tbuckley/cabot-search huggingface dataset:
Abstract P029: Inflammation Measured by Glyc-A as a Mediating Factor Between Subclinical Thyroid and Cardiovascular Diseases. The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)
Authors: Isabela M Bensenor, Alessandra C Goulart, Paulo A Lotufo
Journal: Circulation (2019)

Introduction: An auto-immune process strongly determines subclinical thyroid disorders generating a high grade of inflammation. However, the evidence from epidemiologic studies of the association between subclinical thyroid disorders with coronary heart disease has not been reported as mediated or moderated by a traditional inflammatory marker such as the high-sensitivity C-Reactive Protein. Recently, another inflammatory marker that reflects protein glycosylation in acute-phase reactant proteins - GlycA was associated with coronary heart disease events. Hypothesis: The association of GlycA, a more comprehensive biomarker of inflammation, with subclinical hypothyroidism, and subclinical hyperthyroidism, should explain some mechanisms of the association subclinical thyroid disorders and coronary heart disease. Methods: We tested this hypothesis among 5060 men and women aged 35 to 74 years-old enrolled in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) at baseline. Subclinical thyroid disorders were defined as thyroid-stimulating hormone (TSH) &gt;4 IU/ml (subclinical hypothyroidism) and TSH &lt;0.4 IU/ml (subclinical hyperthyroidism) with normal free-thyroxine levels. The variable of exposure was GlycA measured in serum by proton nuclear magnetic resonance (1H NMR) spectroscopy at (LabCorp, Raleigh, NC). We excluded participants who reported previous cardiovascular disease, use of lipid-lowering agents or drugs that interfere with thyroid function. The cross-sectional relationship between GlycA and subclinical hyperthyroidism and subclinical thyroid was evaluated separately by linear regression models using the category of the subjects with euthyroidism as the reference. Both crude unadjusted and adjusted (age, sex, race, education, smoking, alcohol use, physical activity body-mass index, hypertension, diabetes, smoking, alcohol use, and physical activity data are presented Results: After exclusions, we analyzed 47 individuals with subclinical hyperthyroidism (mean age 53.1 (±9.4) years; 61.7% women), 258 with subclinical hypothyroidism (mean age 52.3 (±8.9); 58.1% of women) and 3,642 participants with normal thyroid function (mean age: 50.1 (±8.6); 52% of women). Crude linear regression models showed no significant association between GlycA and subclinical hyperthyroidism (Beta-coefficient [B], 15.77; P = 0.10) or subclinical hypothyroidism (B, 3.60; P=0.39). Results remained nonsignificant after multivariate adjustment for subclinical hyperthyroidism (B, 12.96; P=0.15) and subclinical hypothyroidism (B, 0.44; (P=0.91). Conclusions: There is no association between subclinical thyroid disorders and GlycA. Other presumptive inflammatory pathways should be contemplated in further studies addressing the link between subclinical thyroid disorders and coronary heart disease.
A circulating tumor cell RNA assay for dynamic assessment of androgen receptor signaling inhibitors sensitivity in metastatic castration-resistant prostate cancer.
Authors: Yu Jen Jan, Junhee Yoon, Jie-Fu Chen, Pin-Jung Chen, Pai-Chi Teng, Nu Yao, Shirley Cheng, Amber Lozano, Michael Freeman, Sungyong You, Hsian-Rong Tseng, Edwin M. Posadas
Journal: Journal of Clinical Oncology (2019)

