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Purpose Secondary hyperparathyroidism (SHPT) is common among dialysis patients, and calcimimetics are a mainstay of treatment. This study assessed whether cinacalcet use is associated with gastrointestinal bleeding in a large hemodialysis cohort. Methods A linked database of clinical records and medical claims for patients receiving hemodialysis in a large dialysis organization, 2007-2010, was used. A nested case-control study was performed among patients aged ≥18 years who had received hemodialysis for ≥90 days, had Medicare Parts A, B, and D coverage for ≥1 year, and had clinical evidence of SHPT (parathyroid hormone >300 pg/mL). Cases were those who experienced death or hospitalization caused by gastrointestinal bleeding. Each case was matched to up to four controls. Exposure was measured by any cinacalcet use, current use, past use, cumulative exposure days, and cumulative dosage. Conditional logistic models were used to assess the association. Results Of 48 437 patients included, 2570 experienced gastrointestinal bleeding events (2498 non-fatal, 72 fatal), and 2465 (2397 non-fatal, 68 fatal) were matched to 9500 controls; 17.2% of cases and 15.8% of controls had cinacalcet exposure and 11.1% of both cases and controls had current use. The adjusted odds ratios (95% CI) of gastrointestinal bleeding for any use, current use, and past use of cinacalcet were 1.04 (0.91-1.19), 0.97 (0.83-1.13), and 1.22 (0.99-1.50), respectively, with no use as the reference. Conclusion The results do not suggest an elevated risk of gastrointestinal bleeding resulting in hospitalization or death for hemodialysis patients exposed to cinacalcet.

Background: Rates for recurrent coronary heart disease (CHD) events have declined in the United States. However, few studies have assessed whether this decline has been similar among women and men. Methods: Data were used from 770 408 US women and 700 477 US men Results: From 2008 to 2017, age-standardized recurrent MI rates per 1000 person-years decreased from 89.2 to 72.3 in women and from 94.2 to 81.3 in men (multivariable-adjusted P interaction by sex P interaction P interaction=0.001). All-cause mortality rates decreased from 403.2 to 389.5 in women and from 436.1 to 417.9 in men ( P interaction=0.82). In 2017, the multivariable-adjusted rate ratios comparing women with men were 0.90 (95% CI, 0.86–0.93) for recurrent MI, 0.80 (95% CI, 0.78–0.82) for recurrent CHD events, 0.99 (95% CI, 0.96–1.01) for heart failure hospitalization, and 0.82 (95% CI, 0.80–0.83) for all-cause mortality. Conclusions: Rates of recurrent MI, recurrent CHD events, heart failure hospitalization, and mortality in the first year after an MI declined considerably between 2008 and 2017 in both men and women, with proportionally greater reductions for women than men. However, rates remain very high, and rates of recurrent MI, recurrent CHD events, and death continue to be higher among men than women.

Background The 2013 ACC/AHA cholesterol treatment guidelines removed the recommendation to treat adults at risk of cardiovascular disease to goal levels of low-density lipoprotein cholesterol (LDL-C). We anticipated that the frequency of LDL-C testing in clinical practice would decline as a result. To test this hypothesis, we evaluated the frequency of LDL-C testing before and after the guideline release. Methods We used the MarketScan® Commercial and Medicare Supplemental claims data (1/1/2007-12/31/2016) to identify four cohorts: 1) statin initiators (any intensity), 2) high-intensity statin initiators, 3) ezetimibe initiators, and 4) patients at very high cardiovascular risk (≥2 hospitalizations for myocardial infarction or ischemic stroke, with prevalent statin use). Rates of LDL-C testing by calendar year quarter were estimated for each cohort. To estimate rates in the absence of a guideline change, we fit a time-series model to the pre-guideline rates and extrapolated to the post-guideline period, adjusting for covariates, seasonality, and time trend. Results Pre- and post-guideline rates (LDL-C tests per 1,000 persons per quarter) were 248 and 235, respectively, for 3.9 million statin initiators; 263 and 246 for 1.3 million high-intensity statin initiators; 277 and 261 for 323,544 ezetimibe initiators; and 180 and 158 for 42,108 very high-risk patients. For all cohorts, observed post-guideline rates were similar to model-predicted rates. On average, the difference between observed and predicted rates was 8.5 for patients initiating any statin; 2.6 for patients initiating a high-intensity statin; 11.4 for patients initiating ezetimibe, and -0.5 for high-risk patients. Conclusion We observed no discernible impact of the release of the 2013 ACC/AHA guidelines on LDL-C testing rates. Rather, there was a gradual decline in testing rates starting prior to the guideline change and continuing throughout the study period. Our findings suggest that the guidelines had little to no impact on use of LDL-C testing.

