tbuckley/cabot-search huggingface dataset:
Sacubitril/valsartan reduces serum uric acid concentration, an independent predictor of adverse outcomes in PARADIGM‐HF
Authors: Ulrik M. Mogensen, Lars Køber, Pardeep S. Jhund, Akshay S. Desai, Michele Senni, Søren L. Kristensen, Andrej Dukát, Chen‐Huan Chen, Felix Ramires, Martin P. Lefkowitz, Margaret F. Prescott, Victor C. Shi, Jean L. Rouleau, Scott D. Solomon, Karl Swedberg, Milton Packer, John J.V. McMurray
Journal: European Journal of Heart Failure (2017)

Aims Elevated serum uric acid concentration (SUA) has been associated with an increased risk of cardiovascular disease, but this may be due to unmeasured confounders. We examined the association between SUA and outcomes as well as the effect of sacubitril/valsartan on SUA in patients with heart failure with reduced ejection fraction (HFrEF) in PARADIGM‐HF. Methods and results The association between SUA and the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization, its components, and all‐cause mortality was examined using Cox regression analyses among 8213 patients using quintiles (Q1–Q5) of SUA adjusted for baseline prognostic variables including estimated glomerular filtration rate (eGFR), diuretic dose, and log N‐terminal pro‐brain natriuretic peptide. Change in SUA from baseline over 12 months was also evaluated in each treatment group. Patients in Q5 (SUA ≥8.6 mg/dL) compared with Q1 (&lt;5.4 mg/dL) were younger (62.8 vs. 64.2 years), more often male (88.7% vs. 63.1%), had lower systolic blood pressure (119 vs. 123 mmHg), lower eGFR (57.4 vs. 76.6 mL/min/1.73 m 2 ), and greater diuretic use. Higher SUA was associated with a higher risk of the primary outcome (adjusted hazard ratios) Q5 vs. Q1 = 1.28 [95% confidence intervals (1.09–1.50), P = 0.003], cardiovascular death [1.44 (1.11–1.77), P = 0.001], HF hospitalization [1.37 (1.11–1.70), P = 0.004], and all‐cause mortality [1.36 (1.13–1.64), P = 0.001]. Compared with enalapril, sacubitril/valsartan reduced SUA by 0.24 (0.17–0.32) mg/dL over 12 months ( P &lt; 0.0001). Sacubitril/valsartan improved outcomes, irrespective of SUA concentration. Conclusion Serum uric acid concentration was an independent predictor of worse outcomes after multivariable adjustment in patients with HFrEF. Compared with enalapril, sacubitril/valsartan reduced SUA and improved outcomes irrespective of SUA.
A Patient Risk Model of Chemotherapy-Induced Febrile Neutropenia: Lessons Learned From the ANC Study Group
Authors: Gary H. Lyman, Marek S. Poniewierski
Journal: Journal of the National Comprehensive Cancer Network (2017)

Neutropenia and its complications, including febrile neutropenia (FN), represent major toxicities associated with cancer chemotherapy, resulting in considerable morbidity, mortality, and costs. The myeloid growth factors such as granulocyte colony-stimulating factor (G-CSF) have been shown to reduce the risk of neutropenia complications while enabling safe and effective chemotherapy dose intensity. Concerns about the high costs of these agents along with limited physician adherence to clinical practice guidelines, resulting in both overuse and underuse, has stimulated interest in models for individual patient risk assessment to guide appropriate use of G-CSF. In a model developed and validated by the ANC Study Group, half of patients were classified as high risk and half as low risk based on patient-, disease-, and treatment-related factors. This model has been further validated in an independent patient population. Physician-assessed risk of FN, as well as the decision to use prophylactic CSF, has been shown to correlate poorly with the FN risk estimated by the model. Additional modeling efforts in both adults and children receiving cancer treatment have been reported. Identification of patients at a high individual risk for FN and its consequences may offer the potential for optimal chemotherapy delivery and patient outcomes. Likewise, identification of patients at low risk for neutropenic events may reduce costs when such supportive care is not warranted. This article reviews and summarizes FN modeling studies and the opportunities for personalizing supportive care in patients receiving chemotherapy.
Generation of stable PDX derived cell lines using conditional reprogramming
Authors: Alexandra Borodovsky, Travis J. McQuiston, Daniel Stetson, Ambar Ahmed, David Whitston, Jingwen Zhang, Michael Grondine, Deborah Lawson, Sharon S. Challberg, Michael Zinda, Brian A. Pollok, Brian A. Dougherty, Celina M. D’Cruz
Journal: Molecular Cancer (2017)

