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Liver cancer incidence has tripled since the early 1980s, making this disease one of the fastest rising types of cancer and the third leading cause of cancerrelated deaths worldwide. In the US, incidence varies by geographic location and race, with the highest incidence in the southwestern and southeastern states and among racial minorities such as Hispanic and Black individuals. Prognosis is also poorer among these populations. The observed ethnic disparities do not fully reflect differences in the prevalence of risk factors, e.g., for cirrhosis that may progress to liver cancer or from genetic predisposition. Likely substantial contributors to risk are environmental factors, including chemical and non-chemical stressors; yet, the paucity of mechanistic insights impedes prevention efforts. Here, we review the current literature and evaluate challenges to reducing liver cancer disparities. We also discuss the hypothesis that epigenetic mediators may provide biomarkers for early detection to support interventions that reduce disparities. [ABSTRACT FROM AUTHOR]

Background: High-risk human papillomavirus (hrHPV) testing is utilized in primary cervical cancer screening, generally along with cytology, to triage abnormalities to colposcopy. Most screening-based hrHPV testing involves pooled detection of any hrHPV or of HPV16/18. Cervical neoplasia progression risks based on extended hrHPV genotyping--particularly non-16/18 hrHPV types--are not well characterized. HPV genotype-specific incidence of high-grade cervical intraepithelial neoplasia or more severe (CIN2+) following an abnormal screening result was examined. Methods: We assessed a US-based prospective, multiracial, clinical cohort of 343 colposcopy patients with normal histology (n = 226) or CIN1 (n = 117). Baseline cervical samples underwent HPV DNA genotyping, and participants were followed up to 5 years. Genotype-specific CIN2+ incidence rates (IR) were estimated with accelerated failure time models. Five-year CIN2+ risks were estimated nonparametrically for hierarchical hrHPV risk groups (HPV16; else HPV18/45; else HPV31/33/35/52/58; else HPV39/51/56/59/68). Results: At enrollment, median participant age was 30.1 years; most (63%) were hrHPV-positive. Over follow-up, 24 participants progressed to CIN2+ (7.0%). CIN2+ IR among hrHPV-positive participants was 3.4/1,000 person-months. CIN2+ IRs were highest for HPV16 (8.3), HPV33 (7.8), and HPV58 (4.9). Five-year CIN2+ risk was higher for HPV16 (0.34) compared with HPV18/45 (0.12), HPV31/33/35/52/58 (0.12), and HPV39/51/56/59/68 (0.16) (P = 0.05). Conclusions: Non-16/18 hrHPV types are associated with differential CIN2+ progression rates. HPV16, 33, and 58 exhibited the highest rates over 5 years. HPV risk groups warrant further investigation in diverse US populations. Impact: These novel data assessing extended HPV genotyping in a diverse clinical cohort can inform future directions to improve screening practices in the general population. [ABSTRACT FROM AUTHOR]

BACKGROUND : Lead exposure during early development causes neurodevelopmental disorders by unknown mechanisms. Epidemiologic studies have focused recently on determining associations between lead exposure and global DNA methylation; however, such approaches preclude the identification of loci that may alter human disease risk. OBJECTIVES : The objective of this study was to determine whether maternal, postnatal, and early childhood lead exposure can alter the differentially methylated regions (DMRs) that control the monoallelic expression of imprinted genes involved in metabolism, growth, and development. METHODS : Questionnaire data and serial blood lead levels were obtained from 105 participants (64 females, 41 males) of the Cincinnati Lead Study from birth to 78 months. When participants were adults, we used Sequenom EpiTYPER assays to test peripheral blood DNA to quantify CpG methylation in peripheral blood leukocytes at DMRs of 22 human imprinted genes. Statistical analyses were conducted using linear regression. RESULTS : Mean blood lead concentration from birth to 78 months was associated with a significant decrease in PEG3 DMR methylation (β = -0.0014; 95% CI: -0.0023, -0.0005, p = 0.002), stronger in males (β = -0.0024; 95% CI: -0.0038, -0.0009, p = 0.003) than in females (β = -0.0009; 95% CI: -0.0020, 0.0003, p = 0.1). Elevated mean childhood blood lead concentration was also associated with a significant decrease in IGF2/H19 (β = -0.0013; 95% CI: -0.0023, -0.0003, p = 0.01) DMR methylation, but primarily in females, (β = -0.0017; 95% CI: -0.0029, -0.0006, p = 0.005) rather than in males, (β = -0.0004; 95% CI: -0.0023, 0.0015, p = 0.7). Elevated blood lead concentration during the neonatal period was associated with higher PLAGL1/HYMAI DMR methylation regardless of sex (β = 0.0075; 95% CI: 0.0018, 0.0132, p = 0.01). The magnitude of associations between cumulative lead exposure and CpG methylation remained unaltered from 30 to 78 months. CONCLUSIONS : Our findings provide evidence that early childhood lead exposure results in sex-dependent and gene-specific DNA methylation differences in the DMRs of PEG3, IGF2/H19, and PLAGL1/HYMAI in adulthood. http://dx.doi.org/10.1289/ehp.1408577, Introduction Elevated lead exposure in early life is associated with growth retardation, neurotoxicity, impaired cognitive development in infancy, and deficits in attention and executive function (Bellinger et al. 1986, 1987). [...]