157 Background: Tissue-based gene signatures can predict clinical behavior in prostate cancer (PC). Our objective was to extend their application to circulating tumor cells (CTCs) and to show that changes in the signature were associated with changes in clinical behavior. Methods: Our approach combined the Thermoresponsive(TR)-NanoVelcro CTC purification system with the Nanostring nCounter system for cellular purification and transcriptomic analysis. The Prostate Cancer Classification System (PCS) panel was modified for use in CTCs. We selected 31 blood samples from 23 PC patients receiving androgen receptor signaling inhibitors (ARSI) and measured the PCS1 Z score (probability). These findings were compared with clinical outcome data (responsiveness/resistance). Results: A modified, 16-gene PCS1 signature was established and validated through a rigorous bioinformatics process. We performed analytical validation of our combined CTC-RNA system to ensure reproducibility and specificity. In patient bloods, ARSI-resistant samples (ARSI-R, n = 14) had significantly higher PCS1 Z scores as compared with ARSI-sensitive samples (ARSI-S, n = 17) (Rank-sum test, P = 0.003). The analyzed bloods contained samples from 8 patients who developed resistance to an ARSI allowing for dynamic measurement of gene expression. Our analysis found that the PCS1 Z score increased at the time that ARSI-resistance emerged (Pairwise T-test, P = 0.016). Conclusions: Using this new methodology, contemporary, clinically-relevant gene signatures such as PCS could be measured non-invasively in CTCs. These findings can be used to relate gene expression to clinical drug response. This approach also allowed for measurement of dynamic variations of gene expression in individual patients over time that correlated to ARSI sensitivity.
Abstract P156: Kidney Function and Serum Potassium as Predictors of Spironolactone Initiation in Congestive Heart Failure
Authors: Alex Secora, Jung-Im Shin, Yao Qiao, G. Caleb Alexander, Josef Coresh, Morgan Grams
Journal: Circulation (2019)

Introduction: There are a paucity of data on real-world spironolactone use among patients with congestive heart failure (CHF), and whether spironolactone initiation differs by kidney function and serum potassium. Hypothesis: Patients with reduced kidney function and elevated serum potassium are less likely to be prescribed spironolactone than patients with normal kidney function and serum potassium. Methods: We identified patient cohorts with incident CHF and available laboratory data in the Truven MarketScan Commercial Claims and Encounters database (MS) from 2010-2015 (N=22,881), and the Geisinger Health System Integrated Electronic Health Record (GHS) from 2004-2016 (N=17,470), and assessed medication use through prescription order and dispensing data, and comorbidities using ICD codes. We measured incidence, initial dose, and duration of incident spironolactone use, overall and by levels of kidney function and serum potassium. We used Cox proportional hazards regression models to quantify the association between measures of baseline and time-varying estimated glomerular filtration rate (eGFR) and serum potassium, and incident spironolactone use, adjusting for other medication use and comorbidities. Results: Among 22,881 incident CHF patients in the MS database, mean age at CHF was 54.3 (±8.7) years, 47.2% were female, and the mean eGFR was 78.9 ml/min/1.73m 2 (±21). The 17,470 incident CHF patients in GHS were older (74.0 years ±12.9), more likely to be female (51.5%), and have a lower mean eGFR (62.5 ±24.3). Both cohorts had a mean baseline serum potassium of 4.3 mEq/L (±0.5). There were 1,341 (1,774) incident prescriptions for spironolactone over 34,384 (52,187) person-years in MS (GHS). Median starting dose was 25 mg in both cohorts. Women were less likely to start spironolactone in both cohorts, while older patients were less likely to start spironolactone only in GHS. Compared to patients with eGFR &gt;90 ml/min/1.73m 2 , those with eGFR &lt;30 ml/min/1.73m 2 were less likely to initiate spironolactone in MS (hazard ratio [HR] = 0.57, 95% confidence interval [CI]: 0.38-0.84) and GHS (HR = 0.69, CI: 0.48-0.99). Patients with serum potassium &lt;3.5 mEq/L were more likely to initiate spironolactone compared to those with 3.5-4.9 mEq/L (normal) in both cohorts (HR=1.99 [95% CI: 1.57-2.52] in MS; HR=2.70 [95% CI: 2.34-3.26] in GHS). Conclusion: Consistent with the labeled guidelines, patients with CHF and reduced kidney function were less likely to use spironolactone, while those with lower serum potassium levels were more likely to use spironolactone.
Reducing the Burden of Fellowship Interviews
Authors: Brian J. Dunkin, Aimee K. Gardner
Journal: JAMA (2019)

