tbuckley/cabot-search huggingface dataset:
Improving clinical practice in breast, lung, and gastrointestinal cancers.
Authors: Timothy Edward Kubal, Douglas D. Letson, John Williamson Peabody, Riti Shimkhada, Megan Chen
Journal: Journal of Clinical Oncology (2015)

e17622 Background: Standardizing the care of cancer patients around best evidence has proven remarkably intransigent to traditional education efforts and incentives. The failure of these efforts is not due to lack of individual effort or interest; rather, it is the inability to engage physicians. Using our experience at the Moffitt Cancer Center, we show pathway adherence can be done rapidly when rigorous measurement and individual accountability is linked to pathways. Methods: We present three rounds of data from a large cohort of providers in the Moffitt breast, lung, and gastrointestinal cancer programs who used the Clinical Performance and Value (CPV) case simulations as part of the M-QURE (Moffitt – Quality, Understanding, Research and Evidence) initiative. Two of twelve CPV cases in each disease area were randomly assigned and given every 4 months to providers who were then given personalized feedback. Results: In just 9 months we found significant improvements in overall CPV pathway adherence and in most, but not all, domain scores (see table). While the workup in GI significantly improved, diagnosis and treatment proved more challenging, indicating an area for improvement. In breast and lung cancer, adherence to treatment was the domain where the most improvement occurred. Conclusions: Learning engagement has been successful in rapidly improving adherence to clinical pathways across three different diseases. At Moffitt, this has contributed to a growing culture of quality improvement and pathway adherence based upon the principle of physician engagement in learning.
Cardiac Catheter Ablation for Heart Rhythm Abnormalities
Authors: Anurag Singh, Ty E. Whisenant, Alan N. Peiris
Journal: JAMA (2019)

Carina Blomström-Lundqvist, MD, PhD; Sigfus Gizurarson, MD, PhD; Jonas Schwieler, MD, PhD; Steen M. Jensen, MD, PhD; Lennart Bergfeldt, MD, PhD; Göran Kennebäck, MD, PhD; Aigars Rubulis, MD, PhD; Helena Malmborg, MD, PhD; Pekka Raatikainen, MD, PhD; Stefan Lönnerholm, MD, PhD; Niklas Höglund, MD, PhD; David Mörtsell, MD
Abstract 17229: First Trimester Elevated Serum Glucose Values Are Associated With Congenital Heart Disease in the Offspring
Authors: Emmi Helle, Preston S Biegley, Joshua W Knowles, Joseph B Leader, Sarah A Pendergrass, Gary Reaven, Marylyn D Ritchie, Gary M Shaw, Wei Yang, James R Priest
Journal: Circulation (2016)

Introduction: Maternal diabetes mellitus (DM) during pregnancy is a well known and prevalent risk factor for congenital heart disease (CHD) in offspring. In mothers without DM, we recently observed...
Abstract P404: Sex-specific Associations of Plasma Endothelin-1 With Incidence of Stroke in African Americans: the Jackson Heart Study
Authors: Hao Fan, Shirin ArdeshirRouhaniFard, Xiang Gao, Solomon Musani, Ervin Fox, Lesley Curtis, Adolfo Correa, Emily O’Brien, Aurelian Bidulescu
Journal: Circulation (2019)

