tbuckley/cabot-search huggingface dataset:
Abstract 19108: Cardiac Myosin Activator Omecamtiv Mecarbil Improves Left Atrial Structure and Function in Chronic Heart Failure (COSMIC-HF)
Authors: Tor Biering-Sørensen, John R Teerlink, G. M Felker, John J McMurray, Fady I Malik, Narimon Honarpour, Maria L Monsalvo, James Johnston, Scott D Solomon
Journal: Circulation (2016)

Introduction:  Left atrial (LA) size is generally increased and LA function reduced in patients with chronic heart failure (CHF). Omecamtiv mecarbil (OM) is a selective cardiac myosin activator which recently was shown to improve measures of left ventricular structure and function.   Hypothesis:  We hypothesized that chronic therapy with OM improves LA structure and function in patients with CHF.   Methods:  In the double-blinded COSMIC-HF trial, 448 patients with stable, symptomatic CHF and left ventricular ejection fraction (LVEF) ≤40% were randomly assigned to oral OM [25 mg twice daily; or 25 mg twice daily with pharmacokinetic-guided uptitration to 50 mg twice daily (PK group)] or placebo for 20 weeks. We assessed changes in measures of LA structure (maximal and minimal LA volume indexed by body surface area) and function (LA emptying fraction, or LA EF) by echocardiography between the placebo (n=149) and PK groups (n=149) at weeks 12 and 20. LS means were calculated from repeated measure models which assessed the treatment differences vs placebo and included the stratification factor of presence or absence of atrial fibrillation/flutter at randomization, baseline value, visit, and the treatment group by visit interaction as covariates.   Results:  Patients were 63±11 years old, predominantly (82%) male, with LVEF of 29.1±7.3%, maximal LA volume of 41.0±15.4 mL/m 2 , minimal LA volume of 28.2± 14.7 mL/m 2  and LA EF of 34.2±13.3%; there were no differences between the placebo and PK group at baseline. Both minimal LA volume and LA EF improved significantly in patients receiving OM ( Figure ).   Conclusion:  In patients with chronic heart failure and reduced systolic function, OM improved measures of LA structure and function. Given the absence of any direct effect on preload or afterload by OM, further analyses will be performed to attempt to assess the relative contributions of intrinsic increases in atrial contractility and improvements in atrial remodeling and loading conditions.
46 Inpatient admissions for lower gastrointestinal bleeding in the belfast trust
Authors: E Clarke, P Cooper, GB Turner
Journal: Gut (2017)

Background  Traditionally, lower GI bleeding (LGIB) is admitted surgically but the recent NCEPOD report has recommended an integrated pathway for all gastrointestinal bleeds.  Aim  To retrospectively assess how LGIB is managed within the Trust.  Method  Inpatient discharge data were gathered over a 12 month period (March 2015-March 2016). Cases included were those with LGIB as the primary reason for admission. Factors including length of stay, inpatient and/or outpatient endoscopic and radiological investigations. 30 day mortality rate was assessed.  Results  350 patients were identified, 174 were excluded (UGIB or not primary reason for admission). 176 patients were included, age range 17–100 (median 66). Median length of stay=3.19 days (range 0–27). Total bed days 562. 30 day mortality=3.9% (n=7, 2 secondary to PR bleeding and 5 due to co-morbidities). n=86 (48.9%) patients had inpatient investigations. See Figure 1.  50 patients had only inpatient endoscopic procedures, 15 had both endoscopic and radiological investigations and 15 had only radiological investigations. Others included EUA and haemorrhoidectomy. n=46 (26.1%) had only outpatient investigations. Total bed days=83. n=44 (25%) had no investigations. Reasons included known pathology, recent endoscopy or CT imaging, recent intervention (surgical or endoscopic) or not fit for investigation. Most common diagnoses were diverticular bleed n=59, haemorrhoids n=12, malignancy n=10.  Conclusions  Less than half had inpatient investigations suggesting that many admissions could have been avoided. The current results show a low mortality rate consistent with other published data. A pathway for the management of stable LGIB bleeding could be developed to minimise unnecessary admissions and streamline access to intervention where needed.
Time to metastasis or death in non-metastatic castrate resistant prostate cancer (nmCRPC) patients by National Comprehensive Cancer Network (NCCN) risk groups.
Authors: Brian Macomson, Jennifer H Lin, Ozgur Tunceli, Ajay S. Behl, Chris Pericone, Siddhant Deshmukh, Neal D. Shore
Journal: Journal of Clinical Oncology (2017)

