June M. Chan

Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men.

OBJECTIVE To investigate the relation between obesity, fat distribution, and weight gain through adulthood and the risk of non-insulin-dependent diabetes melli-tus (NIDDM). RESEARCH DESIGN AND METHODS We analyzed data from a cohort of 51,529 U.S. male health professionals, 40-75 years of age in 1986, who completed biennial questionnaires sent out in 1986, 1988, 1990, and 1992. During 5 years of follow-up (1987-1992), 272 cases of NIDDM were diagnosed among men without a history of diabetes, heart disease, and cancer in 1986 and who provided complete health information. Relative risks (RRs) associated with different anthropometrie measures were calculated controlling for age, and multivariate RRs were calculated controlling for smoking, family history of diabetes, and age. RESULTS We found a strong positive association between overall obesity as measured by body mass index (BMI) and risk of diabetes. Men with a BMI of ≥35 kg/m2 had a multivariate RR of 42.1 (95% confidence interval [CI] 22.0-80.6) compared with men with a BMI <23.0 kg/m2. BMI at age 21 and absolute weight gain throughout adulthood were also significant independent risk factors for diabetes. Fat distribution, measured by waist-to-hip ratio (WHR), was a good predictor of diabetes only among the top 5%, while waist circumference was positively associated with the risk of diabetes among the top 20% of the cohort. CONCLUSIONS These data suggest that waist circumference may be a better indicator than WHR of the relationship between abdominal adiposity and risk of diabetes. Although early obesity, absolute weight gain throughout adulthood, and waist circumference were good predictors of diabetes, attained BMI was the dominant risk factor for NIDDM; even men of average relative weight had significantly elevated RRs.

Role of diet in prostate cancer development and progression

Increasing evidence supports the important role of nutrition in cancer prevention, including prevention of prostate cancer. In this review, we summarize data for some of the most consistently observed dietary associations for prostate cancer incidence, briefly consider possible postdiagnostic effects of nutrition on prostate cancer progression/survival, discuss new but limited data on diet-gene interactions, and comment on current areas of controversy for future research focus. Potential protective dietary elements include tomatoes/lycopene, other carotenoids, cruciferous vegetables, vitamin E, selenium, fish/marine omega-3 fatty acids, soy, isoflavones and polyphenols; whereas milk, dairy, calcium, zinc at high doses, saturated fat, grilled meats, and heterocyclic amines may increase risk. It is important to note that randomized clinical trial data exist only for vitamin E, calcium, beta-carotene, and selenium (all of which suggest inverse or no association). Several genes, such as MnSOD, XRCC1, and GST, may modify the association of specific nutrients and foods with prostate cancer risk; and further research is warranted to confirm these initial observed relationships. Until further clinical trial data are available on specific supplements and prostate cancer prevention, it would be prudent to emphasize a diet consisting of a wide variety of plant-based foods and fish; this is similar to what is recommended (and what is more well established) for the primary prevention of heart disease.

Physical Activity and Survival After Prostate Cancer Diagnosis in the Health Professionals Follow-Up Study

PURPOSE To determine whether higher physical activity after prostate cancer (PCa) diagnosis decreases risk of overall and PCa-specific death. PATIENTS AND METHODS We evaluated physical activity in relation to overall and PCa mortality among 2,705 men in the Health Professionals Follow-Up Study diagnosed with nonmetastatic PCa observed from 1990 to 2008. Proportional hazards models were used to evaluate physical activity and time to overall and PCa-specific death. RESULTS Among men who lived at least 4 years after their postdiagnosis physical activity assessment, we documented 548 deaths, 20% of which were a result of PCa. In multivariable analysis, men who were physically active had lower risk of all-cause mortality (P(trend) < .001) and PCa mortality (P(trend) = .04). Both nonvigorous activity and vigorous activity were associated with significantly lower overall mortality. Those who walked ≥ 90 minutes per week at a normal to very brisk pace had a 46% lower risk of all-cause mortality (hazard ratio [HR] 0.54; 95% CI, 0.41 to 0.71) compared with shorter durations at an easy walking pace. Men with ≥ 3 hours per week of vigorous activity had a 49% lower risk of all-cause mortality (HR, 0.51; 95% CI, 0.36 to 0.72). For PCa-specific mortality, brisk walking at longer durations was suggestively inverse but not statistically significant. Men with ≥ 3 hours per week of vigorous activity had a 61% lower risk of PCa death (HR, 0.39, 95% CI, 0.18 to 0.84; P = .03) compared with men with less than 1 hour per week of vigorous activity. Men exercising vigorously before and after diagnosis had the lowest risk. CONCLUSION In men with PCa, physical activity was associated with lower overall mortality and PCa mortality. A modest amount of vigorous activity such as biking, tennis, jogging, or swimming for ≥ 3 hours a week may substantially improve PCa-specific survival.

