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1.  Personal History of Prostate Cancer and Increased Risk of Incident Melanoma in the United States 
Journal of Clinical Oncology  2013;31(35):4394-4399.
Purpose
Steroid hormones, particularly androgens, play a major role in prostatic carcinogenesis. Personal history of severe acne, a surrogate for higher androgen activity, has been associated with an increased risk of prostate cancer (PCa), and one recent study indicated that severe teenage acne was a novel risk factor for melanoma. These findings suggest a possible relationship between PCa and risk of melanoma. We prospectively evaluated this association among US men.
Methods
A total of 42,372 participants in the Health Professionals' Follow-Up Study (HPFS; 1986 to 2010) were included. Biennially self-reported PCa diagnosis was confirmed using pathology reports. Diagnosis of melanoma and nonmelanoma skin cancer (NMSC) was self-reported biennially, and diagnosis of melanoma was pathologically confirmed. We sought to confirm the association in 18,603 participants from the Physicians' Health Study (PHS; 1982 to 1998).
Results
We identified 539 melanomas in the HPFS. Personal history of PCa was associated with an increased risk of melanoma (multivariate-adjusted hazard ratio [HR], 1.83; 95% CI, 1.32 to 2.54). Although we also detected a marginally increased risk of NMSC associated with PCa (HR, 1.08; 95% CI, 0.995 to 1.16), the difference in the magnitude of the association between melanoma and NMSC was significant (P for heterogeneity = .002). We did not find an altered risk of melanoma associated with personal history of other cancers. The association between PCa and risk of incident melanoma was confirmed in the PHS (HR, 2.17; 95% CI, 1.12 to 4.21).
Conclusion
Personal history of PCa is associated with an increased risk of melanoma, which may not be entirely a result of greater medical scrutiny.
doi:10.1200/JCO.2013.51.1915
PMCID: PMC3842907  PMID: 24190118
2.  Prediagnostic Body Mass Index and Pancreatic Cancer Survival 
Journal of Clinical Oncology  2013;31(33):4229-4234.
Purpose
Although obesity is associated with increased incidence of pancreatic cancer, studies have not prospectively evaluated prediagnostic body mass index (BMI) and survival.
Patients and Methods
We analyzed survival by prediagnostic BMI assessed in 1986 among 902 patients from two large prospective cohorts diagnosed from 1988 to 2010. We estimated hazard ratios (HRs) for death using Cox proportional hazards models, with adjustment for age, sex, race/ethnicity, smoking, diagnosis year, and stage. We evaluated the temporal association of BMI with survival by grouping reported BMI by 2-year lag-time intervals before diagnosis.
Results
The multivariable-adjusted HR for death was 1.53 (95% CI, 1.11 to 2.09) comparing patients with BMI ≥ 35 kg/m2 with those with BMI < 25 kg/m2 (P trend = .001), which was similar after adjustment for stage. The association of BMI with survival was stronger with longer lag times between reported BMI and cancer diagnosis. Among patients with BMI collected 18 to 20 years before diagnosis, HR for death was 2.31 (95% CI, 1.48 to 3.61; P trend < .001), comparing obese with healthy-weight patients. No statistically significant differences were seen by cohort, smoking status, or stage, although the association was stronger among never-smokers (HR, 1.61; 95% CI, 1.01 to 2.57; P trend = .002) than ever-smokers (HR, 1.36; 95% CI, 0.86 to 2.15; P trend = .63), comparing BMI ≥ 35 kg/m2 with BMI < 25 kg/m2. Higher prediagnostic BMI was associated with more advanced stage at diagnosis, with 72.5% of obese patients presenting with metastatic disease versus 59.4% of healthy-weight patients (P = .02).
Conclusion
Higher prediagnostic BMI was associated with statistically significantly decreased survival among patients with pancreatic cancer from two large prospective cohorts.
doi:10.1200/JCO.2013.51.7532
PMCID: PMC3821012  PMID: 24145341
3.  Vitamin D Receptor Protein Expression in Tumor Tissue and Prostate Cancer Progression 
Journal of Clinical Oncology  2011;29(17):2378-2385.
Purpose
Data suggest that circulating 25-hydroxyvitamin D [25(OH)D] interacts with the vitamin D receptor (VDR) to decrease proliferation and increase apoptosis for some malignancies, although evidence for prostate cancer is less clear. How VDR expression in tumor tissue may influence prostate cancer progression has not been evaluated in large studies.
Patients and Methods
We examined protein expression of VDR in tumor tissue among 841 patients with prostate cancer in relation to risk of lethal prostate cancer within two prospective cohorts, the Physicians' Health Study and Health Professionals Follow-Up Study. We also examined the association of VDR expression with prediagnostic circulating 25(OH)D and 1,25-dihydroxyvitamin D levels and with two VDR single nucleotide polymorphisms, FokI and BsmI.
Results
Men whose tumors had high VDR expression had significantly lower prostate-specific antigen (PSA) at diagnosis (P for trend < .001), lower Gleason score (P for trend < .001), and less advanced tumor stage (P for trend < .001) and were more likely to have tumors harboring the TMPRSS2:ERG fusion (P for trend = .009). Compared with the lowest quartile, men whose tumors had the highest VDR expression had significantly reduced risk of lethal prostate cancer (hazard ratio [HR], 0.17; 95% CI, 0.07 to 0.41). This association was only slightly attenuated after adjustment for Gleason score and PSA at diagnosis (HR, 0.33; 95% CI, 0.13 to 0.83) or, additionally, for tumor stage (HR, 0.37; 95% CI, 0.14 to 0.94). Neither prediagnostic plasma vitamin D levels nor VDR polymorphisms were associated with VDR expression.