5027 Background: Interventions in nmCRPC are the last defense against metastasis, which drives health care cost and mortality. To assess the value of such interventions we must analyze risk factors for metastasis and death. Methods: This was a retrospective study of data (Optum electronic health record database, 2007 – 2016) from men with a prostate cancer diagnosis, 2 rising PSA levels ≥1 week apart, castrate level ( &lt; 50 ng/dL) testosterone (T) and no ICD-9/10 code or therapy indicating metastasis. Gleason grade (G) and PSA data up to and including nmCRPC index date (ie, date of 2nd PSA rise) were used to assign NCCN risk groups: Low (G ≤6 and PSA &lt; 10 ng/mL), Intermediate (IM) (G = 7 or 10 ≤ PSA ≤ 20 ng/mL) or High (G ≥ 8 or PSA &gt; 20 ng/mL). The LP/NG group comprised men with PSA &lt; 10 ng/mL (LP) and missing G (NG). A Cox proportional hazard model, adjusted for age, race, comorbidity index score, T level, therapy type and bone scans was used to compare LP/NG, IM and High with the Low risk group. Results: Among 1008 men with nmCRPC (mean age 76 years; 12% African American), 553 developed metastases and 430 died during follow-up. Mean time to metastasis was 28, 22, 15, 13 months in the Low, LP/NG, IM, and High groups, respectively. In the Low group, 9 of 29 (31%) men developed metastases, vs 131/285 (46%) in the LP/NG group (hazard ratio [HR] = 1.70, 95% confidence interval [CI]: 0.86-3.35), 175/320 (55%) in the IM group (HR = 2.52, 95% CI: 1.28-4.91) and 238/374 (64%) in the High group (HR = 3.63, 95% CI: 1.85-7.10). Mean time to death was 32, 30, 24, 21 months in the Low, LP/NG, IM, High groups, respectively. There were 8 deaths in the Low group (27.6%), vs 101 (35.4%) (HR = 1.35, 95% CI: 0.65-2.79) in the LP/NG group, 124 (38.8%) (HR = 1.79, 95% CI: 0.87-3.70) in the IM group and 197 (52.7%) (HR = 2.96, 95% CI: 1.45-6.05) in the High group. The High risk group was more likely to develop metastasis during the first year and die within the first 2 years. Conclusions: Metastasis and death occurred earlier and more frequently in the Intermediate and High groups relative to the Low risk group. These findings may further inform diagnostic and management strategies for combating disease progression.
Cost-effectiveness of short course radiation therapy versus long-course chemoradiation for locally advanced rectal adenocarcinoma.
Authors: Ann C. Raldow, Percy Lee, Marcia McGory Russell, Theodore S. Hong, David P. Ryan, Jennifer Yon-Li Wo
Journal: Journal of Clinical Oncology (2018)

