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Background Intraprostatic inflammation is an emerging prostate cancer risk factor. Estrogens are pro-inflammatory while androgens are anti-inflammatory. Thus, we investigated whether serum sex steroid hormone concentrations are associated with intraprostatic inflammation to inform mechanistic links among hormones, inflammation, and prostate cancer. Methods We conducted a cross-sectional study among 247 men in the placebo arm of the Prostate Cancer Prevention Trial who had a negative end-of-study biopsy, most (92.7%) performed without clinical indication per trial protocol. Serum estradiol, estrone, and testosterone were previously measured by immunoassay in pooled baseline and Year 3 serum. Free estradiol and free testosterone were calculated. Inflammation was visually assessed (median of three prostate biopsy cores per man). Polytomous or logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of some or all cores inflamed (both vs none) or any core inflamed (vs none) by hormone tertile, adjusting for age, race, and family history. We evaluated effect modification by waist circumference and body mass index (BMI). Results In all, 51.4% had some and 26.3% had all cores inflamed. Free (P-trend = .11) but not total estradiol was suggestively inversely associated with all cores inflamed. In men with waist circumference greater than or equal to 102 cm (P-trend = .021) and BMI ≥ 27.09 kg/m2 (P-trend = .0037) free estradiol was inversely associated with any core inflamed. Estrone was inversely associated with all cores inflamed (T3: OR = 0.36, 95% CI 0.14-0.95, P-trend = .036). Total (T3: OR = 1.91, 95% CI 0.91-4.02, P-trend = .11) and free (T3: OR = 2.19, 95% CI 1.01-4.74, P-trend = .05) testosterone were positively associated with any core inflamed, especially free testosterone in men with waist circumference less than 102 cm (T3: OR = 3.51, 95% CI 1.03-12.11, P-trend = .05). Conclusions In this first study in men without prostate cancer and irrespective of clinical indication for biopsy, contrary to the hypothesis, circulating estrogens appeared to be inversely associated, especially in heavy men, whereas androgens appeared to be positively associated with intraprostatic inflammation.

BACKGROUND The protist Trichomonas vaginalis causes a common, sexually transmitted infection and has been proposed to contribute to the development of chronic prostate conditions, including benign prostatic hyperplasia and prostate cancer. However, few studies have investigated the extent to which it involves the prostate in the current antimicrobial era. We addressed this question by investigating the relation between T. vaginalis antibody serostatus and serum prostate-specific antigen (PSA) concentration, a marker of prostate infection, inflammation, and/or cell damage, in young, male, US military members. METHODS We measured T. vaginalis serum IgG antibodies and serum total PSA concentration in a random sample of 732 young, male US active duty military members. Associations between T. vaginalis serostatus and PSA were investigated by linear regression. RESULTS Of the 732 participants, 341 (46.6%) had a low T. vaginalis seropositive score and 198 (27.0%) had a high score, with the remainder seronegative. No significant differences were observed in the distribution of PSA by T. vaginalis serostatus. However, slightly greater, nonsignificant differences were observed when men with high T. vaginalis seropositive scores were compared with seronegative men, and when higher PSA concentrations were examined (≥0.70 ng/mL). Specifically, 42.5% of men with high seropositive scores had a PSA concentration greater than or equal to 0.70 ng/mL compared with 33.2% of seronegative men (adjusted P = .125). CONCLUSIONS Overall, our findings do not provide strong support for prostate involvement during T. vaginalis infection, although our suggestive positive findings for higher PSA concentrations do not rule out this possibility entirely. These suggestive findings may be relevant for prostate condition development because higher early- to mid-life PSA concentrations have been found to predict greater prostate cancer risk later in life.

We previously observed a positive association between seropositivity for the parasite Trichomonas vaginalis and risk of clinically significant prostate cancer at diagnosis. Here, we examined whether T. vaginalis seropositivity was associated with increased prostate cancer-specific or all-cause mortality among prostate cancer patients. We studied 736 men with prostate cancer from the Physicians' Health Study (PHS) and 749 men with prostate cancer from the Health Professionals Follow-Up Study (HPFS). We used Cox proportional hazards regression models to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of the association between T. vaginalis serostatus and progression to death from prostate cancer and from all causes. In PHS, 423 men died of any cause during a median follow-up of 13.8 years from the date of cancer diagnosis, among whom 131 died of prostate cancer. In HPFS, there were 287 deaths, including 77 deaths from prostate cancer, during a median follow-up of 12.8 years. We found no association between T. vaginalis serostatus and either prostate cancer mortality or all-cause mortality in either the PHS or HPFS. While previous studies suggest a possible role for T. vaginalis in the development of clinically significant prostate cancer, our findings do not support the hypothesis that T. vaginalis serostatus is associated with mortality among prostate cancer patients.

BACKGROUND: Prostate cancer cells produce high levels of the serine protease Prostate-Specific Antigen (PSA). PSA is enzymatically active in the tumor microenvironment but is presumed to be enzymatically inactive in the blood due to complex formation with serum protease inhibitors α−1-antichymotrypsin and α−2-macroglobulin (A2M). PSA-A2M complexes cannot be measured by standard ELISA assays and are also rapidly cleared from the circulation. Thus the exact magnitude of PSA production by prostate cancer cells is not easily measured. The PSA complexed to A2M is unable to cleave proteins but maintains the ability to cleave small peptide substrates. Thus, in advanced prostate cancer, sufficient PSA-A2M may be in circulation to effect total A2M levels, levels of cytokines bound to A2M and hydrolyze small circulating peptide hormones. METHODS: Total A2M levels in men with advanced prostate cancer and PSA levels above 1000 ng/mL were measured by ELISA and compared to controls. Additional ELISA assays were used to measure levels of IL-6 and TGF-beta which can bind to A2M. The ability of PSA-A2M complexes to hydrolyze protein and peptide substrates was analyzed ± PSA inhibitor. Enzymatic activity of PSA-A2M in serum of men with high PSA levels was also assayed. RESULTS: Serum A2M levels are inversely correlated with PSA levels in men with advanced prostate cancer. Il-6 Levels are significantly elevated in men with PSA >1000 ng/mL compared to controls with PSA 1000 ng/mL can hydrolyze small fluorescently labeled peptide substrates but not large proteins that are PSA substrates. PSA can hydrolyze small peptide hormones like PTHrP and osteocalcin. PSA complexed to A2M retains the ability to degrade PTHrP. CONCLUSIONS: In advanced prostate cancer with PSA levels >1000 ng/mL, sufficient PSA-A2M is present in circulation to produce enzymatic activity against circulating small peptide hormones. Sufficient PSA is produced in advanced prostate cancer to alter total A2M levels, which can potentially alter levels of a variety of growth factors such as IL-6, TGF-beta, basic FGF, and PDGF. Alterations in levels of these cytokines and proteolytic degradation of small peptide hormones may have profound effect on host-cancer interaction.