Abstract Background Lower concentrations of the insulin���like growth factor binding protein-1 (IGFBP-1) and elevated concentrations of insulin or C-peptide have been associated with an increase in colorectal cancer risk (CRC). However few studies have evaluated IGFBP-1 and C-peptide in relation to adenomatous polyps, the only known precursor for CRC. Methods Between November 2001 and December 2002, we examined associations between circulating concentrations of insulin, C-peptide, IGFBP-1 and apoptosis among 190 individuals with one or more adenomatous polyps and 488 with no adenomatous polyps using logistic regression models. Results Individuals with the highest concentrations of C-peptide were more likely to have adenomas (OR = 2.2, 95% CI 1.4-4.0) than those with the lowest concentrations; associations that appeared to be stronger in men (OR = 4.4, 95% CI 1.7-10.9) than women. Individuals with high insulin concentrations also had a higher risk of adenomas (OR = 3.5, 95% CI 1.7-7.4), whereas higher levels of IGFBP-1 were associated with a reduced risk of adenomas in men only (OR = 0.3, 95% CI 0.1-0.7). Overweight and obese individuals with higher C-peptide levels (>1st Q) were at increased risk for lower apoptosis index (OR = 2.5, 95% CI 0.9-7.1), an association that remained strong in overweight and obese men (OR = 6.3, 95% CI 1.0-36.7). Higher levels of IGFBP-1 in overweight and obese individuals were associated with a reduced risk of low apoptosis (OR = 0.3, 95% CI 0.1-1.0). Conclusions Associations between these peptides and the apoptosis index in overweight and obese individuals, suggest that the mechanism by which C-peptide could induce adenomas may include its anti-apoptotic properties. This study suggests that hyperinsulinemia and IGF hormones predict adenoma risk, and that outcomes associated with colorectal carcinogenesis maybe modified by gender.

Abstract Background Infection with human papillomavirus (HPV) is associated with uterine cervical intraepithelial neoplasia (CIN) and invasive cancers (ICC). Approximately 80% of ICC cases are diagnosed in under-developed countries. Vaccine development relies on knowledge of HPV genotypes characteristic of LSIL, HSIL and cancer; however, these genotypes remain poorly characterized in many African countries. To contribute to the characterization of HPV genotypes in Northeastern Tanzania, we recruited 215 women from the Reproductive Health Clinic at Kilimanjaro Christian Medical Centre. Cervical scrapes and biopsies were obtained for cytology and HPV DNA detection. Results 79 out of 215 (36.7%) enrolled participants tested positive for HPV DNA, with a large proportion being multiple infections (74%). The prevalence of HPV infection increased with lesion grade (14% in controls, 67% in CIN1 cases and 88% in CIN2-3). Among ICC cases, 89% had detectable HPV. Overall, 31 HPV genotypes were detected; the three most common HPV genotypes among ICC were HPV16, 35 and 45. In addition to these genotypes, co-infection with HPV18, 31, 33, 52, 58, 68 and 82 was found in 91% of ICC. Among women with CIN2-3, HPV53, 58 and 84/83 were the most common. HPV35, 45, 53/58/59 were the most common among CIN1 cases. Conclusions In women with no evidence of cytological abnormalities, the most prevalent genotypes were HPV58 with HPV16, 35, 52, 66 and 73 occurring equally. Although numerical constraints limit inference, findings that 91% of ICC harbor only a small number of HPV genotypes suggests that prevention efforts including vaccine development or adjuvant screening should focus on these genotypes.

