Jay H. Fowke

Effects of obesity and height on prostate-specific antigen (PSA) and percentage of free PSA levels among African-American and Caucasian men

Prior studies suggest that obese men have lower prostate‐specific antigen (PSA) levels than leaner men. Caucasian (CA) men also may have lower PSA levels than African‐American (AA) men, but the relevance of body size to racial disparities in PSA levels is unclear. The association between body mass index (BMI) and height on PSA and percentage of free PSA (%fPSA) was investigated within AA and CA men without a prior prostate cancer diagnosis.

Urinary estrogen metabolites and breast cancer: differential pattern of risk found with pre- versus post-treatment collection.

INTRODUCTION The products of estrogen metabolism may affect breast carcinogenesis. The 16alpha-hydroxyestrone (16-OHE) metabolite has a higher affinity for the estrogen receptor (ER) than the 2-hydroxyestrone (2-OHE) metabolite, while conjugated 2-OHE metabolite may inhibit angiogenesis. We investigated the association between the relative concentrations of these metabolites in urine (2-OHE/16-OHE) and breast cancer in a case-control study of Chinese women living in Shanghai. METHODS Incident breast cancer cases between 25 and 65 years of age (n=110) were identified from hospital or population tumor registries in Shanghai, China. Controls (n=110) were randomly selected from a complete registry of the Shanghai population, and individually matched to cases by menopausal status, age, and pre-treatment or post-treatment urine collection time. Urine samples were collected prior to any breast cancer treatment or surgery among 78 case-control pairs, while urine was collected after surgery, and perhaps other treatments, among 32 case-control pairs. A commercial enzyme-immunoassay kit was used to measure urinary estrogen metabolite concentrations. Conditional logistic regression was used to calculate odds ratios summarizing the 2-OHE/16-OHE and breast cancer association within subjects providing either pre-treatment or post-treatment urine samples. RESULTS Subjects with a higher urinary 2-OHE/16-OHE ratio were less likely to be diagnosed with breast cancer, but only when urine samples were collected prior to breast cancer treatment (OR(Tertile3(T3)versusTertile1(T1))=0.5, 95% CI (0.2, 1.1)). In contrast, a higher 2-OHE/16-OHE ratio was significantly associated with breast cancer among subjects providing urine specimens after treatment initiation (OR(T3versusT1)=8.7, 95% CI (1.6, 47.1)). This observed cross-over modification occurred within both pre-menopausal and post-menopausal women, and independent of body mass index or recent dietary intake. CONCLUSION Cross-study differences in urine collection protocols may explain observed inconsistencies in the 2-OHE/16-OHE and breast cancer association. Our case-control analysis using pre-treatment urine samples suggested that a lower 2-OHE/16-OHE ratio was associated with an increased risk of pre-menopausal and post-menopausal breast cancer diagnosis among Chinese women.

Validation of a Previous-Day Recall Measure of Active and Sedentary Behaviors

PURPOSE A previous-day recall (PDR) may be a less error-prone alternative to traditional questionnaire-based estimates of physical activity and sedentary behavior (e.g., past year), but the validity of the method is not established. We evaluated the validity of an interviewer administered PDR in adolescents (12-17 yr) and adults (18-71 yr). METHODS In a 7-d study, participants completed three PDR, wore two activity monitors, and completed measures of social desirability and body mass index. PDR measures of active and sedentary time was contrasted against an accelerometer (ActiGraph) by comparing both to a valid reference measure (activPAL) using measurement error modeling and traditional validation approaches. RESULTS Age- and sex-specific mixed models comparing PDR to activPAL indicated the following: 1) there was a strong linear relationship between measures for sedentary (regression slope, β1 = 0.80-1.13) and active time (β1 = 0.64-1.09), 2) person-specific bias was lower than random error, and 3) correlations were high (sedentary: r = 0.60-0.81; active: r = 0.52-0.80). Reporting errors were not associated with body mass index or social desirability. Models comparing ActiGraph to activPAL indicated the following: 1) there was a weaker linear relationship between measures for sedentary (β1 = 0.63-0.73) and active time (β1 = 0.61-0.72), (2) person-specific bias was slightly larger than random error, and (3) correlations were high (sedentary: r = 0.68-0.77; active: r = 0.57-0.79). CONCLUSIONS Correlations between the PDR and the activPAL were high, systematic reporting errors were low, and the validity of the PDR was comparable with the ActiGraph. PDR may have value in studies of physical activity and health, particularly those interested in measuring the specific type, location, and purpose of activity-related behaviors.

