proliferation-related pathways. In addition, LAR and M (Mesenchymal) pts formed overlapping clusters, using either method. Two new subtypes did not associate significantly with any of the previous subtypes. The majority of the tumors from the Vanderbilt BL2 and MSL were reclassified into a CL5 (ANGIO) cluster, which was enriched in angiogenesis geneset, including targetable genes like VEGF and FGFR. Also, an MYO (CL3) subtype was identified, with myogenesis-related genes. Of note, TIL (tumor infiltrating lymphocytes) and LAR quantification using IHC were associated with respective ARTEMIS subtypes. Finally, the IM subtype was significantly associated with higher rates of RCB 0-I and the M (CL4) subtype was associated with higher rates of RCB II-III, irrespective of the neoadjuvant treatment regimen. ARTEMIS subtypes are a novel classification system for TNBC that is focused on therapeutic translation. Further, we show a possibility to classify previously un-classified (UNS) tumors, which will be validated using additional cohorts (TCGA/METABRIC). Citation Format: Seth S, Huo L, Rauch G, Lau R, Gilcrease M, Adrada B, Piwnica-Worms H, Symmans WF, Draetta G, Futreal AP, Moulder S, Chang JT. Towards a therapeutically relevant subtyping scheme for triple-negative breast cancer (TNBC), profiling results from A Randomized, TNBC Enrolling trial to confirm Molecular profiling Improves Survival (ARTEMIS) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-07-01.
Epigenetic Therapy Targets Th1/Th17 Polarization to Reversing Immune Evasion and Treating Leukemia Relapse Post Allogeneic Stem Cell Transplantation in Non-APL AML Patients
Authors: Xi Yang, Hong Zheng, Jingying Dai, Chenglong Li, Rong Zhang, Xiaodong WANG, Chunsen Wang, Xiaobing Huang
Journal: Blood (2018)
Abstract 44: Cardiorespiratory Fitness Decreases Stroke Incidence in Hypertensive Veterans
Authors: Peter Kokkinos, Charles Faselis, Puneet Narayan, Jonathan Myers, Pamela Karasik, Hans Moore
Journal: Circulation (2017)

Introduction: Stroke incidence is significantly higher in hypertensive patients compared to normotensive subjects. Cardiorespiratory fitness (CRF) is associated with a more favorable cardiovascular health. The CRF-stroke incidence association in hypertensive patients has not been fully explored. Hypothesis: We assessed the hypothesis that CRF is inversely and independently associated with stroke incidence in hypertensive patients. Methods: From 1985 to 2014, we identified 12,933 hypertensive patients (mean age: 60±11 years) with a normal response to an exercise tolerance test and no prior history of stroke. We established five fitness categories based on age-stratified quintiles of peak metabolic equivalents (MET) achieved: Least-Fit (4.1±1.0 METs; n=2,516); Low-Fit (5.6±1.0; n=2,772); Moderate-Fit (7.0±1.0 METs; n=2,803); Fit (8.4±1.3 METs; n=3,282); and High-Fit (11.4±2.0 METs; n=1,560). A multivariable Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% confidence intervals [CI] for incidence of stroke across fitness categories. The model was adjusted for age, resting blood pressure, BMI, atrial fibrillation, gender, race, other cardiac risk factors, alcohol dependence and medications. The Least-fit category was used as the reference group. Results: During follow-up (median=11.4 years; 152,408 person-years), 694 individuals (4.5 events per 1,000 person-years) developed stroke. The risk for stroke was 5% lower for each 1-MET increase in exercise capacity (HR=0.95, CI: 0.92-0.98; p&lt;0.001). When considering fitness categories, stroke risk was lower by 28% (HR=0.72; CI: 0.57-0.90) for the Moderate-Fit and Fit individuals (HR=0.72; CI: 0.58-0.89) and 33% for High-Fit individuals (HR= 0.67; CI: 0.50-0.88). Conclusions: Increased CRF was inversely related to stroke incidence in hypertensive patients. The association was independent and graded.
Ocular Prophylaxis for Gonococcal Ophthalmia Neonatorum
Authors: Susan J. Curry, Alex H. Krist, Douglas K. Owens, Michael J. Barry, Aaron B. Caughey, Karina W. Davidson, Chyke A. Doubeni, John W. Epling, Alex R. Kemper, Martha Kubik, C. Seth Landefeld, Carol M. Mangione, Michael Silverstein, Melissa A. Simon, Chien-Wen Tseng, John B. Wong
Journal: JAMA (2019)