Background: Endothelin-1 (ET-1) is a vasoconstrictive peptide with cerebral action, also associated with the degree of atherosclerosis. Previous research found that estrogen has inhibitory effect on ET-1 level, which points to putative differences of ET-1 by sex. As stroke is the fifth leading cause of death in the U.S., killing approximately 133,000 people per year, more among African Americans (AA), we aimed to identify the sex differences of the association between ET-1 and incident stroke among AA. Methods: Our AA study participants (N= 4995), with ages 21-90 years and no prevalent stroke, were enrolled in the Jackson Heart Study in Jackson, Mississippi. Stroke events were ascertained through 2011 by reviewing medical records for hospitalizations of JHS participants. Plasma ET levels were measured at the baseline study visit (2000-2004) and expressed in picograms/ml by QuantiGlo Human Endothelin-1 Immunoassay (R&amp;D Systems Inc). Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated using Cox proportional hazard regression models. Several interactions were assessed such as by sex, smoking and hypertension. Results: Baseline plasma ET-1 level (mean=1.35, median= 1.30) was significantly lower in women (mean =1.32) than in men (mean =1.40; P-value &lt;0.0001). Sex was not an effect modifier of the association between ET-1 and time to stroke event (p for interaction =0.18). After adjusted for age, ET-1 was associated with reduced risk of stroke [HR (95% CI) for all gender: 0.61 (0.40, 0.94), P trend =0.015, among men: 0.32 (0.14, 0.72), P trend =0.003, but not among women: 0.96 (0.54, 1.68), P trend =0.68, for highest vs. lowest quartile, respectively]. After additional adjustment for hypertension and smoking status, the association was still significant among men [0.35 (0.15, 0.79), P trend =0.007, for highest vs. lowest quartile, respectively], but not among women. No statistically significant associations were found among both men and women after additional adjustment for BMI, cigarette smoking, anti-hypercholesterolemic medication status, diabetes and hypertension status, cholesterol levels and homocysteine. No interactions by smoking or hypertension were detected. Conclusion: Our study indicates a non-statistical significant lower risk of stroke with higher levels of endothelin-1, with variation by sex. Our findings warrant confirmation in other epidemiologic studies.
Collagen Remodeling in the Hypoxic Tumor-Mesothelial Niche Promotes Ovarian Cancer Metastasis
Authors: Suchitra Natarajan, Kaitlyn M. Foreman, Michaela I. Soriano, Ninna S. Rossen, Hussein Shehade, Daniel R. Fregoso, Joshua T. Eggold, Venkatesh Krishnan, Oliver Dorigo, Adam J. Krieg, Sarah C. Heilshorn, Subarna Sinha, Katherine C. Fuh, Erinn B. Rankin
Journal: Cancer Research (2019)

Abstract Peritoneal metastases are the leading cause of morbidity and mortality in high-grade serous ovarian cancer (HGSOC). Accumulating evidence suggests that mesothelial cells are an important component of the metastatic microenvironment in HGSOC. However, the mechanisms by which mesothelial cells promote metastasis are unclear. Here, we report that the HGSOC tumor-mesothelial niche was hypoxic, and hypoxic signaling enhanced collagen I deposition by mesothelial cells. Specifically, hypoxic signaling increased expression of lysyl oxidase (LOX) in mesothelial and ovarian cancer cells to promote collagen crosslinking and tumor cell invasion. The mesothelial niche was enriched with fibrillar collagen in human and murine omental metastases. Pharmacologic inhibition of LOX reduced tumor burden and collagen remodeling in murine omental metastases. These findings highlight an important role for hypoxia and mesothelial cells in the modification of the extracellular matrix and tumor invasion in HGSOC. Significance: This study identifies HIF/LOX signaling as a potential therapeutic target to inhibit collagen remodeling and tumor progression in HGSOC.
Evaluation of Efficacy Outcomes Among Relapsed/Refractory Multiple Myeloma Treated Patients in a Real-World Setting
Authors: Ajay Nooka, Peter M. Voorhees, Shaji K Kumar, Maneesha Mehra, Annette Lam, Mary Slavcev, Jon Ukropec, Ravi Potluri, Anandaroop Dasgupta
Journal: Blood (2017)
Symptoms are not the solution but the problem: Why psychiatric research should focus on processes rather than symptoms
Authors: Immanuel G. Elbau, Elisabeth B. Binder, Victor I. Spoormaker
Journal: Behavioral and Brain Sciences (2019)