BACKGROUND We reported that some, but not all single nucleotide polymorphisms (SNPs) in select immune response genes are associated with prostate cancer, but not individually with the prevalence of intraprostatic inflammation in the Prostate Cancer Prevention Trial (PCPT) placebo arm. Here, we investigated whether these same SNPs are associated with risk of lower- and higher-grade prostate cancer in men randomized to finasteride, and with prevalence of intraprostatic inflammation among controls. Methods A total of 16 candidate SNPs in IL1β, IL2, IL4, IL6, IL8, IL10, IL12(p40), IFNG, MSR1, RNASEL, TLR4, and TNFA and 7 tagSNPs in IL10 were genotyped in 625 white prostate cancer cases, and 532 white controls negative for cancer on an end-of-study biopsy nested in the PCPT finasteride arm. We used logistic regression to estimate log-additive odds ratios (OR) and 95% confidence intervals (CI) adjusting for age and family history. RESULTS Minor alleles of rs2243250 (T) in IL4 (OR = 1.46, 95% CI 1.03-2.08, P-trend = 0.03), rs1800896 (G) in IL10 (OR = 0.77, 95% CI 0.61-0.96, P-trend = 0.02), rs2430561 (A) in IFNG (OR = 1.33, 95% CI 1.02-1.74; P-trend = 0.04), rs3747531 (C) in MSR1 (OR = 0.55, 95% CI 0.32-0.95; P-trend = 0.03), and possibly rs4073 (A) in IL8 (OR = 0.81, 95% CI 0.64-1.01, P-trend = 0.06) were associated with higher- (Gleason 7-10; N = 222), but not lower- (Gleason 2-6; N = 380) grade prostate cancer. In men with low PSA (

BACKGROUND Mast cells are of interest in prostate cancer because they possess both pro- and anti-tumorigenic properties and are present in the tumor microenvironment. We studied the association of mast cell count and densities with prostate cancer recurrence using tissue microarrays (TMAs) for 462 men who recurred (cases) and 462 controls that were matched to the cases nested in a cohort of radical prostatectomy patients. METHODS Dual-immunostaining for mast cell tryptase and epithelial cytokeratin-8 and whole slide image analysis were used to assess total mast cell number, mast cell density (mast cell number/tissue area), and mast cell number per epithelial or stromal area in TMA spots containing tumor (up to 4 per man). We used conditional logistic regression to estimate the odds ratio (OR) and 95% confidence interval of recurrence for the mean, minimum, and maximum mast cell parameters in tumor tissue among each man's TMA spots. RESULTS After taking into account matching factors of age, race, Gleason sum, and pathologic stage, higher minimum mast cell density in the tumor (comparing highest to lowest quartiles: OR = 0.58, 95% CI 0.40–0.86; P-trend = 0.004) was associated with a lower risk of recurrence. Patterns for mast cell number and ratio of mast cell number to epithelial or stromal area were similar to those for mast cell density. CONCLUSIONS Our results suggest that intratumoral mast cells may be protective against prostate cancer recurrence and could potentially serve as a prognostic biomarker after prostatectomy. Prostate © 2016 Wiley Periodicals, Inc.

BACKGROUND Intraprostatic inflammation has been associated with lower urinary tract symptom (LUTS) progression. However, prior studies used tissue removed for clinical indications, potentially skewing inflammation extent or biasing the association. We, therefore, evaluated inflammation and LUTS incidence and progression in men who underwent biopsy of the prostate peripheral zone irrespective of indication. MATERIALS AND METHODS We developed nested case–control sets in men in the placebo arm of the Prostate Cancer Prevention Trial who were free of clinical BPH and had a protocol-directed year 7 biopsy. Cases had baseline IPSS 75th percentile (N = 46) and controls had a slope 75th percentile (N = 46) and controls had a slope

Background While family history (FH) has been widely used to provide risk information, it captures only a small proportion of subjects with higher genetic susceptibility. Our objective is to assess whether a genetic risk score (GRS) calculated from prostate cancer (PCa) risk-associated single nucleotide polymorphisms (SNPs) can supplement FH for more effective risk stratification for PCa screening decision-making. Methods A GRS was calculated based on 29 PCa risk-associated SNPs for 4,528 men of European descent in the placebo arm of the Prostate Cancer Prevention Trial (PCPT). At study entry, participants were free of PCa diagnosis. Performance of FH and GRS were measured by observed detection rate of PCa and high-grade PCa (Gleason score ≥7) during the 7-year study. Results GRS was a significant predictor of PCa in men with or without a positive FH (P = 1.18 × 10(-4) and P = 4.50 × 10(-16) , respectively). Using FH alone, as expected, the 17% of men who were FH+ had a PCa detection rate that was significantly higher (29.02%) than FH- men (23.43%, P = 0.001). When both FH+ or GRS >1.4 are considered, more than twice as many men (36%) can be classified as higher risk, as evidenced by a significantly higher PCa detection rate (30.98%) than in the remaining men (20.61%, P = 5.30 × 10(-15) ). If targeting only FH+ men, four out of five PCa cases would go undetected, as would a similarly large fraction (∼80%) of high-grade PCa cases. In comparison, if targeting FH+ or GRS >1.4 men, almost half of all PCa cases would be detected, including 45% of high-grade PCa cases. Conclusions A prostate cancer GRS can supplement family history to better identify higher risk men for targeted intervention. Prostate 76:1120-1129, 2016. © 2016 Wiley Periodicals, Inc.