Conclusion
High VDR expression in prostate tumors is associated with a reduced risk of lethal cancer, suggesting a role of the vitamin D pathway in prostate cancer progression.
doi:10.1200/JCO.2010.30.9880
PMCID: PMC3107752  PMID: 21537045
4.  Circadian clock genes and risk of fatal prostate cancer 
Cancer causes & control : CCC  2014;26(1):25-33.
Purpose
Circadian genes may be involved in regulating cancer-related pathways, including cell proliferation, DNA damage response and apoptosis. We aimed to assess the role of genetic variation in core circadian rhythm genes with the risk of fatal prostate cancer and morning void urinary 6-sulfatoxymelatonin levels.
Methods
We used unconditional logistic regression to evaluate the association of 96 single-nucleotide polymorphisms (SNPs) across twelve circadian-related genes with fatal prostate cancer in the AGES-Reykjavik cohort (n=24 cases), the Health Professionals Follow-Up Study (HPFS) (n=40 cases), and the Physicians’ Health Study (PHS) (n=105 cases). We used linear regression to evaluate the association between SNPs and morning void urinary 6-sulfatoxymelatonin levels in AGES-Reykjavik. We used a kernel machine test to evaluate whether multimarker SNP-sets in the pathway (gene based) were associated with our outcomes.
Results
None of the individual SNPs were consistently associated with fatal prostate cancer across the three cohorts. In each cohort, gene-based analyses showed that variation in the CRY1 gene was nominally associated with fatal prostate cancer (p-values = 0.01, 0.01, 0.05 for AGES-Reykjavik, HPFS, and PHS, respectively). In AGES-Reykjavik, SNPS in TIMELESS (4 SNPs), NPAS2 (6 SNPs), PER3 (2 SNPs) and CSNK1E (1 SNP) were nominally associated with 6-sulfatoxymelatonin levels.
Conclusion
We did not find a strong and consistent association between variation in core circadian clock genes and fatal prostate cancer risk, but observed nominally significant gene-based associations with fatal prostate cancer and 6-sulfatoxymelatonin levels.
doi:10.1007/s10552-014-0478-z
PMCID: PMC4282953  PMID: 25388799
Circadian genes; prostate cancer; genetic polymorphisms
5.  Total antioxidant intake in relation to prostate cancer incidence in the Health Professionals Follow up Study 
Epidemiologic evidence on the association of antioxidant intake and prostate cancer incidence is inconsistent. Total antioxidant intake and prostate cancer incidence has not previously been examined. Using the ferric reducing antioxidant potential (FRAP) assay, the total antioxidant content (TAC) of diet and supplements were assessed in relation to prostate cancer incidence. A prospective cohort of 47,896 men aged 40-75 years was followed from 1986 to 2008 for prostate cancer incidence (N=5,656), and they completed food frequency questionnaires (FFQ) every 4 years. A FRAP value was assigned to each item in the FFQ, and for each individual, TAC scores for diet, supplements and both (total) were calculated. Major contributors of TAC intake at baseline were: coffee (28%), fruit and vegetables (23%) and dietary supplements (23%). In multivariate analyses for dietary TAC a weak inverse association was observed; (highest versus lowest quintiles: 0.91 (0.83-1.00, p-trend=0.03) for total prostate cancer, 0.81 (0.64-1.01, p-trend=0.04) for advanced prostate cancer); this association was mainly due to coffee. No association of total TAC on prostate cancer incidence was observed. A positive association with lethal and advanced prostate cancer was observed in the highest quintile of supplemental TAC intake: 1.28 (0.98-1.65, p-trend<0.01) and 1.15 (0.92-1.43), p-trend=0.04). The weak association between dietary antioxidant intake and reduced prostate cancer incidence may be related to specific antioxidants in coffee, to non-antioxidant coffee compounds, or other effects of drinking coffee. The indication of increased risk for lethal and advanced prostate cancer with high TAC intake from supplements warrants further investigation.
doi:10.1002/ijc.28438
PMCID: PMC4274735  PMID: 23959920
Prostate cancer; Antioxidants; Oxidative stress; Diet; Risk factors
6.  Modification of the Association Between Obesity and Lethal Prostate Cancer by TMPRSS2:ERG  
Background
TMPRSS2:ERG is a hormonally regulated gene fusion present in about half of prostate tumors. We investigated whether obesity, which deregulates several hormonal pathways, interacts with TMPRSS2:ERG to impact prostate cancer outcomes.
Methods
The study included 1243 participants in the prospective Physicians’ Health Study and Health Professionals Follow-Up Study diagnosed with prostate cancer between 1982 and 2005. ERG overexpression (a TMPRSS2:ERG marker) was assessed by immunohistochemistry of tumor tissue from radical prostatectomy or transurethral resection of the prostate. Body mass index (BMI) and waist circumference, measured on average 1.3 years and 5.3 years before diagnosis, respectively, were available from questionnaires. Data on BMI at baseline was also available. We used Cox regression to calculate hazard ratios and 95% confidence intervals (CIs). All statistical tests were two-sided.
Results
During a mean follow-up of 12.8 years, 119 men developed lethal disease (distant metastases or prostate cancer death). Among men with ERG-positive tumors, the multivariable hazard ratio for lethal prostate cancer was 1.48 (95% CI = 0.98 to 2.23) per 5-unit increase in BMI before diagnosis, 2.51 (95% CI = 1.26 to 4.99) per 8-inch increase in waist circumference before diagnosis, and 2.22 (95% CI = 1.35 to 3.63) per 5-unit increase in BMI at baseline. The corresponding hazard ratios among men with ERG-negative tumors were 1.10 (95% CI = 0.76 to1.59; P interaction = .24), 1.14 (95% CI = 0.62 to 2.10; P interaction = .09), and 0.78 (95% CI = 0.52 to 1.19; P interaction = .001).