Abstract Progress in psychiatric research has been hindered by the use of artificial disease categories to map distinct biological substrates. Efforts to overcome this obstacle have led to the misconception that relevant psychiatric dimensions are not biologically reducible. Consequently, the return to phenomenology is once again advocated. We propose a process- centered paradigm of biological reduction compatible with non-reductive materialism.
Polycythemia vera and essential thrombocytemia treated with IFN-ALPHA2a: Evidence of a significant clinical activity and molecular response.
Authors: Giuseppe Altavilla, Carmela Arrigo, Mariacarmela Santarpia, Claudia Garipoli, Vincenzo Pitini
Journal: Journal of Clinical Oncology (2015)

e18075 Background: Recombinant IFN-alpha2a(IFN) has previously been shown to induce hematologic and molecular responses in pts with polycytemia vera(PV) and essential thrombocytemia(ET) ,here we present the results of IFN treatment in these pts. Methods: 42 pts. (20 male, 22 female, median age 58 years) with diagnosis of PV(20pts) or ET(22pts) received IFN subcutaneously at 3MU three times weekly .Alternative dose schedules were allowed to minimize toxicity.JAK2V617F ,CALRETICULIN and MPL were detected in DNA samples extracted from bone marrow and peripheral blood by PCR and quantified by a pyrosequencing assay(sensitivity 5%).DNA resequencing of all coding exons of known mutations in EZH2 and TET2 was performed in all samples. Results: After a median follow-up of 40 months complete hematologic response was achieved in 14 PV pts(70%) and 19 ET pts(86%) .This was accompanied by complete molecular response in 4 PV pts and 5 ET pts. Serial sequencing of TET2 and EZH2 revealed that pts falling to achieve molecular respons had a higher frequency of mutations outside the JAK2 pathway ,furthermore pts with both JAK2 and TET2 mutations had a higher JAK2 mutant allele burden Conclusions: Recombinant IFN-alpha2a induces a sustained molecular response in a subset of PV and ET pts with JAK2mutant/TET2 wild type so genotypic context seems influence molecular responses to IFN.
Abstract 037: The U.S. Food and Drug Administration’s Metformin Label Change Reduces Racial Disparity in Metformin Use by Increasing Its Use Among Black Patients With Type 2 Diabetes and Moderately Impaired Kidney Function
Authors: Jung-Im Shin, Alex Chang, Josef Coresh, Lesley A Inker, Elizabeth Selvin, Morgan Grams
Journal: Circulation (2019)

Introduction: Historically, metformin was contraindicated in people with type 2 diabetes (T2D) and kidney disease due to concerns of lactic acidosis. The U.S. Food and Drug Administration (FDA) recently changed metformin label from serum creatinine (sCr)-based to estimated glomerular filtration (eGFR)-based indication, expanding its use for people with eGFR≥30 mL/min/1.73 m 2 . The purpose of our study is to assess the effects of the label change on metformin use among people with T2D, stratified by race and eGFR. Hypothesis: Because sCr levels are higher in blacks than in whites at the same level of eGFR, we hypothesized that the label change increases metformin use in people with T2D and kidney disease and magnitude of increase is greater in blacks than in whites. Methods: One-year period prevalence cohort was created for each of before and after the FDA’s label change (April 8, 2016) in Johns Hopkins Medicine, including people with T2D and eGFR≥30 mL/min/1.73 m 2 . We estimated the prevalence of metformin use in each cohort, stratified by eGFR within each race. Results: Mean age of study population (N=15,880) was 61 years, 52% were women, 48% were black, mean eGFR was 81 mL/min/1.73 m 2 , and mean HbA1c was 7.8%. Before the label change, blacks with eGFR 30-44 mL/min/1.73 m 2 were less likely to use metformin compared to whites, controlling for age, sex, eGFR, and HbA1c (odds ratio [OR]=0.49 [95% confidence interval: 0.37-0.65]). The label change did not increase metformin use among whites across all categories of eGFR, whereas it increased metformin use from 26.1% to 32.6% (P=0.03) among blacks with eGFR 30-44 ml/min/1.73 m 2 ( Figure ). As a result, magnitude of racial disparity in metformin use after the label change was attenuated (OR=0.75 [0.57-0.99]). Conclusions: The recent eGFR-based metformin label change increased its use in black people with T2D and moderately impaired kidney function, with reducing racial disparity of metformin use. Further studies to assess impact of metformin label change with longer study period are warranted.
Genomic analyses of microdissected Hodgkin and Reed-Sternberg cells: mutations in epigenetic regulators and p53 are frequent in refractory classic Hodgkin lymphoma
Authors: Elena Mata, Sara Fernández, Aurora Astudillo, Rubén Fernández, Mónica García-Cosío, Margarita Sánchez-Beato, Mariano Provencio, Mónica Estévez, Carlos Montalbán, Miguel A. Piris, Juan F. García
Journal: Blood Cancer Journal (2019)

