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Background: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood., Methods: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies., Results: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer., Conclusion: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

With improvements in both early detection and treatments for breast cancer, the number of survivors has increased dramatically in recent decades. One of the most common lingering symptoms posttreatment for cancer survivors is chronic fatigue. Based on family stress theory and Rolland's typology of illness, this qualitative study extends our understanding of the impact of persistent posttreatment fatigue on families and how breast cancer survivors manage the family issues that arise because of this chronic stressor. Participants included 35 female survivors of breast cancer (mean age = 54 years) who experienced fatigue after the completion of active cancer treatment, with the exception of long-term hormonal therapy. Data were generated from (a) observations of group sessions from a randomized controlled fatigue intervention designed to reduce fatigue in breast cancer survivors, (b) individual in-depth interviews, and (c) family sessions. Qualitative analysis revealed two broad themes that illustrate how the survivors manage the impact of fatigue on their families: Interpreting the meaning of the fatigue and Dealing with the inability to perform family roles. Study findings describe the difficulties in family adaptation when the family is not able to assign a clear meaning to a chronic symptom posttreatment and build upon family stress theory by highlighting interrelationships among communication patterns and role shifts in the family system., (©2011 APA)

Diabetes, characterized by perturbations in insulin production and signaling, is inversely associated with prostate cancer risk irrespective of stage. Obesity, a diabetes risk factor, is inversely associated with localized disease but positively associated with advanced disease. To understand the complex association between hyperinsulinemia and prostate cancer, we evaluated the association of plasma C-peptide, an insulin secretion marker, with prostate cancer risk in a case-control study nested in a prospective community cohort. Prostate cancer cases (n = 264) and matched controls (n = 264) were identified in the CLUE II cohort between 1989 (baseline) and 2002. C-peptide concentration was measured in baseline plasma by ELISA. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using conditional logistic regression, adjusting for being overweight or obese and family history. Median C-peptide concentration was lower in cases (1,180 pmol/L) than in controls (1,365 pmol/L; P = 0.03). Men in the highest (versus lowest) fourth of C-peptide had a lower risk for prostate cancer (OR, 0.65; 95% CI, 0.37-1.14; P-trend = 0.08), primarily localized disease (OR, 0.44; 95% CI, 0.19-1.03; P-trend = 0.04). Associations were similar to overall, when excluding cases diagnosed during the first 5 years of follow-up, men with diabetes, or men who had not had a prostate-specific antigen test. C-peptide concentration was inversely associated with subsequent diagnosis of prostate cancer, primarily localized disease, similar to the association for obesity. However, we cannot rule out detection bias that might result if men with higher C-peptide have lower prostate-specific antigen irrespective of whether prostate cancer is present or not., (©2010 AACR.)

Background: Due predominantly to cigarette smoking, lung cancer is the leading cancer-related cause of death worldwide. Cruciferous vegetables may reduce lung cancer risk. The association between intake of cruciferous vegetables and lung cancer risk was investigated in the CLUE II study, a community-based cohort established in 1989., Methods: We matched 274 incident cases of lung cancer diagnosed from 1990 to 2005 to 1,089 cancer-free controls on age, sex, and cigarette smoking. Dietary information was collected at baseline. Multivariable odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression., Results: Intake of cruciferous vegetables was inversely associated with lung cancer risk (highest-versus-lowest fourth: OR (Q4vsQ1), 0. 57; 95% CI, 0.38-0.85; P-trend = 0.01). The inverse associations held true for former smokers (OR(Q4vsQ1), 0.49; 95% CI, 0.27-0.92; P-trend = 0.05) and current smokers (OR(Q4vsQ1), 0.52; 95% CI, 0.29-0.95; P-trend = 0.02)., Conclusions: After carefully controlling for cigarette smoking, higher intake of cruciferous vegetable was associated with lower risk of lung cancer., Impact: The observed inverse association coupled with accumulating evidence suggests that intake of cruciferous vegetables is inversely associated with lung cancer risk, and this association seems to hold true beyond the confounding effects of cigarette smoking., (©2010 AACR.)

The Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP) brought together 10 cohorts to conduct a prospective study of the association between vitamin D status, measured as serum concentrations of 25-hydroxyvitamin D (25(OH)D), and the development of 7 rarer cancer sites: endometrial, esophageal, gastric, kidney, non-Hodgkin lymphoma, ovarian, and pancreatic cancers. The cohorts come from 3 continents, with participants from a wide range of latitude who are racially diverse. Across each cancer site, there was no evidence of a protective association between higher concentrations of 25-hydroxyvitamin D (>75 nmol/L) and cancer outcome. An increased risk at very high levels (> or =100 nmol/L) was noted for pancreatic cancer, confirming previous reports. The articles included in this issue detail the overall design and governance of the project, correlates of vitamin D status, and results from the cancer site-specific investigations. The Vitamin D Pooling Project realizes a major goal of consortium efforts, namely, to rigorously test hypotheses for rarer cancer outcomes that may not be adequately addressed in any one prospective cohort study. The results of this study have application for the planning and conduct of intervention trials, especially in determining potential risks.

The Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP), a consortium of 10 prospective cohort studies from the United States, Finland, and China, was formed to examine the associations between circulating 25-hydroxyvitamin D (25(OH)D) concentrations and the risk of rarer cancers. Cases (total n = 5,491) included incident primary endometrial (n = 830), kidney (n = 775), ovarian (n = 516), pancreatic (n = 952), and upper gastrointestinal tract (n = 1,065) cancers and non-Hodgkin lymphoma (n = 1,353) diagnosed in the participating cohorts. At least 1 control was matched to each case on age, date of blood collection (1974-2006), sex, and race/ethnicity (n = 6,714). Covariate data were obtained from each cohort in a standardized manner. The majority of the serum or plasma samples were assayed in a central laboratory using a direct, competitive chemiluminescence immunoassay on the DiaSorin LIAISON platform (DiaSorin, Inc., Stillwater, Minnesota). Masked quality control samples included serum standards from the US National Institute of Standards and Technology. Conditional logistic regression analyses were conducted using clinically defined cutpoints, with 50-<75 nmol/L as the reference category. Meta-analyses were also conducted using inverse-variance weights in random-effects models. This consortium approach permits estimation of the association between 25(OH)D and several rarer cancers with high accuracy and precision across a wide range of 25(OH)D concentrations.

A role for vitamin D in ovarian cancer etiology is supported by ecologic studies of sunlight exposure, experimental mechanism studies, and some studies of dietary vitamin D intake and genetic polymorphisms in the vitamin D receptor. However, few studies have examined the association of circulating 25-hydroxyvitamin D (25(OH)D), an integrated measure of vitamin D status, with ovarian cancer risk. A nested case-control study was conducted among 7 prospective studies to evaluate the circulating 25(OH)D concentration in relation to epithelial ovarian cancer risk. Logistic regression models were used to estimate odds ratios and 95% confidence intervals among 516 cases and 770 matched controls. Compared with 25(OH)D concentrations of 50-<75 nmol/L, no statistically significant associations were observed for <37.5 (odds ratio (OR) = 1.21, 95% confidence interval (CI): 0.87, 1.70), 37.5-<50 (OR = 1.03, 95% CI: 0.75, 1.41), or > or =75 (OR = 1.11, 95% CI: 0.79, 1.55) nmol/L. Analyses stratified by tumor subtype, age, body mass index, and other variables were generally null but suggested an inverse association between 25(OH)D and ovarian cancer risk among women with a body mass index of > or =25 kg/m(2) (P(interaction) < 0.01). In conclusion, this large pooled analysis did not support an overall association between circulating 25(OH)D and ovarian cancer risk, except possibly among overweight women.

Background: Metabolic syndrome components have been associated with colorectal cancer in several studies; however, evidence for colorectal adenomas is limited. Thus, we evaluated the association between markers of the metabolic syndrome with colorectal adenoma development in a nested case-control study., Methods: Colorectal adenoma cases (n = 132) and matched controls, who had a negative sigmoidoscopy or a colonoscopy (n = 260), were identified between baseline in 1989 and 2000 among participants in the CLUE II cohort of Washington County, Maryland. Concentrations of C-peptide, insulin-like growth factor binding protein-1, glycosylated hemoglobin, total cholesterol, high-density lipoprotein cholesterol, and triglycerides were measured in baseline blood specimens. Body mass index was calculated using baseline height and weight. Use of medications to treat diabetes mellitus was self-reported at baseline. Blood pressure was measured at baseline. Distributional cutpoints of the latter markers were used to define the metabolic syndrome components (hyperinsulinemia, hyperglycemia, obesity, dyslipidemia, and hypertension) present at baseline., Results: No statistically significant associations with adenomas were observed for the markers of the metabolic syndrome, with the exception of a strong positive association for use of diabetes medications (OR, 8.00; 95% CI, 1.70-37.67), albeit based on small numbers., Conclusion: Our findings do not support that components of the metabolic syndrome influence risk of colorectal adenomas, except possibly for severe diabetes mellitus warranting medical treatment.