Testosterone levels and physical activity each play important roles in men's health, but the relationship between the two remains unclear. We evaluated the cross-sectional association between self-reported total physical activity and serum testosterone levels in 738 men (mean age 42.4 years, range 20-≥85 years) who participated in National Health and Nutrition Examination Survey 1999-2004. We compared geometric mean testosterone concentrations measured by radioimmunoassay (RIA) and calculated the odds ratio (OR) of having low or low normal testosterone (≤3.46 ng/mL) across tertiles of total physical activity in all men, and men stratified by age (20-49, ≥50 years), and obesity status (BMI

Reports relating meat intake to prostate cancer risk are inconsistent. Associations between these dietary factors and prostate cancer were examined in a consortium of 15 cohort studies. During follow-up, 52,683 incident prostate cancer cases, including 4,924 advanced cases, were identified among 842,149 men. Cox proportional hazard models were used to calculate study-specific relative risks (RR) and then pooled using random effects models. Results do not support a substantial effect of total red, unprocessed red and processed meat for all prostate cancer outcomes, except for a modest positive association for tumors identified as advanced stage at diagnosis (advanced(r)). For seafood, no substantial effect was observed for prostate cancer regardless of stage or grade. Poultry intake was inversely associated with risk of advanced and fatal cancers (pooled multivariable RR [MVRR], 95% confidence interval, comparing ≥ 45 vs.

Although Epstein-Barr virus has been detected in prostate tissue, no associations have been observed with prostate cancer in the few studies conducted to date. One possible reason for these null findings may be use of cumulative exposure measures that do not inform the timing of infection, i.e., childhood versus adolescence/early adulthood when infection is more likely to manifest as infectious mononucleosis (IM). We sought to determine the influence of young adult-onset IM on the prostate by measuring prostate-specific antigen (PSA) as a marker of prostate inflammation/damage among U.S. military members. We defined IM cases as men diagnosed with IM from 1998 to 2003 (n = 55) and controls as men without an IM diagnosis (n = 255). We selected two archived serum specimens for each participant, the first collected after diagnosis for cases and one randomly selected from 1998 to 2003 for controls (index), as well as the preceding specimen (preindex). PSA was measured in each specimen. To explore the specificity of our findings for prostate as opposed to systemic inflammation, we performed a post hoc comparison of other infectious disease cases without genitourinary involvement (n = 90) and controls (n = 220). We found that IM cases were more likely to have a large PSA rise than controls (≥ 20 ng/mL: 19.7% versus 8.8%, p = 0.027; ≥ 40% rise: 25.7% versus 9.4%, p = 0.0021), as were other infectious disease cases (25.7% versus 14.0%, p = 0.020; 27.7% versus 18.0%, p = 0.092). These findings suggest that, in addition to rising because of prostate infection, PSA may also rise because of systemic inflammation, which could have implications for PSA interpretation in older men.

BACKGROUND We previously reported that both intraprostatic inflammation and SNPs in genes involved in the immune response are associated with prostate cancer risk and disease grade. In the present study, we evaluated the association between these SNPs and intraprostatic inflammation in men without a prostate cancer diagnosis. METHODS Included in this cross-sectional study were 205 white controls from a case-control study nested in the placebo arm of the Prostate Cancer Prevention Trial. We analyzed inflammation data from the review of HE 7 tagSNPs in IL10). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between carrying at least one minor allele and having at least one biopsy core (of a mean of three reviewed) with inflammation. RESULTS None of the SNPs evaluated was statistically significantly associated with having at least one core with inflammation. However, possible inverse associations were present for carrying the minor allele of rs2069762 (G) in IL2 (OR = 0.51, 95%CI 0.25–1.02); carrying two copies of the minor allele of rs1800871 (T) of IL10 (OR = 0.29, 95%CI 0.08–1.00); and carrying the minor allele of rs486907 (A) in RNASEL (OR = 0.52, 95%CI 0.26–1.06). After creating a genetic risk score from the three SNPs possibly associated with inflammation, the odds of inflammation increased with increasing number of risk alleles (P-trend = 0.008). CONCLUSION While our findings do not generally support a cross-sectional link between individual SNPs in key genes involved in the immune response and intraprostatic inflammation in men without a prostate cancer diagnosis, they do suggest that some of these variants when in combination may be associated with intraprostatic inflammation in benign tissue. Prostate. © 2016 Wiley Periodicals, Inc.

We previously investigated the association between single nucleotide polymorphisms (SNPs) in genes related to obesity and inflammation and colorectal cancer in the CLUE II cohort. However, the relationships between these SNPs and colorectal adenomas have not been well evaluated. In a nested case-control study of 135 incident adenoma cases and 269 matched controls in the CLUE II cohort (1989–2000), we genotyped 17 candidate SNPs in 12 genes (PPARG, TCF7L2, ADIPOQ, LEP, IL10, CRP, TLR4, IL6, IL1B, IL8, TNF, RNASEL) and 19 tagSNPs in three genes (IL10, CRP, and TLR4). Conditional logistic regression was used to calculate odds ratios (OR) for adenomas (overall and by size, histology, location, number). Polymorphisms in the inflammatory-related genes CRP, ADIPOQ, IL6, and TLR4 were observed to be associated with adenoma risk. At rs1205 in CRP, T (minor allele) carriers had a higher risk (OR 1.67, 95%CI 1.07–2.60; reference: CC) of adenomas overall and adenomas with aggressive characteristics. At rs1201299 in ADIPOQ, the AC genotype had a higher risk (OR 1.58, 95%CI 1.00–2.49) of adenomas, while the minor AA genotype had a borderline inverse association (OR 0.44, 95%CI 0.18–1.08; reference: CC). At rs1800797 in IL6, the AA genotype had a borderline inverse association (OR 0.53, 95%CI 0.27–1.05; reference: GG). Three TLR4 tagSNPs (rs10116253, rs1927911, rs7873784) were associated with adenomas among obese participants. None of these SNPs were associated with colorectal cancer in our prior study in CLUE II, possibly suggesting a different genetic etiology for early colorectal neoplasia.