Purpose: Circulating inflammatory markers may predict prostate cancer (PC) outcomes. For example, a recent study showed that higher peripheral blood monocyte counts were associated with aggressive PC in Asian men undergoing radical prostatectomy (RP). Herein, we investigated whether peripheral monocyte count can predict long-term PC outcomes after RP in black and white men. Methods: We retrospectively reviewed data on 2345 men undergoing RP from 2000 to 2017 at eight Veterans Affairs hospitals. Data on monocyte count within 6 and 12 months prior to surgery were collected. The study outcomes were biochemical recurrence (BCR), castration-resistant PC (CRPC), metastasis, all-cause mortality (ACM), and PC-specific morality (PCSM). Cox-proportional hazard models were used to assess the associations between pre-operative monocyte count and the above-mentioned outcomes accounting for confounders. Results: Of 2345 RP patients, 972 (41%) were black and 1373 (59%) were white men. In multivariable analyses, we found no associations between monocyte count and BCR among all men (HR: 1.36, 95%CI 0.90–2.07) or when analyses were stratified by race (HR: 1.30, 95%CI 0.69–2.46, in black men; HR:1.33, 95%CI 0.76–02.33, in white men). Likewise, no overall or race-specific associations were found between monocyte count and CRPC, metastases, ACM, and PCSM, all p ≥ 0.15. Results were similar for monocyte count measured at 12 months prior to RP. Conclusion: In black and white PC patients undergoing RP, peripheral monocyte count was not associated with long-term PC outcomes. Contrary to what was found in Asian populations, monocyte count was not associated with PC outcomes in this study. [ABSTRACT FROM AUTHOR]

Background: Global prostate cancer incidence rates are lower in Asian men than Caucasian men. Whether this is the result of less screening in Asian men remains to be determined. We examined whether Asian race was associated with prostate cancer diagnosis in the Reduction by Dutasteride of Cancer Events (REDUCE) study. Methods: REDUCE was a 4-year, multicenter, randomized trial of dutasteride versus placebo for prostate cancer prevention among men who underwent prostate-specific antigen (PSA)-independent biopsies at 2 and 4 years. Eligible men were ages 50 to 75 years, had PSA between 2.5 and 10 ng/mL, and a negative prestudy prostate biopsy. We tested the association between Asian and Caucasian race and prostate cancer diagnosis using logistic regression. Results: Of 8,122 men in REDUCE, 5,755 (71%) were Caucasian and 105 (1.8%) were Asian. Asians had lower body mass index (24.8 vs. 26.9 kg/m2, P < 0.001), had smaller prostate volume (35.0 vs. 43.5 cc, P < 0.001), and were less likely to have abnormal digital rectal exams (P = 0.048), but were similar in baseline age, PSA, family history of prostate cancer, and smoking status compared with Caucasian men (all P = 0.164). Asian men were equally likely to receive any on-study biopsy compared with Caucasian men (P = 0.634). After adjusting for potential confounders, Asian men were less likely to be diagnosed with prostate cancer during the 4-year study (OR = 0.49; 95% confidence interval, 0.28-0.88; P = 0.016), compared with Caucasian men. Conclusions: In REDUCE, where all men underwent biopsies largely independent of PSA, Asian race was associated with lower prostate cancer diagnosis. [ABSTRACT FROM AUTHOR]

Background: The authors previously found that obesity was linked with prostate cancer (PC)-specific mortality (PCSM) among men who underwent radical prostatectomy (RP). Herein, in a larger RP cohort, the authors investigated whether the association between obesity and long-term PC outcomes, including PCSM, differed by race.Methods: Data from 5929 patients who underwent RP and were in the Shared Equal Access Regional Cancer Hospital (SEARCH) database were analyzed. Prior to RP, body mass index (BMI) was measured and recorded in the medical records. BMI was categorized as normal weight (<25 kg/m2 ), overweight (25-29.9 kg/m2 ), and obese (≥30 kg/m2 ). The authors assessed the association between BMI and biochemical disease recurrence (BCR), castration-resistant prostate cancer (CRPC), metastasis, and PCSM, accounting for confounders.Results: Of the 5929 patients, 1983 (33%) were black, 1321 (22%) were of normal weight, 2605 (44%) were overweight, and 2003 (34%) were obese. Compared with white men, black men were younger; had higher prostate-specific antigen levels; and were more likely to have a BMI ≥30 kg/m2 , seminal vesicle invasion, and positive surgical margins (all P ≤ .032). During a median follow-up of 7.4 years, a total of 1891 patients (32%) developed BCR, 181 patients (3%) developed CRPC, 259 patients (4%) had metastasis, and 135 patients (2%) had died of PC. On multivariable analysis, obesity was found to be associated with an increased risk of PCSM (hazard ratio, 1.78; 95% confidence interval, 1.04-3.04 [P = .035]). No interaction was found between BMI and race in predicting PCSM (P ≥ .88), BCR (P ≥ .81), CRPC (P ≥ .88), or metastasis (P ≥ .60). Neither overweight nor obesity was associated with risk of BCR, CRPC, or metastasis (all P ≥ .18).Conclusions: Obese men undergoing RP at several Veterans Affairs hospitals were found to be at an increased risk of PCSM, regardless of race. [ABSTRACT FROM AUTHOR]

