Associations between intake of calcium, magnesium and phosphorus and risk of pancreatic cancer: a population-based, case-control study in Minnesota.

Experimental studies suggest that abnormal levels of Ca, Mg and phosphorus are implicated in pancreatic carcinogenesis. We investigated the associations between intakes of these minerals and the risk of pancreatic cancer in a case-control study conducted in 1994-1998. Cases of pancreatic cancer (n 150) were recruited from all hospitals in the metropolitan area of the Twin Cities and Mayo Clinic, Minnesota. Controls (n 459) were randomly selected from the general population and frequency matched to cases by age, sex and race. All dietary variables were adjusted for energy intake using the residual method prior to data analysis. Logistic regression was performed to evaluate the associations between intake of three nutrients examined and the risk of pancreatic cancer. Total intake of Ca (936 v. 1026 mg/d) and dietary intake of Mg (315 v. 331 mg/d) and phosphorus (1350 v. 1402 mg/d) were significantly lower in cases than in controls. After adjustment for confounders, there were not significant associations of total and dietary intakes of Ca, Mg and phosphorus with the risk of pancreatic cancer. In addition, no significant interactions exist between intakes of these minerals and total fat on pancreatic cancer risk. In conclusion, the present study does not suggest that intakes of Ca, Mg and phosphorus were significantly associated with the risk of pancreatic cancer.

Associations between tissue-based CD3+ T-lymphocyte count and colorectal cancer survival in a prospective cohort of older women.

Tumor-infiltrating lymphocytes in colorectal cancer (CRC) predict better survival. However, associations between T-lymphocyte count in histologically normal tissues from patients with CRC and survival remain uncertain. We examined associations of CD3+ T-cells in colorectal tumor and histologically normal tissues with CRC-specific and all-cause mortality in the prospective Iowa Women's Health Study. Tissue microarrays were constructed using paraffin-embedded colorectal tissue samples from 464 women with tumor tissues and 314 women with histologically normal tissues (55-69 years at baseline) diagnosed with incident CRC from 1986 to 2002 and followed through 2014 (median follow-up 20.5 years). Three tumor and two histologically normal tissue cores for each patient were immunostained using CD3+ antibody and quantified, and the counts were averaged across the cores in each tissue. Cox proportional hazards regression estimated hazard ratios (HR) and 95% confidence interval (CI) for CRC-specific and all-cause mortality. After adjustment for age at diagnosis, body mass index, smoking status, tumor grade, and stage, HRs (95% CI) for the highest versus lowest tertile of tumor CD3+ score were 0.59 (0.38-0.89) for CRC-specific mortality and 0.82 (0.63-1.05) for all-cause mortality; for histologically normal CD3+ score, the corresponding HRs (95% CI) were 0.47 (0.19-1.17) and 0.50 (0.27-0.90), respectively. The CD3+ score combining the tumor and histologically normal scores was inversely associated with CRC-specific and all-cause mortality. Although the association between tumor CD3+ score and all-cause mortality was not significant, both higher CD3+ T-lymphocyte counts in tumor and histologically normal scores tended to be associated with lower CRC-specific and all-cause mortality.

Diabetes and kidney cancer risk among post-menopausal women: The Iowa women's health study.

