Mara M. Epstein

Temporal Trends in Cause of Death Among Swedish and US Men with Prostate Cancer

BACKGROUND A growing proportion of men diagnosed with localized prostate cancer detected through prostate-specific antigen testing are dying from causes other than prostate cancer. Temporal trends in specific causes of death among prostate cancer patients have not been well described. METHODS We analyzed causes of death among all incident prostate cancer cases recorded in the nationwide Swedish Cancer Registry (1961-2008; n = 210 112) and in the US Surveillance, Epidemiology, and End Results Program (1973-2008; n = 490 341). We calculated the cumulative incidence of death due to seven selected causes that accounted for more than 80% of the reported deaths (including ischemic heart disease and non-prostate cancer) and analyzed mortality trends by calendar year and age at diagnosis and length of follow-up. RESULTS During follow-up through 2008, prostate cancer accounted for 52% of all reported deaths in Sweden and 30% of reported deaths in the United States among men with prostate cancer; however, only 35% of Swedish men and 16% of US men diagnosed with prostate cancer died from this disease. In both populations, the cumulative incidence of prostate cancer-specific death declined during follow-up, while the cumulative incidences of death from ischemic heart disease and non-prostate cancer remained constant. The 5-year cumulative incidence of death from prostate cancer among all men was 29% in Sweden and 11% in the United States. CONCLUSIONS In Sweden and the United States, men diagnosed with prostate cancer are less likely to die from prostate cancer than from another cause. Because many of these other causes of death are preventable through changes in lifestyle, interventions that target lifestyle factors should be integrated into prostate cancer management.

Dietary zinc and prostate cancer survival in a Swedish cohort

BACKGROUND Zinc is involved in many essential cellular functions, including DNA repair and immune system maintenance. Although experimental evidence supports a role for zinc in prostate carcinogenesis, epidemiologic data are inconsistent; no data on cancer-specific survival have been reported. OBJECTIVE Our objective was to determine whether dietary zinc assessed near the time of prostate cancer diagnosis is associated with improved disease-specific survival. DESIGN This population-based cohort consists of 525 men aged <80 y from Örebro County, Sweden, with a diagnosis of prostate cancer made between 1989 and 1994. Study participants completed self-administered food-frequency questionnaires, and zinc intake was derived from nutrient databases. Cox proportional hazards regression was used to estimate multivariate hazard ratios (HRs) and 95% CIs for time to death from prostate cancer as well as death from all causes through February 2009 by quartile (Q) of dietary zinc intake. Models were also stratified by disease stage at diagnosis (localized or advanced). RESULTS With a median follow-up of 6.4 y, 218 (42%) men died of prostate cancer and 257 (49%) died of other causes. High dietary zinc intake was associated with a reduced risk of prostate cancer-specific mortality (HR(Q4 vs Q1): 0.64; 95% CI: 0.44, 0.94; P for trend = 0.05) in the study population. The association was stronger in men with localized tumors (HR: 0.24; 95% CI: 0.09, 0.66; P for trend = 0.005). Zinc intake was not associated with mortality from other causes. CONCLUSION These results suggest that high dietary intake of zinc is associated with lower prostate cancer-specific mortality after diagnosis, particularly in men with localized disease.

Vasectomy and Risk of Aggressive Prostate Cancer: A 24-Year Follow-Up Study

PURPOSE Conflicting reports remain regarding the association between vasectomy, a common form of male contraception in the United States, and prostate cancer risk. We examined prospectively this association with extended follow-up and an emphasis on advanced and lethal disease. PATIENTS AND METHODS Among 49,405 U.S. men in the Health Professionals Follow-Up Study, age 40 to 75 years at baseline in 1986, 6,023 patients with prostate cancer were diagnosed during the follow-up to 2010, including 811 lethal cases. In total, 12,321 men (25%) had vasectomies. We used Cox proportional hazards models to estimate the relative risk (RR) and 95% CIs of total, advanced, high-grade, and lethal disease, with adjustment for a variety of possible confounders. RESULTS Vasectomy was associated with a small increased risk of prostate cancer overall (RR, 1.10; 95% CI, 1.04 to 1.17). Risk was elevated for high-grade (Gleason score 8 to 10; RR, 1.22; 95% CI, 1.03 to 1.45) and lethal disease (death or distant metastasis; RR, 1.19; 95% CI, 1.00 to 1.43). Among a subcohort of men receiving regular prostate-specific antigen screening, the association with lethal cancer was stronger (RR, 1.56; 95% CI, 1.03 to 2.36). Vasectomy was not associated with the risk of low-grade or localized disease. Additional analyses suggested that the associations were not driven by differences in sex hormone levels, sexually transmitted infections, or cancer treatment. CONCLUSION Our data support the hypothesis that vasectomy is associated with a modest increased incidence of lethal prostate cancer. The results do not appear to be due to detection bias, and confounding by infections or cancer treatment is unlikely.