BackgroundPrior studies have developed a chronic kidney disease–mineral and bone disorder (CKD-MBD) composite score based on combinations of calcium (Ca), phosphorus (P) and parathyroid hormone (PTH) that have been shown to be associated with an increased risk of clinical outcomes in the USA. We examined this association in a contemporary, international cohort of hemodialysis patients.MethodsWe studied 19 313 patients surviving ≥12 months in the Dialysis Outcomes and Practice Patterns Study Phases 3–5 (2005–15) from Europe, Canada and the USA. The CKD-MBD composite score was defined as the number of markers above target levels (P, 3.5–5.5 mg/dL; Ca, 8.4–10.2 mg/dL; PTH, 150–600 pg/mL). Using Cox models, we estimated hazard ratios (HRs) for death and a composite event (death or hospitalization), contrasting MBD 2/3 (2–3 parameters above target) with MBD 0 (all in target), adjusted for a disease risk score (DRS).ResultsMBD 2/3 above target was observed in 10–14% of patients across regions and was associated with greater DRS-adjusted mortality {HR 1.41 [95% confidence interval (CI) 1.10–1.82]} and composite events [HR 1.23 (95% CI 1.10–1.38)] in the USA compared with MBD 0; the mortality association was stronger for patients ≥ 65 years of age [HR 1.82 (95% CI 1.28–2.58)] compared with patients ConclusionsSimultaneous consideration of Ca, P and PTH may help in identifying patients on dialysis with a higher risk of major clinical outcomes related to CKD-MBD.

Aims Clinical trials have demonstrated that a reduction in low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular (CV) events. This has, however, not yet been shown in a real-world setting. We aimed to investigate the association between LDL-C changes and statin intensity with prognosis after a myocardial infarction (MI). Methods and results Patients admitted with MI were followed for mortality and major CV events. Changes in LDL-C between the MI and a 6- to 10-week follow-up visit were analysed. The associations between quartiles of LDL-C change and statin intensity with outcomes were assessed using adjusted Cox regression analyses. A total of 40 607 patients were followed for a median of 3.78 years. The median change in LDL-C was a 1.20 mmol/L reduction. Patients with larger LDL-C reduction (1.85 mmol/L, 75th percentile) compared with a smaller reduction (0.36 mmol/L, 25th percentile) had lower hazard ratios (HR) for all outcomes (95% confidence interval): composite of CV mortality, MI, and ischaemic stroke 0.77 (0.70–0.84); all-cause mortality 0.71 (0.63–0.80); CV mortality 0.68 (0.57–0.81); MI 0.81 (0.73–0.91); ischaemic stroke 0.76 (0.62–0.93); heart failure hospitalization 0.73 (0.63–0.85), and coronary artery revascularization 0.86 (0.79–0.94). Patients with ≥50% LDL-C reduction using high-intensity statins at discharge had a lower incidence of all outcomes compared with those using a lower intensity statin. Conclusions Larger early LDL-C reduction and more intensive statin therapy after MI were associated with a reduced hazard of all CV outcomes and all-cause mortality. This supports clinical trial data suggesting that earlier lowering of LDL-C after an MI confers the greatest benefit., Graphical Abstract

Background Women have lower age-specific rates of incident coronary heart disease (CHD) than men. However, it remains unclear whether women maintain the same advantage once they have had a cardiac event. Purpose To assess whether sex differences in the rates of cardiac events and all-cause mortality among individuals without a history of CHD persist following a myocardial infarction (MI). Methods We identified 171,897 women and 167,993 men Results The age-standardized rates of MI per 1,000 person-years were 4.5 in women and 5.7 in men without a history of CHD (multivariable-adjusted hazard ratio [HR] [95% confidence interval] of female sex: 0.64 [0.62; 0.67]) and 60.2 in women and 59.8 in men with a history of MI (HR: 0.94 [0.92, 0.96]) (Figure 1). Rates of CHD events in women vs. men were 6.3 vs. 10.7 among those without CHD (HR: 0.53 [0.51, 0.54]) and 84.5 vs. 99.3 among those with MI (HR: 0.87 [0.85, 0.89]). Heart failure hospitalization rates in women vs. men were 9.3 vs. 6.6 for those without CHD (HR: 0.93 [0.90, 0.96]) and 114.9 vs. 97.9 among those with MI (HR: 1.02 [1.00, 1.04]). All-cause mortality rates in women vs. men were 63.7 vs. 59.0 among those without CHD (HR: 0.72 [0.71; 0.73]) and 311.6 vs. 284.5 among those with a MI (HR: 0.90 [0.89, 0.92]). Conclusion The women advantage against MI, CHD, heart failure and all-cause mortality is considerably attenuated following a MI, suggesting that a prior MI puts women at almost the same high-risk of subsequent events as men. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): This work was funded by an industry/academic collaboration between Amgen Inc. and University of Alabama at Birmingham.