BACKGROUND: Many studies have reported a positive association between diabetes and kidney cancer. However, it is unclear whether diabetes is a risk factor for kidney cancer independent of other risk factors, such as obesity and hypertension. We comprehensively examined the association of diabetes and its duration with incident kidney cancer in the prospective cohort Iowa Women's Health Study (1986-2011). METHODS: Diabetes status was self-reported at baseline (1986) and on five follow-up questionnaires. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of baseline and time-dependent diabetes with the risk of incident kidney cancer. RESULTS: During the 25 years of follow-up, 245 cases of kidney cancer occurred among 36,975 post-menopausal women. In an age-adjusted model, there was a significant association between time-dependent diabetes and the risk of kidney cancer [HR (95% CI) = 1.76 (1.26, 1.45)]; the association was attenuated after multivariable adjustment for age, body mass index (BMI), waist-to-hip ratio (WHR), hypertension, physical activity, diuretic use, pack-years of smoking, alcohol intake, and total caloric intake [HR = 1.35 (0.94, 1.94)]. However, among non-obese women or women with a waist circumference less than 34.6 in., diabetes was significantly associated with kidney cancer risk: for time-dependent diabetes, HRs (95% CIs) were 1.82 (1.10, 3.00) among those with BMI < 30 kg/m2 and 2.18 (1.08, 4.38) among those with a waist circumference <34.6 in.. CONCLUSIONS: Our results suggest that diabetes is associated with kidney cancer risk among non-obese post-menopausal women.

Pregnancy outcomes and risk of endometrial cancer: A pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium.

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further ~15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.

Telomere Maintenance Variants and Survival after Colorectal Cancer: Smoking- and Sex-Specific Associations.

BACKGROUND: Telomeres play an important role in colorectal cancer prognosis. Variation in telomere maintenance genes may be associated with survival after colorectal cancer diagnosis, but evidence is limited. In addition, possible interactions between telomere maintenance genes and prognostic factors, such as smoking and sex, also remain to be investigated. METHODS: We conducted gene-wide analyses of colorectal cancer prognosis in 4,896 invasive colorectal cancer cases from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO); 1,871 common variants within 13 telomere maintenance genes were included. Cox models were fit to estimate associations of these variants individually with overall and colorectal cancer-specific survival. Likelihood ratio tests were used to test for interaction by smoking and sex. P values were adjusted using Bonferroni correction. RESULTS: The association between minor allele of rs7200950 (ACD) with colorectal cancer-specific survival varied significantly by smoking pack-years (corrected P = 0.049), but no significant trend was observed. By sex, minor alleles for rs2975843 (TERF1), rs75676021 (POT1), and rs74429678 (POT1) were associated with decreased overall and/or colorectal cancer-specific survival in women but not in men. CONCLUSIONS: Our study reported a gene-wide statistically significant interaction with sex (TERF1, POT1). Although significant interaction by smoking pack-years (ACD) was observed, there was no evidence of a dose response. Validation of these findings in other large studies and further functional annotation on these SNPs are warranted. IMPACT: Our study found a gene-smoking and gene-sex interaction on survival after colorectal cancer diagnosis, providing new insights into the role of genetic polymorphisms in telomere maintenance on colorectal cancer prognosis.

Association between MICA polymorphisms, s-MICA levels, and pancreatic cancer risk in a population-based case-control study.

BACKGROUND: Pancreatic tumor cells may avoid immune surveillance by releasing the transmembrane major histocompatibility complex class I chain-related A (MICA) protein in soluble form (s-MICA). We hypothesized that the presence of the A5.1 polymorphism in the MICA gene, which encodes a truncated MICA protein, is associated with higher s-MICA levels and increased pancreatic cancer risk. METHODS: MICA alleles and s-MICA levels were measured in 121 pancreatic cancer cases and 419 controls. General linear regression with a log transformation assessed geometric means of s-MICA levels across MICA alleles. Unconditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence intervals (CI) for pancreatic cancer associated with MICA alleles. RESULTS: After multivariate adjustment, participants with at least one copy of the A5.1 allele versus no A5.1 allele had 1.35 (95% CI: 1.05-1.74) times greater s-MICA levels (1.65 times higher for cases and 1.28, for controls) and increased risk of pancreatic cancer (OR = 1.91, 95% CI: 1.05-3.48). CONCLUSIONS: Our study suggests higher risk of pancreatic cancer among those with the MICA A5.1 polymorphism, which may be explained by an increase in s-MICA secretion and impaired immune response. IMPACT: These findings provide further evidence at the genetic and molecular level of the important role of MICA in pancreatic cancer development, and may have important implications with regards to pancreatic cancer screening.