Oxidative stress measured by urine F2-isoprostane level is associated with prostate cancer

PURPOSE Oxidative stress is implicated in prostate cancer by several lines of evidence. We studied the relationship between the level of F2-isoprostanes, a validated biomarker of oxidative stress, and prostate cancer and high grade prostatic intraepithelial neoplasia. MATERIALS AND METHODS This case-control analysis within the Nashville Mens Health Study included men recruited at prostate biopsy. Body morphometrics, health history and urine were collected from more than 2,000 men before biopsy. F2-isoprostanes were measured by gas chromatography/mass spectrometry within an age matched sample of Nashville Mens Health Study participants that included 140 patients with high grade prostatic intraepithelial neoplasia, 160 biopsy negative controls and 200 prostate cancer cases. Multivariable linear and logistic regression was used to determine the associations between F2-isoprostane level, and high grade prostatic intraepithelial neoplasia and prostate cancer. RESULTS Mean patient age was 66.9 years (SD 7.2) and 10.1% were nonwhite. Adjusted geometric mean F2-isoprostane levels were higher in patients with prostate cancer (1.82, 95% CI 1.66-2.00) or high grade prostatic intraepithelial neoplasia (1.82, 95% CI 1.68-1.96) than in controls (1.63, 95% CI 1.49-1.78, p <0.001), but were similar across Gleason scores (p = 0.511). The adjusted odds of high grade prostatic intraepithelial neoplasia and prostate cancer increased with increasing F2-isoprostane quartile (p-trend = 0.015 and 0.047, respectively) and the highest F2-isoprostane quartile was associated with significantly increased odds of prostate cancer (OR 2.44, 95% CI 1.17-5.09, p = 0.017). CONCLUSIONS Pre-diagnosis urine F2-isoprostane level is increased in men with high grade prostatic intraepithelial neoplasia or prostate cancer, suggesting urinary F2-isoprostane provides a biomarker for the role for oxidative stress in prostate carcinogenesis. F2-isoprostanes may also serve to estimate the efficacy of interventions targeting oxidative stress mechanisms in prostate cancer prevention or treatment.

Physical Activity, Body Size, and Estrogen Metabolism in Women

AbstractObjectives: Physical activity has demonstrable effects on estrogen levels in pre- and postmenopausal women. Increased oxidation of estrone to 2-hydroxyestrone (2HE) relative to 16α-hydroxyestrone (16HE) has been hypothesized to reduce breast cancer risk, but little is known about the effect of physical activity and body size in relation to the ratio of 2HE and 16HE in women. We examined these relationships in cross-sectional analyses of 157 North American and Chinese women. Methods: Physical activity was assessed using validated questionnaires. Adiposity was assessed as body mass index (BMI, kg/m2) and by anthropometric methods (% body fat). Estrone metabolites, 2HE and 16HE, were determined from urine via ELISA. Results: Regression analyses on the 2HE/16HE ratio revealed an interaction between leisure-time physical activities and adiposity in both North American and Chinese women (p≤ 0.05). Women reporting low levels of leisure-time physical activity who had higher BMI levels had 2HE/16HE ratios that were lower than their lean counterparts. In contrast, women with higher BMI levels that were physically active maintained higher 2HE/16HE ratios. Conclusion: These findings suggest that physical activity participation has the potential to modify the adverse effect of increased adiposity on estrogen metabolism in North American and Chinese women.