Background: In this study among men who underwent radical prostatectomy (RP), African American men (AAM) were 28% more likely to develop recurrent disease compared with Caucasian men (CM). However, among those who had nonmetastatic, castration-resistant prostate cancer (CRPC), race did not predict metastases or overall survival. Whether race predicts metastases among men who receive androgen-deprivation therapy (ADT) after a biochemical recurrence (BCR) (ie, before CRPC but after BCR) is untested.Methods: The authors identified 595 AAM and CM who received ADT for a BCR that developed after RP between 1988 and 2015 in the Shared Equal-Access Regional Cancer Hospital (SEARCH) database. Univariable and multivariable Cox models were used to test the association between race and the time from ADT to metastases. Secondary outcomes included the time to CRPC, all-cause mortality, and prostate cancer-specific mortality.Results: During a median follow-up of 66 months after ADT, 62 of 354 CM (18%) and 38 of 241 AAM (16%) developed metastases. AAM were younger at the time they received ADT (63 vs 67 years; P < .001), had received ADT in a more recent year (2008 vs 2006; P < .001), had higher prostate-specific antigen levels at RP (11.1 vs 9.2 ng/mL; P < .001), lower pathologic Gleason scores (P = .004), and less extracapsular extension (38% vs 48%; P = .022). On multivariable analysis, there was no association between race and metastases (hazard radio, 1.20; P = .45) or any of the other secondary outcomes (all P > .5).Conclusions: Among veterans who received ADT post-BCR after RP, race was not a predictor of metastases or other adverse outcomes. The current findings suggest that research efforts to understand racial differences in prostate cancer biology should focus on early stages of the disease (ie, closer to the time of diagnosis). [ABSTRACT FROM AUTHOR]

The role of host epigenetic mechanisms in the natural history of low‐grade cervical intraepithelial neoplasia (CIN1) is not well characterized. We explored differential methylation of imprinted gene regulatory regions as predictors of the risk of CIN1 regression. A total of 164 patients with CIN1 were recruited from 10 Duke University clinics for the CIN Cohort Study. Participants had colposcopies at enrollment and up to five follow‐up visits over 3 years. DNA was extracted from exfoliated cervical cells for methylation quantitation at CpG (cytosine‐phosphate‐guanine) sites and human papillomavirus (HPV) genotyping. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression to quantify the effect of methylation on CIN1 regression over two consecutive visits, compared to non‐regression (persistent CIN1; progression to CIN2+; or CIN1 regression at a single time‐point), adjusting for age, race, high‐risk HPV (hrHPV), parity, oral contraceptive and smoking status. Median participant age was 26.6 years (range: 21.0–64.4 years), 39% were African‐American, and 11% were current smokers. Most participants were hrHPV‐positive at enrollment (80.5%). Over one‐third of cases regressed (n = 53, 35.1%). Median time‐to‐regression was 12.6 months (range: 4.5–24.0 months). Probability of CIN1 regression was negatively correlated with methylation at IGF2AS CpG 5 (HR = 0.41; 95% CI = 0.23–0.77) and PEG10 DMR (HR = 0.80; 95% CI = 0.65–0.98). Altered methylation of imprinted IGF2AS and PEG10 DMRs may play a role in the natural history of CIN1. If confirmed in larger studies, further research on imprinted gene DMR methylation is warranted to determine its efficacy as a biomarker for cervical cancer screening. [ABSTRACT FROM AUTHOR]