<h3>Importance</h3> In the United States, the rate of gonococcal ophthalmia neonatorum was an estimated 0.4 cases per 100 000 live births per year from 2013 to 2017. Gonococcal ophthalmia neonatorum can cause corneal scarring, ocular perforation, and blindness as early as 24 hours after birth. In the absence of ocular prophylaxis, transmission rates of gonococcal infection from mother to newborn are 30% to 50%. <h3>Objective</h3> To reaffirm the US Preventive Services Task Force (USPSTF) 2011 recommendation on ocular prophylaxis for gonococcal ophthalmia neonatorum. <h3>Evidence Review</h3> The USPSTF commissioned a reaffirmation evidence update to identify new and substantial evidence sufficient enough to change its prior recommendation. <h3>Findings</h3> Using a reaffirmation process, the USPSTF found no new data that would change its previous conclusion that topical ocular prophylaxis is effective in preventing gonococcal ophthalmia neonatorum and related ocular conditions. The USPSTF found no new data that would change its previous conclusion that there is convincing evidence that topical ocular prophylaxis of all newborns is not associated with serious harms. Therefore, the USPSTF reaffirms its previous conclusion that there is convincing evidence that topical ocular prophylaxis for all newborns provides substantial benefit. <h3>Conclusions and Recommendation</h3> The USPSTF recommends prophylactic ocular topical medication for all newborns to prevent gonococcal ophthalmia neonatorum. (A recommendation)
Results from phase I study of the oncolytic viral immunotherapy agent canerpaturev (C-REV) in combination with gemcitabine plus nab-paclitaxel for unresectable pancreatic cancer.
Authors: Yusuke Hashimoto, Makoto Ueno, Maki Tanaka, Masafumi Ikeda
Journal: Journal of Clinical Oncology (2019)

325 Background: Canerpaturev (C-REV, formerly HF10) is an oncolytic, spontaneous mutant Herpes Simplex Virus type 1, and is one of immunotherapies that combine direct tumor cell killing with immune modulation. The purpose of this study is to determine the recommended dose of C-REV in combination with chemotherapy (Gemcitabine + Nab-paclitaxel; G-nP) in Japanese patients with stage III or IV unresectable pancreatic cancer. We report the safety and antitumor activity data of this study. Methods: This study was a “3 + 3” design with a 2-dose escalation scheme evaluating 2 doses of C-REV. The subjects received C-REV at 1x10 6 or 1x10 7 TCID 50 /mL (up to 2mL, depending on tumor size) intratumorally by EUS-guidance at a 2-week interval in addition to 1000 mg/m 2 gemcitabine and 125 mg/m 2 nab-paclitaxel by intravenous infusion on days 1, 8, and 15 of a 4-week cycle. The study treatment could continue up to 1 year if eligible for injection. The primary endpoint was Dose Limiting Toxicity (DLT); the secondary endpoints were adverse events (AEs) assessed per NCI CTCAE v4.0, Best Overall Response Rate (BORR) at 16-week by RECIST and progression-free survival. Results: Six patients (pts) were enrolled and treated: 33% (2/6) men, age range 63 to 72 yrs, disease stage 33% III, 66% IV. Of 6 safety evaluable pts, no DLTs were reported. 16% (1/6) pt(s) had C-REV-related ≥ G3 AE, and it was acute pancreatitis (G3). G-nP-related ≥ G3 AEs observed in more than 2 pts were neutropenia (50%), and the majority of ≥ G3 AEs were similar as the AEs previously reported in G-nP therapy. As of 01 Sep 2018, of the 6 efficacy evaluable pts, BORR at 16-week was 66% (4 PR). Disease control rate was 100% (2 SD), and 1 of 2 SD pts continues the study treatment. We will present the updated data. Conclusions: The recommended dose was determined as 1x10 7 TCID 50 /mL. The combination of C-REV and the standard chemotherapy demonstrated a favorable benefit/risk profile and encouraging antitumor activity in Japanese patients with unresectable pancreatic cancer. Clinical trial information: NCT03252808.
Quality-of-Life Outcomes in Patients with Relapsed/Refractory Multiple Myeloma Treated with Elotuzumab Plus Pomalidomide and Dexamethasone: Results from the Phase 2 Randomized Eloquent-3 Study
Authors: Katja Weisel, Agne Paner, Monika Engelhardt, Fiona Taylor, Kim Cocks, Ashlee Espensen, Mihaela Popa-McKiver, Clara Chen, Michele Cavo
Journal: Blood (2018)
Proliferative Sickle Cell Retinopathy in SS and SC Hemoglobinopathies: Identification of New Candidate Genes
Authors: Sueli Matilde da Silva Costa, Mirta Tomie Ito, Bruno Batista Souza, Pedro Rodrigues Souza Cruz, Letícia de Carvalho Bapista, Vinicius Mandolesi Rios, Marina Gonçalves Monteiro Viturino, Stephanie Ospina Pietro, Margareth C Ozelo, Fernando F. Costa, Monica Barbosa Melo
Journal: Blood (2018)
CRISPR-Based Tools in Immunity
Authors: Dimitre R. Simeonov, Alexander Marson
Journal: Annual Review of Immunology (2019)