Efforts to develop effective cancer therapeutics have been hindered by a lack of clinically predictive preclinical models which recapitulate this complex disease. Patient derived xenograft (PDX) models have emerged as valuable tools for translational research but have several practical limitations including lack of sustained growth in vitro. In this study, we utilized Conditional Reprogramming (CR) cell technology- a novel cell culture system facilitating the generation of stable cultures from patient biopsies- to establish PDX-derived cell lines which maintain the characteristics of the parental PDX tumor. Human lung and ovarian PDX tumors were successfully propagated using CR technology to create stable explant cell lines (CR-PDX). These CR-PDX cell lines maintained parental driver mutations and allele frequency without clonal drift. Purified CR-PDX cell lines were amenable to high throughput chemosensitivity screening and in vitro genetic knockdown studies. Additionally, re-implanted CR-PDX cells proliferated to form tumors that retained the growth kinetics, histology, and drug responses of the parental PDX tumor. CR technology can be used to generate and expand stable cell lines from PDX tumors without compromising fundamental biological properties of the model. It offers the ability to expand PDX cells in vitro for subsequent 2D screening assays as well as for use in vivo to reduce variability, animal usage and study costs. The methods and data detailed here provide a platform to generate physiologically relevant and predictive preclinical models to enhance drug discovery efforts.
Weight Change During the Early Rheumatoid Arthritis Period and Risk of Subsequent Mortality in Women With Rheumatoid Arthritis and Matched Comparators
Authors: Jeffrey A. Sparks, Shun‐Chiao Chang, Uyen‐Sa Nguyen, Medha Barbhaiya, Sara K. Tedeschi, Bing Lu, David J. Kreps, Karen H. Costenbader, Yuqing Zhang, Hyon K. Choi, Elizabeth W. Karlson
Journal: Arthritis & Rheumatology (2017)

Objective To investigate whether weight change during the early rheumatoid arthritis ( RA ) period is associated with subsequent mortality and to evaluate whether there is an RA ‐specific effect. Methods We identified patients with incident RA during the Nurses’ Health Study (NHS; 1976–2016) and created a comparison cohort by matching each RA patient with up to 10 non‐ RA comparators by age and calendar year of the RA diagnosis (index date). To capture weight change around the early RA period (“peri‐ RA /index”), we used weight measurements collected 2–4 years before and 2–4 years after the index date. We used Cox regression analysis to estimate hazard ratios ( HR s) for mortality according to peri‐ RA /index weight change categories, separately in each cohort and in the combined cohorts, evaluating for an RA ‐specific effect. Results Among 121,701 women in the NHS , 902 patients with incident RA were identified and matched to 7,884 non‐ RA comparators. In the RA cohort, 371 deaths (41.1%) occurred during a mean follow‐up of 17.0 years after the early RA period, and 2,303 deaths (29.2%) occurred in the comparison cohort during a mean follow‐up of 18.4 years. Weight loss of &gt;30 pounds during the peri‐ RA period had a hazard ratio ( HR ) for mortality of 2.78 (95% confidence interval [95% CI ] 1.58–4.89) compared to stable weight; results in the comparison cohort were similar ( HR 2.16, 95% CI 1.61–2.88). A weight gain of &gt;30 pounds had no association with mortality in patients with RA ( HR 1.45, 95% CI 0.69–3.07) or comparators ( HR 1.19, 95% CI 0.89–1.59). For mortality, there was no statistically significant interaction between RA /comparator status and weight change category ( P = 0.68). Conclusion Severe weight loss during the early RA period was associated with an increased subsequent mortality risk for women with and those without RA . These results extend prior observations by including non‐ RA comparators and finding no protective association between weight gain and mortality, providing evidence against an RA ‐specific obesity paradox for mortality.
Implementation of a checklist before colonoscopy: a quality improvement initiative
Authors: Omar Kherad, Sophie Restellini, Charles Ménard, Myriam Martel, Alan Barkun
Journal: Endoscopy (2017)