Intake of methyl-related nutrients and risk of pancreatic cancer in a population-based case-control study in Minnesota.

BACKGROUND/OBJECTIVES: Folate, vitamin B6, vitamin B12, and methionine are involved in DNA synthesis and methylation and thus may modulate pancreatic cancer risk. We investigated these associations in a population-based case-control study conducted in 1994-1998. SUBJECTS/METHODS: Cases (n = 150) were identified from all hospitals in the metropolitan areas of the Twin Cities and the Mayo Clinic, Minnesota. Controls (n = 459) were selected randomly from the general population and were frequency matched to cases by age, sex, and race. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for risk of pancreatic cancer in relation to intake of nutrients considered. RESULTS: Dietary intake of folate was associated with a reduced pancreatic cancer risk [OR (95% CI) for quartile (Q) 4 vs. Q1: 0.31 (0.12-0.78)]. A composite score (range from 2 to 8), reflecting combined dietary intake of folate and vitamin B6, was also inversely associated with pancreatic cancer risk [OR (95% CI) for Q4 vs. Q1: 0.24 (0.08-0.70)]. Null associations were found for intake of vitamin B12 and methionine. CONCLUSIONS: Dietary folate intake was associated with a reduced pancreatic cancer risk, and this association became stronger when dietary intake of folate and vitamin B6 was combined in analysis.

Pancreatic cancer risk is modulated by inflammatory potential of diet and ABO genotype: a consortia-based evaluation and replication study.

Diets with high inflammatory potential are suspected to increase risk for pancreatic cancer (PC). Using pooled analyses, we examined whether this association applies to populations from different geographic regions and population subgroups with varying risks for PC, including variation in ABO blood type. Data from six case-control studies (cases, n = 2414; controls, n = 4528) in the Pancreatic Cancer Case-Control Consortium (PanC4) were analyzed, followed by replication in five nested case-control studies (cases, n = 1268; controls, n = 4215) from the Pancreatic Cancer Cohort Consortium (PanScan). Two polymorphisms in the ABO locus (rs505922 and rs8176746) were used to infer participants' blood types. Dietary questionnaire-derived nutrient/food intake was used to compute energy-adjusted dietary inflammatory index (E-DII®) scores to assess inflammatory potential of diet. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable-adjusted logistic regression. Higher E-DII scores, reflecting greater inflammatory potential of diet, were associated with increased PC risk in PanC4 [ORQ5 versus Q1=2.20, 95% confidence interval (CI) = 1.85-2.61, Ptrend < 0.0001; ORcontinuous = 1.20, 95% CI = 1.17-1.24], and PanScan (ORQ5 versus Q1 = 1.23, 95% CI = 0.92-1.66, Ptrend = 0.008; ORcontinuous = 1.09, 95% CI = 1.02-1.15). As expected, genotype-derived non-O blood type was associated with increased PC risk in both the PanC4 and PanScan studies. Stratified analyses of associations between E-DII quintiles and PC by genotype-derived ABO blood type did not show interaction by blood type (Pinteraction = 0.10 in PanC4 and Pinteraction=0.13 in PanScan). The results show that consuming a pro-inflammatory diet and carrying non-O blood type are each individually, but not interactively, associated with increased PC risk.

Ingested nitrate and nitrite, disinfection by-products, and pancreatic cancer risk in postmenopausal women.