Classical studies have consistently identified some specific gene mutations in classic Hodgkin lymphoma (cHL), mainly affecting members of the NF-kappaB and JAK/ STAT pathways 1-4 .However, this knowledge is yet to be exploited in the clinical milieu.Molecular analyses of cHL have been limited because of the paucity of Hodgkin and Reed-Sternberg (HRS) cells, which usually account for < 5% of cells as identified by standard CD30 immunostaining.Various enrichment strategies, such as laser capture microdissection (LCM), could facilitate the identification of genetic alterations 5 .Also, in recent years, the sensitivity and specificity of next-generation sequencing (NGS) techniques have been greatly improved by simultaneously testing selected genes, arranged in comprehensive gene panels.This is even possible with formalin-fixed, paraffin-embedded (FFPE) tissue samples.However, very few NGS studies have described the genomic landscape of the disease.The first whole-exome sequencing analyses of primary Hodgkin and Reed-Sternberg (HRS) cells found beta-2-microglobulin (B2M) to be the most commonly altered gene 6 .Recently, our group have identified concurrent genetic lesions in relevant signaling pathways, such as those of JAK-STAT, NF-kappaB, and BCR, as well as in epigenetic regulators 7 .These findings are largely concordant with other NGS
Abstract MP24: Women Experience Higher Rates of Surgical Repair and Mortality for Abdominal Aortic Aneurysm
Authors: Niveditta Ramkumar, Bjoern D Suckow, Art Sedrakyan, Philip P Goodney, Jeremiah R Brown
Journal: Circulation (2019)

Background: It is unknown how gender disparities in the clinical presentation of abdominal aortic aneurysm (AAA) affects AAA repair type and long-term survival. We assessed the hypothesis that compared to men, women face a higher risk of death after AAA repair due to differences in demographics, disease severity, and repair type. Methods: We analyzed all endovascular (EVAR) and open surgical (OPEN) AAA repairs from 2003-2015 in the Vascular Quality Initiative-Medicare linked registry. Using inverse probability weighting, we balanced patient demographics, comorbidities, and disease severity among men and women. Then, we evaluated the effect of gender on AAA treatment and subsequent survival using Poisson and Cox regression, respectively. Results: In this cohort (n=16,085), patients undergoing EVAR (79%) or OPEN (21%) had up to 12 years of follow-up. Women comprised 22% of the cohort and were older (mean age 77 ±6.6 vs. 75 ±6.5 years, p&lt;0.001), less likely to smoke (28% vs. 33%, p&lt;0.001), and had smaller aneurysms (58.7 ±18.5 mm vs 56.5 ±12 mm) than men (Figure). After balancing key risk factors, women were 1.6 times more likely to receive OPEN vs. EVAR (RR: 1.59, 95% CI: 1.46-1.72). The 12-year mortality rate after AAA repair was 74% in men vs 84% in women. After adjustment, women faced a 12% increased risk of death (HR: 1.12, 95% CI: 1.04-1.21). Sub-analysis by repair type revealed a gender discrepancy among EVAR patients, where women experienced poorer survival (HR: 1.18, 95% CI: 1.09-1.29), while men and women faced an equal risk of death after OPEN (HR: 1.00, 95% CI: 0.90-1.12). Conclusion: In conclusion, women were 1.6 times more likely to undergo OPEN repair than men, despite balancing key baseline AAA risk factors associated between men and women. After EVAR, women were 12% more likely to die than men, though no gender-based morality difference exists following OPEN repair. The differential treatment benefit of EVAR in women is concerning given the trend toward an endovascular-first treatment approach to AAA.
Abstract P299: Racial and Sex-Related Differences in Aortic and Mitral Valve Disease
Authors: Petro Gjini, Jodie Franzil, Joseph Nicolazzi, Ajay Dharod, Min Pu, Richard B Stacey
Journal: Circulation (2019)