Checklists can prevent errors and have a positive impact on patient morbidity and mortality in different surgical settings, and possibly also in gastrointestinal endoscopy. The aims of this study were to reinforce commitment in safety culture and better communication among team members in endoscopy, and to prove the feasibility of successful checklist adoption before colonoscopy.The study involved a pre - post quality improvement intervention involving all consecutive patients undergoing a colonoscopy at a single academic endoscopy unit. The first part of the study was a retrospective audit, carried out over a 3-month period (July to September 2016). A checklist developed through a formal validation process was implemented during the intervention period (October to December 2016). Primary outcomes were changes in patient and team satisfaction after the quality improvement intervention, using validated 5-point scale questionnaires. Secondary outcomes included successful procedure completion rates and safety outcomes.During the baseline and comparative intervention period, 1317 and 1141 colonoscopies, respectively, were performed. Overall, checklists were fully completed by nurses and physicians for 791 patients (69.3 %). Mean overall patient satisfaction was high at baseline and did not differ following the quality improvement intervention (4.66 vs. 4.63; P = 0.5). Perception of team communication and teamwork was improved after checklist implementation. Comparative analyses of per-procedure and safety outcomes did not differ between the pre- and post-checklist implementation.Adoption of an endoscopy checklist before colonoscopy is feasible, and significantly increases perception of team communication and teamwork. Additional studies are needed to assess the generalizability of these results to complex endoscopic procedures and to characterize any improvement in patient safety outcomes.
Altered brain morphology after focal radiation reveals impact of off-target effects: implications for white matter development and neurogenesis
Authors: Kiran G Beera, Yu-Qing Li, Jun Dazai, James Stewart, Shannon Egan, Mashal Ahmed, C Shun Wong, David A Jaffray, Brian J Nieman
Journal: Neuro-Oncology (2017)

Children with brain tumors treated with cranial radiation therapy (RT) often exhibit cognitive late effects, commonly associated with reduced white matter (WM) volume and decreased neurogenesis. The impact of radiation damage in particular regions or tissues on brain development as a whole has not been elucidated. We delivered whole-brain or focal radiation (8 Gy single dose) to infant mice. Focal treatments targeted white matter (anterior commissure), neuronal (olfactory bulbs), or neurogenic (subventricular zone) regions. High-resolution ex vivo MRI was used to assess radiation-induced volume differences. Immunohistochemistry for myelin basic protein and doublecortin was performed to assess associated cellular changes within white matter and related to neurogenesis, respectively. Both whole-brain and focal RT in infancy resulted in volume deficits in young adulthood, with whole-brain RT resulting in the largest deficits. RT of the anterior commissure, surprisingly, showed no impact on its volume or on brain development as a whole. In contrast, RT of the olfactory bulbs resulted in off-target volume reduction in the anterior commissure and decreased subventricular zone neurogenesis. RT of the subventricular zone likewise produced volume deficits in both the olfactory bulbs and the anterior commissure. Similar off-target effects were found in the corpus callosum and parietal cortex. Our results demonstrate that radiation damage locally can have important off-target consequences for brain development. These data suggest that WM may be less radiosensitive than volume change alone would indicate and have implications for region-sparing radiation treatments aimed at reducing cognitive late effects.
Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients
Authors: M.E. Rodríguez-Ruiz, J.L. Perez-Gracia, I. Rodríguez, C. Alfaro, C. Oñate, G. Pérez, I. Gil-Bazo, A. Benito, S. Inogés, A. López-Diaz de Cerio, M. Ponz-Sarvise, L. Resano, P. Berraondo, B. Barbés, S. Martin-Algarra, A. Gúrpide, M.F. Sanmamed, C. de Andrea, A.M. Salazar, I. Melero
Journal: Annals of Oncology (2018)

Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects.In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24 h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days +8 and +10 of each cycle, patients received intratumoral image-guided 0.25 mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m2 was administered 1 week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating peripheral blood mononuclear cell (PBMCs) and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and post-treatment PBMC from patients achieving durable stable disease (SD) were studied by IFNγ ELISPOT-assays responding to tumor-lysate loaded DC and by TCRβ sequencing.Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR+ immunotherapy. No objective responses were observed, while nine patients presented SD (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-β and IFN-α mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1β concentrations, especially in patients presenting SD. IFNγ-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD.This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.
Connections Between Hospital Financial Distress, Physician Incentive, and Patient Access to Breast Reconstruction
Authors: Tomer Avraham, Cary P. Gross, Brigid K. Killelea
Journal: JAMA Surgery (2017)

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Biomarkers for severe eosinophilic asthma
Authors: Steven W. Yancey, Oliver N. Keene, Frank C. Albers, Hector Ortega, Stewart Bates, Eugene R. Bleecker, Ian Pavord
Journal: Journal of Allergy and Clinical Immunology (2017)

The last decade has seen the approval of several new biologics for the treatment of severe asthma-targeting specific endotypes and phenotypes. This review will examine how evidence generated from the mepolizumab clinical development program showed that blood eosinophil counts, rather than sputum or tissue eosinophil counts, evolved as a pharmacodynamic and predictive biomarker for the efficacy of treatment with mepolizumab in patients with severe eosinophilic asthma. Based on the available evidence and combined with clinical judgement, a baseline blood eosinophil threshold of 150 cells/μL or greater or a historical blood eosinophil threshold of 300 cells/μL or greater will allow selection of patients with severe eosinophilic asthma who are most likely to achieve clinically significant reductions in the rate of exacerbations with mepolizumab treatment.
Active Surveillance for Prostate Cancer
Authors: Richard S. Matulewicz, Adam B. Weiner, Edward M. Schaeffer
Journal: JAMA (2017)

