Impact of Histology and Tumor Grade on Clinical Outcomes Beyond 5 Years of Follow-Up in a Large Cohort of Renal Cell Carcinomas.

INTRODUCTION: The optimal length for clinical follow-up of renal cell carcinoma (RCC) patients is unclear. We evaluated the impact of ISUP/WHO tumor grade and histological subtype on short- and long-term survival and risk of recurrence/metastasis in a large cohort of RCC patients. PATIENTS AND METHODS: We studied 1679 RCC patients from a single referral center in Italy. Adjusted hazard ratios for overall survival were estimated using Cox regression models. Adjusted absolute risk of developing recurrence or metastasis was computed considering competing risks of mortality. RESULTS: During up to 13 years of follow-up, 175 (10.4%) RCC patients died, of whom 92% beyond 5 years. Hazard ratio of grade IV clear cell carcinomas (ccRCC) was 3.82 compared to grade II. Notably, 33% of recurrences and 56% of distant metastases occurred beyond 5 years of follow-up. The estimated probabilities of recurrence/metastasis were 15% and 45% within and beyond 5 years of follow-up, respectively. After 5 years, the absolute risk of recurrences increased also for papillary renal cell carcinoma type I (35.2%) and grade I ccRCC (17%). CONCLUSION: After 5 years of follow-up, both risk of mortality and recurrences or metastases were high and were modified by histological types and tumor grade. These data strongly support histology- and grade-tailored surveillance strategies and long-term follow-up for RCC patients.

Pesticide exposure and incident thyroid cancer among male pesticide applicators in agricultural health study.

BACKGROUND: Many pesticides are known to have thyroid-disrupting properties. However, few studies have evaluated the association between specific pesticide ingredients and risk of thyroid cancer. We investigated self-reported pesticide use and incident thyroid cancer in the Agricultural Health Study (AHS), a large cohort of occupationally-exposed male pesticide applicators. METHODS: The AHS is a prospective cohort of licensed pesticide applicators in Iowa and North Carolina. At enrollment (1993-1997) and follow-up (1999-2005), participants reported use of 50 pesticides. We characterized exposure as ever use (44 pesticides with ≥5 exposed cases) and by cumulative intensity-weighted lifetime days (22 pesticides with ≥10 exposed cases), a metric that accounts for factors that influence exposure. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression for incident thyroid (n = 85 cases) cancer among male participants using follow-up through 2014/2015. RESULTS: Use of the fungicide metalaxyl (HR = 2.03, CI:1.16-3.52) and the organochlorine insecticide lindane (HR = 1.74, CI:1.06-2.84) was associated with increased risk of thyroid cancer. The herbicide chlorimuron-ethyl was inversely associated with risk when we restricted to papillary thyroid cancer, the most common subtype (HR = 0.52, CI:0.28-0.96). High use of the insecticide carbaryl (>median intensity-weighted days) was inversely associated with thyroid cancer (HR = 0.20, CI:0.08-0.53, ptrend = 0.001). CONCLUSIONS: In this large cohort study, we observed increased risk of thyroid cancer associated with use of metalaxyl and lindane, and an inverse association with carbaryl. More work is needed to understand the potential role of these chemicals in thyroid carcinogenesis.

Ingested nitrate, disinfection by-products, and risk of colon and rectal cancers in the Iowa Women's Health Study cohort.