Obesity, body composition, and prostate cancer

BackgroundEstablished risk factors for prostate cancer have not translated to effective prevention or adjuvant care strategies. Several epidemiologic studies suggest greater body adiposity may be a modifiable risk factor for high-grade (Gleason 7, Gleason 8-10) prostate cancer and prostate cancer mortality. However, BMI only approximates body adiposity, and may be confounded by centralized fat deposition or lean body mass in older men. Our objective was to use bioelectric impedance analysis (BIA) to measure body composition and determine the association between prostate cancer and total body fat mass (FM) fat-free mass (FFM), and percent body fat (%BF), and which body composition measure mediated the association between BMI or waist circumference (WC) with prostate cancer.MethodsThe study used a multi-centered recruitment protocol targeting men scheduled for prostate biopsy. Men without prostate cancer at biopsy served as controls (n = 1057). Prostate cancer cases were classified as having Gleason 6 (n = 402), Gleason 7 (n = 272), or Gleason 8-10 (n = 135) cancer. BIA and body size measures were ascertained by trained staff prior to diagnosis, and clinical and comorbidity status were determined by chart review. Analyses utilized multivariable linear and logistic regression.ResultsBody size and composition measures were not significantly associated with low-grade (Gleason 6) prostate cancer. In contrast, BMI, WC, FM, and FFM were associated with an increased risk of Gleason 7 and Gleason 8-10 prostate cancer. Furthermore, BMI and WC were no longer associated with Gleason 8-10 (ORBMI = 1.039 (1.000, 1.081), ORWC = 1.016 (0.999, 1.033), continuous scales) with control for total body FFM (ORBMI = 0.998 (0.946, 1.052), ORWC = 0.995 (0.974, 1.017)). Furthermore, increasing FFM remained significantly associated with Gleason 7 (ORFFM = 1.030 (1.008, 1.052)) and Gleason 8-10 (ORFFM = 1.044 (1.014, 1.074)) after controlling for FM.ConclusionsOur results suggest that associations between BMI and WC with high-grade prostate cancer are mediated through the measurement of total body FFM. It is unlikely that FFM causes prostate cancer, but instead provides a marker of testosterone or IGF1 activities involved with retaining lean mass as men age.

Obesity, Physical Activity and Lower Urinary Tract Symptoms: Results From the Southern Community Cohort Study

PURPOSE Obesity and physical activity have been posited as modifiable risk factors to delay lower urinary tract symptom progression. In this study we determined the independent associations of physical activity and obesity with lower urinary tract symptoms at followup among white and African-American men. MATERIALS AND METHODS Male participants 40 to 79 years old were identified from the Southern Community Cohort Study, a prospective cohort based in the southeastern United States. Baseline data collection included a validated physical activity questionnaire, height and weight, health history and other information. We excluded participants with a history of or medication use for benign prostatic hyperplasia or prostate cancer. Participants (7,318, 60% African-American) completed the International Prostate Symptom Score approximately 5 years after baseline. Patients with an International Prostate Symptom Score greater than 8 or 20 were classified as having moderate or severe lower urinary tract symptoms, respectively, at followup. Multivariable logistic regression was used to assess the relationships among obesity, physical activity and lower urinary tract symptoms. RESULTS Moderate to severe lower urinary tract symptom severity at followup was significantly associated with a body mass index of 35 kg/m(2) or more (OR 1.38, 95% CI 1.17-1.63). Similarly the lowest categories of physical activity were associated with the onset of severe lower urinary tract symptoms in men with a normal body mass index (OR 1.38, 95% CI 1.05-1.82). These associations were independent of race. CONCLUSIONS Severe obesity is associated with an increased risk of lower urinary tract symptoms at followup, while physical inactivity may permit progression of lower urinary tract symptoms in normal weight men regardless of race. These variables should be considered in future research into modifiable risk factors for lower urinary tract symptoms.

Physical Activity, Sedentary Behavior, and Cause-Specific Mortality in Black and White Adults in the Southern Community Cohort Study