Insulin-like Growth Factors, Their Binding Proteins, and Prostate Cancer Risk: Analysis of Individual Patient Data from 12 Prospective Studies

Context Insulin-like growth factors (IGFs) and IGF binding proteins may be associated with some cancers. Contribution This reanalysis of individual patient data from 12 studies of the association between IGFs and IGF binding proteins and prostate cancer suggests that higher levels of serum IGF-I are associated with higher risk for prostate cancer. Caution The 12 studies varied in the types of patients they studied and in how they measured IGFs. Implication High IGF-I levels seem to be a risk factor for prostate cancer. The Editors Prostate cancer is one of the most common types of cancer in men, yet few risk factors for the disease, other than age, race, and a family history, have been established (1, 2). Insulin-like growth factors (IGFs) and their associated binding proteins (IGFBPs) have been the subject of many epidemiologic investigations of prostate cancer because they are known to help regulate cell proliferation, differentiation, and apoptosis (3). Although results from some, but not all, studies suggest an association between IGFs and IGFBPs and prostate cancer risk, there has been much uncertainty about its consistency and magnitude. A previous meta-analysis that included only 3 prospective studies suggested that high levels could be associated with more than a 2-fold increase in risk (4), although recent studies have suggested the risk is lower. Furthermore, given that these peptides are correlated with each other, uncertainty remains about any observed relationships. The individual studies are rarely large enough to allow proper mutual adjustment for these correlated factors, and they are insufficiently powered to investigate the consistency of their findings in key subgroups (for example, stage and grade of disease). Such analyses are important because studies have suggested that IGF-I might be more associated with advanced than with localized disease (5, 6). The Endogenous Hormones and Prostate Cancer Collaborative Group was established to conduct collaborative reanalyses of individual data from prospective studies on the relationships between circulating levels of sex hormones and IGFs and subsequent prostate cancer risk. Results for the sex hormones have been reported elsewhere and show no statistically significant relation between androgen or estrogen levels in men and the subsequent risk for prostate cancer (7). We report results for concentrations of IGFs and IGFBPs. Methods Participants The Endogenous Hormones and Prostate Cancer Collaborative Group is described in detail elsewhere (7). In brief, the group invited principal investigators of all studies, found by searching PubMed, Web of Science, and CancerLit, that provided data on circulating concentrations of sex steroids, IGFs or IGFBPs, and prostate cancer risk by using prospectively collected blood samples to join the collaboration. Thirteen studies collected data on circulating IGF concentrations and the subsequent risk for prostate cancer (5, 6, 820), of which 1 contributed only data on sex hormones (20). Eleven of the studies used a matched casecontrol design nested within a prospective cohort study (5, 6, 812, 16, 19) or a randomized trial (1315, 17). One study used a casecohort design (18) and was converted into a matched casecontrol design by randomly matching up to 3 control participants to each case patient by age at recruitment, time between blood collection and diagnosis, time of blood draw, and race. (Table 1 provides a full description of the studies and matching criteria used.) Most of the prospective studies were population-based, with the exception of 1 based on health plan members (9), 1 that recruited male health professionals (16), and 1 that was a combination of an intervention study and a monitoring study for cardiovascular disease (6, 10). Two of the randomized trials did not have prostate cancer as a primary end point (5, 8, 15); the other 2 were based within a screening trial (13) or were about treatment of prostate-specific antigen (PSA)detected prostate cancer (14). Table 1. Study Characteristics Individual participant data were available for age; height; weight; smoking status; alcohol consumption; marital status; socioeconomic status (assessed by educational achievement); race; concentrations of IGFs, IGFBPs, and endogenous sex steroids; and PSA level. Information sought about prostate cancer included date of diagnosis, stage and grade of disease, and method of case patient ascertainment. Some studies (5, 6, 8, 10, 16) published more than 1 article or performed assays at different times on the association between IGFs and prostate cancer risk, sometimes with different matched casecontrol sets, laboratory measurements, and durations of follow-up. For each study, we created a single data set in which each participant appeared only once. In our analysis, we treated any participant who appeared in a study as both a control participant and