BACKGROUND: N-nitroso compounds (NOC) formed endogenously after nitrate/nitrite ingestion and disinfection by-products (DBPs) are suspected colorectal carcinogens, but epidemiologic evidence of these associations is limited. OBJECTIVES: We investigated the relationship between drinking water exposures and incident colorectal cancers in a cohort of postmenopausal women. METHODS: Using historical nitrate-nitrogen (NO3-N) measurements and estimates of total trihalomethanes (TTHM), the sum of 5 or 6 haloacetic acids (HAAs), and individual DBPs in public water supplies (PWS), we computed average exposures and years of exposure above one-half the U.S. maximum contaminant level (>1/2-MCL; >5 mg/L NO3-N and >40 µg/L TTHM). Nitrate/nitrite intakes from dietary sources were estimated using a food frequency questionnaire. We estimated hazard ratios (HR) and 95% confidence intervals (CI) from Cox regression models. We assessed NO3-N interactions with DBPs and with factors influencing endogenous NOC formation. RESULTS: We identified 624 colon and 158 rectal cancers (1986-2010) among 15,910 women reporting PWS use >10 years. Ingestion of NO3-N from drinking water was not associated with risk. Colon cancer risks were non-significantly associated with the average TTHM levels >17.7 µg/L (HRQ5vsQ1 = 1.13, CI = 0.89-1.44; ptrend = 0.11) and were elevated for any duration of exposure >1/2-MCL. Rectal cancer risks were associated with the highest TTHM levels (HRQ5vsQ1 = 1.71, CI = 1.00-2.92; ptrend = 0.22) but not with years >1/2-MCL. Bromodichloromethane (HRQ4vsQ1 = 1.89, CI = 1.17-3.00; ptrend = 0.09) and trichloroacetic acid (HRQ4vsQ1 = 1.92, CI = 1.20-3.09; ptrend = 0.18) levels were also associated with risk of rectal cancer. We found no evidence of interaction between TTHM and NO3-N on the risk of either cancer. Dietary analyses yielded a positive colon cancer association with red meat, but not with processed meat intake or estimated nitrate/nitrite from specific dietary sources. CONCLUSIONS: Our results suggest that exposure to TTHM in drinking water is associated with increased risk of rectal cancer. Positive findings for individual THMs and HAAs for both colon and rectal cancers require replication in other studies. We found no associations for nitrate overall or in subgroups with presumed higher NOC exposure.

Combining common genetic variants and non-genetic risk factors to predict risk of cutaneous melanoma.

Melanoma heritability is among the highest for cancer and single nucleotide polymorphisms (SNPs) contribute to it. To date, only SNPs that reached statistical significance in genome-wide association studies or few candidate SNPs have been included in melanoma risk prediction models. We compared four approaches for building polygenic risk scores (PRS) using 12 874 melanoma cases and 23 203 controls from Melanoma Meta-Analysis Consortium as a training set, and newly genotyped 3102 cases and 2301 controls from the MelaNostrum consortium for validation. We estimated adjusted odds ratios (ORs) for melanoma risk using traditional melanoma risk factors and the PRS with the largest area under the receiver operator characteristics curve (AUC). We estimated absolute risks combining the PRS and other risk factors, with age- and sex-specific melanoma incidence and competing mortality rates from Italy as an example. The best PRS, including 204 SNPs (AUC = 64.4%; 95% confidence interval (CI) = 63-65.8%), developed using winner's curse estimate corrections, had a per-quintile OR = 1.35 (95% CI = 1.30-1.41), corresponding to a 3.33-fold increase comparing the 5th to the 1st PRS quintile. The AUC improvement by adding the PRS was up to 7%, depending on adjusted factors and country. The 20-year absolute risk estimates based on the PRS, nevus count and pigmentation characteristics for a 60-year-old Italian man ranged from 0.5 to 11.8% (relative risk  = 26.34), indicating good separation.

Occupational pesticide exposure and subclinical hypothyroidism among male pesticide applicators.

OBJECTIVES: Animal studies suggest that exposure to pesticides may alter thyroid function; however, few epidemiologic studies have examined this association. We evaluated the relationship between individual pesticides and thyroid function in 679 men enrolled in a substudy of the Agricultural Health Study, a cohort of licensed pesticide applicators. METHODS: Self-reported lifetime pesticide use was obtained at cohort enrolment (1993-1997). Intensity-weighted lifetime days were computed for 33 pesticides, which adjusts cumulative days of pesticide use for factors that modify exposure (eg, use of personal protective equipment). Thyroid-stimulating hormone (TSH), thyroxine (T4), triiodothyronine (T3) and antithyroid peroxidase (anti-TPO) autoantibodies were measured in serum collected in 2010-2013. We used multivariate logistic regression to estimate ORs and 95% CIs for subclinical hypothyroidism (TSH >4.5 mIU/L) compared with normal TSH (0.4-<4.5 mIU/L) and for anti-TPO positivity. We also examined pesticide associations with TSH, T4 and T3 in multivariate linear regression models. RESULTS: Higher exposure to the insecticide aldrin (third and fourth quartiles of intensity-weighted days vs no exposure) was positively associated with subclinical hypothyroidism (ORQ3=4.15, 95% CI 1.56 to 11.01, ORQ4=4.76, 95% CI 1.53 to 14.82, ptrend <0.01), higher TSH (ptrend=0.01) and lower T4 (ptrend=0.04). Higher exposure to the herbicide pendimethalin was associated with subclinical hypothyroidism (fourth quartile vs no exposure: ORQ4=2.78, 95% CI 1.30 to 5.95, ptrend=0.02), higher TSH (ptrend=0.04) and anti-TPO positivity (ptrend=0.01). The fumigant methyl bromide was inversely associated with TSH (ptrend=0.02) and positively associated with T4 (ptrend=0.01). CONCLUSIONS: Our results suggest that long-term exposure to aldrin, pendimethalin and methyl bromide may alter thyroid function among male pesticide applicators.