Background: With the proliferation of echocardiography, clinicians are detecting more patients with valve disease and identifying valve disease much earlier in its natural course. Understanding the gender and racial differences in prevalence of valve disease may help guide clinicians to allocate resources in researching strategies to prevent progression of valve disease. Methods: We identified 9,625 patients from the echocardiography laboratory database between September 2013 to April 2018 who had a LV ejection fraction ≥ 50%. Data related to left-sided valvular disease, baseline demographics, and clinical history were obtained from our clinical data repository. Crude analyses by sex and race were performed to identify the prevalence of certain valve lesions. Logistic regression was used to adjust these relationships by baseline demographics. Results: Our population was 58% female, 21% African-American (AA) with a mean age of 59 ± 17 years. For moderate/severe aortic stenosis (AS), AA had 2.4% compared to 7.5% in Caucasians (CA; p&lt;0.001), and women had 4.8% compared to 8.5% for men (p&lt;0.001). For moderate/severe aortic regurgitation (AR), AA had 4.1% compared to 7.5% in CA (p&gt;0.2), and women had 4.0% compared to 5.4% for men (p=0.003). For moderate/severe mitral regurgitation, AA had 6.6% vs 7.8% for CA (p=0.056), and women had 8.3% vs 6.3% for men (p=0.003). Adjusting for age, race, sex, height, and weight, AA had lower odds ratio (OR) for AS than CA (OR: 0.47; 95% CI: 0.34-0.64; p&lt;0.001), and women had less AS than men (OR: 0.60; 95% CI: 0.50-0.72; p&lt;0.001), less AR (OR: 0.67; 95% CI: 0.54-0.83; p&lt;0.001), but more MR (OR: 1.29; 95% CI: 1.08-1.53; p=0.004). Conclusion: African-Americans have a lower prevalence of moderate/severe aortic stenosis than Caucasians. Compared to men, women have a lower prevalence of moderate/severe aortic stenosis, lower prevalence of moderate/severe aortic regurgitation, but a higher prevalence of mitral regurgitation.
Phase III study of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC): The ARCHES trial.
Authors: Andrew J. Armstrong, Russell Zelig Szmulewitz, Daniel Peter Petrylak, Arnauld Villers, Arun Azad, Antonio Alcaraz, Boris Y. Alekseev, Taro Iguchi, Neal D. Shore, Brad Rosbrook, Jennifer Sugg, Benoit Baron, Lucy F. Chen, Arnulf Stenzl
Journal: Journal of Clinical Oncology (2019)