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A Trial of a Shorter Regimen for Rifampin-Resistant Tuberculosis
Authors: Andrew J. Nunn, Patrick P.J. Phillips, Sarah K. Meredith, Chen-Yuan Chiang, Francesca Conradie, Doljinsuren Dalai, Armand van Deun, Phan-Thuong Dat, Ngoc Lan, Iqbal Master, Tesfamarium Mebrahtu, Daniel Meressa, Ronelle Moodliar, Nosipho Ngubane, Karen Sanders, Stephen Bertel Squire, Gabriela Torrea, Bazarragchaa Tsogt, I.D. Rusen
Journal: New England Journal of Medicine (2019)

Cohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommended by the World Health Organization (WHO) in 2011.We conducted a phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy outcome was a favorable status at 132 weeks, defined by cultures negative for Mycobacterium tuberculosis at 132 weeks and at a previous occasion, with no intervening positive culture or previous unfavorable outcome. An upper 95% confidence limit for the between-group difference in favorable status that was 10 percentage points or less was used to determine noninferiority.Of 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population. Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group - a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentage point (95% confidence interval [CI], -7.5 to 9.5) (P = 0.02 for noninferiority). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population (adjusted difference, -0.7 percentage points; 95% CI, -10.5 to 9.1). An adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group. Prolongation of either the QT interval or the corrected QT interval (calculated with Fridericia's formula) to 500 msec occurred in 11.0% of participants in the short-regimen group, as compared with 6.4% in the long-regimen group (P = 0.14); because of the greater incidence in the short-regimen group, participants were closely monitored and some received medication adjustments. Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively.In persons with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a long regimen with respect to the primary efficacy outcome and was similar to the long regimen in terms of safety. (Funded by the U.S. Agency for International Development and others; Current Controlled Trials number, ISRCTN78372190; ClinicalTrials.gov number, NCT02409290.).
A phase I clinical trial of PSMA-directed/TGFβ-insensitive CAR-T cells in metastatic castration-resistant prostate cancer.
Authors: Vivek Narayan, Whitney Gladney, Gabriela Plesa, Neha Vapiwala, Erica L. Carpenter, Shannon L. Maude, Priti Lal, Simon F. Lacey, Jan J. Melenhorst, Joseph Fraietta, Ronnie Sebro, Michael Farwell, Michael Moniak, Joan Gilmore, Lester Lledo, Karen Dengel, Amy Marshall, Christina Marie Coughlin, Carl H. June, Naomi B. Haas
Journal: Journal of Clinical Oncology (2020)

TPS269 Background: Adoptive immunotherapy with Chimeric Antigen Receptor (CAR)-T cells is a novel approach for the treatment of prostate cancer. However, the prostate cancer immunosuppressive microenvironment, including high levels of TGFβ, may limit the therapeutic potential of re-directed T cells upon tumor infiltration. The inhibition of TGFβ signaling via co-expression of a dominant negative TGFβ receptor (TGFβRdn) can enhance antitumor immunity. Co-expression of TGFβRdn on PSMA-redirected CAR-T cells in in vivo disseminated tumor models led to increased T cell proliferation, enhanced cytokine secretion, resistance to exhaustion, long-term persistence, and greater induction of tumor eradication. Methods: We are conducting a first-in-human phase 1 clinical trial evaluating the safety and preliminary efficacy of lentivirally-transduced PSMA-redirected/TGFβ-insensitive CAR-T cells (CART-PSMA-TGFβRdn) in metastatic CRPC (NCT03089203). In a 3+3 dose-escalation design, patients received a single dose of 1-3 x 10 7 /m 2 (Cohort 1) or 1-3 x 10 8 /m 2 (Cohort 2) CART-PSMA-TGFβRdn cells without lymphodepleting chemotherapy. In Cohort 3, 1-3 x 10 8 /m 2 CART-PSMA-TGFβRdn cells are administered following a lymphodepleting chemotherapy regimen of cyclophosphamide and fludarabine (cy/flu). A currently accruing modified protocol seeks to optimize the therapeutic window with CART-PSMA-TGFβRdn (CAR-T dose of 1-3 x 10 7 /m2 following lymphodepleting cy/flu). Eight patients have received a single dose of CART-PSMA-TGFβRdn. CAR-T expansion and persistence in peripheral blood and trafficking to target tissues is evaluated via quantitative PCR of CART-PSMA-TGFβRdn DNA. Bioactivity of CAR-T cells in peripheral blood is evaluated via multiplex immunoassays. Additional correlative analyses will interrogate the therapeutic contribution of TGFβRdn, as well as early markers of response and resistance to CART-PSMA-TGFβRdn therapy. Clinical trial information: NCT03089203.
Primary chemo-radiotherapy 5-year outcomes for locally advanced head and neck cancers.
Authors: Ravi Kumar Dandamudi
Journal: Journal of Clinical Oncology (2015)