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 The association between serum sex steroid hormones and PSA in a general population has not been described. METHODS Included were 378 men aged 40–85 years who participated in the National Health and Nutrition Examination Survey in 2001–2004, who did not have a prostate cancer diagnosis, and had not had a recent biopsy, rectal examination, cystoscopy, or prostate infection or inflammation. Serum total PSA, total testosterone, androstanediol glucuronide (3α-diol-G), estradiol, and sex hormone binding globulin (SHBG) concentrations were previously measured. Free testosterone was estimated by mass action. We applied sampling weights and calculated geometric mean PSA concentration by hormone quintiles adjusting for age and race/ethnicity, and also for body mass index, waist circumference, smoking, diabetes, and mutually for hormones. We estimated the OR of PSA ≥2.5 ng/ml per hormone quintile using logistic regression. RESULTS Geometric mean PSA increased across testosterone quintiles after age and race/ethnicity (Q1: 0.80, Q5: 1.14 ng/ml; P-trend = 0.002) and multivariable (Q1: 0.79, Q5: 1.16 ng/ml; P-trend = 0.02) adjustment; patterns were similar for free testosterone and 3α-diol-G. SHBG was inversely associated with PSA only after multivariable adjustment (Q1: 1.32, Q5: 0.82 nmol/L; P-trend = 0.01). Estradiol and PSA were not associated. The OR of PSA ≥2.5 ng/ml was 1.54 (95%CI 1.18–2.01) per testosterone quintile after age and race/ethnicity adjustment, and 1.78 (95%CI 1.16–2.73) after multivariable adjustment. CONCLUSIONS In this nationally representative sample, men with higher testosterone had higher PSA even after taking into account other hormones and modifiable factors. Men with higher SHBG had lower PSA, but only after multivariable adjustment. Prostate 75: 1167–1176, 2015. © 2015 Wiley Periodicals, Inc.

Background Telomeres are repetitive nucleoproteins that help maintain chromosomal stability by inhibiting exonucleolytic degradation, prohibiting inappropriate homologous recombination, and preventing chromosomal fusions by suppressing double-strand break signals. We recently observed that men treated for clinically localized prostate cancer with shorter telomeres in their cancer-associated stromal cells, in combination with greater variation in cancer cell telomere lengths, were significantly more likely to progress to distant metastases, and die from their disease. Here, we hypothesized that shorter stromal cell telomere length would be associated with prostate cancer risk at time of biopsy. Methods Telomere-specific fluorescence in situ hybridization (FISH) analysis was performed in normal-appearing stromal, basal epithelial, and luminal epithelial cells in biopsies from men randomized to the placebo arm of the Prostate Cancer Prevention Trial. Prostate cancer cases (N = 32) were either detected on a biopsy performed for cause or at the end of the study per trial protocol, and controls (N = 50), defined as negative for cancer on an end-of-study biopsy performed per trial protocol (e.g., irrespective of indication), were sampled. Logistic regression was used to estimate the association between mean telomere length of the particular cell populations, cell-to-cell telomere length variability, and risk of prostate cancer. Results Men with short stromal cell telomere lengths (below median) had 2.66 (95% CI 1.04–3.06; P = 0.04) times the odds of prostate cancer compared with men who had longer lengths (at or above median). Conversely, we did not observe statistically significant associations for short telomere lengths in normal-appearing basal (OR = 2.15, 95% CI 0.86–5.39; P= 0 .10) or luminal (OR = 1.15, 95% CI 0.47–2.80; P = 0.77) cells. Conclusions These findings suggest that telomere shortening in normal stromal cells is associated with prostate cancer risk. It is essential to extend and validate these findings, while also identifying the cellular milieu that comprises the subset of cells with short telomeres within the prostate tumor microenvironment. Prostate 75: 1160–1166, 2015. © 2015 Wiley Periodicals, Inc.

Inflammation, and more generally, the immune response are thought to influence the development of prostate cancer. To determine components of the immune response that are potentially contributory, we prospectively evaluated the association of immune-mediated conditions, asthma and hayfever, with lethal prostate cancer risk in the Health Professionals Follow-Up Study. We included 47,880 men ages 40-75 years with no prior cancer diagnosis. On the baseline questionnaire in 1986 the men reported diagnoses of asthma and hayfever and year of onset. On follow-up questionnaires, they reported new asthma and prostate cancer diagnoses. We used Cox proportional hazards regression to estimate relative risks (RR). 9.2% reported ever having been diagnosed with asthma. 25.3% reported a hayfever diagnosis at baseline. During 995,176 person-years of follow-up by 2012, we confirmed 798 lethal prostate cancer cases (diagnosed with distant metastases, progressed to distant metastasis, or died of prostate cancer [N=625]). Ever having a diagnosis of asthma was inversely associated with risk of lethal (RR=0.71, 95% confidence interval [CI] 0.51-1.00) and fatal (RR=0.64, 95% CI 0.42-0.96) disease. Hayfever with onset in the distant past was possibly weakly positively associated with risk of lethal (RR=1.10, 95% CI 0.92-1.33) and fatal (RR=1.12, 95% CI 0.91-1.37) disease. Men who were ever diagnosed with asthma were less likely to develop lethal and fatal prostate cancer. Our findings may lead to testable hypotheses about specific immune profiles in the etiology of lethal prostate cancer.