Women have lower age-specific rates of incident coronary heart disease (CHD) than men. It is unclear whether women remain at lower risk for CHD events versus men following a myocardial infarction (MI).This study assessed sex differences in recurrent MI, recurrent CHD events, and mortality among patients with MI and compared these associations with sex differences in a control group without a history of CHD.This study analyzed data for 171,897 women and 167,993 men age 21 years or older with health insurance in the United States who had a MI hospitalization in 2015 or 2016. Patients with a MI were frequency matched by age and calendar year to 687,588 women and 671,972 men without CHD. Beneficiaries were followed until December 2017 for MI, CHD (i.e., MI or coronary revascularization), and in Medicare for all-cause mortality.Age-standardized rates of MI per 1,000 person-years were 4.5 in women and 5.7 in men without CHD (hazard ratio [HR]: 0.64; 95% confidence interval [CI]: 0.62 to 0.67) and 60.2 in women and 59.8 in men with MI (HR: 0.94; 95% CI: 0.92 to 0.96). CHD rates in women versus men were 6.3 versus 10.7 among those without CHD (HR: 0.53; 95% CI: 0.51 to 0.54) and 84.5 versus 99.3 among those with MI (HR: 0.87; 95% CI: 0.85 to 0.89). All-cause mortality rates in women versus men were 63.7 versus 59.0 among those without CHD (HR: 0.72; 95% CI: 0.71 to 0.73) and 311.6 versus 284.5 among those with MI (HR: 0.90; 95% CI: 0.89 to 0.92).The lower risk for MI, CHD, and all-cause mortality in women versus men is considerably attenuated following a MI.

Background In the 2000s, adults with HIV had a higher risk for atherosclerotic cardiovascular disease ( ASCVD ) compared with those without HIV . There is uncertainty if this excess risk still exists in the United States given changes in antiretroviral therapies and increased statin use. Methods and Results We compared the risk for ASCVD events between US adults aged ≥19 years with and without HIV who had commercial or supplemental Medicare health insurance between January 1, 2011, and December 31, 2016. Beneficiaries with HIV (n=82 426) were frequency matched 1:4 on age, sex, and calendar year to those without HIV (n=329 704). Beneficiaries with and without HIV were followed up through December 31, 2016, for ASCVD events, including myocardial infarction, stroke, and lower extremity artery disease hospitalizations. Most beneficiaries were aged ASCVD events, 2190 myocardial infarctions, 891 strokes, and 322 lower extremity artery disease events. The rate per 1000 person‐years among beneficiaries with and without HIV was 5.53 and 3.49 for ASCVD , respectively, 3.58 and 2.34 for myocardial infarction, respectively, 1.49 and 0.94 for stroke, respectively, and 0.65 and 0.31 for lower extremity artery disease hospitalizations, respectively. The multivariable‐adjusted hazard ratio (95% CI ) for ASCVD , myocardial infarction, stroke, and lower extremity artery disease hospitalizations comparing beneficiaries with versus without HIV was 1.29 (1.18–1.40), 1.26 (1.13–1.39), 1.30 (1.11–1.52), and 1.46 (1.11–1.92), respectively. Conclusions Adults with HIV in the United States continue to have a higher ASCVD risk compared with their counterparts without HIV .

Background Although the risk of recurrent events among adults with coronary heart disease (CHD) has declined considerably from the 1970's in the US and many Western countries, studies from the 2000's show that rates remain high. Women have lower rates of incident CHD but little is known about sex differences in recurrent events in adults with CHD. Purpose To examine trends in rates of recurrent myocardial infarction (MI), recurrent CHD, and all-cause mortality following a MI hospitalization between 2008 and 2015 among US men and women. Also, we compared sex differences in event rates among individuals with a MI hospitalization versus their counterparts without a history of CHD. Methods Data were used from 1,232,024 (53% women) US adults Results From 2008 to 2015, age-standardized rates over 365 days of follow-up for recurrent MI declined by 15%, from 94 to 80 per 1000 person-years, in men and by 14%, from 89 to 77 per 1000 person-years, in women. Age-standardized recurrent CHD rates decreased by 16%, from 163 to 138 per 1000 person-years, in men and by 17%, from 142 to 118 per 1000 person-years, in women. In the Medicare population, age-standardized all-cause mortality rates following MI decreased by 6%, from 446 to 421 per 1000 person-years, in men and by 3%, from 412 to 398 per 1000 person-years, in women. In the secondary analyses, the women-to-men hazard ratios for those with a history of MI and those without prior CHD were 0.97 (0.94–0.99) and 0.67 (0.65–0.69), respectively, for MI, 0.89 (0.87–0.91) and 0.52 (0.51–0.54), respectively, for CHD, and 0.84 (0.83–0.85) and 0.74 (0.73–0.75) respectively, for all-cause mortality. Conclusion Reductions in rates of recurrent MI, recurrent CHD, and all-cause mortality within 365 days after hospitalization for MI have been similar for US women and men. The lower risk for events comparing women versus men without prior CHD is attenuated after a MI. Acknowledgement/Funding The design and conduct of the study was supported through a research grant from Amgen, Inc.