There is limited evidence demonstrating the benefits of physical activity with regard to mortality risk or the harms associated with sedentary behavior in black adults, so we examined the relationships between these health behaviors and cause-specific mortality in a prospective study that had a large proportion of black adults. Participants (40-79 years of age) enrolled in the Southern Community Cohort Study between 2002 and 2009 (n = 63,308) were prospectively followed over 6.4 years, and 3,613 and 1,394 deaths occurred in blacks and whites, respectively. Black adults who reported the highest overall physical activity level (≥32.3 metabolic equivalent-hours/day vs. <9.7 metabolic equivalent-hours/day) had lower risks of death from all causes (hazard ratio (HR) = 0.76. 95% confidence interval (CI): 0.69, 0.85), cardiovascular disease (HR = 0.81, 95% CI: 0.67, 0.98), and cancer (HR = 0.76, 95% CI: 0.62, 0.94). In whites, a higher physical activity level was associated with a lower risk of death from all causes (HR = 0.76, 95% CI: 0.64, 0.90) and cardiovascular disease (HR = 0.69, 95% CI: 0.49, 0.99) but not cancer (HR = 0.95, 95% CI: 0.67, 1.34). Spending more time being sedentary (>12 hours/day vs. <5.76 hours/day) was associated with a 20%-25% increased risk of all-cause mortality in blacks and whites. Blacks who reported the most time spent being sedentary (≥10.5 hours/day) and lowest level of physical activity (<12.6 metabolic equivalent-hours/day) had a greater risk of death (HR = 1.47, 95% CI: 1.25, 1.71). Our study provides evidence that suggests that health promotion efforts to increase physical activity level and decrease sedentary time could help reduce mortality risk in black adults.

Racial differences in the association between body mass index and serum IGF1, IGF2, and IGFBP3

African-American (AA) race/ethnicity, lower body mass index (BMI), and higher IGF1 levels are associated with premenopausal breast cancer risk. This cross-sectional analysis investigated whether BMI or BMI at age 21 years contributes to racial differences in IGF1, IGF2, IGF-binding protein 3 (IGFBP3), or free IGF1. Participants included 816 white and 821 AA women between ages 40 and 79 years across a wide BMI range (18.5-40 kg/m(2)). Compared with white women, AA women had higher mean IGF1 (146.3 vs 134.4 ng/ml) and free IGF1 (0.145 vs 0.127) levels, and lower IGF2 (1633.0 vs 1769.3 ng/ml) and IGFBP3 (3663.3 vs 3842.5 ng/ml) levels (all P<0.01; adjusted for age, height, BMI, BMI at age 21 years, and menopausal status). Regardless of race, IGF1 and free IGF1 levels rose sharply as BMI increased to 22-24 kg/m(2), and then declined thereafter, while IGF2 and IGFBP3 levels tended to rise with BMI. In contrast, BMI at age 21 years was inversely associated with all IGF levels, but only among white women (P-interaction=0.01). With the decline in IGF1 with BMI at age 21 years among whites, racial differences in IGF1 significantly increased among women who were obese in early adulthood. In summary, BMI was associated with IGF1 levels regardless of race/ethnicity, while obesity during childhood or young adulthood may have a greater impact on IGF1 levels among white women. The effects of obesity throughout life on the IGF axis and racial differences in breast cancer risk require study.

Smaller Prostate Size Predicts High Grade Prostate Cancer at Final Pathology

PURPOSE Prostate size may influence the likelihood of detecting high grade prostate cancer at final pathology. We evaluated the association between prostate size and high grade (Gleason score 7 or greater) cancer. MATERIALS AND METHODS We analyzed data from 2,880 patients who underwent surgical treatment of prostate cancer between January 2000 and June 2008. Prostate size measured at prostatectomy was compared across a strata of clinical variables (age, body mass index, prostate specific antigen, biopsy Gleason score, clinical stage and year of surgery) and pathological outcomes (final Gleason score, extraprostatic extension, positive surgical margin, seminal vesicle invasion and lymph node involvement). Multivariate logistic regression was used to assess prostate size as a predictor of high grade cancer. RESULTS Older age, higher prostate specific antigen and later year of surgery were associated with larger gland size. Small prostate size was associated with high grade prostate cancer as well as extraprostatic extension and positive surgical margins on univariate and adjusted analysis. The probability of high grade disease decreased approximately 15% across the lowest vs highest prostate sizes. On multivariate analysis adjusted for age, race, prostate specific antigen, clinical stage, biopsy Gleason score and date of surgery prostate size was an important predictor of high grade disease (OR 0.94; 95% CI 0.92, 0.97 per 2 gm increments, p <0.001). The area under the ROC curve was 0.82 (95% CI 0.81, 0.84). CONCLUSIONS Prostate size was inversely associated with the risk of high grade cancer at final pathology. The ability to predict high grade disease could have implications for the management of prostate cancer.