a case patient as a case patient only. We removed matched set identifiers, and we generated a series of strata (equivalent to matched sets) in which participants in each study were grouped according to age at recruitment (2-year age bands) and date of recruitment (by year), because these matching criteria were common to most studies (Table 1). The number of strata used in the collaborative analysis was slightly less than that of matched sets used in the original analyses. To ensure that this process did not introduce any bias, we checked that the results for each study, using the original matched sets, were the same as those using the strata described above. Tumors were classified as advanced if the tumor was described as extending beyond the prostate capsule (T3/T4), and/or there was lymph node involvement (N1/N2/N3), and/or there were distant metastases (M1); tumors were classified as localized if they were T0/T1/T2 and N0/NX and M0. We classified tumors as high-grade if they had a Gleason score of 7 or more or were moderately poorly or poorly differentiated; otherwise, they were classified as low-grade. Statistical Analysis We calculated partial correlation coefficients between log-transformed IGF and IGFBP concentrations among control participants, adjusted for age at blood collection (<50, 50 to 59, 60 to 69, or 70 years) and study. For each IGF and IGFBP, we categorized men into quintiles of IGF and IGFBP serum concentrations, with cut-points defined by the study-specific quintiles of the distribution within control participants. For studies with more than 1 publication or in which the serum assays were done at different times, resulting in different absolute levels of IGFs (5, 6, 8, 10, 16), we calculated cut-points separately for each substudy. We used a conditional logistic regression stratified by study, age at recruitment (2-year age bands), and date of recruitment (single year) as our main method of analysis. To provide a summary measure of risk, we calculated a linear trend by scoring the quintiles of the serum IGF or IGFBP concentrations as 0, 0.25, 0.5, 0.75, and 1. Under the assumption of linearity, a unit change in this trend variable is equivalent to the odds ratio (OR) comparing the highest with the lowest quintile. All results are unadjusted for participant characteristics, except for those controlled by the stratification variables. We examined the possible influence of 5 participant characteristics by adjusting the relevant conditional logistic regression models for body mass index (BMI) (<22.5, 22.5 to 24.9, 25.0 to 27.4, 27.5 to 29.9, or >30 kg/m2), marital status (married or cohabiting, or not married or cohabiting), educational status (did not attend college or university, or attended college or university), smoking (never, previous, or current), and alcohol consumption (<10 or 10 g/d). We excluded participants from the analysis if they had a missing value for the characteristic under examination. We assessed heterogeneity in linear trends among studies by using a chi-square statistic to test whether the study-specific ORs were statistically different from the overall OR (21). Heterogeneity among studies was also quantified by calculating the H and I 2 statistics (22). To test whether the linear trend OR estimates for each IGF and IGFBP varied according to case patient characteristics, we estimated a series of subsets for each characteristic: stage at diagnosis (localized or advanced), grade at diagnosis (low or high), year of diagnosis (before 1990, 1990 to 1994, or 1995 onward; these year cutoffs were chosen to attempt to reflect differences in the use of the PSA test for cancer detection), age at diagnosis (<60, 60 to 69, or 70 years), and time between blood collection and diagnosis (<3, 3 to 6, or 7 years). We excluded case patients from the analyses of stage and grade at diagnosis if the relevant information was not available. For each of these case patient characteristics, we calculated a heterogeneity chi-square statistic to assess whether the estimated ORs statistically differed from each other (21). To assess whether the OR estimate of the linear trend for each IGF or IGFBP varied according to PSA level at recruitment (<2 g/L or 2 g/L), we entered an interaction term into the conditional logistic regression model for each IGF or IGFBP, and we tested the statistical significance of the interaction term with a likelihood ratio test. Statistical significance was set at the 5% level. All statistical tests were 2-sided. All statistical analyses were done with Stata, version 9.0 (StataCorp, College Station, Texas). Results Table 1 shows the characteristics of the studies. The 12 prospective studies included approximately 3700 case patients with prostate cancer and 5200 control participants. Insulin-like growth factor I and IGFBP-III measurements were available for all and 3600 case patients, respectively. However, IGF-II and IGFBP-II measurements were available for only 379 and 419 case patients, respectively (Table 2). Mean age at blood collection