Nitrate and nitrite are precursors of N-nitroso compounds (NOC), probable human carcinogens that cause pancreatic tumors in animals. Disinfection by-products (DBP) exposures have also been linked with digestive system cancers, but few studies have evaluated relationships with pancreatic cancer. We investigated the association of pancreatic cancer with these drinking water contaminants and dietary nitrate/nitrite in a cohort of postmenopausal women in Iowa (1986-2011). We used historical monitoring and treatment data to estimate levels of long-term average nitrate and total trihalomethanes (TTHM; the sum of the most prevalent DBP class) and the duration exceeding one-half the maximum contaminant level (>½ MCL; 5 mg/L nitrate-nitrogen, 40 µg/L TTHM) among participants on public water supplies (PWS) >10 years. We estimated dietary nitrate and nitrite intakes using a food frequency questionnaire. We computed hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression and evaluated nitrate interactions with smoking and vitamin C intake. We identified 313 cases among 34,242 women, including 152 with >10 years PWS use (N = 15,710). Multivariable models of average nitrate showed no association with pancreatic cancer (HRp95vs. Q1 = 1.16, 95% CI: 0.51-2.64). Associations with average TTHM levels were also null (HRQ4vs. Q1 = 0.70, 95% CI:0.42-1.18). We observed no trend with increasing years of exposure to either contaminant at levels >½ MCL. Positive associations were suggested in the highest dietary nitrite intake from processed meat (HRp95vs. Q1 = 1.66, 95% CI 1.00-2.75;ptrend = 0.05). We found no interactions of nitrate with known modifiers of endogenous NOC formation. Our results suggest that nitrite intake from processed meat may be a risk factor for pancreatic cancer.

Soluble MICA is elevated in pancreatic cancer: Results from a population based case-control study.

Pancreatic cancer is diagnosed at a late stage and has one of the highest cancer mortality rates in the United States, creating an urgent need for novel early detection tools. A candidate biomarker for use in early detection is the soluble MHC class I-related chain A (s-MICA) ligand, which pancreatic tumors shed to escape immune detection. The objective of this study was to define the association between s-MICA levels and pancreatic cancer, in a population-based case-control study. S-MICA was measured in 143 pancreatic cancer cases and 459 controls. Unconditional logistic regression was used to calculate odds ratio (OR) for pancreatic cancer and 95% confidence intervals (CI). There was a positive association between increasing s-MICA levels and pancreatic cancer: compared to the lowest tertile, the ORs for pancreatic cancer were 1.25 (95%CI: 0.75-2.07) and 2.10 (95%CI: 1.29-3.42) in the second and highest tertiles, respectively (P-trend = 0.02). Our study supports previous work demonstrating a positive association between plasma s-MICA levels and pancreatic cancer.

Association between Alcohol Consumption, Folate Intake, and Risk of Pancreatic Cancer: A Case-Control Study.

Pancreatic cancer is one of the most fatal common cancers affecting both men and women, representing about 3% of all new cancer cases in the United States. In this study, we aimed to investigate the association of pancreatic cancer risk with alcohol consumption as well as folate intake. We performed a case-control study of 384 patients diagnosed with pancreatic cancer from May 2004 to December 2009 and 983 primary care healthy controls in a largely white population (>96%). Our findings showed no significant association between risk of pancreatic cancer and either overall alcohol consumption or type of alcohol consumed (drinks/day). Our study showed dietary folate intake had a modest effect size, but was significantly inversely associated with pancreatic cancer (odds ratio (OR) = 0.99, p < 0.0001). The current study supports the hypothesis that pancreatic cancer risk is reduced with higher food-based folate intake.

Sun Exposure and Protection Behaviors among Long-term Melanoma Survivors and Population Controls.