Conclusions
These results suggest that obesity is linked with poorer prostate cancer prognosis primarily in men with tumors harboring the gene fusion TMPRSS2:ERG.
doi:10.1093/jnci/djt332
PMCID: PMC3866157  PMID: 24292212
7.  Prostate-specific membrane antigen protein expression in tumor tissue and risk of lethal prostate cancer 
Background
Over-expression of prostate-specific membrane antigen (PSMA) in tumor tissue and serum has been linked to increased risk of biochemical recurrence in surgically treated prostate cancer patients, but no studies have assessed its association with disease-specific mortality.
Methods
We examined whether high PSMA protein expression in prostate tumor tissue was associated with lethal disease, and with tumor biomarkers of progression, among participants of two US-based cohorts (n=902, diagnosed 1983–2004). We used Cox proportional hazards regression to calculate multivariable hazard ratios (HR) and 95% confidence intervals (CI) of lethal prostate cancer, defined as disease-specific death or development of distant metastases (n=95). Partial Spearman rank correlation coefficients were used to correlate PSMA with tumor biomarkers.
Results
During an average 13 years of follow-up, higher PSMA expression at prostatectomy was significantly associated with lethal prostate cancer (age-adjusted HRQuartile(Q)4vs.Q1=2.42; p-trend<0.01). This association was attenuated and non-significant (multivariable-adjusted HRQ4vs.Q1=1.01; p-trend=0.52) after further adjusting for Gleason score and PSA at diagnosis. High PSMA expression was significantly (p<0.05) correlated with higher Gleason score and PSA at diagnosis, increased tumor angiogenesis, lower vitamin D receptor and androgen receptor expression, and absence of ERG expression.
Conclusions
High tumor PSMA expression was not an independent predictor of lethal prostate cancer in the current study. PSMA expression likely captures, in part, malignant features of Gleason grade and tumor angiogenesis.
Impact
PSMA is not a strong candidate biomarker for predicting prostate cancer-specific mortality in surgically treated patients.
doi:10.1158/1055-9965.EPI-13-0668
PMCID: PMC3893763  PMID: 24130224
prostate-specific membrane antigen; prostate cancer; tumor biomarkers; prognosis; angiogenesis
8.  Protein expression of PTEN, insulin-like growth factor I receptor (IGF1R), and lethal prostate cancer: a prospective study 
Background
Loss of PTEN has been shown to be associated with aggressive behavior of prostate cancer. It is less clear that loss of PTEN also increases the risk of cancer mortality. We investigated the association between PTEN expression and prostate cancer mortality, and the potential effect modification by IGF1R, a direct activator of the PI3K pathway.
Methods
Protein expression in tumor were evaluated using tumor tissues obtained from 805 participants of the Physicians’ Health and the Health Professionals Follow-up studies who were diagnosed with prostate cancer and underwent radical prostatectomy. Proportional hazard models were used to assess PTEN expression, and its interaction with IGF1R, in relation to lethal prostate cancer (cancer-specific death or distant metastases).
Results
Low PTEN expression was associated with an increase risk of lethal prostate cancer (HR = 1.7, 95% CI: 0.98-3.2, P for trend = 0.04). The association was attenuated after adjustment for Gleason grade, tumor stage, and PSA at diagnosis. A significant negative interaction between PTEN and IGF1R was found (P for interaction = 0.03). Either reduction in PTEN or increase in IGF1R expression was sufficient to worsen prognosis. Models including PTEN and IGF1R expression offer additional predicting power to prostate cancer survival, comparing to those only including demographic and clinical factors.
Conclusions
Low PTEN protein expression significantly increases the risk of lethal prostate cancer, particularly when the IGF1R expression remains at normal level.
Impact
PTEN and IGF1R expression in tumor are promising candidates for independent prognostic factors to predict lethal prostate cancer.
doi:10.1158/1055-9965.EPI-13-0349
PMCID: PMC3818474  PMID: 23983239
Prostate cancer; PTEN; Tumor biomarker; Survival; Interaction
9.  Blood Levels of Saturated and Monounsaturated Fatty Acids as Markers of De Novo Lipogenesis and Risk of Prostate Cancer 
American Journal of Epidemiology  2013;178(8):1246-1255.
De novo lipogenesis has been implicated in prostate carcinogenesis, and blood levels of specific saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) could reflect activity of this pathway. We used gas chromatography to measure blood SFA and MUFA levels in prediagnostic samples from 476 incident prostate cancer cases (1982–1995) in the Physicians' Health Study and an equal number of controls matched on age and smoking status. Five tagging polymorphisms in the fatty acid synthase (FASN) gene (rs1127678, rs6502051, rs4246444, rs12949488, and rs8066956) were related to blood SFA and MUFA levels. Conditional logistic regression was used to estimate the rate ratios, with 95% confidence intervals, of prostate cancer across quintiles of blood fatty acid levels. The polymorphisms rs6502051 and rs4246444 were associated with lower levels of 14:1n-5, 16:1n-7, and 18:1n-9. Blood levels of 16:1n-7 were associated with higher prostate cancer incidence, with rate ratios for men in increasing quintiles of 1.00, 1.40, 1.35, 1.44, and 1.97 (95% confidence interval: 1.27–3.06; Ptrend = 0.003). Furthermore, 16:1n-7 levels were positively related to incidence of high-grade (Gleason score ≥7) tumors (rate ratioQ5–Q1 = 3.92; 95% confidence interval: 1.72–8.94) but not low-grade tumors (rate ratioQ5–Q1 = 1.51; 95% confidence interval: 0.87–2.62) (Pheterogeneity = 0.02). Higher activity of enzymes involved in de novo lipogenesis, as reflected in blood levels of 16:1n-7, could be involved in the development of high-grade prostate cancer.
doi:10.1093/aje/kwt136
PMCID: PMC3792734  PMID: 23989197
biomarkers; epidemiology; fatty acids; nutrition; prostate cancer
10.  Prostate Cancer Cell Telomere Length Variability and Stromal Cell Telomere Length as Prognostic Markers for Metastasis and Death 
Cancer discovery  2013;3(10):1130-1141.