e17063 Background: To evaluate the 5-year cause-specific and overall survival (OS), loco-regional control rates and late toxicities of locally advanced Head and Neck cancer patients treated with Primary Chemo-radiotherapy (CRT). Methods: Between June 2006 and May 2008, sixty patients with locally advanced Head & Neck cancer who had not undergone previous surgery were consented for primary CRT with a curative intent. Primary CRT was delivered using concurrent 3 weekly Cisplatin (75-80 (mg/m2) and radiotherapy dose of 66-70 Gy in 33- 35 fractions, treated daily in three phases by conformal 3-dimensional CT-planning. Treatment response was assessed radiologically 3 months post primary CRT. Survival was calculated from the start date of CRT and Time to Treatment Failure (TTF) from the completion of treatment. Results: The median age was 57 years (range 18-79) with a Male: Female ratio of 3:1. Out of 60 patients who have completed intended treatment, the 5-year OS was 61.66 % and loco- regional control rate was 83.33 %. The primary treatment failure rate was 16.66 % (10/60 patients) of which 3 patients had residual disease at 3 months imaging and rest of the 7 had loco-regional recurrence. The median TTF was 16 months (range = 3 to 44 months). Twenty three patients (38.3%) died with in 5 years of treatment of which ten patients (16.3 %) died of loco-regional disease progression and six patients (10 %) died of distant recurrence. Remaining seven died of other causes including four (6.6%) from second primary (lung and oesophageal) cancers. The incidence of persistent oral mucositis was 8.3 % (RTOG grade 3) and none had grade 3/4 skin toxicity. The incidence of late toxicities was 8.3 % for Osteoradionecrosis (ORN) of the mandible, 6.6 % for severe trismus and 1.6 % had sinus formation. The incidence of severe oropharyngeal stenosis/ total dysphagia was 6.6 % and 3 patients (5 %) were on long term (15-32 months) gastrostomy feeding tube for nutrition. None of the patients had treatment related death. Conclusions: The 5 year survival and loco-regional control rates for locally advanced head & neck cancers treated with primary CRT (conventionally) from this single institute in UK were on par with international standards published in the literature.
Abstract P274: Association Between Atrial Fibrillation and Central Sleep Apnea in Older Japanese-American Men
Authors: Tagayasu Anzai, Andrew Grandinetti, Alan Katz, Kamal Masaki
Journal: Circulation (2019)