Introduction Red blood cell transfusions have been associated with infection risk. We investigated whether hospital transfusions are associated with infections in maintenance hemodialysis patients requiring transfusions for chronic anemia. Methods In this retrospective cohort study, hemodialysis patients who experienced an incident hospitalization during 2012-2013 were identified from the Medicare end-stage renal disease database. Hospital transfusions were first categorized into one of five groups based on adjusted likelihood of administering red blood cell transfusions during inpatient hospital stays that occurred over the previous year (2011) among the general Medicare cohort. Next, in a patient-level analysis, patients were categorized according to transfusion use at the incident hospitalization hospital. Outcomes were infection-related rehospitalization and a composite of infection-related hospitalization and all-cause mortality during the 60 days following hospital discharge. We estimated adjusted rate ratios for the association between hospital transfusion use and risk of rehospitalization or the composite endpoint using Poisson regression models. Findings The study included 1578 hospitals and 61,455 hemodialysis patients. Patient characteristics were balanced across hospital transfusion use groups. The overall transfusion rate was 16.0%. The overall 30-day infection-related hospitalization rate (95% confidence interval) per 100 patient-months was 8.8 (8.6-9.1); rates did not differ by transfusion use group. Rate ratios for infection-related rehospitalization were 1.00 (0.91-1.10) over 30 days and 0.98 (0.91-1.05) over 60 days comparing the lowest and highest transfusion use groups. Discussion We found no differences in risk of infection-related rehospitalization for patients receiving maintenance hemodialysis across the varying blood transfusion rates of US hospitals.

Rationale & Objective The 2018 American Heart Association/American College of Cardiology (AHA/ACC) cholesterol guideline uses risk stratification to guide the decision to initiate nonstatin lipid-lowering medication among adults with atherosclerotic cardiovascular disease (CVD). We determined atherosclerotic CVD (ASCVD) event rates among adults with chronic kidney disease (CKD) taking statin therapy within 2018 AHA/ACC cholesterol guideline risk categories. Study Design Observational cohort study. Setting & Participants Adults with CKD not on dialysis in the Chronic Renal Insufficiency Cohort (CRIC) study who were taking a moderate/high-intensity statin 1 year after enrollment (baseline for the current analysis, n = 1,753). Exposure 2018 AHA/ACC cholesterol guideline risk categories: without a history of ASCVD, a history of 1 major ASCVD event and multiple high-risk conditions, and a history of ≥2 major ASCVD events. Outcome Adjudicated ASCVD events after the year 1 study visit. Analytical Approach We calculated age-sex standardized rates for ASCVD events and age-sex adjusted hazard ratios for ASCVD events accounting for the competing risk of death. Results There were 394 ASCVD events over a median follow-up period of 8 years. The ASCVD event rates (with 95% CI) per 1,000 person-years among participants without a history of ASCVD, with a history of 1 major ASCVD event and multiple high-risk conditions, and with a history of ≥2 major ASCVD events were 21.7 (18.4-25.1), 45.0 (37.8-52.3), and 73.3 (53.3-93.4), respectively. Compared with participants without a history of ASCVD, the HR (95% CI) rates for ASCVD events among those with a history of 1 major ASCVD event and multiple high-risk conditions, and with a history of ≥2 major ASCVD events were 1.89 (1.52-2.36) and 2.50 (1.85-3.39), respectively. Limitations Data on whether participants were taking a maximally tolerated statin dosage were unavailable. Conclusions The 2018 AHA/ACC cholesterol guideline identifies adults with CKD who have very high ASCVD risk despite taking a moderate/high-intensity statin., Graphical abstract

Purpose Missed in-center hemodialysis treatments (MHT) are a general indicator of health status in hemodialysis patients. This analysis was conducted to estimate the association between cinacalcet use and MHT rate. Methods We studied patients receiving hemodialysis and prescription benefits services from a large dialysis organization. Incident cinacalcet users were propensity score matched to controls on 31 demographic, clinical, and laboratory variables. We applied inverse probability (IP) of censoring and crossover weights to account for informative censoring. Weighted negative binomial modeling was used to estimate MHT rates and pooled logistics models were used to estimate the association between cinacalcet use and MHT. Results Baseline demographic and clinical variables included serum calcium, phosphorus, parathyroid hormone, and vitamin D use, and were balanced between 15,474 new cinacalcet users and 15,474 matched controls. In an analysis based on intention-to-treat principles, 40.8% of cinacalcet users and 46.5% of nonusers were censored. MHT rate was 13% lower among cinacalcet initiators versus controls: IP of censoring weighted incidence rate ratio was 0.87 (95% confidence interval [CI]: 0.84–0.90 p