BACKGROUND MicroRNAs (miRNAs) are small non-coding RNAs that regulate a broad array of cellular and disease processes. Several miRNAs are differentially expressed in cancer and many are being considered as biomarkers for predicting clinical outcomes. Here we quantified the expression of three miRNAs, miR-21, miR-141, and miR-221, from prostate cancer surgical specimens and evaluated their association with disease recurrence after primary therapy. METHODS A pilot nested case-control study was designed from a large cohort of men who underwent radical prostatectomy between 1993 and 2001. Total RNA was extracted from malignant prostate tissue of 59 cases (recurrence) and 59 controls. Cases and controls were matched on age, race, pathologic stage, and grade. The relative expression of each miRNA was then determined for each sample by quantitative real-time RT-PCR. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of recurrence for tertiles of miRNA expression. We noted block storage time effects and thus, used separate tertile cutpoints based on the controls by calendar year of prostatectomy. RESULTS Lower miR-221 expression was associated with a higher risk of recurrence; the ORs were 3.21 for the lowest tertile and 2.63 for the middle tertile compared with the highest tertile of expression (P-trend = 0.02). This pattern was unchanged after multivariable adjustment (P-trend = 0.05). No statistically significant trends were observed for miR-21 or miR-141 after multivariable adjustment. CONCLUSIONS Based on this small pilot study, men with localized prostate cancers with lower miR-221 expression may have a greater risk for recurrence after surgery. Prostate 74: 1655–1662, 2014. © 2014 Wiley Periodicals, Inc.

Obesity later in adulthood is associated with increased risks of many cancers. However, the effect of body fatness in early adulthood, and change in weight from early to later adulthood on cancer risk later in life is less clear. We used data from 13,901 people aged 45-64 in the Atherosclerosis Risk in Communities cohort who at baseline (1987-1989) self-reported their weight at the age of 25 and had weight and height measured. Incident cancers were identified through 2006 and cancer deaths were ascertained through 2009. Multivariable Cox proportional hazard models were used to relate body mass index (BMI) at age 25 and percent weight change from age 25 to baseline to cancer incidence and mortality. After adjusting for weight change from age 25 until baseline, a 5 kg/m(2) increment in BMI at age 25 was associated with a greater risk of incidence of all cancers in women [hazard ratio (95% confidence interval): 1.10 (1.02-1.20)], but not in men. Associations with incident endometrial cancer were strong [1.83 (1.47-2.26)]. After adjusting for BMI at age 25, a 5% increment in weight from age 25 to baseline was associated with a greater risk of incident postmenopausal breast cancer [1.05 (1.02-1.07)] and endometrial cancer [1.09 (1.04-1.14)] in women and incident colorectal cancer [1.05 (1.00-1.10)] in men. Excess weight during young adulthood and weight gain from young to older adulthood may be independently associated with subsequent cancer risk. Excess weight and weight gain in early adulthood should be avoided.

Sex steroid hormones are associated with chronic diseases and mortality with risk associations that differ between racial and ethnic groups. However, it is currently unclear whether sex steroid hormone levels differ between black and white men. The aim of this study was to assess racial variation in circulating testosterone, free testosterone, sex hormone-binding globulin (SHBG) and estradiol levels in men. We searched PubMed for articles comparing circulating hormones in black and white men. A meta-analysis was performed using weighted mean differences (WMD) to compare hormones levels between black and white men. Fifteen eligible studies were identified; three did not report adjusted means. After age adjustment, free testosterone levels were significantly higher in black than in white men (WMD = 4.07 pg/mL, 95% CI 1.26, 6.88). Depending on the free testosterone concentration in white men, this WMD translates into a racial difference ranging from 2.5 to 4.9%. Total testosterone (WMD = 0.10 ng/mL, 95% CI -0.02, 0.22), estradiol (WMD = 0.67 pg/mL, 95% CI -0.04, 1.38) and SHBG (WMD = -0.45 nmol/L, 95% CI -1.75, 0.85) concentrations did not differ comparing blacks with whites. After adjustment for age, black men have a modestly but significantly 2.5 to 4.9% higher free testosterone level than white men. Based on previous studies on effects of sex steroid hormones on risk of chronic diseases or mortality, this modest difference is unlikely to explain racial differences in disease risk.

BACKGROUND Telomeres are repetitive nucleotide sequences that stabilize the ends of chromosomes. Critically short telomeres are thought to contribute to cancer development by increasing chromosomal instability. We hypothesized that shorter leukocyte telomere length, a surrogate for inherited prostate cell telomere length, would be associated with increased risk of prostate cancer in hereditary prostate cancer (HPC) families. METHODS One hundred twelve affected and 63 unaffected men from 28 families were drawn from the Johns Hopkins HPC family database. Relative mean telomere length was measured in isolated peripheral leukocyte DNA by quantitative PCR. Conditional logistic regression was used to estimate the association between quartile of age-adjusted telomere length and prostate cancer. RESULTS Men in the shortest quartile of telomere length did not have increased odds of prostate cancer compared to men in the other three quartiles (OR = 0.84, 95% CI: 0.32–2.20, P = 0.73). However, when the analysis was restricted to affected men with blood drawn before or within a year of diagnosis (N = 39) and all unaffected men, shorter telomere length was moderately associated with increased odds of prostate cancer (OR = 3.55, 95% CI: 0.82–15.43, P = 0.09). CONCLUSIONS Though we found no association overall, shorter leukocyte telomere length may be associated with increased odds of prostate cancer when measured in pre-diagnostic samples. Further prospective research is warranted exploring the utility of telomere length as a prostate cancer biomarker. Prostate 74:359–364, 2014. © 2013 Wiley Periodicals, Inc.

Objective To investigate the association between serum prostate-specific antigen (PSA) concentration at active surveillance (AS) entry and disease reclassification on subsequent AS biopsy (‘biopsy reclassification’) in men with low PSA density (PSAD). To investigate whether a clinically meaningful PSA threshold for AS eligibility/ineligibility for men with low PSAD can be identified based on risk of subsequent biopsy reclassification. Patients and Methods We included men enrolled in the Johns Hopkins AS Study (JHAS) who had a PSAD of

Objective A small randomized controlled trial suggested that vitamin D might increase the production of testosterone in men, which is supported by experimental studies in animals and a cross-sectional study showing positive associations between plasma 25-hydroxyvitamin D [25(OH)D] and testosterone and concordant seasonal variation of both biomarkers.