Introduction: Several studies have indicated that central sleep apnea (CSA) is associated with atrial fibrillation (AF) in older populations. However, there are few studies of this association in older Asian populations. Hypothesis: The hypothesis being tested is that there is an association between AF and CSA in older Japanese-American men. Methods: The Kuakini Honolulu-Asia Aging Study is a longitudinal cohort study of Japanese-American men living in Hawaii. We did a cross- sectional analysis using data from the 1999- 2000 7th exam cycle. Participants were 718 Japanese-American men between 79 and 97 years old, who had overnight polysomnography (PSG) conducted in their homes using criteria established by the large multicenter Sleep Heart Health Study. Obstructive Apnea-Hypopnea Index (OAHI) was the measure of the number of obstructive apneas and hypopneas with &gt;4% oxygen desaturation. Additionally, the Central Apnea Index (CAI) was the measure of the number of central apneas. Obstructive sleep apnea (OSA) was categorized as none (OAHI &lt;5), mild (OAHI 5-14), moderate (OAHI 15-29) and severe (OAHI 30 or more). CSA was defined by CAI of 5 or more. Cheyne-Stokes Breathing (CSB) was defined as a minimum consecutive 10-minute period of a crescendo-decrescendo respiratory pattern associated with CSA. A board-certified physician confirmed AF by single lead electrocardiography of PSG. Results: The mean age of participants was 83.2±0.2 years. The prevalence of AF was 5.5% (39 of 709). The prevalence proportions of severe OSA, CSA, and CSB were 20.5% (145 of 709), 6.3% (43 of 681) and 3.2%, (22 of 681) respectively. In multivariable-adjusted logistic regression models, CSA and CSB were significantly associated with AF prevalence [Odds Ratio (OR) 4.78; 95% Confidential interval (CI), 1.91-11.95] and [OR 5.48; 95% CI, 1.70-17.66], respectively. In contrast, OSA was not significantly associated with AF prevalence (severe OSA [OR 1.17; 95% CI, 0.44-3.11], moderate OSA [OR 0.72; 95% CI, 0.26-2.05], mild OSA [OR 0.97; 95% CI, 0.39-2.44]). Conclusion: There is an association of AF prevalence with CSA and CSB in older Japanese-American Men. In older Japanese men, screening for CSA and CSB might be important to prevent AF.
Most associations of early‐life environmental exposures and genetic risk factors poorly differentiate between eczema phenotypes: the Generation R Study
Authors: C. Hu, L. Duijts, N.S. Erler, N.J. Elbert, C. Piketty, V. Bourdès, S. Blanchet‐Réthoré, J.C. Jongste, S.G.M.A. Pasmans, J.F. Felix, T. Nijsten
Journal: British Journal of Dermatology (2019)

Childhood eczema is variable in onset and persistence. To identify eczema phenotypes during childhood, and their associations with early‐life environmental and genetic factors. In this study of 5297 children from a multiethnic population‐based prospective cohort study, phenotypes based on parent‐reported physician‐diagnosed eczema from age 6 months to 10 years were identified using latent class growth analysis. Information on environmental factors was obtained using postal questionnaires. Four filaggrin mutations were genotyped and a risk score was calculated based on 30 genetic variants. Weighted adjusted multinomial models were used for association analyses. We identified the following five eczema phenotypes: never (76%), early transient (8%), mid‐transient (6%) and late transient (8%) and persistent eczema (2%). Early transient and persistent eczema were most common in first‐born children, those with a parental history of eczema, allergy or asthma and those with persistent wheezing [range of odds ratio (OR): 1.37, 95% confidence interval (CI) 1.07–1.74 and OR 3.38, 95%CI 1.95–5.85]. Early transient eczema was most common in male children only (OR 1·49, 95% CI 1·18–1·89). Children with late transient or persistent eczema were more often of Asian ethnicity (OR 2·04, 95% CI 1·14–3·65 and OR 3·08, 95% CI 1·34–7·10, respectively). Children with early, late transient and persistent eczema more often had a filaggrin mutation or additional risk alleles (range OR: 1.07, 95%CI 1.02–1.12 and OR 2.21, 95%CI 1.39–3.50). Eczema phenotypes were not associated with maternal education, breastfeeding, day care attendance and pet exposure. Five eczema phenotypes were identified in a multiethnic paediatric population with limited differences in risk profiles, except for sex and ethnicity. What's already known about this topic? Two previous studies in longitudinal birth cohorts identified four and six different eczema phenotypes, predominantly in children of European ethnicity. What does this study add? Five eczema phenotypes were identified in a multiethnic paediatric population using latent class growth analysis. Children with early transient and persistent eczema were most often first‐born children and had persistent wheezing, filaggrin mutation or additional risk alleles. Previously known eczema risk factors had limited differentiating capabilities for eczema phenotypes, except for the association of early transient eczema with male children, and late transient and persistent eczema with Asian ethnicity.