Faculty Bibliography

Purpose The association between exposure to testosterone replacement therapy (TRT) and prostate cancer risk is controversial. The objective was to examine this association through nationwide, population-based registry data. Methods We performed a nested case-control study in the National Prostate Cancer Register of Sweden, which includes all 38,570 prostate cancer cases diagnosed from 2009 to 2012, and 192,838 age-matched men free of prostate cancer. Multivariable conditional logistic regression was used to examine associations between TRT and risk of prostate cancer (overall, favorable, and aggressive). Results Two hundred eighty-four patients with prostate cancer (1%) and 1,378 control cases (1%) filled prescriptions for TRT. In multivariable analysis, no association was found between TRT and overall prostate cancer risk (odds ratio [OR], 1.03; 95% CI, 0.90 to 1.17). However, patients who received TRT had more favorable-risk prostate cancer (OR, 1.35; 95% CI, 1.16 to 1.56) and a lower risk of aggressive prostate cancer (OR, 0.50; 95% CI, 0.37 to 0.67). The increase in favorable-risk prostate cancer was already observed within the first year of TRT (OR, 1.61; 95% CI, 1.10 to 2.34), whereas the lower risk of aggressive disease was observed after > 1 year of TRT (OR, 0.44; 95% CI, 0.32 to 0.61). After adjusting for previous biopsy findings as an indicator of diagnostic activity, TRT remained significantly associated with more favorable-risk prostate cancer and lower risk of aggressive prostate cancer. Conclusion The early increase in favorable-risk prostate cancer among patients who received TRT suggests a detection bias, whereas the decrease in risk of aggressive prostate cancer is a novel finding that warrants further investigation.

RATIONALE: Development of cervical squamous carcinoma (CXCA) is accompanied by changes in estrogen receptors (ERs, ERalpha and ERbeta) and ezrin expression; however, reports have been conflicting. Using histologically documented staging of cervical biopsies, we determined ezrin and ER relationships during CXCA development. METHODS: Immunoreactive (ir) ezrin, ir-ERalpha, and ir-ERbeta were studied in normal epithelium, carcinoma in situ/cervical intraepithelial neoplasia (CIN) 1 to 3, and local invasion or metastatic CXCA. Results were compared using H scoring. Cultures of Caski metastatic CXCA cells were treated with estradiol and/or tamoxifen and studied for ER-driven ir-ezrin and the morphologic response. RESULTS: Koilocytosis was present and indicated viral presence. The ezrin H score increased from CIN1 to CIN3, reaching significant differences from normal by CIN3 (P = .004) and 2x normal in metastatic CXCA. Estrogen receptor alpha and ERbeta H scores fell, reaching significance by CIN3 (ERalpha, P = .0001; ERbeta, P = .024). During estradiol treatment, ezrin in Caski cells increased and localized to the periphery, in ruffles and processes. The selective ER modulator tamoxifen blocked the estradiol-induced changes. CONCLUSIONS: During cervical carcinogenesis, the usual relationship between estrogen and ezrin induction is abridged. This is consistent with the effects of human papilloma virus viral proteins such as E6 and E7 that upregulate SIX1, a protein that induces ezrin. Cervical carcinogenesis is progressive but arrests at the preinvasive stage for varying lengths of time. These studies suggest that changes in ezrin may be associated with the development of the invasive phenotype and penetration of the basement membrane. They also raise the possibility that inhibiting ezrin expression could be a target for the prevention of invasive CXCA.

Background: A comprehensive geriatric assessment clinic (GAC) was established in collaboration with a health plan within a markedly impoverished region in the US. Evaluation objectives were to assess the quality of chronic illness care from the perspective of member-patients and providers. Methods: We abstracted medical records of patients attending the GAC during one quarter of 2014 and administered the 20-item Patient Assessment of Chronic Illness Care (PACIC) survey in English and Spanish in 2015. We anonymously surveyed patients before and directly after visits. Survey questions, modified for low health literacy, used a 1-to-5-likert scale (1=none of the time to 5=always) for 5 domains: patient activation, decision support, goal setting, problem solving, and care coordination. We administered a 7-item quality assessment survey to providers for: relevance, ease of use, ability to apply findings, and agreement with diagnostic findings and recommendations, using a 1-to-5-likert scale (1=strongly disagree to 5=strongly agree). Results: Abstracted data for 193 patients demonstrated 51% had not finished high school and their chronic condition burden was high (mean: 7.2 conditions; 31% with diabetes). For patient surveys (n=165; 19% Spanish), post-visit PACIC domain scores ranged from 4.0-4.5 and post-visit ratings were higher across all domains (1.4 to 1.7 higher; p<0.001 for each). For each of 20 questions, aggregate post scores improved, indicating higher quality. For provider surveys, respondents (n=14) felt the GAC provided useful (50%) and relevant (64%) information for their practices, taught them how to provide better care for other patients (64%), and made it easier to provide care (50%). Less than one third (29%) felt their experience discouraged them from using the service again. Discussion: The AC greatly improved member-perceived care quality and facilitated provider care among patients with high chronic condition burden, suggesting a useful strategy for patients with high need. Since some providers did not find this service useful, provider focus groups are underway to understand and improve unmet provider needs

Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 × 10^-53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 × 10^-17), rs219779 adjacent to CLDN14 (P=3.5 × 10^-16), rs4443100 near RTDR1 (P=8.7 × 10^-9), and rs73186030 near CASR (P=4.8 × 10^-8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.

OBJECTIVES:This study sought to evaluate the association of physical activity with chronic myocardial damage, assessed by elevated high-sensitivity cardiac troponin T (hs-cTnT), in individuals with and without obesity. BACKGROUND:Physical activity is associated with reduced risk of heart failure (HF), particularly among obese people. The role of chronic myocardial damage in this association is uncertain. METHODS:. Physical activity was categorized per American Heart Association guidelines as recommended, intermediate, or poor. We evaluated cross-sectional associations of physical activity and obesity with elevated hs-cTnT (≥14 ng/l). In prospective analyses, we quantified the association of elevated hs-cTnT with HF risk within cross-categories of baseline physical activity and obesity. RESULTS:People with poor physical activity were more likely to have elevated hs-cTnT than those with recommended levels (odds ratio [OR]: 1.39; 95% confidence interval [CI]: 1.15 to 1.68). In cross-categories of physical activity and obesity, using the non-obese/recommended activity group as the reference, individuals with obesity and poor activity were most likely to have elevated hs-cTnT (OR: 2.46; 95% CI: 1.91 to 3.19), whereas the obese/recommended activity group had a weaker association (OR: 1.68; 95% CI: 1.28 to 2.21; p < 0.001 for interaction between physical activity and obesity). In prospective analyses, elevated hs-cTnT was strongly associated (p < 0.001) with incident HF in all obesity/physical activity cross-categories (p > 0.20 for interaction). CONCLUSIONS:Physical activity is inversely associated with chronic subclinical myocardial damage. Physical activity might lessen the association between obesity and subclinical myocardial damage, which could represent a mechanism by which physical activity reduces HF risk.