Introduction Heart failure with reduced ejection fraction (HFrEF) incurs significant mortality, morbidity and cost. Despite recent advances, opportunities for therapeutic improvement remains. Omecamtiv mecarbil (OM) is a first-in-class cardiac myotrope currently in a phase-3 clinical trial (GALACTIC-HF) for HFrEF treatment. Given known differences between real world (RW) and clinical trial populations, we sought to characterize RW patients who might benefit from OM. Methods In the Vanderbilt University Medical Center de-identified electronic health record of in- and outpatients (Synthetic Derivative) from 2006-2019, we created two RW cohorts of HFrEF patients: 1) Based on the validated eMERGE Network phenotype of HFrEF (left ventricular ejection fraction (LVEF) ≤ 40%; ‘clinical cohort’) and 2) Mirroring eligibility criteria of the GALACTIC-HF trial (LVEF ≤ 35%; ‘GALACTIC-HF-like cohort’) including hospitalizations, medications and laboratory values. Diagnosis and procedure codes, structured and unstructured problem lists, laboratory values, and medications were used to characterize demographics, clinical characteristics and outcomes. HF hospitalization rates were calculated from 5 days post HF index date to last encounter or death. Results The clinical cohort included 3,955 HFrEF patients and the GALACTIC-HF-like cohort included 1,541 (median age at index date 65 and 61 years, respectively), both approximately 67% male and 80% white. Aside from higher median BNP level in the GALACTIC-HF-like cohort, clinical characteristics such as blood pressure and heart rate of the two cohorts were similar. (Table). Comorbidities and utilization of cardiac devices were somewhat higher in the GALACTIC-HF-like cohort including chronic kidney disease (39 v 30%), atrial fibrillation (52 v 48%), and cardiac resynchronization or implantable cardioverter defibrillator (52 v 40%). HF hospitalization rate (per 1000py) was 242 (95% CI 203, 280) in the clinical and 396 (95% CI 350, 442) in the GALACTIC-HF like cohorts during median follow up of 2.7 and 4.1 years, respectively. Conclusions Approximately 40% of RW HFrEF patients met GALACTIC-HF trial criteria, suggesting that RW HFrEF populations may benefit from new therapies such as OM. The higher prevalence of comorbidities and higher rate of HF hospitalization in the GALACTIC-HF-like cohort may indicate a high-need, high-risk population that may achieve better clinical outcomes with OM.

Background: In the US, morbidity and mortality from coronary heart disease (CHD) has declined considerably from the 1970’s through the 2000’s. We examined whether rates of recurrent MI, recurrent CHD, heart failure hospitalization, and all-cause mortality among US men and women with a MI hospitalization have continued to decline between 2008 and 2016, and whether this differs between the sexes. Methods: Data were used from 1,369,617 (53% women) US adults Results: Between 2008 and 2016, rates of recurrent MI declined by 15%, from 190 to 162/1000 person-years, in men and by 27%, from 220 to 160/1000 person-years, in women. CHD recurrence rates decreased by 22%, from 311 to 244/1000 person-years, in men and by 32%, from 318 to 216/1000 person-years, in women (Figure). Heart failure hospitalization decreased by 4%, from 367 to 352/1000 person-years, in men and by 18%, from 517 to 425/1000 person-years, in women. Rates of 30-day mortality reduced by 5%, from 1,208 to 1,142/1000 person-years, in men and by 4%, from 1,416 to 1,358/1000 person-years, in women. Conclusion: Rates of recurrent MI, recurrent CHD, heart failure hospitalization, and all-cause mortality within 30 days after hospitalization for MI continue to decline in US adults, with greater reductions in the recurrence of CHD among women than men. Factors underpinning these trends warrant further investigation.

Background The putative benefits of cinacalcet therapy for management of secondary hyperparathyroidism (SHPT) are thought to be most manifested when patients are taking it consistently and as prescribed. Real-world descriptions of cinacalcet prescription discontinuation and reinitiation in European hemodialysis patients are lacking. To address this knowledge gap, we used Dialysis Outcomes and Practice Patterns Study (DOPPS) data, based on dialysis facility medical records, from seven European countries to estimate rates and predictors of cinacalcet prescription discontinuation and reinitiation in hemodialysis patients and to describe the trajectories of CKD-MBD laboratory values after discontinuation. Methods Cox regression analyses were used to predict (1) cinacalcet discontinuation among 613 patients with ≥3 consecutive months without cinacalcet prescription immediately prior to a new cinacalcet prescription and (2) cinacalcet reinitiation among 415 patients with a newly discontinued cinacalcet prescription immediately after ≥3 consecutive months of prescribed use. Results Cinacalcet was discontinued in 21 and 35% of new users after 6 and 12 months, respectively. Cinacalcet was reinitiated in 38 and 49% of newly-discontinued users after 6 and 12 months, respectively. Predictors of discontinuation included lower parathyroid hormone (PTH) in the previous month (