Current prognostic indicators are imperfect predictors of outcome in men with clinicallylocalized prostate cancer. Thus, tissue-based markers are urgently needed to improve treatment and surveillance decision-making. Given that shortened telomeres enhance chromosomal instability and such instability is a hallmark of metastatic lesions, we hypothesized that alterations in telomere length in the primary cancer would predict risk of progression to metastasis and prostate cancer death. To test this hypothesis, we conducted a prospective cohort study of 596 surgically treated men who participated in the ongoing Health Professionals Follow-up Study. Men who had the combination of more variable telomere length among prostate cancer cells (cell-to-cell) and shorter telomere length in prostate cancer-associated stromal cells were substantially more likely to progress to metastasis or die of their prostate cancer. These findings point to the translational potential of this telomere biomarker for prognostication and risk stratification for individualized therapeutic and surveillance strategies.
doi:10.1158/2159-8290.CD-13-0135
PMCID: PMC3797255  PMID: 23779129
Telomere; prostate cancer; prognostic marker
11.  Circulating Fatty Acids and Prostate Cancer Risk: Individual Participant Meta-Analysis of Prospective Studies 
Background
Individual studies have suggested that some circulating fatty acids are associated with prostate cancer risk, but have not been large enough to provide precise estimates of associations, particularly by stage and grade of disease.
Methods
Principal investigators of prospective studies on circulating fatty acids and prostate cancer were invited to collaborate. Investigators provided individual participant data on circulating fatty acids (weight percent) and other characteristics of prostate cancer cases and controls. Prostate cancer risk by study-specific fifths of 14 fatty acids was estimated using multivariable-adjusted conditional logistic regression. All statistical tests were two-sided.
Results
Five thousand and ninety-eight case patients and 6649 control patients from seven studies with an average follow-up of 5.1 (SD = 3.3) years were included. Stearic acid (18:0) was inversely associated with total prostate cancer (odds ratio [OR] Q5 vs Q1 = 0.88, 95% confidence interval [CI] = 0.78 to 1.00, P trend = .043). Prostate cancer risk was, respectively, 14% and 16% greater in the highest fifth of eicosapentaenoic acid (20:5n-3) (OR = 1.14, 95% CI = 1.01 to 1.29, P trend = .001) and docosapentaenoic acid (22:5n-3) (OR = 1.16, 95% CI = 1.02 to 1.33, P trend = .003), but in each case there was heterogeneity between studies (P = .022 and P < .001, respectively). There was heterogeneity in the association between docosapentaenoic acid and prostate cancer by grade of disease (P = .006); the association was statistically significant for low-grade disease but not high-grade disease. The remaining 11 fatty acids were not statistically associated with total prostate cancer risk.
Conclusion
There was no strong evidence that circulating fatty acids are important predictors of prostate cancer risk. It is not clear whether the modest associations of stearic, eicosapentaenoic, and docosapentaenoic acid are causal.
doi:10.1093/jnci/dju240
PMCID: PMC4188122  PMID: 25210201
12.  Gleason Grade Progression Is Uncommon 
Cancer research  2013;73(16):5163-5168.
Gleason grade is universally used for pathologic scoring the differentiation of prostate cancer. However, it is unknown whether prostate tumors arise well-differentiated and then progress to less differentiated forms or if Gleason grade is an early and largely unchanging feature. Prostate Specific Antigen (PSA) screening has reduced the proportion of tumors diagnosed at advanced stage, which allows assessment of this question on a population level. If Gleason grade progresses as stage does, one would expect a similar reduction in high grade tumors. We studied 1,207 Physicians’ Health Study and Health Professionals Follow-up Study participants diagnosed with prostate cancer 1982–2004 and treated with prostatectomy. We compared the distribution of grade and clinical stage across the pre-PSA and PSA screening eras. We re-reviewed grade using the ISUP 2005 revised criteria. The proportion of advanced stage tumors dropped more than six-fold, from the earliest period (12/1982–1/1993), 19.9% stage ≥T3, to the latest (5/2000–12/2004), 3% stage T3, none T4. The proportion of Gleason score ≥8 decreased substantially less, from 25.3% to 17.6%. A significant interaction between stage and diagnosis date predicting grade (p=0.04) suggests the relationship between grade and stage varies by time period. As the dramatic shift in stage since the introduction of PSA screening was accompanied by a more modest shift in Gleason grade, these findings suggest grade may be established early in tumor pathogenesis. This has implications for the understanding of tumor progression and prognosis, and may help patients diagnosed with lower grade disease feel more comfortable choosing active surveillance.
doi:10.1158/0008-5472.CAN-13-0427
PMCID: PMC3775342  PMID: 23946472
prostate cancer; Gleason score; dedifferentiation
13.  5α-reductase Inhibitors and Risk of High-grade or Lethal Prostate Cancer 
JAMA internal medicine  2014;174(8):1301-1307.
Importance
5α-reductase inhibitors (5ARIs) are widely used for benign prostatic hyperplasia despite controversy regarding potential risk of high-grade prostate cancer with use. Furthermore, the effect of 5ARIs on progression and prostate cancer death remains unclear.
Objective
To determine the association between 5ARI use and development of high-grade or lethal prostate cancer.
Design, Setting, and Participants
Prospective observational study of 38,058 men followed for prostate cancer diagnosis and outcomes between 1996–2010 in the Health Professionals Follow-up Study.
Exposure
Use of 5ARIs between 1996–2010.
Main Outcome Measures
Cox proportional hazards models were used to estimate risk of prostate cancer diagnosis or development of lethal disease with 5ARI use, adjusting for possible confounders including prostate specific antigen testing.