Introduction: Melanoma is considered a generally preventable cancer, with excessive ultraviolet radiation (UVR) exposure being a strong causal factor. UVR exposure following a melanoma diagnosis can be modified to reduce risk of second primary melanomas. The goal of this study was to compare measures of UVR exposure and protection behaviors between long-term melanoma survivors and controls.Methods: Participants from a previously conducted case-control study were recruited for a cross-sectional survey. Melanoma cases were 25 to 59 years old at diagnosis; controls were age and sex matched. Participants were asked about UVR exposure and protection measures used in the past year, and comparisons between melanoma survivors and controls were conducted using logistic regression models, adjusting for potential confounders.Results: A total of 724 (62.0%) long-term melanoma survivors and 660 (59.9%) controls completed the follow-up survey. Melanoma survivors were significantly less likely to report high sun exposure on a typical weekday [OR, 0.72 (0.55-0.94)], sunburns [OR, 0.40 (0.30-0.53)], or indoor tanning [OR, 0.20 (0.09-0.44)] than controls; however, high sun exposure on a typical weekend day was similar. Report of optimal sun protection behaviors was higher in melanoma survivors compared with controls. However, a few melanoma survivors reported indoor tanning, 10% reported intentionally seeking sun to tan, and 20% reported sunburns.Conclusions: Although long-term melanoma survivors reported healthier UVR exposure and protection behaviors compared with controls, a sizeable proportion still reported elevated sun exposure, sunburns, and suboptimal UVR protection behaviors.Impact: Opportunities remain for improving sun protection to reduce future melanoma risk among melanoma survivors. Cancer Epidemiol Biomarkers Prev; 26(4); 607-13. ©2017 AACR.

Comparison of quality of life among long-term melanoma survivors and non-melanoma controls: a cross-sectional study.

PURPOSE: Little is known about specific concerns facing long-term melanoma survivors. The goal of this study was to compare quality of life (QOL) and mental health between long-term melanoma survivors and population controls. METHODS: Participants from a previously conducted case-control study of risk factors for melanoma were recruited for a cross-sectional survey. Generic QOL and emotional health were measured using the SF-36 and Hospital Anxiety and Depression Scale questionnaires. A total of 724 melanoma survivors and 660 controls participated. Most melanoma survivors had stage I disease (85.6%); mean time from diagnosis was 9.6 ± 1.0 years. Comparisons of QOL measures between melanoma survivors and controls were conducted using regression models, adjusting for potential confounders. RESULTS: Melanoma survivors, compared to controls, reported statistically significant but only slightly higher physical functioning and bodily pain QOL subscale scores than controls and otherwise similar QOL as measured by the remaining six SF-36 subscale scores. Prevalence of anxiety (18.1% vs. 19.3%, adjusted OR = 1.00 (0.74, 1.36); p = 1.00) and depression (7.2% vs. 9.8%, adjusted OR = 0.74 (0.48, 1.16); p = 1.00) were similar between melanoma survivors and controls. CONCLUSION: Long-term early stage melanoma survivors report similar general QOL and mental health compared to population controls. Further research is needed to identify concerns more specific to melanoma.

Cytotoxic T Cells and Granzyme B Associated with Improved Colorectal Cancer Survival in a Prospective Cohort of Older Women.

Background: Host immune response may predict the course of colorectal cancer. We examined the survival of 468 colorectal cancer patients associated with two tumor-infiltrating immune biomarkers, the number of cytotoxic T lymphocytes (CTLs), and the activated CTLs, as reflected by the number of cells expressing granzyme B (GZMB) in the prospective Iowa Women's Health Study.Methods: Using paraffin-embedded tissue samples, we constructed and immunostained tumor microarrays with CD8 (for CTL) and GZMB antibodies. We scored CTL and GZMB densities in tumor epithelial and stromal tissues and also created a composite score for each biomarker (sum of the scores across tissue compartments). Cox regression estimated the HR and 95% confidence intervals (CI) for all-cause and colorectal cancer-specific death associated with each composite score.Results: CTL and GZMB composite scores were positively correlated (r = 0.65) and each biomarker was inversely correlated with stage at diagnosis. Both composite scores were higher in proximal colon tumors and tumors characterized by MSI-high, CIMP-high, or BRAF mutation status. HRs (95% CI) were 0.53 (0.38-0.75; Ptrend = 0.0004) and 0.66 (0.51-0.86; Ptrend = 0.002) for all-cause death, respectively, and 0.30 (0.18-0.51; Ptrend < 0.0001) and 0.41 (0.27-0.63; Ptrend < 0.0001) for colorectal cancer-related death, respectively. Including CTL and GZMB scores simultaneously in the model significantly improved the predictive performance of the models for all-cause and colorectal cancer-related death.Conclusions: Higher tumor infiltration with CTL and GZMB cells is associated with improved all-cause and cancer-specific survival of colorectal cancer patients.Impact: Both the number of CTLs and GZMB appear to be useful prognostic factors in colorectal cancer, irrespective of stage. Cancer Epidemiol Biomarkers Prev; 26(4); 622-31. ©2016 AACR.