Statin drugs appear to protect against advanced and possibly high-grade prostate cancer, perhaps through cholesterol-lowering. Thus, we evaluated the association between plasma cholesterol and prostate cancer. We conducted a prospective study in the CLUE II cohort of Washington County, MD. Included were 6,816 male county residents aged 35+ years old who did not have a cancer diagnosis at baseline in 1989. Plasma cholesterol, measured enzymatically at baseline, was categorized by clinical cutpoints. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) for total (n = 438) and high-grade (Gleason sum > or =7, n = 137) prostate cancer. Compared to men with high cholesterol (> or =240 mg/dl), men with desirable (<200 mg/dl) or borderline (200 to <240 mg/dl) levels were less likely to develop high-grade prostate cancer, particularly when restricting to organ-confined cases (HR: 0.68, 95% CI 0.40-1.18; P trend = 0.12) and among men with higher BMI (HR: 0.36, 95% CI 0.16-0.79; P trend = 0.02). Results were unchanged after excluding cholesterol-lowering drug users. Cholesterol was not associated with total prostate cancer. Our study supports two prior ones suggesting that cholesterol influences risk of high-grade prostate cancer, and indirectly supports the hypothesis that cholesterol-lowering is a mechanism by which statins are protective.

Objective and Methods: The association of 17 candidate single nucleotide polymorphisms (SNPs) in IL10 and other immune response genes (CRP, TLR4, IL6, IL1B, IL8, TNF, RNASEL) and genes related to obesity (PPARG, TCF7L2, ADIPOQ, LEP) with colorectal cancer was investigated. Haplotype tagging SNPs were chosen for IL10, CRP, and TLR4. Incident colorectal cancer cases (n = 208) and matched controls (n = 381) were identified between baseline in 1989 and 2003 among participants in the CLUE II cohort. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using conditional logistic regression., Results: Compared with the AA genotype at the candidate IL10-1082 locus (rs1800896), carrying one (OR, 0.79; 95% CI, 0.53-1.18) or two (OR, 0.58; 95% CI, 0.35-0.95) G alleles, a known higher producer of the anti-inflammatory cytokine IL-10, was associated with lower risk of colorectal cancer (p trend = 0.03). Statistically significant associations with colorectal cancer were observed for three tagSNPs in IL10 (rs1800890, rs3024496, rs3024498) and one common haplotype, but these associations were due to high linkage disequilibrium with IL10-1082. Two CRP haplotypes (global p = 0.04) and TLR4 tagSNPs (rs7873784, rs11536891), but not TLR4 haplotypes, were associated with colorectal cancer., Conclusions: Our study suggests that polymorphisms in IL10, and also possibly in CRP and other genes related to immune response or obesity may be associated with colorectal cancer.

Background: The aim of this study was to examine the associations between 16 specific single nucleotide polymorphisms (SNPs) in 8 obesity-related genes and overall and cause-specific mortality. We also examined the associations between the SNPs and body mass index (BMI) and change in BMI over time., Methods: Data were analyzed from 9,919 individuals who participated in two large community-based cohort studies conducted in Washington County, Maryland in 1974 (CLUE I) and 1989 (CLUE II). DNA from blood collected in 1989 was genotyped for 16 SNPs in 8 obesity-related genes: monoamine oxidase A (MAOA), lipoprotein lipase (LPL), paraoxonase 1 and 2 (PON1 and PON2), leptin receptor (LEPR), tumor necrosis factor-alpha (TNFalpha), and peroxisome proliferative activated receptor-gamma and -delta (PPARG and PPARD). Data on height and weight in 1989 (CLUE II baseline) and at age 21 were collected from participants at the time of blood collection. All participants were followed from 1989 to the date of death or the end of follow-up in 2005. Cox proportional hazards regression was used to obtain the relative risk (RR) estimates and 95% confidence intervals (CI) for each SNP and mortality outcomes., Results: The results showed no patterns of association for the selected SNPs and the all-cause and cause-specific mortality outcomes, although statistically significant associations (p < 0.05) were observed between PPARG rs4684847 and all-cause mortality (CC: reference; CT: RR 0.99, 95% CI 0.89, 1.11; TT: RR 0.60, 95% CI 0.39, 0.93) and cancer-related mortality (CC: reference; CT: RR 1.01, 95% CI 0.82, 1.25; TT: RR 0.22, 95% CI 0.06, 0.90) and TNFalpha rs1799964 and cancer-related mortality (TT: reference; CT: RR 1.23, 95% CI 1.03, 1.47; CC: RR 0.83, 95% CI 0.54, 1.28). Additional analyses showed significant associations between SNPs in LEPR with BMI (rs1137101) and change in BMI over time (rs1045895 and rs1137101)., Conclusion: Findings from this cohort study suggest that the selected SNPs are not associated with overall or cause-specific death, although several LEPR SNPs may be related to BMI and BMI change over time.