Results
During 448,803 person-years of follow-up, we ascertained 3681 incident prostate cancer cases. Of these, 289 were lethal (metastatic or fatal), 456 were high-grade (Gleason 8–10), 1238 were Gleason grade 7, and 1600 were low-grade (Gleason 2–6). A total of 2878 (7.6%) men reported use of 5ARIs between 1996 and 2010. After adjusting for confounders, men who reported ever using 5ARIs over the study period had a reduced risk of overall prostate cancer (HR 0.77; 95% CI, 0.65–0.91). 5ARI users had a reduced risk of Gleason 7 (HR 0.67; 95% CI, 0.49–0.91) and low-grade (Gleason 2–6) prostate cancer (HR 0.74; 95% CI, 0.57–0.95). 5ARI use was not associated with risk of high-grade (Gleason 8–10, HR 0.97; 95% CI, 0.64–1.46) or lethal disease (HR 0.99; 95% CI, 0.58–1.69). Increased duration of use was associated with significantly lower risk of overall prostate cancer (HR for 1 year of additional use 0.95; 95% CI, 0.92–0.99), localized (HR 0.95; 95% CI, 0.90–1.00), and low-grade disease (HR 0.92; 95% CI, 0.85–0.99). There was no association for lethal, high-grade, or grade 7 disease.
Conclusions and Relevance
While 5ARI use was not associated with developing high-grade or lethal prostate cancer, they were associated with a reduction in low-grade, Gleason 7 and overall prostate cancer. Since the number of patients with high-grade or lethal prostate cancer in our cohort was limited, we cannot rule out potential risk of harm with 5ARI use.
doi:10.1001/jamainternmed.2014.1600
PMCID: PMC4122627  PMID: 24887392
14.  Coffee consumption and the risk of overall and fatal prostate cancer in the NIH-AARP Diet and Health study 
Cancer causes & control : CCC  2013;24(8):1527-1534.
Purpose
Evidence on the association between coffee consumption and prostate cancer risk is inconsistent; furthermore, few studies have examined the relationship between coffee consumption and fatal prostate cancer. The aim of this study was to investigate whether coffee intake is associated with the risk of overall and fatal prostate cancer.
Methods
We conducted a prospective analysis among 288,391 men in the National Institutes of Health (NIH)-AARP Diet and Health Study who were between 50–71 years old at baseline in 1995–96. Coffee consumption was assessed at baseline. Cox proportional hazards models were used to calculate the age- and multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI).
Results
Over 11 years of follow-up, 23,335 cases of prostate cancer were ascertained, including 2,927 advanced and 917 fatal cases. Coffee consumption was not significantly associated with prostate cancer risk. The multivariable-adjusted HRs (95% CI), comparing those who drank six or more cups per day to non-drinker were; 0.94 (0.86–1.02), p-trend=0.08 for overall prostate cancer, 1.13 (0.91–1.40), p-trend=0.62 for advanced prostate cancer and 0.79 (0.53–1.17), p-trend=0.20 for fatal prostate cancer. The findings remained nonsignificant when we stratified by prostate specific antigen (PSA) testing history or restricted to non-smokers.
Conclusions
We found no statistically significant association between coffee consumption and the risk of overall, advanced or fatal prostate cancer in this cohort, though a modest reduction in risk could not be excluded.
doi:10.1007/s10552-013-0229-6
PMCID: PMC3717413  PMID: 23681472
Coffee; caffeine; prostatic neoplasms; prospective studies
15.  Renal Function Following Three Distinct Weight Loss Dietary Strategies During 2 Years of a Randomized Controlled Trial 
Diabetes Care  2013;36(8):2225-2232.
OBJECTIVE
This study addressed the long-term effect of various diets, particularly low-carbohydrate high-protein, on renal function on participants with or without type 2 diabetes.
RESEARCH DESIGN AND METHODS
In the 2-year Dietary Intervention Randomized Controlled Trial (DIRECT), 318 participants (age, 51 years; 86% men; BMI, 31 kg/m2; mean estimated glomerular filtration rate [eGFR], 70.5 mL/min/1.73 m2; mean urine microalbumin-to-creatinine ratio, 12:12) with serum creatinine <176 μmol/L (eGFR ≥30 mL/min/1.73 m2) were randomized to low-fat, Mediterranean, or low-carbohydrate diets. The 2-year compliance was 85%, and the proportion of protein intake significantly increased to 22% of energy only in the low-carbohydrate diet (P < 0.05 vs. low-fat and Mediterranean). We examined changes in urinary microalbumin and eGFR, estimated by Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration formulas.
RESULTS
Significant (P < 0.05 within groups) improvements in eGFR were achieved in low-carbohydrate (+5.3% [95% CI 2.1–8.5]), Mediterranean (+5.2% [3.0–7.4]), and low-fat diets (+4.0% [0.9–7.1]) with similar magnitude (P > 0.05) across diet groups. The increased eGFR was at least as prominent in participants with (+6.7%) or without (+4.5%) type 2 diabetes or those with lower baseline renal function of eGFR <60 mL/min/1.73 m2 (+7.1%) versus eGFR ≥60 mL/min/1.73 m2 (+3.7%). In a multivariable model adjusted for age, sex, diet group, type 2 diabetes, use of ACE inhibitors, 2-year weight loss, and change in protein intake (confounders and univariate predictors), only a decrease in fasting insulin (β = −0.211; P = 0.004) and systolic blood pressure (β = −0.25; P < 0.001) were independently associated with increased eGFR. The urine microalbumin-to-creatinine ratio improved similarly across the diets, particularly among participants with baseline sex-adjusted microalbuminuria, with a mean change of −24.8 (P < 0.05).
CONCLUSIONS
A low-carbohydrate diet is as safe as Mediterranean or low-fat diets in preserving/improving renal function among moderately obese participants with or without type 2 diabetes, with baseline serum creatinine <176 μmol/L. Potential improvement is likely to be mediated by weight loss–induced improvements in insulin sensitivity and blood pressure.
doi:10.2337/dc12-1846
PMCID: PMC3714527  PMID: 23690533
16.  Fat intake after diagnosis and risk of lethal prostate cancer and all-cause mortality 
JAMA internal medicine  2013;173(14):1318-1326.