Objective: To assess whether obesity is associated with progression to metastasis, prostate cancer‐specific mortality (PCSM), and all‐cause mortality (ACM), in patients with non‐metastatic castration‐resistant prostate cancer (non‐mCRPC). At the population level, obesity is associated with prostate cancer mortality; however, some studies have found that higher body mass index (BMI) is associated with better long‐term prostate cancer outcomes amongst men with mCRPC. Patients and Methods: We identified 1 192 patients with non‐mCRPC from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. BMI was calculated from height and weight abstracted from the medical records at the time closest to but prior to CRPC diagnosis and categorised as underweight (<21 kg/m2), normal weight (21–24.9 kg/m2), overweight (25–29.9 kg/m2), and obese (≥30 kg/m2). Competing risks regression and Cox models were used to test associations between obesity and progression to metastasis, PCSM, and ACM, accounting for confounders. Results: Overall, 51 (4%) men were underweight, 239 (25%) were normal weight, 464 (39%) were overweight, and 438 (37%) were obese. In adjusted analysis, higher BMI was significantly associated with reduced ACM (hazard ratio [HR] 0.98, P = 0.012) but not PCSM (HR 1.00, P = 0.737) or metastases (HR 0.99, P = 0.225). Likewise, when BMI was treated as a categorical variable in adjusted models, obesity was not associated with PCSM (HR 1.11, P = 0.436) or metastases (HR 1.06, P = 0.647), but was associated with decreased ACM (HR 0.79, P = 0.016) compared to normal weight. No data were available on treatments received after CRPC diagnosis. Conclusions: Amongst patients with non‐mCRPC obesity was associated with better overall survival. Although this result mirrors evidence from men with mCRPC, obesity was not associated with prostate cancer outcomes. Larger studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer incidence rates vary 25-fold worldwide. Differences in PSA screening are largely, but not entirely, responsible. We examined geographic differences in prevalence of histologic prostate inflammation and subsequent prostate cancer risk. Methods: Seven thousand nonHispanic white men were enrolled in the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial from Europe (n = 4,644), North America (n = 1,746), South America (n = 466), and Australia/New Zealand (n = 144). Histologic inflammation in baseline negative prostate biopsies was classified as chronic (lymphocytes/macrophages) or acute (neutrophils). Multivariable logistic regression was used to examine associations between region and prostate inflammation, and between region and prostate cancer risk at 2-year biopsy. Results: Prevalence of prostate inflammation varied across region, with broadly similar patterns for acute and chronic inflammation. Relative to Europe, prevalence of acute inflammation was higher in North America [odds ratio (OR), 1.77; 95% confidence interval (CI), 1.51-2.08] and Australia/New Zealand (OR, 2.07; 95% CI, 1.40-3.06). Men from these regions had lower prostate cancer risk than Europeans at biopsy. Among North Americans, prevalence of acute inflammation was higher in Canada versus the United States (OR, 1.40; 95% CI, 1.07-1.83), but prostate cancer risk did not differ between these regions. Among Europeans, prevalence of acute inflammation was lower in Northern and Eastern (OR, 0.79; 95% CI, 0.65-0.97 and OR 0.62; 95% CI, 0.45-0.87, respectively), relative to Western Europe, and these men had higher prostate cancer risk at biopsy. Conclusions: Prevalence of histologic prostate inflammation varied by region. Geographic differences in prostate inflammation tracked inversely with geographic differences in prostate cancer risk. [ABSTRACT FROM AUTHOR]