749 Background: Long-course chemoradiation (LCRT; 50.4 Gy in 28 fractions with concurrent chemotherapy) followed by surgery and adjuvant chemotherapy is the standard of care in the United States for locally advanced rectal cancer. However, many countries follow a protocol of short course radiation therapy (SCRT; 25 Gy in 5 fractions). The purpose of this study was to analyze the cost-effectiveness of SCRT versus LCRT. Methods: We developed a cost-effectiveness model simulating 10-year outcomes for 65-year-old patients treated with either SCRT or LCRT. For the base case analysis, we assumed 3D-conformal radiation treatment. We used probabilities, utilities and costs based on the literature and Medicare Fee schedules to determine the incremental cost-effectiveness ratio (ICER) of SCRT versus LCRT. We defined cost effectiveness at an ICER of $100,000/quality-adjusted life-year (QALY) or less. We assumed that SCRT would not result in tumor downstaging adequate enough to change rates of sphincter preservation, while LCRT resulted in higher rates of low anterior resection (LAR). To model preference-sensitive care, we conducted a two-way sensitivity analysis in which we simultaneously varied the utilities of the no evidence of disease states with LAR (NED-LAR) and abdominoperineal resection (APR; NED-APR). To model current practice, we repeated the analysis assuming 3D-conformal treatment for LCRT but intensity modulated radiation therapy (IMRT) for SCRT. Results: With an ICER of $351,731/QALY, SCRT was cost-effective as compared to LCRT. SCRT remained the cost-effective strategy with 3D-conformal treatment for LCRT but IMRT for SCRT (ICER of $314,022/QALY). On one-way sensitivity analysis, LCRT became the cost-effective approach when the utility of NED-APR was below 0.61. Two-way sensitivity analysis revealed that the cost-effective approach for a given patient depended on the utilities for the NED-LAR and NED-APR states. Conclusions: SCRT was the cost-effective strategy as compared to LCRT. However, the cost effectiveness of SCRT versus LCRT was sensitive to the utilities of NED-LAR and NED-APR, highlighting the importance of patient preference-sensitive care.
Abstract 15444: Sex Differences in Response to Chemical Cardioversion of Atrial Fibrillation by Dofetilide; a Retrospective Cohort of 160 Persistent Atrial Fibrillation Patients
Authors: Hafeez Hassan, Waqas Qureshi, ShilpKumar Arora, Philippe Akhrass, Nektarious Souvaliotis, Emad Aziz
Journal: Circulation (2016)

Introduction:  Dofetilide is class 3 antiarrhythmic drug which is FDA approved for persistent AF patients. Studies have shown sex based differences in response to treatment of atrial fibrillation (AF) by anti-arrhythmic drugs. Impact of dofetilide on successful cardioversion of AF by sex has not been well studied.   Methods:  We retrospectively analyzed 160 (mean age 63.3±11.6, 26.2% women) AF patients who were started on dofetilide and were followed for 1 year. We examined relationship of sex to failure to cardiovert in multivariable logistic regression model adjusted for age, race, hypertension, diabetes, dyslipidemia, coronary artery disease, smoking, ejection fraction, dose, creatinine and BMI. We examined association of sex with AF related readmission in Cox proportional hazard models adjusted for same covariates   Results:  Out of 160 patients, 42 (26.2%) were women. Out of 42 women, 9 (21%) did not convert after 10 consecutive doses of dofetilide as compared to 11 men (9.3%) who did not convert. Out of those who converted, 5 (15%) women compared with 8 (7.5%) men were readmitted with AF during 1 year follow- up. In multivariable adjusted analysis, women were at higher risk of not converting on dofetilide than men (OR 3.92; 95% CI 1.12-13.7, p=0.03). Similarly, there was higher risk of 1-year AF related readmission for women than men (HR 3.60; 95% CI 1.11-11.76, p=0.03).   Conclusions:  We observed that men were more likely to achieve sinus rhythm in the short term treatment with Dofetilide. Men were also shown to have less readmissions within 1 year of treatment with Dofetilide. This association needs to be validated in larger studies to devise sex appropriate therapies for AF.
EBV Reactivation Incidence and Severity in Multiple Sclerosis Patients Treated with Autologous Haematopoietic Stem Cell Transplant and Comparing with Aplastic Anaemia Treated with ATG- Single Site Experience
Authors: Varun Mehra, Elijah Rhone, Stefanie Widya, Victoria Potter, Kavita Raj, Donal McLornan, Hugues De Lavallade, Jill Mccormick, Carmel Rice, Nana Benson-quarm, Christina Lim, Sarah Ware, Mark Zuckerman, Omar Malik, Paolo Murano, Richard Nicholas, Antonio Pagliuca, Ghulam Mufti, Judith Marsh, Majid A. Kazmi
Journal: Blood (2017)
Margaret McCartney: Tech companies, healthcare, and a clash of cultures
Authors: Margaret McCartney
Journal: BMJ (2018)

Facebook stands accused of misusing data on a grand scale. Millions of people’s information has been used in ways they didn’t fully expect or explicitly permit. This has been done most notably by Cambridge Analytica, which has been implicated in influencing voting patterns.