Study Type – Diagnostic (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Although non-recommended PSA testing has been reported in men younger than 40 years of age, there are few recognized data on PSA in younger American men, particularly younger African-American men, to provide age- and race-specific references. Using data from an existing large study of young, male members of the US military, aged 28–36 years, the present study provides PSA reference distributions for young Caucasian-American men (median = 0.56, 95th percentile = 1.42, range

Objectives To investigate the relationship between non-steroidal anti-inflammatory drug (NSAID) use and the incidence of benign prostatic hyperplasia (BPH)-related outcomes and nocturia, a lower urinary tract symptom (LUTS) of BPH, in light of accumulating evidence suggesting a role for inflammation in BPH/LUTS development. Patients and methods At baseline, participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial completed questions on recent, regular aspirin and ibuprofen use, BPH surgery, diagnosis of an enlarged prostate/BPH, and nocturia. Participants in the intervention arm also underwent a digital rectal examination (DRE), from which prostate dimensions were estimated, as well as a prostate-specific antigen (PSA) test. Only participants in the intervention arm without BPH/LUTS at baseline were included in the analysis (n = 4771). During follow-up, participants underwent annual DREs and PSA tests, provided annual information on finasteride use, and completed a supplemental questionnaire in 2006–2008 that included additional questions on diagnosis of an enlarged prostate/BPH and nocturia. Information collected was used to investigate regular aspirin or ibuprofen use in relation to the incidence of six BPH/LUTS definitions: diagnosis of an enlarged prostate/BPH, nocturia (waking two or more times per night to urinate), finasteride use, any self-reported BPH/LUTS, prostate enlargement (estimated prostate volume ≥ 30 mL on any follow-up DRE) and elevation in PSA level (> 1.4 ng/mL on any follow-up PSA test). Results Generally, null results were observed for any recent, regular aspirin or ibuprofen use (risk ratio = 0.92–1.21, P = 0.043–0.91) and frequency of use (risk ratio for one category increase in NSAID use = 0.98–1.11, P-trends = 0.10–0.99) with incident BPH/LUTS. Conclusions The findings obtained in the present study do not support a protective role for recent NSAID use in BPH/LUTS development. Keywords: aspirin, benign prostatic hyperplasia, ibuprofen, lower urinary tract symptoms, non-steroidal anti-inflammatory drugs Introduction BPH is a common condition of ageing men characterized histologically by hyperplastic nodules in the peri-urethral region and transition zone of the prostate, and clinically by a palpably enlarged prostate and LUTS [1]. Accumulating evidence suggests that inflammation may be involved in BPH/LUTS development [2]. In rodent models, induced prostatic inflammation has been shown to contribute to prostatic hyperplasia [3,4], whereas, in humans, inflammatory infiltrates are frequently observed in prostate tissue specimens from men with BPH [5–8] and the presence or degree of inflammation has been found to be correlated with prostate volume/weight [8,9], LUTS severity [10] and surgery for acute urinary retention independent of urinary tract infection [9]. Finally, in a trial of BPH/LUTS therapy, chronic prostatic inflammation was associated with a greater risk of clinical BPH progression and subsequent acute urinary retention [11]. Given these observations suggesting that inflammation may contribute to BPH/LUTS, it is plausible to hypothesize that anti-inflammatory agents (e.g. NSAIDs) may reduce the risk of BPH/LUTS [12]. To our knowledge, only three previous studies have investigated the association between NSAID use and BPH/LUTS. The first of these studies observed no association between aspirin use and prevalent BPH/LUTS; however, the results were unstable as a result of low numbers of aspirin users [13]. The second study, conducted in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, observed a weak positive association between regular NSAID use and prevalent BPH/LUTS [14], whereas the third study, conducted in the Olmsted County Study of Urinary Symptoms and Health Status among Men, observed a strong inverse association between daily NSAID use and incident BPH/LUTS [12]. Given these strong latter findings for risk (as opposed to the prevalence) of BPH/LUTS, we have now extended the previous analysis in the PLCO to investigate NSAID use in relation to risk of BPH/LUTS.

Summary Background Physiologic processes during ageing leading to multi-morbidity and diseases that increase risk of premature death may be influenced by ageing-associated changes in endogenous hormone production. Objective To evaluate the decline in sex steroid hormone levels across age and estimate the number of US men 40+ years old who may have low hormone levels. Design We measured serum testosterone, oestradiol and sex hormone binding globulin by immunoassay in 1351 men 20+ years old in Third National Health and Nutrition Examination Survey. We estimated free hormones by mass action. Results Free testosterone declined most rapidly with age (a 2% decline in geometric mean concentration occurred after ageing 1·3 years), followed by total testosterone (2·4 years), free oestradiol (4·1 years) and total oestradiol (8·1 years). These hormone changes with age translated into 25·0% and 30·2% of men 70+ years old having low total (which we defined as

The insulin-like growth factor (IGF) axis plays a role in growth and progression of prostate cancer. High circulating IGF-1 levels have been associated with an increased risk of prostate cancer. Results for IGF binding protein 3 (IGFBP-3) are inconclusive. Some studies have indicated that the positive association with IGF-1 is observed only for low-grade prostate cancer (Gleason sum < 7). We previously reported in the Health Professionals Follow-up Study (HPFS) a direct positive association between ELISA-measured plasma IGF-1 and IGFBP-3 and risk of prostate cancer (462 cases diagnosed after providing a blood specimen (between 1993 and 1995), but before February 1998). With additional follow-up through January 31st 2004, and 1,331 case-control pairs in total, we were now able to investigate low-grade (Gleason sum < 7, n = 635) and high-grade (Gleason sum ≥ 7, n = 515) prostate cancer separately. Matched odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. ORs of total prostate cancer comparing top to bottom quartiles were 1.41 (95% CI 1.12-1.78, p-trend = 0.001) for IGF-1 and 1.58 (95% CI 1.24-2.01, p-trend = 0.003) for IGFBP-3. IGF-1 was more strongly associated with low-grade (OR = 1.61 top versus bottom quartile, 95% CI 1.16-2.25, p-trend = 0.01), than with high-grade (OR = 1.29, 95% CI 0.89-1.88, p-trend = 0.12) prostate cancer (p-heterogeneity = 0.08). We hypothesize that these findings reflect that high-grade prostate cancers are more autonomous, and, thus, less sensitive to the action of IGF-1 than low-grade cancers.