Dietary Fatty Acid Intake and Prostate Cancer Survival in Örebro County, Sweden

Although dietary fat has been associated with prostate cancer risk, the association between specific fatty acids and prostate cancer survival remains unclear. Dietary intake of 14 fatty acids was analyzed in a population-based cohort of 525 Swedish men with prostate cancer in Örebro County (1989-1994). Multivariable hazard ratios and 95% confidence intervals for time to prostate cancer death by quartile and per standard deviation increase in intake were estimated by Cox proportional hazards regression. Additional models examined the association by stage at diagnosis (localized: T0-T2/M0; advanced: T0-T4/M1, T3-T4/M0). Among all men, those with the highest omega-3 docosahexaenoic acid and total marine fatty acid intakes were 40% less likely to die from prostate cancer (P(trend) = 0.05 and 0.04, respectively). Among men with localized prostate cancer, hazard ratios of 2.07 (95% confidence interval: 0.93, 4.59; P(trend) = 0.03) for elevated total fat, 2.39 (95% confidence interval: 1.06, 5.38) for saturated myristic acid, and 2.88 (95% confidence interval: 1.24, 6.67) for shorter chain (C4-C10) fatty acid intakes demonstrated increased risk for disease-specific mortality for the highest quartile compared with the lowest quartile. This study suggests that high intake of total fat and certain saturated fatty acids may worsen prostate cancer survival, particularly among men with localized disease. In contrast, high marine omega-3 fatty acid intake may improve disease-specific survival for all men.

Temporal Stability of Serum Concentrations of Cytokines and Soluble Receptors Measured Across Two Years in Low-Risk HIV-Seronegative Men

Background: Prospective cohort studies often quantify serum immune biomarkers at a single time point to determine risk of cancer and other chronic diseases that develop years later. Estimates of the within-person temporal stability of serum markers partly assess the utility of single biomarker measurements and may have important implications for the design of prospective studies of chronic disease risk. Methods: Using archived sera collected from 200 HIV-seronegative men at three visits spaced over approximately 2 years, concentrations of 14 biomarkers (ApoA1, sCD14, sgp130, sIL-6R, sIL-2Rα, sTNFR2, BAFF/BLyS, CXCL13, IFN-γ, interleukin [IL]-1β, IL-6, IL-8, IL-10, and TNF-α) were measured in a single laboratory. Age- and ethnicity-adjusted intraclass correlation coefficients (ICC) were calculated for each biomarker, and mixed linear regression models were used to examine the influence of age, ethnicity, season, and study site on biomarker concentrations. Results: Across all three study visits, most biomarkers had ICC values indicating fair to excellent within-person stability. ApoA1 (ICC = 0.88) and TNF-α (ICC = 0.87) showed the greatest stability; the ICC for IL-8 (ICC = 0.33) was remarkably less stable. The ICCs were similar when calculated between pairs of consecutive visits. The covariables did not influence biomarker levels or their temporal stability. All biomarkers showed moderate to strong pairwise correlations across visits. Conclusions: Serum concentrations of most evaluated immune biomarkers displayed acceptable to excellent within-person temporal reliability over a 2-year period. Further investigation may be required to clarify the stability of IL-8. Impact: These findings lend support to using these serologic immune biomarkers in prospective studies investigating associations with chronic diseases. Cancer Epidemiol Biomarkers Prev; 22(11); 2009–15. ©2013 AACR.

A Single Nucleotide Polymorphism in Inflammatory Gene RNASEL Predicts Outcome after Radiation Therapy for Localized Prostate Cancer

Purpose: To study associations between single nucleotide polymorphisms (SNP) in Ribonuclease L (RNASEL), a gene implicated in inflammation and prostate cancer risk, and outcomes after radiation therapy. Experimental Design: We followed participants in the prospective US Health Professionals Follow-Up Study treated with radiation therapy for early-stage prostate cancer. Three SNPs were genotyped based on previously determined functional and biological significance. We used multivariable Cox proportional hazards models to assess per-allele associations with the primary outcome defined as time to a composite endpoint including development of lethal prostate cancer or biochemical recurrence. Results: We followed 434 patients treated with radiation therapy for a median of 9 years. On multivariate analysis, the rs12757998 variant allele was associated with significantly decreased risk of the composite endpoint [HR: 0.65; 95% confidence interval (CI), 0.45–0.94%; P = 0.02] driven by decreased biochemical recurrence (HR: 0.60; 95% CI, 0.40–0.89%; P = 0.01) and men treated with external beam (HR: 0.58; 95% CI, 0.36–0.93%; P = 0.02). In contrast, in 516 men from the same cohort treated with radical prostatectomy, we found no significant impact of this variant on outcome. Furthermore, the rs12757998 variant allele significantly modified the association between androgen deprivation therapy and outcomes after radiation therapy (p-interaction = 0.02). Conclusion: We show an association between RNASEL SNP rs12757998 and outcome after radiation therapy for prostate cancer. This SNP is associated with increased circulating C-reactive protein and interleukin-6, suggesting a potential role for inflammation in the response to radiation. If validated, genetic predictors of outcome may help inform prostate cancer management. Clin Cancer Res; 19(6); 1612–9. ©2013 AACR.