Active Surveillance for Prostate CancerOf all men diagnosed as having prostate cancer, one-third have a cancer that grows very slowly.Treating men with slow-growing prostate cancers with surgery, radiation, or hormone therapy may not extend their life span and could lead to unwanted complications.These cancers can instead be managed usingactivesurveillance,whichmeansthatthecancerisevaluatedover time to see if it starts to grow to a point at which treatment is necessary.
Abstract 16562: Cardiac Device Implantation Post TAVR: Mortality and Rates of Pacemaker Dependency
Authors: Deepak Padmanabhan, Mackram Eleid, Abhishek Deshmukh, Christopher Scott, Christopher Mcleod, Yong-Mei M Cha, Samuel P Asirvatham, Paul Friedman, Kevin L Greason,, Rajiv M Gulati, Peter A. M Noseworthy,
Journal: Circulation (2015)

Background: Transcatheter aortic valve replacement (TAVR) is often complicated by AV block requiring pacing, but whether patients recover AV conduction and whether the need for pacing affects outcomes is unknown. Methods: We retrospectively studied 534 patients who underwent TAVR at Mayo Clinic in Rochester, Minnesota between November 2008 and January 2015. Of these, 115 patients had implantable cardiac devices. Data was collected from subsequent device follow-ups to determine pacemaker dependency and percentage pacing. Results: 44 patients (8.2%) had devices implanted in the immediate post procedural period. The most common indications for implantation were high grade AV block (18 patients) and complete heart block (14 patients). 17/44 (38.6%) patients were pacemaker-dependent at implant and only 4 of these patients were no longer pacemaker-dependent during subsequent followup. The indication for pacing among these four patients was high grade atrio-ventricular block (2 patients), asystole (1 patient) and complete heart block (1). Among non-pacemaker-dependent patients, no significant change in the ventricular pacing percentages was noted over time. Survival was similar between patients who required device implantation post TAVR and those who did not after adjustment for age and gender (HR 0.73 [0.39-1.36], p=ns; figure) Conclusion: Patients requiring pacing after TAVR are often pacemaker-dependent at the time of implant. It is uncommon for patients who are dependent at the time of implant to regain AV conduction, but the need for cardiac pacing is not associated with increased mortality.
“Double‐hit” chronic lymphocytic leukemia: An aggressive subgroup with 17p deletion and 8q24 gain
Authors: Elise Chapiro, Claude Lesty, Clémentine Gabillaud, Eric Durot, Simon Bouzy, Marine Armand, Magali Le Garff‐Tavernier, Nadia Bougacha, Stéphanie Struski, Audrey Bidet, Elodie Laharanne, Carole Barin, Lauren Veronese, Nolwen Prié, Virginie Eclache, Baptiste Gaillard, Lucienne Michaux, Christine Lefebvre, Jean‐Baptiste Gaillard, Christine Terré, Dominique Penther, Christian Bastard, Nathalie Nadal, Sandra Fert‐Ferrer, Nathalie Auger, Catherine Godon, Laurent Sutton, Olivier Tournilhac, Santos A. Susin, Florence Nguyen‐Khac
Journal: American Journal of Hematology (2017)

Chronic lymphocytic leukemia (CLL) with 17p deletion (17p-) is associated with a lack of response to standard treatment and thus the worst possible clinical outcome. Various chromosomal abnormalities (including unbalanced translocations, deletions, ring chromosomes and isochromosomes) result in the loss of 17p and one copy of the TP53 gene. The objective of the present study was to determine whether the type of chromosomal abnormality leading to 17p- and the additional aberrations influenced the prognosis in a series of 195 patients with 17p-CLL. Loss of 17p resulted primarily from an unbalanced translocation (70%) with several chromosome partners (the most frequent being chromosome 18q), followed by deletion 17p (23%), monosomy 17 (8%), isochromosome 17q [i(17q)] (5%) and a ring chromosome 17 (2%). In a univariate analysis, monosomy 17, a highly complex karyotype (≥5 abnormalities), and 8q24 gain were associated with poor treatment-free survival, and i(17q) (P = .04), unbalanced translocations (P = .03) and 8q24 gain (P = .001) were significantly associated with poor overall survival. In a multivariate analysis, 8q24 gain remained a significant predictor of poor overall survival. We conclude that 17p deletion and 8q24 gain have a synergistic impact on outcome, and so patients with this "double-hit" CLL have a particularly poor prognosis. Systematic, targeting screening for 8q24 gain should therefore be considered in cases of 17p- CLL.