Background: Black race is associated with prostate cancer (PC) diagnosis and poor outcome. Previously, the authors reported that black men undergoing radical prostatectomy (RP) in equal-access hospitals had an increased risk of biochemical disease recurrence (BCR), but recurrences were equally aggressive as those occurring in white men. The authors examined the association between race and long-term outcomes after RP.Methods: Data regarding 1665 black men (37%) and 2791 white men (63%) undergoing RP were analyzed. Using Cox models, the authors tested the association between race and BCR, BCR with a prostate-specific antigen (PSA) doubling time <9 months (aggressive disease recurrence), metastases, PC-specific death, and overall death.Results: At a median follow-up of 102 months, 1566 men (35%) developed BCR, 217 men (5%) experienced aggressive disease recurrence, 193 men (4%) developed metastases, and 1207 men (27%) had died, 107 of whom (2%) died of PC. White men were older and had a lower preoperative PSA level, a lower biopsy and pathological grade group, and more capsular penetration but less seminal vesicle invasion and positive surgical margins versus black men (all P<.05). Black men were found to have a more recent surgery year (P<.001). On univariable analysis, black race was associated with increased BCR (P = .003) and reduced overall death (P = .017). On multivariable analysis, black race was not found to be associated with BCR (hazard ratio [HR], 1.07; P = .26), aggressive recurrence (HR, 1.14; P = .42), metastasis (HR, 1.24; P = .21), PC-specific death (HR, 1.03; P = .91), or overall death (HR, 1.03; P = .67).Conclusions: Among men undergoing RP at equal-access centers, although black men were found to have an increased risk of BCR, they had similar risks of aggressive disease recurrence, metastasis, and PC-specific death compared with white men, and the risk of BCR was found to be similar after controlling for risk parameters. Longer follow-up is needed to confirm these findings. Cancer 2017;123:4199-4206. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Uridine 5'-diphosphate-glucuronosyltransferase 2B (UGT2B) genes code for enzymes that catalyze the clearance of testosterone, dihydrotestosterone (DHT), and DHT metabolites in the prostate basal and luminal tissue. The expression of the UGT2B15, UGT2B17, and UGT2B28 enzymes has not been evaluated in prostate tissue samples from hormone therapy-naïve patients.Methods: We determined the expression of UGT2B15, UGT2B17, and UGT2B28 enzymes in 190 prostate tissue samples from surgical specimens of a multiethnic cohort of patients undergoing radical prostatectomy at the Durham Veterans Affairs Medical Center. The association between each protein's percent positive and H-score, a weighted score of staining intensity, and the risk of biochemical recurrence (BCR) was tested using separate Cox proportional hazards models. In an exploratory analysis, UGT2B17 total positive and H-score were divided at the median and we tested the association between UGT2B17 group and risk of BCR.Results: The median follow-up for all patients was 118 months (IQR: 85-144). Of 190, 83 (44%) patients developed BCR. We found no association between UGT2B15 or UGT2B28 and risk of BCR. However, there was a trend for an association between UGT2B17 and BCR (HR = 1.01, 95% CI 1.00-1.02, p = 0.11), though not statistically significant. Upon further investigation, we found that patients with UGT2B17 higher levels of expression had a significant increased risk of BCR on univariable analysis (HR = 1.57, 95% CI 1.02-2.43, p = 0.041), although this association was attenuated in the multivariable model (HR = 1.50, 95% CI 0.94-2.40, p = 0.088).Conclusions: Our findings suggest that UGT2B17 overexpression may be associated with a significant increased risk of BCR. These results are consistent with previous reports which showed UGT2B17 significantly expressed in advanced prostate cancer including prostate tumor metastases. [ABSTRACT FROM AUTHOR]

Context In 2012, we published a detailed review on obesity and prostate cancer. Since then, new studies have brought further understanding regarding the role of obesity in selecting active surveillance candidates, and differing associations between obesity and prostate cancer as a function of race and molecular subtype of prostate cancer. Objective To review new manuscripts on these new concepts for which there were limited data before 2012. Evidence acquisition A PubMed search from July 2012 to March 2016 was performed using the terms “prostate cancer” and “obesity”. Of 450 articles, we included 15 related to these three topics. Evidence synthesis Among men on active surveillance or candidates for active surveillance, multiple studies suggest that the risk of upgrading is higher for obese men. No study has shown long-term oncologic differences, and the risk of prostate cancer mortality remains low. One study suggested that the link between obesity and prostate cancer risk is stronger among black men; however, other studies found that obesity is correlated with aggressive disease regardless of race. Two studies found that the associations between obesity and prostate cancer (ie, fewer low-grade cancers and yet more aggressive cancers) was limited to men with TMPRSS2-ERG -positive tumors. Conclusions The past 4 yr has seen much new work on the obesity-prostate cancer link. If confirmed in other studies, these findings provide novel insights into not only the link between obesity and prostate cancer but also prostate cancer biology in general. Patient summary While their outcomes may be slightly worse, obese men with localized prostate cancer should not be discouraged from active surveillance. Early studies suggest there may be subtypes of patients in whom obesity is more strongly linked to aggressive disease. [ABSTRACT FROM AUTHOR]