A 17-gene Assay to Predict Prostate Cancer Aggressiveness in the Context of Gleason Grade Heterogeneity, Tumor Multifocality, and Biopsy Undersampling

BACKGROUND Prostate tumor heterogeneity and biopsy undersampling pose challenges to accurate, individualized risk assessment for men with localized disease. OBJECTIVE To identify and validate a biopsy-based gene expression signature that predicts clinical recurrence, prostate cancer (PCa) death, and adverse pathology. DESIGN, SETTING, AND PARTICIPANTS Gene expression was quantified by reverse transcription-polymerase chain reaction for three studies-a discovery prostatectomy study (n=441), a biopsy study (n=167), and a prospectively designed, independent clinical validation study (n=395)-testing retrospectively collected needle biopsies from contemporary (1997-2011) patients with low to intermediate clinical risk who were candidates for active surveillance (AS). OUTCOME MEASURES AND STATISTICAL ANALYSIS The main outcome measures defining aggressive PCa were clinical recurrence, PCa death, and adverse pathology at prostatectomy. Cox proportional hazards regression models were used to evaluate the association between gene expression and time to event end points. Results from the prostatectomy and biopsy studies were used to develop and lock a multigene-expression-based signature, called the Genomic Prostate Score (GPS); in the validation study, logistic regression was used to test the association between the GPS and pathologic stage and grade at prostatectomy. Decision-curve analysis and risk profiles were used together with clinical and pathologic characteristics to evaluate clinical utility. RESULTS AND LIMITATIONS Of the 732 candidate genes analyzed, 288 (39%) were found to predict clinical recurrence despite heterogeneity and multifocality, and 198 (27%) were predictive of aggressive disease after adjustment for prostate-specific antigen, Gleason score, and clinical stage. Further analysis identified 17 genes representing multiple biological pathways that were combined into the GPS algorithm. In the validation study, GPS predicted high-grade (odds ratio [OR] per 20 GPS units: 2.3; 95% confidence interval [CI], 1.5-3.7; p<0.001) and high-stage (OR per 20 GPS units: 1.9; 95% CI, 1.3-3.0; p=0.003) at surgical pathology. GPS predicted high-grade and/or high-stage disease after controlling for established clinical factors (p<0.005) such as an OR of 2.1 (95% CI, 1.4-3.2) when adjusting for Cancer of the Prostate Risk Assessment score. A limitation of the validation study was the inclusion of men with low-volume intermediate-risk PCa (Gleason score 3+4), for whom some providers would not consider AS. CONCLUSIONS Genes representing multiple biological pathways discriminate PCa aggressiveness in biopsy tissue despite tumor heterogeneity, multifocality, and limited sampling at time of biopsy. The biopsy-based 17-gene GPS improves prediction of the presence or absence of adverse pathology and may help men with PCa make more informed decisions between AS and immediate treatment. PATIENT SUMMARY Prostate cancer (PCa) is often present in multiple locations within the prostate and has variable characteristics. We identified genes with expression associated with aggressive PCa to develop a biopsy-based, multigene signature, the Genomic Prostate Score (GPS). GPS was validated for its ability to predict men who have high-grade or high-stage PCa at diagnosis and may help men diagnosed with PCa decide between active surveillance and immediate definitive treatment.

Active surveillance for early-stage prostate cancer: Review of the current literature

The natural history of prostate cancer is remarkably heterogeneous and, at this time, not completely understood. The widespread adoption and application of prostate‐specific antigen (PSA) screening has led to a dramatic shift toward the diagnosis of low‐volume, nonpalpable, early‐stage tumors. Autopsy and early observational studies have shown that approximately 1 in 3 men aged >50 years has histologic evidence of prostate cancer, with a significant portion of tumors being small and possibly clinically insignificant. Utilizing the power of improved contemporary risk stratification schema to better identify patients with a low risk of cancer progression, several centers are gaining considerable experience with active surveillance and delayed, selective, and curative therapy. A literature review was performed to evaluate the rationale behind active surveillance for prostate cancer and to describe the early experiences from surveillance protocols. It appears that a limited number of men on active surveillance have required treatment, with the majority of such men having good outcomes after delayed selective intervention for progressive disease. The best candidates for active surveillance are being defined, as are predictors of active treatment. The psychosocial ramifications of surveillance for prostate cancer can be profound and future needs and unmet goals will be discussed. Cancer 2008.

Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study

BACKGROUND Telomere shortness in human beings is a prognostic marker of ageing, disease, and premature morbidity. We previously found an association between 3 months of comprehensive lifestyle changes and increased telomerase activity in human immune-system cells. We followed up participants to investigate long-term effects. METHODS This follow-up study compared ten men and 25 external controls who had biopsy-proven low-risk prostate cancer and had chosen to undergo active surveillance. Eligible participants were enrolled between 2003 and 2007 from previous studies and selected according to the same criteria. Men in the intervention group followed a programme of comprehensive lifestyle changes (diet, activity, stress management, and social support), and the men in the control group underwent active surveillance alone. We took blood samples at 5 years and compared relative telomere length and telomerase enzymatic activity per viable cell with those at baseline, and assessed their relation to the degree of lifestyle changes. FINDINGS Relative telomere length increased from baseline by a median of 0·06 telomere to single-copy gene ratio (T/S)units (IQR-0·05 to 0·11) in the lifestyle intervention group, but decreased in the control group (-0·03 T/S units, -0·05 to 0·03, difference p=0·03). When data from the two groups were combined, adherence to lifestyle changes was significantly associated with relative telomere length after adjustment for age and the length of follow-up (for each percentage point increase in lifestyle adherence score, T/S units increased by 0·07, 95% CI 0·02-0·12, p=0·005). At 5 years, telomerase activity had decreased from baseline by 0·25 (-2·25 to 2·23) units in the lifestyle intervention group, and by 1·08 (-3·25 to 1·86) units in the control group (p=0·64), and was not associated with adherence to lifestyle changes (relative risk 0·93, 95% CI 0·72-1·20, p=0·57). INTERPRETATION Our comprehensive lifestyle intervention was associated with increases in relative telomere length after 5 years of follow-up, compared with controls, in this small pilot study. Larger randomised controlled trials are warranted to confirm this finding. FUNDING US Department of Defense, NIH/NCI, Furlotti Family Foundation, Bahna Foundation, DeJoria Foundation, Walton Family Foundation, Resnick Foundation, Greenbaum Foundation, Natwin Foundation, Safeway Foundation, Prostate Cancer Foundation.

Smoking and Prostate Cancer Survival and Recurrence

CONTEXT Studies of smoking in relation to prostate cancer mortality or recurrence in prostate cancer patients are limited, with few prostate cancer-specific outcomes. OBJECTIVE To assess the relation of cigarette smoking and smoking cessation with overall, prostate cancer-specific, and cardiovascular disease (CVD) mortality and biochemical recurrence among men with prostate cancer. DESIGN, SETTING, AND PARTICIPANTS Prospective observational study of 5366 men diagnosed with prostate cancer between 1986 and 2006 in the Health Professionals Follow-Up Study. MAIN OUTCOME MEASURES Hazard ratios (HRs) for overall, prostate cancer-specific, and CVD mortality, and biochemical recurrence, defined by an increase in prostate-specific antigen (PSA) levels. RESULTS There were 1630 deaths, 524 (32%) due to prostate cancer and 416 (26%) to CVD, and 878 biochemical recurrences. Absolute crude rates for prostate cancer-specific death for never vs current smokers were 9.6 vs 15.3 per 1000 person-years; for all-cause mortality, the corresponding rates were 27.3 and 53.0 per 1000 person-years. In multivariable analysis, current vs never smokers had an increased risk of prostate cancer mortality (HR, 1.61; 95% confidence interval [CI], 1.11-2.32), as did current smokers with clinical stage T1 through T3 (HR, 1.80; 95% CI, 1.04-3.12). Current smokers also had increased risk of biochemical recurrence (HR, 1.61; 95% CI, 1.16-2.22), total mortality (HR, 2.28; 95% CI, 1.87-2.80), and CVD mortality (HR, 2.13; 95% CI, 1.39-3.26). After adjusting for clinical stage and grade (likely intermediates of the relation of smoking with prostate cancer recurrence and survival), current smokers had increased risk of prostate cancer mortality (HR, 1.38; 95% CI, 0.94-2.03), as did current smokers with clinical stage T1 through T3 (HR, 1.41; 95% CI, 0.80-2.49); they also had an increased risk of biochemical recurrence (HR, 1.47; 95% CI, 1.06-2.04). Greater number of pack-years was associated with significantly increased risk of prostate cancer mortality but not biochemical recurrence. Current smokers of 40 or more pack-years vs never smokers had increased prostate cancer mortality (HR, 1.82; 95% CI, 1.03-3.20) and biochemical recurrence (HR, 1.48; 95% CI, 0.88-2.48). Compared with current smokers, those who had quit smoking for 10 or more years (HR, 0.60; 95% CI, 0.42-0.87) or who have quit for less than 10 years but smoked less than 20 pack-years (HR, 0.64; 95% CI, 0.28-1.45) had prostate cancer mortality risks similar to never smokers (HR, 0.61; 95% CI, 0.42-0.88). CONCLUSIONS Smoking at the time of prostate cancer diagnosis is associated with increased overall and CVD mortality and prostate cancer-specific mortality and recurrence. Men who have quit for at least 10 years have prostate cancer-specific mortality risks similar to those who have never smoked.