It’s been clear for years that Facebook took the rights to reuse content with few limitations. Even deleting your account wouldn’t end the company’s licence.1 I doubt that most were aware of this on signing up—terms and conditions are boring. In 2014, in an experiment run by a firm called F-Secure to demonstrate the fragility of internet security, six Londoners agreed without realising it “to assign their first born child . . . for the duration of eternity” in return for access …
Geoffrey Francis Norris
Authors: Paul Norris
Journal: BMJ (2018)

Geoffrey Francis Norris (“Geoff”) was born to Frank and Hilda Norris in Cardiff on 20 October 1934. His early life was spent in Cardiff and Porthcawl, south Wales. He attended Bishop Llandaff School in Cardiff and then boarded at Mill Hill School in London before studying medicine at Downing College, Cambridge, and Westminster Hospital Medical School.

He married Margaret Davis in 1960. They adopted a daughter, Elizabeth, and a son, Paul.

Before he became a general practitioner in 1962, Geoff was house …
Associations between Parasympathetic Activity in the Month after Birth and Wheeze at Age 2–3 Years
Authors: Matthew S. Perzanowski, Khalil W. Savary, Emilio Arteaga-Solis, Laura A. Lautenbacher, Natalie H. Brito, Virginia A. Rauh, J. David Nugent, Amy J. Elliott, Michael M. Myers, William P. Fifer
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Tumor Elastography and Its Association with Collagen and the Tumor Microenvironment
Authors: Johannes Riegler, Yassin Labyed, Stephen Rosenzweig, Vincent Javinal, Alessandra Castiglioni, Claudia X. Dominguez, Jason E. Long, Qingling Li, Wendy Sandoval, Melissa R. Junttila, Shannon J. Turley, Jill Schartner, Richard A.D. Carano
Journal: Clinical Cancer Research (2018)

Purpose: The tumor microenvironment presents with altered extracellular matrix (ECM) and stroma composition, which may affect treatment efficacy and contribute to tissue stiffness. Ultrasound (US) elastography can visualize and quantify tissue stiffness noninvasively. However, the contributions of ECM and stromal components to stiffness are poorly understood. We therefore set out to quantify ECM and stroma density and their relation to tumor stiffness.Experimental Design: A modified clinical ultrasound system was used to measure tumor stiffness and perfusion during tumor growth in preclinical tumor models. In vivo measurements were compared with collagen mass spectroscopy and automatic analysis of matrix and stromal markers derived from immunofluorescence images.Results: US elastography estimates of tumor stiffness were positively correlated with tumor volume in collagen and myofibroblast-rich tumors, while no correlations were found for tumors with low collagen and myofibroblast content. US elastography measurements were strongly correlated with ex vivo mechanical testing and mass spectroscopy-based measurements of total collagen and immature collagen crosslinks. Registration of ultrasound and confocal microscopy data showed strong correlations between blood vessel density and T-cell density in syngeneic tumors, while no correlations were found for genetic tumor models. In contrast to collagen density, which was positively correlated with stiffness, no significant correlations were observed for hyaluronic acid density. Finally, localized delivery of collagenase led to a significant reduction in tumor stiffness without changes in perfusion 24 hours after treatment.Conclusions: US elastography can be used as a potential biomarker to assess changes in the tumor microenvironment, particularly changes affecting the ECM. Clin Cancer Res; 24(18); 4455-67. ©2018 AACR.
Defining Value of Cancer Therapeutics—A Health System Perspective
Authors: Christine Leopold, Jeffrey M Peppercorn, S Yousuf Zafar, Anita K Wagner
Journal: JNCI Journal of the National Cancer Institute (2018)