Purpose Cinacalcet is indicated for treatment of secondary hyperparathyroidism in patients receiving hemodialysis. Cinacalcet reduces serum calcium concentrations by decreasing parathyroid hormone secretion, but the frequency and degree of calcium reduction following cinacalcet initiation, subsequent physician response, and ultimate calcium recovery in clinical practice are not well described. Methods Patients receiving hemodialysis at a large dialysis organization who enrolled in the organization's prescription benefits service and initiated cinacalcet at serum calcium ≥8.4 mg/dL were studied (N = 13 723). Patients were categorized by whether they experienced a reduction in calcium to

BACKGROUND We previously found that inflammation in benign prostate tissue is associated with an increased odds of prostate cancer, especially higher-grade disease. Since part of this link may be due to genetics, we evaluated the association between single nucleotide polymorphisms (SNPs) in immune response genes and prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial. METHODS We genotyped 16 candidate SNPs in IL1β, IL2, IL4, IL6, IL8, IL10, IL12(p40), IFNG, MSR1, RNASEL, TLR4, and TNFA and seven tagSNPs in IL10 in 881 prostate cancer cases and 848 controls negative for cancer on an end-of-study biopsy. Cases and controls were non-Hispanic white and frequency matched on age and family history. We classified cases as lower (Gleason sum

Background: Genome-wide association studies (GWAS) have produced weak (OR = 1.1–1.5) but significant associations between single nucleotide polymorphisms (SNPs) and prostate cancer. However, these associations may be explained by detection bias caused by SNPs influencing PSA concentration. Thus, in a simulation study, we quantified the extent of bias in the association between a SNP and prostate cancer when the SNP influences PSA concentration. Methods: We generated 2,000 replicate cohorts of 20,000 men using real-world estimates of prostate cancer risk, prevalence of carrying ≥1 minor allele, PSA concentration, and the influence of a SNP on PSA concentration. We modeled risk ratios (RR) of 1.00, 1.25, and 1.50 for the association between carrying ≥1 minor allele and prostate cancer. We calculated mean betas from the replicate cohorts and quantified bias under each scenario. Results: Assuming no association between a SNP and prostate cancer, the estimated mean bias in betas ranged from 0.02 to 0.10 for ln PSA being 0.05 to 0.20 ng/mL higher in minor allele carriers; the mean biased RRs ranged from 1.03 to 1.11. Assuming true RRs = 1.25 and 1.50, the biased RRs were as large as 1.39 and 1.67, respectively. Conclusion: Estimates of the association between SNPs and prostate cancer can be biased to the magnitude observed in published GWAS, possibly resulting in type I error. However, large associations (RR > 1.10) may not fully be explained by this bias. Impact: The influence of SNPs on PSA concentration should be considered when interpreting results from GWAS on prostate cancer. Cancer Epidemiol Biomarkers Prev; 24(1); 88–93. ©2014 AACR.

Background Secondary hyperparathyroidism (SHPT) is associated with adverse outcomes in patients receiving maintenance dialysis. Parathyroidectomy is a treatment for SHPT; whether parathyroidectomy utilization varies geographically in the US is unknown. Methods A retrospective cohort analysis was undertaken to identify all patients aged 18 years or older who were receiving in-center hemodialysis between 2007 and 2009, were covered by Medicare Parts A and B, and had been receiving hemodialysis for at least 1 year. Parathyroidectomy was identified from inpatient claims using relevant International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes. Patient characteristics and End-Stage Renal Disease Network (a proxy for geography) were ascertained. Adjusted odds ratios for parathyroidectomy were estimated from a logistic model. Results A total of 286,569 patients satisfied inclusion criteria, of whom 4435 (1.5%) underwent PTX. After adjustment for a variety of patient characteristics, there was a 2-fold difference in adjusted odds of parathyroidectomy between the most- and least-frequently performing regions. Adjusted odds ratios were more than 20% higher than average in four networks, and more than 20% lower in four networks. Conclusions Parathyroidectomy use varies substantially by geography in the US; the factors responsible should be further investigated.

Background: To evaluate the association of variation in genes involved in immune response, including IL10, production and detoxification of reactive oxygen species, and repair of oxidative DNA damage with risk of recurrence after surgery for localized prostate cancer. Methods: We conducted a nested case-control study of men who had a radical prostatectomy in 1993 to 2001. A total of 484 recurrence cases and 484 controls were matched on age, race, and pathologic stage and grade. Germline DNA was extracted from paraffin-embedded unaffected lymph nodes. We genotyped candidate single-nucleotide polymorphisms (SNP) in IL10, CRP, GPX1, GSR, GSTP1, hOGG1, IL1B, IL1RN, IL6, IL8, MPO, NOS2, NOS3, SOD1, SOD2, SOD3, TLR4, and TNF and tagging SNPs in IL10, CRP, GSR, IL1RN, IL6, NOS2, and NOS3. We used conditional logistic regression to estimate OR and 95% confidence intervals (CI). Results: The minor allele (A) in IL10 rs1800872, known to produce less interleukin-10 (IL-10), was associated with a higher risk of recurrence (OR = 1.76, 95% CI: 1.00–3.10), and the minor allele (G) in rs1800896, known to produce more IL-10, was associated with a lower risk of recurrence (OR = 0.66, 95% CI: 0.48–0.91). We also observed associations for candidate SNPs in CRP, GSTP1, and IL1B. A common IL10 haplotype and 2 common NOS2 haplotypes were associated with recurrence. Conclusion: Variation in IL10, CRP, GSTP1, IL1B, and NOS2 was associated with prostate cancer recurrence independent of pathologic prognostic factors. Impact: This study supports that genetic variation in immune response and oxidation influence prostate cancer recurrence risk and suggests genetic variation in these pathways may inform prognosis. Cancer Epidemiol Biomarkers Prev; 21(10); 1774–82. ©2012 AACR.