Genetic variation in the toll-like receptor 4 and prostate cancer incidence and mortality.

Common genetic variants in the Toll‐like receptor 4 (TLR4), which is involved in inflammation and immune response pathways, may be important for prostate cancer.

Factors influencing survival among Kenyan children diagnosed with endemic Burkitt lymphoma between 2003 and 2011: A historical cohort study

Discovering how to improve survival and establishing clinical reference points for children diagnosed with endemic Burkitt lymphoma (eBL) in resource‐constrained settings has recaptured international attention. Using multivariate analyses, we evaluated 428 children with eBL in Kenya for age, gender, tumor stage, nutritional status, hemoglobin, lactate dehydrogenase (LDH), Epstein‐Barr virus (EBV) and Plasmodium falciparum prior to induction of chemotherapy (cyclophosphamide, vincristine, methotrexate and doxorubicin) to identify predictive and prognostic biomarkers of survival. During this 10 year prospective study period, 22% died in‐hospital and 78% completed six‐courses of chemotherapy. Of those, 16% relapsed or died later; 31% achieved event‐free‐survival; and 31% were lost to follow‐up; the overall one‐year survival was 45%. After adjusting for covariates, low hemoglobin (<8 g/dL) and high LDH (>400 mU/ml) were associated with increased risk of death (adjusted Hazard Ratio (aHR) = 1.57 [0.97–2.41]) and aHR = 1.84, [0.91–3.69], respectively). Anemic children with malaria were 3.55 times more likely to die [1.10–11.44] compared to patients without anemia or malarial infection. EBV load did not differ by tumor stage nor was it associated with survival. System‐level factors can also contribute to poor outcomes. Children were more likely to die when inadvertently overdosed by more than 115% of the correct dose of cyclophosphamide (aHR = 1.43 [0.84–2.43]) or doxorubicin (aHR = 1.25, [0.66–2.35]), compared with those receiving accurate doses of the respective agent in this setting. This study codifies risk factors associated with poor outcomes for eBL patients in Africa and provides a benchmark by which to assess improvements in survival for new chemotherapeutic approaches.

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 have not previously been examined. Using the ferric‐reducing antioxidant potential (FRAP) assay, the total antioxidant content (TAC) of diet and supplements was 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 (FFQs) 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 and 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 cancers 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 nonantioxidant coffee compounds or other effects of drinking coffee. The indication of increased risk for lethal and advanced prostate cancers with high TAC intake from supplements warrants further investigation.

Dairy intake in relation to prostate cancer survival

Dairy intake has been associated with increased risk of advanced prostate cancer. Two US cohort studies reported increased prostate cancer‐specific mortality with increased high‐fat milk intake. We examined whether dairy and related nutrient intake were associated with prostate cancer progression in a Swedish patient population with high dairy consumption. We prospectively followed 525 men with newly diagnosed prostate cancer (diagnosed 1989–1994). We identified and confirmed deaths through February 2011 (n = 222 prostate cancer‐specific, n = 268 from other causes). Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the associations between food or nutrient intake and prostate cancer‐specific death. On average, patients consumed 5.0 servings/day of total dairy products at diagnosis. In the whole population, high‐fat milk intake was not associated with prostate cancer‐specific death (95% CI: 0.78, 2.10; p‐trend = 0.32; multivariate‐adjusted model). However, among patients diagnosed with localized prostate cancer, compared to men who consumed <1 servings/day of high‐fat milk, those who drank ≥3 servings/day had an increased hazard of prostate cancer mortality (HR = 6.10; 95% CI: 2.14, 17.37; p‐trend = 0.004; multivariate‐adjusted model). Low‐fat milk intake was associated with a borderline reduction in prostate cancer death among patients with localized prostate cancer. These associations were not observed among patients diagnosed with advanced stage prostate cancer. Our data suggest a positive association between high‐fat milk intake and prostate cancer progression among patients diagnosed with localized prostate cancer. Further studies are warranted to investigate this association and elucidate the mechanisms by which high‐fat milk intake may promote prostate cancer progression.