Sexual dysfunction and prostate cancer are common among older men. Few studies explored the association between these two illnesses. We examined whether sexual function is associated with prostate cancer risk among older men. Among 448 men undergoing prostate biopsy at the Durham Veterans Affairs Hospital, sexual function was ascertained from the Expanded Prostate Cancer Index Composite sexual assessment. We tested the link between sexual function and prostate cancer risk adjusting for multiple demographic and clinical characteristics using logistic regression. Multinomial logistic regression was used to test the associations with risk of low-grade (Gleason ≤6) and high-grade (Gleason ≥7 or ≥4 + 3) disease versus no cancer. Of 448 men, 209 (47%) had a positive biopsy; these men were less likely to be white (43% vs 55%, P = 0.013), had higher prostate-specific antigen (PSA) (6.0 vs 5.4 ng ml-1, P < 0.001), but with lower mean sexual function score (47 vs 54, P = 0.007). There was no difference in age, BMI, pack years smoked, history of heart disease and/or diabetes. After adjusting for baseline differences, sexual function was linked with a decreased risk of overall prostate cancer risk (OR: 0.91 per 10-point change in sexual function, P = 0.004) and high-grade disease whether defined as Gleason ≥7 (OR: 0.86, P = 0.001) or ≥4 + 3 (OR: 0.85, P = 0.009). Sexual function was unrelated to low-grade prostate cancer (OR: 0.94, P = 0.13). Thus, among men undergoing prostate biopsy, higher sexual function was associated with a decreased risk of overall and high-grade prostate cancer. Confirmatory studies are needed. [ABSTRACT FROM AUTHOR]

Purpose Despite routine use of phosphodiesterase type 5 inhibitor to treat erectile dysfunction the role in prostate cancer chemoprevention remains unclear. Only a few studies have explored the link between phosphodiesterase type 5 inhibitor use and prostate cancer. We tested the association between phosphodiesterase type 5 inhibitor and prostate cancer risk in the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial. Materials and Methods REDUCE was a 4-year multicenter study testing the effect of daily dutasteride on prostate cancer risk in men with prostate specific antigen 2.5 to 10.0 ng/ml and negative biopsy who underwent study mandated biopsies at 2 and 4 years. The association of phosphodiesterase type 5 inhibitor with overall prostate cancer risk and disease grade (Gleason 2-6 and 7-10) was examined using adjusted logistic and multinomial regression analysis. Secondary analysis was performed to explore the association between phosphodiesterase type 5 inhibitor and prostate cancer risk in North American men, given the significantly higher use of phosphodiesterase type 5 inhibitor in these subjects. Results Phosphodiesterase type 5 inhibitor was not associated with prostate cancer diagnosis (OR 0.90, 95% CI 0.68–1.20, p = 0.476), low grade disease (OR 0.93, 95% CI 0.67–1.27, p = 0.632) or high grade disease (OR 0.85, 95% CI 0.51–1.39, p = 0.508). An inverse trend was seen between phosphodiesterase type 5 inhibitor and prostate cancer diagnosis in North American men but this was not statistically significant (OR 0.67, 95% CI 0.42–1.07, p = 0.091). Conclusions Phosphodiesterase type 5 inhibitor use was not associated with decreased prostate cancer diagnoses on post-hoc analysis of REDUCE. In North American men, who had much higher baseline use of phosphodiesterase type 5 inhibitor, this treatment was associated with an inverse trend of prostate cancer diagnosis that approached but did not reach statistical significance. [ABSTRACT FROM AUTHOR]

Objective To determine whether there are subsets of men with pathological high grade prostate cancer (Gleason score 8-10) with particularly high or low 2-year biochemical recurrence ( BCR) risk after radical prostatectomy ( RP) when stratified into groups based on combinations of pathological features, such as surgical margin status, extracapsular extension ( ECE) and seminal vesicle invasion ( SVI). Materials and Methods We identified 459 men treated with RP with pathological Gleason score 8-10 prostate cancer in the SEARCH database. The men were stratified into five groups based on pathological characteristics: group 1, men with negative surgical margins ( NSMs) and no ECE; group 2, men with positive surgical margin ( PSMs) and no ECE; group 3, men with NSMs and ECE; group 4, men with PSMs and ECE; and group 5, men with SVI. Cox proportional hazards models and the log-rank test were used to compare BCR among the groups. Results At 2 years after RP, pathological group was significantly correlated with BCR (log-rank, P < 0.001) with patients in group 5 (+ SVI) having the highest BCR risk (66%) and those in group 1 ( NSMs and no ECE) having the lowest risk (14%). When we compared groups 2, 3, and 4, with each other, there was no significant difference in BCR among the groups (~50% 2-year BCR risk; log-rank P = 0.28). Results were similar when adjusting for prostate-specific antigen, age, pathological Gleason sum and clinical stage, or after excluding men who received adjuvant therapy. Conclusions In patients with high grade (Gleason score 8-10) prostate cancer after RP, the presence of either PSMs, ECE or SVI was associated with an increased risk of early BCR, with a 2-year BCR risk of ≥50%. Conversely, men with organ-confined margin-negative disease had a very low risk of early BCR despite Gleason score 8-10 disease. [ABSTRACT FROM AUTHOR]