Pooled analysis of active cigarette smoking and invasive breast cancer risk in 14 cohort studies.

Background: The 2014 US Surgeon General's report noted research gaps necessary to determine a causal relationship between active cigarette smoking and invasive breast cancer risk, including the role of alcohol consumption, timing of exposure, modification by menopausal status and heterogeneity by oestrogen receptor (ER) status. Methods: To address these issues, we pooled data from 14 cohort studies contributing 934 681 participants (36 060 invasive breast cancer cases). Cox proportional hazard regression models were used to calculate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Smoking duration before first birth was positively associated with risk ( P -value for trend = 2 × 10 -7 ) with the highest HR for initiation >10 years before first birth (HR = 1.18, CI 1.12-1.24). Effect modification by current alcohol consumption was evident for the association with smoking duration before first birth ( P -value=2×10 -4 ); compared with never-smoking non-drinkers, initiation >10 years before first birth was associated with risk in every category of alcohol intake, including non-drinkers (HR = 1.15, CI 1.04-1.28) and those who consumed at least three drinks per day (1.85, 1.55-2.21). Associations with smoking before first birth were limited to risk of ER+ breast cancer ( P -value for homogeneity=3×10 -3 ). Other smoking timing and duration characteristics were associated with risk even after controlling for alcohol, but were not associated with risk in non-drinkers. Effect modification by menopause was not evident. Conclusions: Smoking, particularly if initiated before first birth, was modestly associated with ER+ breast cancer risk that was not confounded by amount of adult alcohol intake. Possible links with breast cancer provide additional motivation for young women to not initiate smoking.

Aspirin use and the incidence of breast, colon, ovarian, and pancreatic cancers in elderly women in the Iowa Women's Health Study.

PURPOSE: Few studies have evaluated the chemopreventive effect of aspirin on the cancer risk in elderly women. We examined associations between frequency, dose, and duration of aspirin use with incidence of 719 aspirin-sensitive cancers (cancers of colon, pancreas, breast, and ovaries) in the Iowa Women's Health Study (IWHS), a prospective cohort of women over 70 years old. METHODS: Aspirin frequency, dose, and duration were self-reported in the 2004 IWHS questionnaire. Women were followed-up to 2011. Cancer cases were ascertained by linkage to the Iowa State Health Registry. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CI). RESULTS: Among the 14,386 women, 30 % were nonusers of aspirin; 34 % used low-dose aspirin, and 36 % used regular- or high-dose aspirin. Compared with nonuse of aspirin, the HRs (95 % CI) for incidence of aspirin-sensitive cancers were 0.87 (0.72-1.06) for regular to high doses of aspirin use, 0.95 (0.80-1.13) for aspirin use 6+ times per week, and 0.93 (0.74-1.17) for aspirin use for 10+ years. For cumulative aspirin use, HR (95 % CI) was 0.87 (0.70-1.09) for >60,000 mg of aspirin per year and 0.95 (0.75-1.21) for >280,000 mg of aspirin in their lifetime, versus nonuse of aspirin. Results were similar for the all-cause cancer death as an endpoint, with a significant inverse association observed between lifetime aspirin dose and cancer mortality [<95,000 mg vs nonuser HR 0.76 (0.61-0.95)]. CONCLUSIONS: These findings suggest that aspirin use may prevent incident breast, colon, pancreatic, and ovarian cancer in elderly women.

Nitrate from Drinking Water and Diet and Bladder Cancer Among Postmenopausal Women in Iowa.