OBJECTIVES Prostate cancer treatment should depend on the characteristics of a patient's prostate cancer as well as overall health status. A possible adverse consequence of poor patient selection is a lack of benefit because of premature death from another cause. We evaluated the association between perioperative comorbidity and risk of death from causes other than prostate cancer in men who underwent radical prostatectomy (RP). METHODS We conducted a retrospective cohort study of 14,052 men who underwent RP from 1983 to 2006. The Charlson Comorbidity Index (CCI) score was calculated using the discharge records for the prostatectomy hospitalization. Mortality status and cause of death were obtained via chart review and searches of national databases. Cox proportional hazards regression was used to estimate the hazard ratio (HR) of death from causes other than prostate cancer after RP by CCI score (0, 1, 2+). RESULTS The median age at RP was 58.1 years. The median follow-up was 7.6 years (interquartile range 4.3-11.5). Of 849 deaths, 599 (70.6%) resulted from causes other than prostate cancer. On multivariable analysis, men with a CCI ≥2 had a statistically significantly higher risk of death from causes other than prostate cancer compared with those with lower CCI scores (HR 2.18, 95% CI 1.30-3.64, P = .0003). CONCLUSIONS Greater perioperative comorbidity was associated with a higher risk of death from causes other than prostate cancer in men who underwent RP. Physicians should consider using a standardized tool to assess perioperative comorbidities to enhance appropriate recommendation for surgical treatment.

C-reactive protein (CRP), an inflammation marker, is associated with colorectal cancer (CRC) risk in some prospective studies. Whether increased CRP is indicative of colonic inflammation, a possible CRC cause, or of other sources of inflammation (e.g., adiposity), is unknown. Thus, we evaluated the association between CRP and colonic mucosal measures of inflammation.151 adults undergoing colonoscopy provided a blood sample and random left- and right-side colonic mucosal biopsies. Height and weight were measured, and lifestyle information was collected. High-sensitivity C-reactive protein (hsCRP) was measured by immunoturbidometric assay. A gastrointestinal pathologist evaluated biopsies for seven colonic inflammation measures. Of 119 participants with complete information, 24 had an inflammatory bowel disease (IBD) history and were analyzed separately. We calculated the number of colonic inflammation measures present in both biopsies, and separately for right and left biopsies. Adjusted geometric mean hsCRP was calculated using linear regression, overall, by demographic and lifestyle factors, and inflammation measures.Most participants had ≥ 1 colonic inflammation measure (0: 21 %, 1: 39 %, ≥ 2: 40 %). Adjusted mean hsCRP did not increase with increasing number of inflammation measures (0: 1.67; 1: 1.33; ≥ 2: 1.01 mg/L; p trend = 0.21). Obese (2.03 mg/L) and overweight (1.61 mg/L) participants had higher adjusted mean hsCRP than normal-weight participants (0.62 mg/L; p trend0.0001). Patterns were similar for participants with a history of IBD.hsCRP concentration was not associated with colonic inflammation, although hsCRP increased with adiposity. The hsCRP-CRC association may be explained by residual confounding by other risk factors, such as adiposity, rather than by CRP marking colonic inflammation.

Diabetes is a risk factor for many cancers; chronic hyperglycemia is hypothesized to be, in part, explanatory. We evaluated the association between glycated hemoglobin, a time-integrated glycemia measure, and cancer incidence and mortality in non-diabetic and diabetic men and women. We conducted a prospective study of 12,792 cancer-free participants attending the second visit (1990–1992) of the Atherosclerosis Risk in Communities (ARIC) Study. We measured glycated hemoglobin in whole-blood samples using HPLC. Incident cancers were ascertained from registries and hospital records through 2006. We estimated multivariable-adjusted hazard ratios (HR) of cancer incidence and mortality for non-diabetic participants with values ≥5.7% (elevated), non-diabetic participants with