Importance
Nearly 2.5 million men currently live with prostate cancer in the United States, yet little is known about diet after diagnosis and prostate cancer progression and overall mortality.
Objective
Examine post-diagnostic fat intake in relation to lethal prostate cancer and all-cause mortality.
Design, Setting, Participants
Prospective study of 4577 men with non-metastatic prostate cancer in the Health Professionals Follow-up Study (1986–2010).
Exposures
Post-diagnostic saturated, monounsaturated, polyunsaturated, trans, animal, and vegetable fat intakes.
Outcomes
Lethal prostate cancer (distant metastases or prostate cancer-specific death) and all-cause mortality.
Results
We observed 315 events of lethal prostate cancer and 1064 deaths (median follow-up = 8.4 y). Crude rates per 1000 person-years for lethal prostate cancer were (highest v. lowest quintile): 7.6 v. 7.3 for saturated, 6.4 v. 7.2 for monounsaturated, 5.8 v. 8.2 for polyunsaturated, 8.7 v. 6.1 for trans, 8.3 v. 5.7 for animal, and 4.7 vs. 8.7 for vegetable fat. For all-cause mortality, the rates were: 28.4 v. 21.4 for saturated, 20.0 v. 23.7 for monounsaturated, 17.1 v. 29.4 for polyunsaturated, 32.4 v. 17.1 for trans, 32.0 v. 17.2 for animal, and 15.4 v. 32.7 for vegetable fat. Post-diagnostic vegetable fat was associated with lower risk of lethal prostate cancer [hazard ratio (HR; 10% energy): 0.71; 95%CI: 0.51, 0.98; p: 0.04] and all-cause mortality [HR (10% energy): 0.74; 95%CI: 0.61, 0.88; p: 0.001]. No other fats were associated with lethal prostate cancer. Saturated and trans fats after diagnosis were associated with higher all-cause mortality [HR (5% energy): 1.30; 95% CI: 1.05, 1.60; p: 0.02 and HR (1% energy): 1.25; 95% CI: 1.05, 1.49; p: 0.01, respectively].
Conclusions
Among men with non-metastatic prostate cancer, replacing carbohydrate and animal fat with vegetable fat may reduce risk of all-cause mortality. The potential benefit of vegetable fat for prostate cancer-specific outcomes merits further research.
doi:10.1001/jamainternmed.2013.6536
PMCID: PMC3935610  PMID: 23752662
17.  Hyperglycemia, Insulin Resistance, Impaired Pancreatic β-Cell Function, and Risk of Pancreatic Cancer 
Background
Obesity and diabetes mellitus are associated with an increased risk of pancreatic cancer. These associations may be secondary to consequences of peripheral insulin resistance, pancreatic β-cell dysfunction, or hyperglycemia itself. Hemoglobin A1c (HbA1c) is a measure of hyperglycemia, whereas plasma insulin and proinsulin are markers of peripheral insulin resistance, and the proinsulin to insulin ratio marks pancreatic β-cell dysfunction.
Methods
This was a prospective, nested case-control study of 449 case patients and 982 control subjects with prediagnostic blood samples and no diabetes history from five prospective US cohorts followed through 2008. Two or three control subjects were matched to each case patient by year of birth, cohort, smoking, and fasting status. Pancreatic cancer risk was assessed by prediagnostic HbA1c, insulin, proinsulin, and proinsulin to insulin ratio with multivariable-adjusted logistic regression. All P values were two-sided.
Results
The highest vs lowest quintiles of HbA1c, insulin, and proinsulin were associated with with an increased risk for pancreatic cancer (odds ratio [OR] = 1.79; 95% confidence interval [CI] = 1.17 to 2.72, P trend = .04 for HbA1c; OR = 1.57; 95% CI = 1.08 to 2.30; Ptrend = .002 for insulin; and OR = 2.22; 95% CI = 1.50 to 3.29; P trend < .001 for proinsulin). Proinsulin to insulin ratio was not associated with pancreatic cancer risk. Results were similar across studies (all P heterogeneity > .29). In cancers developing 10 or more years after blood collection, the associations with insulin and proinsulin became stronger (highest vs lowest quintile, OR = 2.77; 95% CI = 1.28 to 5.99 for insulin and OR = 3.60; 95% CI = 1.68 to 7.72 for proinsulin). In mutually adjusted models including HbA1c, insulin, and proinsulin, only proinsulin remained statistically significant ( highest vs lowest quintile, OR = 2.55; 95% CI = 1.54 to 4.21; Ptrend < .001).
Conclusions
Among participants from five large prospective cohorts, circulating markers of peripheral insulin resistance, rather than hyperglycemia or pancreatic β-cell dysfunction, were independently associated with pancreatic cancer risk.
doi:10.1093/jnci/djt123
PMCID: PMC3714020  PMID: 23847240
19.  Association of Nut Consumption with Total and Cause-Specific Mortality 
The New England journal of medicine  2013;369(21):2001-2011.
BACKGROUND
Increased nut consumption has been associated with a reduced risk of major chronic diseases, including cardiovascular disease and type 2 diabetes mellitus. However, the association between nut consumption and mortality remains unclear.
METHODS
We examined the association between nut consumption and subsequent total and cause-specific mortality among 76,464 women in the Nurses’ Health Study (1980–2010) and 42,498 men in the Health Professionals Follow-up Study (1986–2010). Participants with a history of cancer, heart disease, or stroke were excluded. Nut consumption was assessed at baseline and updated every 2 to 4 years.