Ingested Nitrate, Disinfection By-products, and Kidney Cancer Risk in Older Women.

BACKGROUND: N-nitroso compounds formed endogenously after nitrate/nitrite ingestion are animal renal carcinogens. Previous epidemiologic studies of drinking water nitrate did not evaluate other potentially toxic water contaminants, including the suspected renal carcinogen chloroform. METHODS: In a cohort of postmenopausal women in Iowa (1986-2010), we used historical measurements to estimate long-term average concentrations of nitrate-nitrogen (NO3-N) and disinfection by-products (DBP) in public water supplies. For NO3-N and the regulated DBP (total trihalomethanes [THM] and the sum of five haloacetic acids [HAA5]), we estimated the number of years of exposure above one-half the current maximum contaminant level (>½-MCL NO3-N; >5 mg/L). Dietary intakes were assessed via food frequency questionnaire. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) with Cox models, and evaluated interactions with factors influencing N-nitroso compound formation. RESULTS: We identified 125 incident kidney cancers among 15,577 women reporting using water from public supplies >10 years. In multivariable models, risk was higher in the 95th percentile of average NO3-N (HRp95vsQ1 = 2.3; CI: 1.2, 4.3; Ptrend = 0.33) and for any years of exposure >½-MCL; adjustment for total THM did not materially change these associations. There were no independent relationships with total THM, individual THMs chloroform and bromodichloromethane, or with haloacetic acids. Dietary analyses yielded associations with high nitrite intake from processed meats but not nitrate or nitrite overall. We found no interactions. CONCLUSIONS: Relatively high nitrate levels in public water supplies were associated with increased risk of renal cancer. Our results also suggest that nitrite from processed meat is a renal cancer risk factor.

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.

Polycyclic aromatic hydrocarbons: determinants of residential carpet dust levels and risk of non-Hodgkin lymphoma.

PURPOSE: To investigate the risk of non-Hodgkin lymphoma (NHL) associated with residential carpet dust measurements of polycyclic aromatic hydrocarbons (PAHs). METHODS: We evaluated the relationship between residential carpet dust PAH concentrations (benz(a)anthracene, benzo(a)pyrene, benzo(b)fluoranthene, benzo(k)fluoranthene, chrysene, dibenz(a,h)anthracene, and indeno(1,2,3-c,d)pyrene, and their sum) and risk of NHL (676 cases, 511 controls) in the National Cancer Institute Surveillance Epidemiology and End Results multicenter case-control study. As a secondary aim, we investigated determinants of dust PAH concentrations. We computed odds ratios (OR) and 95 % confidence interval (CI) for associations between NHL and concentrations of individual and summed PAHs using unconditional logistic regression, adjusting for age, gender, and study center. Determinants of natural log-transformed PAHs were investigated using multivariate least-squares regression. RESULTS: We observed some elevated risks for NHL overall and B cell lymphoma subtypes in association with quartiles or tertiles of PAH concentrations, but without a monotonic trend, and there was no association comparing the highest quartile or tertile to the lowest. In contrast, risk of T cell lymphoma was significantly increased among participants with the highest tertile of summed PAHs (OR = 3.04; 95 % CI, 1.09-8.47) and benzo(k)fluoranthene (OR = 3.20; 95 % CI, 1.13-9.11) compared with the lowest tertile. Predictors of PAH dust concentrations in homes included ambient air PAH concentrations and the proportion of developed land within 2 km of a residence. Older age, more years of education, and white race were also predictive of higher levels in homes. CONCLUSION: Our results suggest a potential link between PAH exposure and risk of T cell lymphoma and demonstrate the importance of analyzing risk by NHL histologic type.