BACKGROUND: Nitrate is a drinking water contaminant arising from agricultural sources, and it is a precursor in the endogenous formation of N-nitroso compounds (NOC), which are possible bladder carcinogens. OBJECTIVES: We investigated the ingestion of nitrate and nitrite from drinking water and diet and bladder cancer risk in women. METHODS: We identified incident bladder cancers among a cohort of 34,708 postmenopausal women in Iowa (1986-2010). Dietary nitrate and nitrite intakes were estimated from a baseline food frequency questionnaire. Drinking water source and duration were assessed in a 1989 follow-up. For women using public water supplies (PWS) > 10 years (n = 15,577), we estimated average nitrate (NO3-N) and total trihalomethane (TTHM) levels and the number of years exceeding one-half the maximum contaminant level (NO3-N: 5 mg/L, TTHM: 40 µg/mL) from historical monitoring data. We computed hazard ratios (HRs) and 95% confidence intervals (CIs), and assessed nitrate interactions with TTHM and with modifiers of NOC formation (smoking, vitamin C). RESULTS: We identified 258 bladder cancer cases, including 130 among women > 10 years at their PWS. In multivariable-adjusted models, we observed nonsignificant associations among women in the highest versus lowest quartile of average drinking water nitrate concentration (HR = 1.48; 95% CI: 0.92, 2.40; ptrend = 0.11), and we found significant associations among those exposed ≥ 4 years to drinking water with > 5 mg/L NO3-N (HR = 1.62; 95% CI: 1.06, 2.47; ptrend = 0.03) compared with women having 0 years of comparable exposure. TTHM adjustment had little influence on associations, and we observed no modification by vitamin C intake. Relative to a common reference group of never smokers with the lowest nitrate exposures, associations were strongest for current smokers with the highest nitrate exposures (HR = 3.67; 95% CI: 1.43, 9.38 for average water NO3-N and HR = 3.48; 95% CI: 1.20, 10.06 and ≥ 4 years > 5 mg/L, respectively). Dietary nitrate and nitrite intakes were not associated with bladder cancer. CONCLUSIONS: Long-term ingestion of elevated nitrate in drinking water was associated with an increased risk of bladder cancer among postmenopausal women. Citation: Jones RR, Weyer PJ, DellaValle CT, Inoue-Choi M, Anderson KE, Cantor KP, Krasner S, Robien K, Beane Freeman LE, Silverman DT, Ward MH. 2016. Nitrate from drinking water and diet and bladder cancer among postmenopausal women in Iowa. Environ Health Perspect 124:1751-1758; http://dx.doi.org/10.1289/EHP191.

Disposition of the Dietary Mutagen 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline in Healthy and Pancreatic Cancer Compromised Humans.

Pancreatic cancer is the fourth leading cause of cancer death in the U.S. Once diagnosed, prognosis is poor with a 5-year survival rate of less than 5%. Exposure to carcinogenic heterocyclic amines (HCAs) derived from cooked meat has been shown to be positively associated with pancreatic cancer risk. To evaluate the processes that determine the carcinogenic potential of HCAs for human pancreas, 14-carbon labeled 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a putative human carcinogenic HCA found in well-done cooked meat, was administered at a dietary relevant dose to human volunteers diagnosed with pancreatic cancer undergoing partial pancreatectomy and healthy control volunteers. After (14)C-MeIQx exposure, blood and urine were collected for pharmacokinetic and metabolite analysis. MeIQx-DNA adducts levels were quantified by accelerator mass spectrometry from pancreatic tissue excised during surgery from the cancer patient group. Pharmacokinetic analysis of plasma revealed a rapid distribution of MeIQx with a plasma elimination half-life of approximately 3.5 h in 50% of the cancer patients and all of the control volunteers. In 2 of the 4 cancer patients, very low levels of MeIQx were detected in plasma and urine suggesting low absorption from the gut into the plasma. Urinary metabolite analysis revealed five MeIQx metabolites with 2-amino-3-methylimidazo[4,5-f]quinoxaline-8-carboxylic acid being the most abundant accounting for 25%-50% of the recovered 14-carbon/mL urine. There was no discernible difference in metabolite levels between the cancer patient volunteers and the control group. MeIQx-DNA adduct analysis of pancreas and duodenum tissue revealed adduct levels indistinguishable from background levels. Although other meat-derived HCA mutagens have been shown to bind DNA in pancreatic tissue, indicating that exposure to HCAs from cooked meat cannot be discounted as a risk factor for pancreatic cancer, the results from this current study show that exposure to a single dietary dose of MeIQx does not readily form measurable DNA adducts under the conditions of the experiment.