BACKGROUND: Lead exposure during early development causes neurodevelopmental disorders by unknown mechanisms. Epidemiologic studies have focused recently on determining associations between lead exposure and global DNA methylation; however, such approaches preclude the identification of loci that may alter human disease risk. OBJECTIVES: The objective of this study was to determine whether maternal, postnatal, and early childhood lead exposure can alter the differentially methylated regions (DMRs) that control the monoallelic expression of imprinted genes involved in metabolism, growth, and development. METHODS: Questionnaire data and serial blood lead levels were obtained from 105 participants (64 females, 41 males) of the Cincinnati Lead Study from birth to 78 months. When participants were adults, we used Sequenom EpiTYPER assays to test peripheral blood DNA to quantify CpG methylation in peripheral blood leukocytes at DMRs of 22 human imprinted genes. Statistical analyses were conducted using linear regression. RESULTS: Mean blood lead concentration from birth to 78 months was associated with a significant decrease in PEG3 DMR methylation (β = -0.0014; 95% CI: -0.0023, -0.0005, p = 0.002), stronger in males (β = -0.0024; 95% CI: -0.0038, -0.0009, p = 0.003) than in females (β = -0.0009; 95% CI: -0.0020, 0.0003, p = 0.1). Elevated mean childhood blood lead concentration was also associated with a significant decrease in IGF2/H19 (β = -0.0013; 95% CI: -0.0023, -0.0003, p = 0.01) DMR methylation, but primarily in females, (β = -0.0017; 95% CI: -0.0029, -0.0006, p = 0.005) rather than in males, (β = -0.0004; 95% CI: -0.0023, 0.0015, p = 0.7). Elevated blood lead concentration during the neonatal period was associated with higher PLAGL1/HYMAI DMR methylation regardless of sex (β = 0.0075; 95% CI: 0.0018, 0.0132, p = 0.01). The magnitude of associations between cumulative lead exposure and CpG methylation remained unaltered from 30 to 78 months. CONCLUSIONS: Our findings provide evidence that early childhood lead exposure results in sex-dependent and gene-specific DNA methylation differences in the DMRs of PEG3, IGF2/H19, and PLAGL1/HYMAI in adulthood. [ABSTRACT FROM AUTHOR]

Background: Cadmium (Cd) is a ubiquitous and environmentally persistent toxic metal that has been implicated in neurotoxicity, carcinogenesis and obesity and essential metals including zinc (Zn) and iron (Fe) may alter these outcomes. However mechanisms underlying these relationships remain limited. Methods: We examined whether maternal Cd levels during early pregnancy were associated with offspring DNA methylation at regulatory sequences of genomically imprinted genes and weight at birth, and whether Fe and Zn altered these associations. Cd, Fe and Zn were measured in maternal blood of 319 women ≤12 weeks gestation. Offspring umbilical cord blood leukocyte DNA methylation at regulatory differentially methylated regions (DMRs) of 8 imprinted genes was measured using bisulfite pyrosequencing. Regression models were used to examine the relationships among Cd, Fe, Zn, and DMR methylation and birth weight. Results: Elevated maternal blood Cd levels were associated with lower birth weight (p = 0.03). Higher maternal blood Cd levels were also associated with lower offspring methylation at the PEG3 DMR in females (β = 0.55, se = 0.17, p = 0.05), and at the MEG3 DMR in males (β = 0.72, se = 0.3, p = 0.08), however the latter association was not statistically significant. Associations between Cd and PEG3 and PLAGL1 DNA methylation were stronger in infants born to women with low concentrations of Fe (p < 0.05). Conclusions: Our data suggest the association between pre-natal Cd and offspring DNA methylation at regulatory sequences of imprinted genes may be sex- and gene-specific. Essential metals such as Zn may mitigate DNA methylation response to Cd exposure. Larger studies are required. [ABSTRACT FROM AUTHOR]