Modeling groundwater nitrate concentrations in private wells in Iowa.

Contamination of drinking water by nitrate is a growing problem in many agricultural areas of the country. Ingested nitrate can lead to the endogenous formation of N-nitroso compounds, potent carcinogens. We developed a predictive model for nitrate concentrations in private wells in Iowa. Using 34,084 measurements of nitrate in private wells, we trained and tested random forest models to predict log nitrate levels by systematically assessing the predictive performance of 179 variables in 36 thematic groups (well depth, distance to sinkholes, location, land use, soil characteristics, nitrogen inputs, meteorology, and other factors). The final model contained 66 variables in 17 groups. Some of the most important variables were well depth, slope length within 1 km of the well, year of sample, and distance to nearest animal feeding operation. The correlation between observed and estimated nitrate concentrations was excellent in the training set (r-square=0.77) and was acceptable in the testing set (r-square=0.38). The random forest model had substantially better predictive performance than a traditional linear regression model or a regression tree. Our model will be used to investigate the association between nitrate levels in drinking water and cancer risk in the Iowa participants of the Agricultural Health Study cohort.

Polybrominated diphenyl ethers and thyroid cancer risk in the Prostate, Colorectal, Lung, and Ovarian Cancer Screening Trial cohort.

Polybrominated diphenyl ethers (PBDEs) alter thyroid hormone homeostasis, but their relationship with thyroid cancer is unknown. To investigate whether serum concentrations of PBDE were associated with thyroid cancer, we conducted a nested, case-control study in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, a large multicenter clinical trial in the United States. Cases with thyroid cancer (n = 104) were recruited from 1992 to 2001 and diagnosed through 2009, and controls (n = 208) were individually matched (2:1) to cases by race, sex, birth date (within 1 year), center, and blood collection date (within 15 days). We used gas chromatography isotope dilution high-resolution mass spectrometry to measure 10 tri- to heptabrominated diphenyl eithers in serum samples. Odds ratios and 95% confidence intervals were calculated using conditional logistic regression for lipid-adjusted PBDE levels detected in more than 50% of controls and for the sum of these BDEs (∑PBDEs). We observed no significant differences between cases and controls in lipid-adjusted concentrations of ∑PBDEs (for cases, median = 12.8 ng/g lipid (interquartile range, 6.2-42.1); for controls, median = 19.4 ng/g lipid (interquartile range, 7.6-50.2)) or for individual congeners. Increasing quartiles of ∑PBDEs and 4 BDE congeners were not associated with risk of thyroid cancer (for the fourth vs. first quartile of ∑PBDEs, adjusted odd ratio = 0.62, 95% confidence interval: 0.29, 1.30; P for trend = 0.56). Our study does not support an association between exposure to PBDEs and thyroid cancer.

Validity of expert assigned retrospective estimates of occupational polychlorinated biphenyl exposure.

Assessment of retrospective exposures based on expert judgment in case-control studies is usually of unknown validity because of the difficulty in finding gold standards for comparison. We investigated the relationship between expert-assigned retrospective occupational polychlorinated biphenyl (PCB) exposure estimates and serum PCB concentrations. Analyses were conducted on a subset of cases (n = 94) and controls (n = 96) in the multi-center National Cancer Institute, Surveillance, Epidemiology, and End Results Case-Control Study of non-Hodgkin lymphoma. Based on the subjects' lifetime work histories, an industrial hygienist assigned each job a probability of PCB exposure [<5% (unexposed), 5-<50% (possibly exposed), ≥50% (probably exposed)]. Ordinary least squares regression was used to investigate associations between the probability rating and log-transformed lipid-adjusted serum levels of 14 PCB congeners and total PCBs (ΓPCBs). Compared to unexposed participants (n = 163), those with a probably exposed job (n = 7) had serum levels that were 87% higher for ΓPCBs (95% confidence interval: 1.33-2.62) and 38% of serum level variability was explained by the probability rating. Statistically significant associations between probability ratings and serum levels for 12 of 14 individual congeners were also observed. In summary, the observed contrast in PCB serum levels by probability rating provides support for the occupational PCB exposure assessment.

Dietary nitrate and nitrite intake and risk of colorectal cancer in the Shanghai Women's Health Study.