Because of the rising costs of cancer care and ongoing challenges in ensuring access to quality care, there is an increasing need to prioritize spending and define the benefits of therapy in proportion to costs. The term "value" has gained favor as means to define the relative utility of a medical intervention in terms of benefits, risks, and financial costs, which in turn can help clinicians, patients, and policy makers prioritize "high-value" care. While numerous value concepts have been proposed, a comprehensive discussion of value initiatives along the care continuum is missing. In this Commentary, we propose a health system taxonomy of value initiatives in cancer care to discuss what the field needs to progress.
Phase II study of autologous mRNA electroporated dendritic cells (TriMixDC-MEL) in combination with ipilimumab in patients with pretreated advanced melanoma.
Authors: Bart Neyns, Sofie Wilgenhof, Jurgen Corthals, Carlo Heirman, Kris Thielemans
Journal: Journal of Clinical Oncology (2014)

3014 Background: Autologous monocyte-derived mRNA electroporated dendritic cells (TriMixDC-MEL) are immunogenic and have anti-tumor activity in patients (pts) with pretreated advanced melanoma (Wilgenhof S. et al. Ann Oncol 2013). Ipilimumab (ipi) is a monoclonal antibody directed against the CTLA-4 receptor that counteracts physiologic suppression of T-cell activation and improves the overall survival of pts with advanced melanoma. Methods: The activity and safety of TriMixDC-MEL (4.106 cells id and 20.106 iv, q3wks x4) combined with ipi (10 mg/kg q3wks x4), followed by ipi maintenance therapy (10 mg/kg q12w, in pts who are progression-free at week 24) was investigated in pts with advanced pretreated melanoma according to a Simon two-stage phase II study design. The primary endpoint was the 6-mths disease control rate (DCR) by irRC. Results: 39 pts initiated study treatment (16F/23M; median age 46y [range 24-70]; AJCC stage IIIc/IV M1a/-M1b/-M1c: 1/6/4/28; prior therapy: BRAF- or MEK-inhibitor: 23 pts, chemotherapy: 18 pts). Following DC-administration, gr2 skin injection site reactions were observed in all pts, post-infusion chills (< gr2) in 15 (38%), and transient flu-like symptoms (< gr2) in 33 pts (85%). Most frequent grade 3/4 adverse events of special interest were: dermatitis (2 pts [5%]); diarrhea/colitis (2 pts [5%]), hypophysitis/hypopituitarism (7 pts [18%]), hepatitis (5 pts [13%]), and pneumonitis (3 pts [8%]). Systemic corticotherapy was used to treat irAE in 18 pts (46%). Best overall tumor response by irRC: 8 CR, and 7 PR (BORR 38%), 6 SD, and 18 PD. All CR, and 3 PR are ongoing after a median duration of 19 mths (range 3-29 mths). The 6-mths DCR by irRC is 50% (95% CI 34-66). Median PFS and OS are respectively 6.2 (95% CI 3-9), and 14.4 mths (95%CI 10-18). Conclusions: This phase II trial of autologous mRNA electroporated dendritic cells in combination with ipilimumab in patients with pretreated advanced melanoma achieved its primary endpoint and resulted in an encouraging rate of durable tumor responses. Further clinical investigation of autologous mRNA electroporated DC-therapy in combination with immune checkpoint modulators is warranted. Clinical trial information: NCT01302496.
Lymph node fibrosis: a structural barrier to unleashing effective vaccine immunity
Authors: Boris Julg, Galit Alter
Journal: Journal of Clinical Investigation (2018)