RESULTS
During 3,038,853 person-years of follow-up, 16,200 women and 11,229 men died. Nut consumption was inversely associated with total mortality among both women and men, after adjustment for other known or suspected risk factors. The pooled multivariate hazard ratios for death among participants who ate nuts, as compared with those who did not, were 0.93 (95% confidence interval [CI], 0.90 to 0.96) for the consumption of nuts less than once per week, 0.89 (95% CI, 0.86 to 0.93) for once per week, 0.87 (95% CI, 0.83 to 0.90) for two to four times per week, 0.85 (95% CI, 0.79 to 0.91) for five or six times per week, and 0.80 (95% CI, 0.73 to 0.86) for seven or more times per week (P<0.001 for trend). Significant inverse associations were also observed between nut consumption and deaths due to cancer, heart disease, and respiratory disease.
CONCLUSIONS
In two large, independent cohorts of nurses and other health professionals, the frequency of nut consumption was inversely associated with total and cause-specific mortality, independently of other predictors of death. (Funded by the National Institutes of Health and the International Tree Nut Council Nutrition Research and Education Foundation.)
doi:10.1056/NEJMoa1307352
PMCID: PMC3931001  PMID: 24256379
20.  Selenoprotein P Genetic Variants and mRNA Expression, Circulating Selenium and Prostate Cancer Risk and Survival 
The Prostate  2012;73(7):700-705.
Background
Low levels of selenium have been associated with increased risk of prostate cancer (PCa). Selenoprotein P is the most abundant selenoprotein in serum and delivers ten selenocysteine residues to tissues. Variation in the selenoprotein P gene (SEPP1) may influence PCa development or modify the effects of selenium. We examined the association of SEPP1 single nucleotide polymorphisms (SNPs) with PCa risk and survival, and tested for interactions.
Methods
The Physicians’ Health Study (PHS) is a prospective cohort of 22,071 US physicians; we utilized a nested case-control study of 1,352 PCa cases and 1,382 controls. We assessed four SNPs capturing common variation within the SEPP1 locus. In a subset of men (n=80), we evaluated SEPP1 mRNA expression in tumors.
Results
Two SNPs were significantly associated with PCa risk. For rs11959466, each T allele increased risk (odds ratio (OR)=1.31; 95% confidence interval (CI): 1.02,1.69; ptrend=0.03). For rs13168440, the rare homozygote genotype decreased risk compared to the common homozygote (OR=0.56, 95% CI: 0.33, 0.96). Moreover, there was a significant interaction of rs13168440 with plasma selenium; increasing selenium levels were associated with decreased PCa risk only among men with the minor allele (pinteraction=0.01). SEPP1 expression was significantly lower in men with lethal PCa than long-term survivors.
Conclusions
SEPP1 genetic variation was associated with PCa incidence; replication of these results in an independent dataset is necessary. These findings further support a causal link between selenium and PCa, and suggest that the effect of selenium may differ by genetics.
doi:10.1002/pros.22611
PMCID: PMC3640488  PMID: 23129481
genetic variation; selenium; prostate cancer
21.  Inflammatory Plasma Markers and Pancreatic Cancer Risk: a Prospective Study of 5 U.S. Cohorts 
Chronic inflammation may play a role in the development of pancreatic cancer. However, few prospective studies have examined the association between plasma inflammatory markers and pancreatic cancer risk. Therefore, we investigated the association of prediagnostic circulating C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α-receptor II (TNF-αR2) with subsequent pancreatic cancer risk in a prospective, nested case-control study of 470 cases and 1094 controls from Health Professionals Follow-up Study, Nurses’ Health Study, Physicians’ Health Study, Women’s Health Initiative, and Women’s Health Study. The median follow-up time of cases was 7.2 years (range 1-26 years). No association was observed between plasma CRP, IL6, and TNF-αR2 and risk of pancreatic cancer. Comparing extreme quintiles, the multivariate ORs were 1.10 (95% CI, 0.74-1.63; Ptrend= 0.81) for CRP, 1.19 (95% CI, 0.81-1.76; Ptrend = 0.08) for IL6, and 0.88 (95% CI, 0.58-1.33; Ptrend = 0.57) for TNF-αR2. In conclusion, pre-diagnostic levels of circulating CRP, IL6, and TNF-αR2 were not associated with risk of pancreatic cancer, suggesting that systemic inflammation as measured by circulating inflammatory factors is unlikely to play a major role in the development of pancreatic cancer.
doi:10.1158/1055-9965.EPI-12-1458
PMCID: PMC3650127  PMID: 23462920
22.  Sleep Disruption Among Older Men and Risk of Prostate Cancer 
Background
While positive associations have consistently been reported between sleep disruption and breast cancer, less is known about its potential role in prostate cancer.
Methods
Within the prospective AGES-Reykjavik cohort study, we followed 2,102 men recruited in 2002–2006 until the end of 2009. Participants answered questions on sleep disruption. Information on the occurrence of prostate cancer was obtained through record-linkages across the Icelandic Cancer Registry. We used Cox regression models with 95% confidence intervals [CIs] to estimate hazard ratios [HR] of prostate cancer by symptoms of sleep disruption.
Results
During follow-up, 135 men (6.4%) were diagnosed with prostate cancer. Compared to men without sleep disruption, those with problems falling and staying asleep were at significantly increased risk of prostate cancer [HR, 1.7 (95% CI, 1.0–2.9) and 2.1 (95% CI, 1.2–3.7)], respectively, with increasing sleep disruption severity. When restricted to advanced prostate cancer (≥ stage T3 or lethal disease), these associations became even stronger [HRs 2.1 (95% CI, 0.7–6.2) and 3.2 (95% CI, 1.1–9.7)]. The results did not change after excluding from the analyses men who woke up during the night, indicative of nocturia, suggesting limited risk of reverse association.
Conclusions
Our data suggest that certain aspects of sleep disruption may confer an increased risk of prostate cancer and call for additional, larger studies with longer follow-up times.