Nitrate and nitrite are precursors of endogenously formed N-nitroso compounds (NOC), known animal carcinogens. Nitrosation reactions forming NOCs can be inhibited by vitamin C and other antioxidants. We prospectively investigated the association between dietary nitrate and nitrite intake and risk of colorectal cancer in the Shanghai Women's Health Study, a cohort of 73,118 women ages 40-70 residing in Shanghai. We evaluated effect modification by factors that affect endogenous formation of NOCs: vitamin C (at or above/below median) and red meat intake (at or above/below median). Nitrate, nitrite and other dietary intakes were estimated from a 77-item food frequency questionnaire administered at baseline. Over a mean of 11 years of follow-up, we identified 619 colorectal cancer cases (n = 383, colon; n = 236, rectum). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazard regression. Overall, nitrate intake was not associated with colorectal cancer risk (HR = 1.08; 95% CI: 0.73-1.59). However, among women with vitamin C intake below the median (83.9 mg day(-1) ) and hence higher potential exposure to NOCs, risk of colorectal cancer increased with increasing quintiles of nitrate intake (highest vs. lowest quintile HR = 2.45; 95% CI: 1.15-5.18; p trend = 0.02). There was no association among women with higher vitamin C intake. We found no association between nitrite intake and risk of colorectal cancer overall or by intake level of vitamin C. Our findings suggest that high dietary nitrate intake among subgroups expected to have higher exposure to endogenously formed NOCs increases risk of colorectal cancer.

Environmental determinants of polychlorinated biphenyl concentrations in residential carpet dust.

Polychlorinated biphenyls (PCBs), banned in the United Sates in the late 1970s, are still found in indoor and outdoor environments. Little is known about the determinants of PCB levels in homes. We measured concentrations of five PCB congeners (105, 138, 153, 170, and 180) in carpet dust collected between 1998 and 2000 from 1187 homes in four sites: Detroit, Iowa, Los Angeles, and Seattle. Home characteristics, occupational history, and demographic information were obtained by interview. We used a geographic information system to geocode addresses and determine distances to the nearest major road, freight route, and railroad; percentage of developed land; number of industrial facilities within 2 km of residences; and population density. Ordinal logistic regression was used to estimate the associations between the covariates of interest and the odds of PCB detection in each site separately. Total PCB levels [all congeners < maximum practical quantitation limit (MPQL) vs at least one congener ≥ MPQL to < median concentration vs at least one congener > median concentration] were positively associated with either percentage of developed land [odds ratio (OR) range 1.01-1.04 for each percentage increase] or population density (OR 1.08 for every 1000/mi(2)) in each site. The number of industrial facilities within 2 km of a home was associated with PCB concentrations; however, facility type and direction of the association varied by site. Our findings suggest that outdoor sources of PCBs may be significant determinants of indoor concentrations.

Risk of total and aggressive prostate cancer and pesticide use in the Agricultural Health Study.

Because pesticides may operate through different mechanisms, the authors studied the risk of prostate cancer associated with specific pesticides in the Agricultural Health Study (1993-2007). With 1,962 incident cases, including 919 aggressive prostate cancers among 54,412 applicators, this is the largest study to date. Rate ratios and 95% confidence intervals were calculated by using Poisson regression to evaluate lifetime use of 48 pesticides and prostate cancer incidence. Three organophosphate insecticides were significantly associated with aggressive prostate cancer: fonofos (rate ratio (RR) for the highest quartile of exposure (Q4) vs. nonexposed = 1.63, 95% confidence interval (CI): 1.22, 2.17; P(trend) < 0.001); malathion (RR for Q4 vs. nonexposed = 1.43, 95% CI: 1.08, 1.88; P(trend) = 0.04); and terbufos (RR for Q4 vs. nonexposed = 1.29, 95% CI: 1.02, 1.64; P(trend) = 0.03). The organochlorine insecticide aldrin was also associated with increased risk of aggressive prostate cancer (RR for Q4 vs. nonexposed = 1.49, 95% CI: 1.03, 2.18; P(trend) = 0.02). This analysis has overcome several limitations of previous studies with the inclusion of a large number of cases with relevant exposure and detailed information on use of specific pesticides at 2 points in time. Furthermore, this is the first time specific pesticides are implicated as risk factors for aggressive prostate cancer.