Physical activity after diagnosis and risk of prostate cancer progression: data from the Cancer of the Prostate Strategic Urologic Research Endeavor

Vigorous activity after diagnosis was recently reported to be inversely associated with prostate cancer-specific mortality. However, men with metastatic disease may decrease their activity due to their disease; thus, a causal interpretation is uncertain. We therefore prospectively examined vigorous activity and brisk walking after diagnosis in relation to risk of prostate cancer progression, an outcome less susceptible to reverse causation, among 1,455 men diagnosed with clinically localized prostate cancer. Cox proportional hazards regression was used to examine vigorous activity, nonvigorous activity, walking duration, and walking pace after diagnosis and risk of prostate cancer progression. We observed 117 events (45 biochemical recurrences, 66 secondary treatments, 3 bone metastases, 3 prostate cancer deaths) during 2,750 person-years. Walking accounted for nearly half of all activity. Men who walked briskly for 3 h/wk or more had a 57% lower rate of progression than men who walked at an easy pace for less than 3 h/wk (HR = 0.43; 95% CI: 0.21-0.91; P = 0.03). Walking pace was associated with decreased risk of progression independent of duration (HR brisk vs. easy pace = 0.52; 95% CI: 0.29-0.91; P(trend) = 0.01). Few men engaged in vigorous activity, but there was a suggestive inverse association (HR ≥3 h/wk vs. none = 0.63; 95% CI: 0.32-1.23; P(trend) = 0.17). Walking duration and total nonvigorous activity were not associated with risk of progression independent of pace or vigorous activity, respectively. Brisk walking after diagnosis may inhibit or delay prostate cancer progression among men diagnosed with clinically localized prostate cancer.

Does cellular aging relate to patterns of allostasis?. An examination of basal and stress reactive HPA axis activity and telomere length.

Long-term exposure to stress and its physiological mediators, in particular cortisol, may lead to impaired telomere maintenance. In this study, we examine if greater cortisol responses to an acute stressor and/or dysregulated patterns of daily cortisol secretion are associated with shorter telomere length. Twenty-three postmenopausal women comprising caregivers for dementia partners (n=14) and age- and BMI-matched non-caregivers provided home sampling of cortisol-saliva samples at waking, 30 min after waking, and bedtime, and a 12-hour overnight urine collection. They were also exposed to an acute laboratory stressor throughout which they provided saliva samples. Peripheral blood mononuclear cells were isolated from a fasting blood sample and assayed for telomere length. As hypothesized, greater cortisol responses to the acute stressor were associated with shorter telomeres, as were higher overnight urinary free cortisol levels and flatter daytime cortisol slopes. While robust physiological responses to acute stress serve important functions, the long-term consequences of frequent high stress reactivity may include accelerated telomere shortening.