Impact
Prostate cancer is one of the leading public health concerns in men; if confirmed in future studies the association between sleep disruption and prostate cancer risk may open new avenues for prevention.
doi:10.1158/1055-9965.EPI-12-1227-T
PMCID: PMC3652595  PMID: 23652374
prostate cancer; circadian disruption; sleep disruption; cohort study; melatonin; light at night
23.  POSTMENOPAUSAL HORMONE THERAPY AND STROKE: THE ROLE OF TIME SINCE MENOPAUSE AND AGE AT HORMONE INITIATION 
Archives of internal medicine  2008;168(8):861-866.
Background
We evaluated stroke risk associated with HT in younger women, women recently menopausal, and in older women.
Methods
Prospective, observational analyses in postmenopausal participants of the Nurses’ Health Study, from 1976–2004, with biennial mailed questionnaires. We used proportional hazards models to calculate multivariable-adjusted relative risks and 95% confidence intervals.
Results
We found a significantly increased risk of stroke for women currently taking HT (estrogen alone: RR=1.39, 95% CI 1.18,1.63; estrogen with progestin: RR=1.27, 95% CI 1.04,1.56); nearly identical results to the Women’s Health Initiative. This increased risk was observed for women initiating hormone therapy at young ages or near menopause, and at older ages or >10 years after menopause. Short-term (<5 years) HT initiated at younger ages was not associated with a clear increase in stroke; however this was based on a small number of cases. The incidence of stroke was relatively low in younger women, and the attributable risk in women aged 50–54 years indicated approximately an additional 2 cases of stroke per 10,000 women per year taking hormones. We found a strong relation between dose of oral conjugated estrogen and stroke, with relative risks of 0.93, 1.54, 1.62, for doses of 0.3, 0.625, and 1.25mg respectively (p-trend<0.0001).
Conclusions
Hormone therapy increases risk of stroke, and this elevation does not appear related to timing of hormone initiation. In younger women, with lower stroke risk, the attributable risk of stroke due to hormone use is modest and might be minimized by lower doses and shorter treatment duration.
doi:10.1001/archinte.168.8.861
PMCID: PMC4001717  PMID: 18443262
24.  THE 2011-2016 TRANSDISCIPLINARY RESEARCH IN ENERGETICS AND CANCER (TREC) INITIATIVE: RATIONALE AND DESIGN 
Cancer causes & control : CCC  2013;24(4):695-704.
Purpose
Recognition of the complex, multidimensional relationship between excess adiposity and cancer control outcomes has motivated the scientific community to seek new research models and paradigms.
Methods
The National Cancer Institute developed an innovative concept to establish a centers grant mechanism in nutrition, energetics, and physical activity; referred to as the Transdisciplinary Research on Energetics and Cancer (TREC) Initiative. This paper gives an overview of the 2011-2016 TREC Collaborative Network and the 15 research projects being conducted at the Centers.
Results
Four academic institutions were awarded TREC center grants in 2011: Harvard University, University of California San Diego, University of Pennsylvania, and Washington University in St. Louis. The Fred Hutchinson Cancer Research Center is the Coordination Center. The TREC research portfolio includes 3 animal studies, 3 cohort studies, 4 randomized clinical trials, 1 cross-sectional study, and 2 modeling studies. Disciplines represented by TREC investigators include basic science, endocrinology, epidemiology, biostatistics, behavior, medicine, nutrition, physical activity, genetics, engineering, health economics, and computer science. Approximately 41,000 participants will be involved in these studies, including children, healthy adults, and breast and prostate cancer survivors. Outcomes include biomarkers of cancer risk, changes in weight and physical activity, persistent adverse treatment effects (e.g., lymphedema, urinary and sexual function), and breast and prostate cancer mortality.
Conclusion
The NIH Science of Team Science group will evaluate the value-added by this collaborative science. However, the most important outcome will be whether this transdisciplinary initiative improves the health of Americans at risk for cancer as well as cancer survivors.
doi:10.1007/s10552-013-0150-z
PMCID: PMC3602225  PMID: 23378138
energetics; obesity; diet; physical activity; cancer; transdisciplinary
25.  Genetic Variation in the Vitamin D Pathway in Relation to Risk of Prostate Cancer – Results from Breast and Prostate Cancer Cohort Consortium (BPC3) 
Background
Studies suggest that vitamin D status may be associated with prostate cancer risk, although the direction and strength of this association differs between experimental and observational studies. Genome-wide association studies have identified genetic variants associated with 25-hydroxyvitamin D (25(OH)D) status. We examined prostate cancer risk in relation to SNPs in four genes shown to predict circulating levels of 25(OH)D.
Methods
SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25(OH)D were genotyped in 10,018 cases and 11,052 controls from the NCI Breast and Prostate Cancer Cohort Consortium. Logistic regression was used to estimate the individual and cumulative association between genetic variants and risk of overall and aggressive prostate cancer.
Results
We observed a decreased risk of aggressive prostate cancer among men with the allele in rs6013897 near CYP24A1 associated with lower serum 25(OH)D (per A allele, OR=0.86, 95%CI=0.80–0.93, p-trend=0.0002), but an increased risk for non-aggressive disease (per a allele: OR=1.10, 95%CI=1.04–1.17, p-trend=0.002). Examination of a polygenic score of the four SNPs revealed statistically significantly lower risk of aggressive prostate cancer among men with a greater number of low vitamin D alleles (OR for 6–8 vs. 0–1 alleles = 0.66, 95% CI = 0.44 – 0.98; p-trend=0.003).
Conclusions
In this large, pooled analysis, genetic variants related to lower 25(OH)D were associated with a decreased risk of aggressive prostate cancer.
Impact
Our genetic findings do not support a protective association between loci known to influence vitamin D levels and prostate cancer risk.
doi:10.1158/1055-9965.EPI-13-0007-T
PMCID: PMC3617077  PMID: 23377224
Vitamin D; prostatic neoplasms; data pooling; genes; SNPs

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