Background: We previously found that inflammation in benign prostate tissue is associated with increased odds of prostate cancer especially higher-grade disease. To understand this link, we evaluated the association between single nucleotide polymorphisms (SNPs) in immune response genes and prostate cancer risk in the placebo arm of the Prostate Cancer Prevention Trial (PCPT). Men were screened yearly and if not diagnosed with prostate cancer during the trial, underwent an end-of-study biopsy. Thus, in a subanalysis, we were able to study associations in men with low PSA; i.e., men in whom bias due to any link between inflammation and elevated PSA, an indication for biopsy, is reduced. Methods: We genotyped 16 candidate SNPs in IL1b, IL2, IL4, IL6, IL8, IL10, IL12(p40), IFNG, MSR1, RNASEL, TLR4, and TNFA and 7 tagSNPs in IL10 in 881 prostate cancer cases and 848 controls negative for cancer on an end-of-study biopsy. Cases and controls were non-Hispanic white and frequency matched on age and family history. We classified cases as lower (Gleason sum Results: The minor allele (C) of rs3212227 in IL12(p40) was associated with an increased risk of total (log additive: OR = 1.30, 95% CI 1.10-1.53; P-trend = 0.0017) and lower-grade (OR = 1.36, 95% CI 1.15-1.62; P-trend = 0.0004) prostate cancer. The minor allele (A) of rs4073 in IL8 was possibly associated with a decreased risk of higher-grade (OR = 0.81, 95% CI 0.64-1.02; P-trend = 0.07), but not total disease. None of the other candidates was associated with risk. The minor alleles of IL10 tagSNPs rs1800890 (A; OR = 0.87, 95% CI: 0.75-0.99; P-trend = 0.04) and rs3021094 (C; OR = 1.31, 95% CI 1.03-1.66, P-trend = 0.03) were associated with prostate cancer risk; the latter also with lower- (P-trend = 0.04) and possibly higher- (P-trend = 0.06) grade disease. These patterns were generally similar among men with prostate specific antigen (PSA) Funding: P01 CA108964, U10 CA37429, UM1 CA182883, T32 CA009314. *A SWOG-Coordinated Study S9217 Citation Format: Danyelle A. Winchester, Cathee Till, Phyllis J. Goodman, Catherine M. Tangen, Regina M. Santella, Teresa L. Johnson-Pais, Robin J. Leach, Jianfeng Xu, S. Lilly Zheng, Ian M. Thompson, M. Scott Lucia, Scott M. Lippmann, Howard L. Parnes, Paul J. Dluzniewski, William B. Isaacs, Angelo M. De Marzo, Charles G. Drake, Elizabeth A. Platz. Variation in genes involved in the immune response and prostate cancer risk in the placebo arm of the Prostate Cancer Prevention Trial. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4605. doi:10.1158/1538-7445.AM2015-4605

Background: Diabetes is a risk factor for many cancers; chronic hyperglycemia is hypothesized to be, in part, explanatory. We evaluated the association between glycated hemoglobin, a time-integrated glycemia measure, and cancer incidence and mortality in non-diabetic and diabetic men and women. Methods: We conducted a prospective study of 12,792 cancer-free participants attending the second visit (1990–1992) of the Atherosclerosis Risk in Communities (ARIC) Study. We measured glycated hemoglobin in whole-blood samples using HPLC. Incident cancers were ascertained from registries and hospital records through 2006. We estimated multivariable-adjusted hazard ratios (HR) of cancer incidence and mortality for non-diabetic participants with values ≥5.7% (elevated), non-diabetic participants with Results: We ascertained 2,349 incident cancer cases and 887 cancer deaths. Compared with non-diabetic women with normal glycated hemoglobin, non-diabetic women with elevated values had an increased risk of cancer incidence (HR:1.24; 95% CI:1.07,1.44) and mortality (HR:1.58; 95% CI:1.23,2.05) as did diabetic women (incidence, HR:1.30; 95% CI:1.06,1.60, mortality, HR:1.96; 95% CI:1.40,2.76). Non-diabetic women with low values also had increased risk. Diabetic women with good glycemic control ( Conclusions: Our findings support the hypothesis that chronic hyperglycemia, even in the non-diabetic range, increases cancer risk in women, but not men. Maintaining normal glycated hemoglobin overall, and good glycemic control among diabetic adults, may reduce the burden of cancer. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A74.

Background Cinacalcet is used to treat secondary hyperparathyroidism among hemodialysis patients. Large-scale epidemiologic studies describing patterns of cinacalcet use, effects on parathyroid hormone (PTH), calcium, and phosphorous levels, and predictors of discontinuation have not been previously reported. Methods This retrospective cohort study used a clinical database of a large U.S. dialysis provider (2007–2010) merged with administrative data from the United States Renal Data System. Among new users of cinacalcet with Medicare coverage, trends in PTH, calcium, and phosphorus were measured in 30-day intervals following cinacalcet initiation. Results Seventeen thousand seven hundred sixty-three eligible initiators contributed 111,047 30-day follow-up intervals. Of these, 56 % discontinued cinacalcet by month 4. Of those discontinuing, 76.3 % reinitiated. Mean values of PTH, calcium, and phosphorus decreased to recommended levels within 4 months following initiation. Proximal PTH levels