Decreased risk of advanced prostate cancer has been reported among men using statins. However, the evidence on overall prostate cancer risk is conflicting. We compared the relative risk between current users and non-users of statins or other cholesterol-lowering medications in a population undergoing systematical prostate cancer screening. The study cohort comprised of 23,320 men participating in the screening arm of the Finnish prostate cancer screening trial during 1996-2004. Information on medication use was obtained from a comprehensive national prescription database. Cox proportional hazards regression was used to calculate multivariable adjusted hazard ratios (HRs) for prostate cancer. Serum prostate-specific antigen (PSA) level was compared between current users and non-users of cholesterol-lowering drugs. Compared with medication non-users, the overall prostate cancer incidence was decreased among statin users [HR 0.75, 95% confidence interval (CI) 0.63-0.89]. The inverse association was dose-dependent with cumulative amount of statin use, and strongest for low-grade and early stage tumors. The incidence was nonsignificantly lower also among users of other types of cholesterol-lowering drugs (HR 0.62, 95% CI 0.28-1.38), but without dose-dependence. Age-adjusted median serum PSA tended to be lower among users of cholesterol-lowering drugs, but the relative risk decrease among statin users was not related to decreased PSA. Overall incidence of prostate cancer was lowered among statin users when bias due to differential PSA testing between medication users and non-users was eliminated by systematical prostate cancer screening. Cholesterol-lowering with statins seems beneficial for prostate cancer prevention.

Summary Context Sex steroid hormones may play a role in the pathogenesis of chronic kidney disease (CKD). Objective To determine whether sex steroid hormone concentrations are associated with kidney function or kidney damage in men in the general US population. We hypothesized that lower serum testosterone and E2 concentrations are associated with CKD. Design patients and measurements Serum sex steroid hormones were measured by electrochemiluminescence immunoassays for 1470 men who attended the morning session of Phase I of the Third National Health and Nutrition Examination Survey (NHANES III). We used two measures of CKD, estimated glomerular filtration rate (eGFR)

C-reactive protein is a sensitive but nonspecific systemic marker of inflammation. Several prospective studies have investigated the association of prediagnostic circulating C-reactive protein concentrations with the development of colorectal cancer, but the results have been inconsistent. We performed a systematic review of prospective studies of the association between prediagnostic measurements of circulating high-sensitivity C-reactive protein and development of invasive colorectal cancer. Authors of original studies were contacted to acquire uniform data. We combined relative risks (RR) for colorectal cancer associated with a one unit change in natural logarithm-transformed high-sensitivity C-reactive protein using inverse variance weighted random effects models. We identified eight eligible studies, which included 1,159 colorectal cancer cases and 37,986 controls. The summary RR per one unit change in natural log-transformed high-sensitivity C-reactive protein was 1.12 (95% confidence intervals [CI], 1.01-1.25) for colorectal cancer, 1.13 (95% CI, 1.00-1.27) for colon cancer, and 1.06 (95% CI, 0.86-1.30) for rectal cancer. The association was stronger in men (RR, 1.18; 95% CI, 1.04-1.34) compared to women (RR, 1.09; 95% CI, 0.93-1.27) but this difference was sensitive to the findings from a single study. Prediagnostic high-sensitivity C-reactive protein concentrations were weakly associated with an increased risk for colorectal cancer. More work is needed to understand the extent to which circulating high-sensitivity C-reactive protein or other blood inflammatory markers are related to colonic inflammation.

Rare germline variants in mismatch repair genes have been linked to hereditary nonpolyposis colorectal cancer; however, it is unknown whether common polymorphisms in these genes alter the risk of colorectal cancer. To examine the association between common variants in mismatch repair genes and colorectal cancer, we conducted a case-cohort study within the CLUE II cohort. Four single nucleotide polymorphisms in 3 mismatch repair genes (MSH3 R940Q, MSH3 T1036A, MSH6 G39E and MLH1 I219V) were genotyped in 237 colorectal cancer cases and a subcohort of 2,189 participants. Incidence rate ratios (RRs) and 95% confidence intervals (95% CIs) for each polymorphism were estimated. The MSH3 1036A variant was found to be associated with an increased risk of colorectal cancer (RR = 1.28, 95% CI: 0.94–1.74 and RR = 1.65, 95% CI: 1.01–2.70 for the AT and TT genotypes, respectively, with ptrend = 0.02), particularly proximal colon cancer. Although the MSH3 940Q variant was only weakly associated with colorectal cancer overall (ptrend = 0.07), it was associated with a significant increased risk of proximal colon cancer (RR = 1.69, 95% CI: 1.10–2.61 and RR = 2.68, 95% CI: 0.96–7.47 for the RQ and QQ genotypes, respectively with ptrend = 0.005). Processed meat intake appeared to modify the association between the MSH3 polymorphisms and colorectal cancer (pinteraction < 0.10 for both). No association was observed with the MSH6 and MLH1 polymorphisms overall. This study suggests that common polymorphisms in the mismatch repair gene, MSH3, may increase the risk of colorectal cancer, especially proximal colon cancer. © 2006 Wiley-Liss, Inc.