There is marked variability in vaccine efficacy among global populations. In particular, individuals in low- to middle-income countries have been shown to be less responsive to vaccines than those from developed nations. Several factors, including endemic infections, nutrition, genetics, and gut microbiome composition, have been proposed to underlie discrepancies in vaccine response. In this issue of the JCI, Kityo et al. evaluated response to yellow fever virus vaccine, inflammation, and lymphatic tissue architecture and fibrosis in three cohorts: two from the U.S. and one from Uganda. Compared with the U.S. subjects, the Ugandan cohort exhibited enhanced cytokine responses, increased lymph node fibrosis, reduced CD4+ T cell levels, and reduced vaccine response. Together, these results provide a link among chronic inflammation, damaged lymphoid architecture, and poor vaccine outcome, and set the stage for future studies to identify strategies to overcome these barriers.
Comprehensive Profiling of DNA Repair Defects in Breast Cancer Identifies a Novel Class of Endocrine Therapy Resistance Drivers
Authors: Meenakshi Anurag, Nindo Punturi, Jeremy Hoog, Matthew N. Bainbridge, Matthew J. Ellis, Svasti Haricharan
Journal: Clinical Cancer Research (2018)

Purpose: This study was undertaken to conduct a comprehensive investigation of the role of DNA damage repair (DDR) defects in poor outcome ER+ disease.Experimental Design: Expression and mutational status of DDR genes in ER+ breast tumors were correlated with proliferative response in neoadjuvant aromatase inhibitor therapy trials (discovery dataset), with outcomes in METABRIC, TCGA, and Loi datasets (validation datasets), and in patient-derived xenografts. A causal relationship between candidate DDR genes and endocrine treatment response, and the underlying mechanism, was then tested in ER+ breast cancer cell lines.Results: Correlations between loss of expression of three genes: CETN2 (P < 0.001) and ERCC1 (P = 0.01) from the nucleotide excision repair (NER) and NEIL2 (P = 0.04) from the base excision repair (BER) pathways were associated with endocrine treatment resistance in discovery dataset, and subsequently validated in independent patient cohorts. Complementary mutation analysis supported associations between mutations in NER and BER genes and reduced endocrine treatment response. A causal role for CETN2, NEIL2, and ERCC1 loss in intrinsic endocrine resistance was experimentally validated in ER+ breast cancer cell lines, and in ER+ patient-derived xenograft models. Loss of CETN2, NEIL2, or ERCC1 induced endocrine treatment resistance by dysregulating G1-S transition, and therefore, increased sensitivity to CDK4/6 inhibitors. A combined DDR signature score was developed that predicted poor outcome in multiple patient cohorts.Conclusions: This report identifies DDR defects as a new class of endocrine treatment resistance drivers and indicates new avenues for predicting efficacy of CDK4/6 inhibition in the adjuvant treatment setting. Clin Cancer Res; 24(19); 4887-99. ©2018 AACR.
Seafood Long-Chain n-3 Polyunsaturated Fatty Acids and Cardiovascular Disease: A Science Advisory From the American Heart Association
Authors: Eric B. Rimm, Lawrence J. Appel, Stephanie E. Chiuve, Luc Djoussé, Mary B. Engler, Penny M. Kris-Etherton, Dariush Mozaffarian, David S. Siscovick, Alice H. Lichtenstein
Journal: Circulation (2018)

Since the 2002 American Heart Association scientific statement "Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and Cardiovascular Disease," evidence from observational and experimental studies and from randomized controlled trials continues to emerge to further substantiate the beneficial effects of seafood long-chain n-3 polyunsaturated fatty acids and cardiovascular disease. A recent American Heart Association science advisory addressed the specific effect of n-3 polyunsaturated fatty acid supplementation on clinical cardiovascular events. This American Heart Association science advisory extends that review and offers further support to include n-3 polyunsaturated fatty acids from seafood consumption. Several potential mechanisms have been investigated, including antiarrhythmic, anti-inflammatory, hematologic, and endothelial, although for most, longer-term dietary trials of seafood are warranted to substantiate the benefit of seafood as a replacement for other important sources of macronutrients. The present science advisory reviews this evidence and makes a suggestion in the context of the