CRISPR technology has opened a new era of genome interrogation and genome engineering. Discovered in bacteria, where it protects against bacteriophage by cleaving foreign nucleic acid sequences, the CRISPR system has been repurposed as an adaptable tool for genome editing and multiple other applications. CRISPR's ease of use, precision, and versatility have led to its widespread adoption, accelerating biomedical research and discovery in human cells and model organisms. Here we review CRISPR-based tools and discuss how they are being applied to decode the genetic circuits that control immune function in health and disease. Genetic variation in immune cells can affect autoimmune disease risk, infectious disease pathogenesis, and cancer immunotherapies. CRISPR provides unprecedented opportunities for functional mechanistic studies of coding and noncoding genome sequence function in immunity. Finally, we discuss the potential of CRISPR technology to engineer synthetic cellular immunotherapies for a wide range of human diseases.
Abstract 11159: Prolonged QRS Duration Predicts Outcomes in Heart Failure With Preserved Ejection Fraction
Authors: Jacob Joseph, Brian L Claggett, Inder S Anand, Jerome L Fleg, Thao Huynh, Akshay S Desai, Scott D Solomon, Eileen O’Meara, Sonja McKinlay, Bertram Pitt, Marc A Pfeffer, Eldrin F Lewis
Journal: Circulation (2015)

Introduction: QRS widening on the surface electrocardiogram (ECG) is a marker of disease progression in heart failure (HF) with reduced ejection fraction. We hypothesized that prolonged QRS duration would similarly identify patients with HF with preserved ejection fraction (HFPEF) at high risk for cardiovascular (CV) events. Methods: We examined the relationship of baseline QRS duration to primary outcome [composite of CV death, aborted cardiac arrest, or HF hospitalization (HFH)] and HFH alone in TOPCAT, a multicenter, randomized, placebo-controlled trial of spironolactone in HFPEF. QRS duration was analyzed as a dichotomous variable (≥ 120 ms or &lt; 120 ms). Multivariable analyses were conducted including variables that were significantly associated with QRS duration ≥ 120 ms (Table 1). Analyses were conducted in the entire study cohort as well as in separate analyses for only subjects enrolled from the Americas or from Russia/Georgia independently. Results: QRS duration was known in 3426 of 3445 TOPCAT patients. Compared to those with QRS duration &lt; 120ms, 613 (17.9%) subjects had a QRS duration ≥ 120 ms and were older (72.9 years vs. 67.8 years; p &lt; 0.0001) and more likely to be men (62% vs. 45%; p&lt;0.0001). A QRS duration ≥ 120 ms was independently associated with an increased risk of primary outcome and HFH in the entire study cohort and in the subset of patients enrolled in the Americas but was of borderline statistical significance in Russia/Georgia (Table 1). No statistical interaction was observed between treatment with spironolactone and QRS duration (p value for interaction= 0.33). Conclusions: QRS duration identifies HFPEF subjects at a higher risk of adverse clinical outcomes; spironolactone had a similar effect on outcomes independent of QRS duration. This easily obtainable marker may be an important component of risk stratification in this syndrome.
Notch1 mutations to define a subgroup of adenoid cystic carcinoma (ACC): Tumor stage, propensity to bone and liver metastasis, risk of relapse, and overall survival.
Authors: Renata Ferrarotto, Yoshitsugu Mitani, Yan Cai, Lixia Diao, Jing Wang, Monique B. Nilsson, Bonnie S. Glisson, Merrill S. Kies, William Nassib William, Michael Elliot Kupferman, Patrick A Zweidler-McKay, Andrew Futreal, Adel K. El-Naggar, John Heymach
Journal: Journal of Clinical Oncology (2015)