Tumor eosinophil infiltration and improved survival of colorectal cancer patients: Iowa Women's Health Study.

The role of the innate immune response in colorectal cancer is understudied. We examined the survival of colorectal cancer patients in relation to eosinophils, innate immune cells, infiltrating the tumor. Tissue microarrays were constructed from paraffin-embedded tumor tissues collected between 1986 and 2002 from 441 post-menopausal women diagnosed with colorectal cancer in the Iowa Women's Health Study. Tissue microarrays were stained with an eosinophil peroxidase antibody. Eosinophils in epithelial and stromal tissues within the tumor (called epithelial and stromal eosinophils, hereafter) were counted and scored into three and four categories, respectively. In addition, the degree of eosinophil degranulation (across epithelial and stromal tissues combined) was quantified and similarly categorized. We used Cox regression to estimate the hazard ratios and 95% confidence interval for all-cause and colorectal cancer death during 5-year follow-up after diagnosis and during follow-up through 2011 ('total follow-up'). The hazard ratios associated with eosinophil scores were adjusted for age of diagnosis, SEER (Surveillance, Epidemiology, and End Results) stage, tumor grade, body mass, and smoking history. High tumor stromal eosinophil score was inversely correlated with age and stage, and was associated with a decreased risk for all-cause and colorectal cancer death: hazard ratios (95% confidence intervals) were 0.61 (0.36-1.02; P-trend=0.02) and 0.48 (0.24-0.93; P-trend=0.01), respectively, during the 5-year follow-up for the highest vs lowest category. The inverse associations also existed for total follow-up for all-cause and colorectal cancer death for the highest vs lowest stromal eosinophil score: hazard ratios (95% confidence intervals) were 0.72 (0.48-1.08; P-trend=0.04) and 0.61 (0.34-1.12; P-trend=0.04), respectively. Further adjustment for treatment, comorbidities, additional lifestyle factors, tumor location, or molecular markers did not markedly change the associations, while adjustment for cytotoxic T cells slightly attenuated all associations. The infiltration of tumors with eosinophils, especially in stromal tissue, may be an important prognostic factor in colorectal cancer.

Role of survivor bias in pancreatic cancer case-control studies.

PURPOSE: The purpose of this study was to evaluate the impact of survivor bias on pancreatic cancer case-control studies. METHODS: The authors constructed five case-loss scenarios based on the Iowa Women's Health Study cohort to reflect how case recruitment in population-based studies varies by case survival time. Risk factors for disease incidence included smoking, body mass index (BMI), waist circumference, diabetes, and alcohol consumption. Odds ratios (ORs) were estimated by conditional logistic regression and quantitatively compared by the interactions between risk factors and 3-month survival time. Additionally, Kaplan-Meier estimates for overall survival were compared within the subset cohort of pancreatic cancer cases. RESULTS: BMI and waist circumference showed a significant inverse relationship with survival time. Decreasing trends in ORs for BMI and waist circumference were observed with increasing case survival time. The interaction between BMI and survival time based on a cutpoint of 3 months was significant (P < .01) as was the interaction between waist circumference and survival time (P < .01). CONCLUSIONS: The findings suggested that case losses could result in survivor bias causing underestimated odds ratios for both BMI and waist circumference, whereas other risk factors were not significantly affected by case losses.