687 Background: ENZA, a potent androgen receptor inhibitor, has demonstrated benefit in men with metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). Efficacy of ENZA with ADT in men with mHSPC is unknown. Methods: ARCHES is a multinational, double-blind, phase 3 study (NCT02677896). Patients (pts) with mHSPC were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume (CHAARTED criteria) and prior docetaxel therapy. Primary endpoint was radiographic progression-free survival (rPFS) assessed centrally or death within 24 weeks of treatment discontinuation. Secondary endpoints included time to prostate-specific antigen (PSA) progression, PSA and radiographic responses and overall survival (OS). Treatment continued until disease progression or unacceptable toxicity. Results: 1150 men were randomized to ENZA (n=574) or PBO (n=576); baseline characteristics were balanced between groups. Overall, 67% had distant metastasis at initial diagnosis; 63% had high volume disease, 18% had prior docetaxel. Median follow-up was 14.4 mo. ENZA + ADT significantly improved rPFS (Table); similar significant improvements in rPFS were reported in prespecified subgroups of disease volume, pattern of spread, region and prior docetaxel (HRs 0.24–0.53). Secondary endpoints improved with ENZA + ADT (Table); OS data are immature. Grade 3–4 adverse events (AEs) were reported in 23.6% of ENZA pts vs 24.7% of PBO pts with no unexpected AEs. Conclusions: ENZA + ADT significantly improved rPFS and other efficacy endpoints vs PBO + ADT in men with mHSPC, with a preliminary safety analysis that appears consistent with the safety profile of ENZA in previous CRPC clinical trials. Acknowledgements: Medical writing and editing assistance was provided by Stephanie Rippon, MBio, and Lauren Smith from Complete HealthVizion, funded by the study sponsors. This study was funded by Astellas Pharma Inc. and Medivation LLC, a Pfizer Company, the co-developers of enzalutamide. Clinical trial information: NCT02677896. [Table: see text]
Follow-up of an Intervention to Reduce Dental Caries in Indigenous Australian Children
Authors: Lisa M. Jamieson, Lisa G. Smithers, Joanne Hedges, Jacqueline Aldis, Helen Mills, Kostas Kapellas, Herenia P. Lawrence, John R. Broughton, Xiangqun Ju
Journal: JAMA Network Open (2019)

Testing the long-term usefulness of a childhood intervention and determining the best age of implementation are important for translation and policy change.To investigate among children aged 3 years the long-term effectiveness an intervention that aimed to reduce dental caries among South Australian Aboriginal children and to assess if children in the delayed intervention (DI) group had any benefit from the intervention from ages 2 to 3 years and if the intervention usefulness was greater when delivered between pregnancy and age 2 years (immediate intervention [II] vs ages 2 to 3 years [DI]).Secondary analysis of a randomized clinical trial. The study enrolled 448 pregnant women across South Australia, Australia, at baseline (February 1, 2011, to May 30, 2012), with 223 randomly allocated to the II group and 225 to the DI group. Three-year follow-up data were collected November 2014 to February 2016.The intervention comprised dental treatment to mothers, fluoride varnish application to children, and motivational interviewing delivered together with anticipatory guidance. This was delivered during pregnancy and at child ages 6, 12, and 18 months for the II group and at child ages 24, 30, and 36 months for the DI group.The mean number of decayed teeth measured at child age 3 years.There were 324 children at age 3 years (52.3% male). The mean number of decayed teeth at age 3 years was 1.44 (95% CI, 1.38-1.50) for the II group and 1.86 (95% CI, 1.89-2.03) for the DI group (mean difference, -0.41; 95% CI, -0.52 to -0.10). The predicted mean number of decayed teeth at age 3 years for the DI group was 2.15. Between ages 2 and 3 years, the caries increment for the II group was 0.82 (95% CI, 0.75-0.89), compared with 0.97 (95% CI, 0.87-1.17) for the DI group (P = .05).At the 3-year follow-up, II children had less dental caries than DI children, DI children developed dental caries at a lower trajectory than predicted had the intervention not been received at ages 2 to 3 years, and the caries increment was less between ages 2 to 3 years among II children compared with DI children. This study suggests that the best time to implement the intervention is earlier rather than later infancy.Australian and New Zealand Clinical Trial Registry Ideintifier: ACTRN12611000111976.
The Histone Demethylase KDM4A Is Required to Sustain H3K9me3/H3K27me3 Epigenetic States and Oncogenesis in MLL-AF9 Acute Myeloid Leukemia
Authors: Matthew E Massett, Niamh Mannion, Laura Monaghan, Joana Bittencourt-Silvestre, Sandra Marmiroli, Robert M J Liskamp, Alison M Michie, David Vetrie, Xu Huang
Journal: Blood (2018)