BACKGROUND Benign growth of the prostate is thought to contribute to lower urinary tract symptoms (LUTS) in older men. It is, however, unclear which factors induce prostate growth in these men. We examined the association of insulin-like growth factor (IGF)-1 and its major binding protein IGFBP-3 with LUTS in a representative US study. METHODS We included men 60 years and older who participated in the morning session of the Third National Health and Examination Survey (NHANES III) between 1988 and 1994. Men were classified as cases (n = 91) if they reported at least three of four LUTS (nocturia, incomplete emptying, hesitancy, or weak stream) but had not had non-cancer prostate surgery in the past. Controls were men without symptoms and surgery (n = 220). All results were weighted to account for sampling probability in NHANES III. IGF-1 and IGFBP-3 were measured by ELISA and IRMA, respectively. RESULTS After mutual adjustment, men in the highest tertile of serum IGF-1 concentration had a non-significantly higher odds of LUTS than men in the lowest tertile (odds ratio (OR) = 3.20; 95% confidence interval (CI) 0.89–11.4; p-trend = 0.09]. A high concentration of IGFBP-3 was inversely related to the odds of LUTS (OR = 0.25; 95% CI 0.08–0.81; p-trend = 0.02). CONCLUSION A high IGFBP-3 level might affect LUTS by decreasing the bioavailability of IGF-1 or independent of IGF-1 by up-regulating apoptosis, and, thus, limiting its growth promoting effects on the prostate. Prostate 67: 1693–1698, 2007. © 2007 Wiley-Liss, Inc.

OBJECTIVES To examine the association of cigarette smoking, alcohol consumption and physical activity with lower urinary tract symptoms (LUTS) in older men. SUBJECTS AND METHODS The study included 2797 men participating in the Third National Health and Nutrition Examination Survey (NHANES III), who were aged ≥ 60 years. During an interview, LUTS, smoking history, alcohol consumption and physical activity were assessed. Cases comprised men with at least three of the symptoms of nocturia, hesitancy, weak stream and incomplete emptying. Men who had had prostate surgery unrelated to cancer were not included as cases. Controls were men with no symptoms or surgery. We adjusted for age and race in logistic regression models and used sampling weights to account for selection probability. RESULTS Current cigarette smokers had no higher odds of LUTS than ‘never’ smokers, but former heavy smokers (≥ 50 pack-years) had a higher odds of LUTS than never smokers (odds ratio 2.01; 95% confidence interval 1.04–3.89). Men who drank alcohol daily had a lower chance of LUTS than non-drinkers (0.59; 0.37–0.95; P trend, 0.07). All levels of moderate and vigorous activity were statistically significantly inversely associated with LUTS (P trend, 0.06), whereas men who reported no leisure-time physical activity had a greater odds of LUTS (2.06; 1.26–3.39). CONCLUSIONS Moderate alcohol consumption and physical activity may be protective against LUTS. Current cigarette smoking was not consistently associated with the condition. The possible association in former smokers warrants further investigation.

Prostate cancer is an increasing threat throughout the world. As a result of a demographic shift in population, the number of men at risk for developing prostate cancer is growing rapidly. For 2002, an estimated 189,000 prostate cancer cases were diagnosed in the U.S., accompanied by an estimated 30,200 prostate cancer deaths [Jemal et al., 2002]. Most prostate cancer is now diagnosed in men who were biopsied as a result of an elevated serum PSA (>4 ng/ml) level detected following routine screening. Autopsy studies [Breslow et al., 1977; Yatani et al., 1982; Sakr et al., 1993], and the recent results of the Prostate Cancer Prevention Trial (PCPT) [Thompson et al., 2003], a large scale clinical trial where all men entered the trial without an elevated PSA (

Objectives: Rare HRAS1 variable number tandem repeats (VNTR) have been associated with increased risks for a variety of cancers. We investigated the relationship of this polymorphism with the risk of prostate cancer among 240 cases and 481 control subjects in the Health Professionals Follow-up Study. Materials and Methods: The HRAS1 VNTR region of leukocyte DNA was polymerase chain reaction amplified, and fragment lengths were determined by automated fluorescence detection and computer analysis. We estimated the odds ratios (OR) of prostate cancer for rare HRAS1 VNTR from logistic regression models. Four common HRAS1 VNTR alleles were identified about which there was a distribution of rare 28-nucleotide repeat units. There was no difference (p = 0.4) in the prevalence of rare alleles between cases (25.8%) and control subjects (23.7%). Compared to common alleles, the OR for prostate cancer was 1.13 (95% confidence interval 0.87–1.45) for rare alleles. Conclusions: This study suggests that rare HRAS1 VNTRs may not be important in the etiology of prostate cancer.

Objectives: Amplified in breast cancer-1 (AIB1) is a steroid receptor coactivator that enhances estrogen-dependent transcriptional activation by the estrogen receptor. It is unknown whether AIB1 also interacts with the androgen receptor. Because the development and progression of prostate cancer is likely to be partially mediated by steroid hormones, we investigated whether a polymorphic CAG/CAA repeat encoding glutamine in the AIB1 gene is related to prostate cancer risk in a nested study of 581 patients and 786 age-matched control subjects in the Physicians' Health Study. Materials and Methods: DNA was extracted from peripheral whole blood, and the region encompassing the repeat was amplified using fluorescent-labeled primers. The fragments were run on polyacrylamide gels and sized by computer software. We estimated the relative risk (RR) of prostate cancer for AIB1 glutamine repeat length from logistic regression models controlling for the matching variables. Results: Three glutamine repeat lengths were prevalent: 29 (47.8% among control subjects), 28 (38.5% among control subjects), and 26 (12.6% among control subjects). Compared to 29 repeats, the RR of prostate cancer was 0.92 (95% confidence interval [CI] 0.72–1.17) for 26 repeats and 1.01 (95% CI 0.86–1.19) for 28 repeats. Compared to 28/29, the RR of prostate cancer was not significantly altered for any of the other common genotypes. No clear associations were present for AIB1 glutamine repeat length genotype by stage at the diagnosis/histologic grade of the tumor. Conclusion: This study does not support an important role in prostate cancer incidence or aggressiveness of AIB1 glutamine repeat length in the range observed in this predominately white cohort.