6081 Background: ACC is chemotherapy refractory and there is no standard of care treatment for patients (pts) with metastatic disease. ACC genotyping revealed alterations in the Notch (N) pathway in 13-29% of cases. An ACC patient identified in our institution with an activating Notch1 (N1) mutation achieved a partial response after 2 cycles of a N1 inhibitor in a phase I trial. In this study, we investigate the clinical and pathologic characteristics of N1 mutant ACC. Methods: N1 sequencing was performed in 97 pts (71 using whole-exome sequencing and 26 using a 50 gene panel including N1 exons 26, 27, 34). Comparisons between tumor characteristics and clinical outcomes in pts with or without activating N1 mutations (PEST or HD domain) were performed. Results: N1 mutations were identified in 13 pts. Pathway activation was confirmed by IHC for N1 intracellular domain. N1 ACC pts had significantly higher disease stage at diagnosis (p = 0.009, Fisher’s exact test), and solid histologic subtype (p = 0.027). Only 1/38 pts who presented with stage I-III disease had N1 mutation compared with 4/12 pts (33%) who presented with distant metastasis. Although lung is the most common site of metastasis in ACC, N1 mutants developed bone (odds ratio [OR] = 7) and liver (OR = 4.5) metastasis more frequently than lung (OR = 0.44). Recurrence-free survival and OS were significantly shorter in the N1 mutant subgroup (p-value = 0.025, Log-rank test). The clinical correlations identified for the N1 mutants were maintained in an extended analysis that included SPEN and N2 mutations (4 pts), with an even higher impact in OS (p = 0.007). Conclusions: A subgroup of ACC harbors N1 (13.4%) or other N pathway activating mutations (17%). N activation defines a more aggressive phenotype, with a distinct pattern of metastatic spread, higher risk of relapse, and shorter OS. The identification of genetic events that activate N and the encouraging response observed in an index case suggest an immense opportunity to further explore this pathway as a therapeutic target in ACC.
Identifying the importance of integrating routine pharmacogenomic testing for <i>UGT1A1</i> and <i>DPYD/tyms</i> genetic variants in patients receiving irinotecan and/or 5-fluorouracil chemotherapy.
Authors: Candice Baldeo, Caren Hughes, Faisal Shahjehan, Saivaishnavi Kamatham, Pashtoon Murtaza Kasi
Journal: Journal of Clinical Oncology (2019)

660 Background: Adverse toxicities to chemotherapy remain a limiting factor for patients receiving treatment for malignancies. In gastrointestinal cancers, particularly metastatic colorectal cancer, the majority of front line treatment remains chemotherapy containing 5-fluorouracil and/or irinotecan. One particular cause that can predispose a patient to increased toxicity from 5-fluorouracil is genetic variation in the DPYD gene, as well as TYMS gene. Similarly, genetic variation in the UGT1A1 gene can increase the risk of irinotecan toxicity. These gene variations may have major implications when deciding on treatment regimens for these types of patients; however, they are not routinely checked. Methods: In Mayo Clinic Florida, patients with metastatic colorectal cancer receiving 5-fluorouracil and/or irinotecan chemotherapy during the period of July 2017-July 2018 were tested for genetic variants in DPYD/TYMS and UGT1A1. This testing was done during routine clinic visit either by buccal swab or blood test. The DPYD/TYMS and UGT1A1 variant results were evaluated together with a pharmacist for recommendations regarding dose reductions on 5-fluorouracil and irinotecan respectively. Results: A total of 292 patients were tested. Total number of patients who had a variation in the DPYD/ TYMS and/or UGT1A1 gene was 169 (57.9%). The UGT1A1 variation was the most prevalent with 154 (52.7%) patients having a variant (115 heterozygous variant, 34 homozygous variant and 5 double heterozygous variant). Specifically there were 3 patients with both UGT1A1 and DPYD variants and 3 patients with both UGT1A1 and TYMS variants. One patient had both DPYD and TYMS variations. Conclusions: Routine pharmacogenomic testing for UGT1A1 and DPYD/TYMS genetic variants should be done in all patients receiving irinotecan and 5-fluorouracil chemotherapy respectively. Avoiding or preemptively dose reducing these agents in patients with gene variations may help prevent toxic adverse events and make treatment more tolerable.