Gonadotropins have been indicted in ovarian carcinogenesis but direct evidence has been limited and inconsistent. The aim of this study was to determine the association between prediagnostic levels of follicle stimulating hormone (FSH) and subsequent development of invasive epithelial ovarian cancer. A nested case-control study was conducted using cases and controls drawn from three cohorts: CLUE I and CLUE II of Washington County, MD, and the Island of Guernsey Study, United Kingdom. In total, 67 incident invasive epithelial ovarian cancer cases were each matched to 1 to 2 controls on age, menopausal status, time since last menstrual period, current hormone use and other relevant factors. FSH concentrations were classified into ranked thirds of low, medium or high based on the distribution among controls. Conditional logistic regression was used to estimate the odds ratio (OR) across increasing thirds of FSH concentrations. Results of the analysis showed that ovarian cancer risk decreased with higher FSH concentrations (p-trend = 0.005). Compared with the lowest third of FSH concentrations, the OR among those in the middle and highest thirds were 0.45 [95% Confidence Interval (CI): 0.20-1.00] and 0.26 (95% CI: 0.10-0.70), respectively. Associations persisted after excluding cases diagnosed within 5 years of follow-up. In conclusion, a reduction in subsequent risk of invasive epithelial ovarian cancer was observed among women with higher circulating FSH concentrations. These findings contradict the hypothesized role of FSH as a risk factor in ovarian carcinogenesis.

Context: Whether immunosuppressive treatment adversely affects survival is unclear., Objective: To assess whether immunosuppressive drugs increase mortality., Design: Retrospective cohort study evaluating overall and cancer mortality in relation to immunosuppressive drug exposure among patients with ocular inflammatory diseases. Demographic, clinical, and treatment data derived from medical records, and mortality results from United States National Death Index linkage. The cohort's mortality risk was compared with US vital statistics using standardised mortality ratios. Overall and cancer mortality in relation to use or non-use of immunosuppressive drugs within the cohort was studied with survival analysis., Setting: Five tertiary ocular inflammation clinics. Patients 7957 US residents with non-infectious ocular inflammation, 2340 of whom received immunosuppressive drugs during follow up. Exposures Use of antimetabolites, T cell inhibitors, alkylating agents, and tumour necrosis factor inhibitors., Main Outcome Measures: Overall mortality, cancer mortality., Results: Over 66 802 person years (17 316 after exposure to immunosuppressive drugs), 936 patients died (1.4/100 person years), 230 (24.6%) from cancer. For patients unexposed to immunosuppressive treatment, risks of death overall (standardised mortality ratio 1.02, 95% confidence interval [CI] 0.94 to 1.11) and from cancer (1.10, 0.93 to 1.29) were similar to those of the US population. Patients who used azathioprine, methotrexate, mycophenolate mofetil, ciclosporin, systemic corticosteroids, or dapsone had overall and cancer mortality similar to that of patients who never took immunosuppressive drugs. In patients who used cyclophosphamide, overall mortality was not increased and cancer mortality was non-significantly increased. Tumour necrosis factor inhibitors were associated with increased overall (adjusted hazard ratio [HR] 1.99, 95% CI 1.00 to 3.98) and cancer mortality (adjusted HR 3.83, 1.13 to 13.01)., Conclusions: Most commonly used immunosuppressive drugs do not seem to increase overall or cancer mortality. Our results suggesting that tumour necrosis factor inhibitors might increase mortality are less robust than the other findings; additional evidence is needed.

Background: Chronic intra-prostatic inflammation and obesity are thought to influence prostate carcinogenesis. Thus, variants in genes in these pathways could be associated with prostate cancer risk., Methods: We genotyped 17 common single nucleotide polymorphisms (SNPs) in RNASEL, TLR4, IL1B, IL6, IL8, IL10, TNF, CRP, ADIPOQ, LEP, PPARG, and TCF7L2 in 258 white prostate cancer cases and 258 matched controls nested in CLUE II. Single-locus analyses were conducted using conditional logistic regression. TagSNPs were selected in IL10, CRP, and TLR4 and haplotype analyses were done., Results: The A allele of IL10 -1082G>A (rs1800896), known to result in lower levels of this anti-inflammatory cytokine, was positively associated with risk (AG vs. GG, OR = 1.69, 95% CI: 1.10-2.60; AA vs. GG, OR = 1.81, 95% CI: 1.11-2.96; P (trend) = 0.02). Associations of IL10 haplotypes with prostate cancer were explained by high linkage disequilibrium between two tagSNPs (rs1800890 and rs3024496) and -1082G>A. A TLR4 candidate SNP (rs4986790; AG/GG vs. AA, OR = 0.60, 95% CI: 0.33-1.08; P(trend) = 0.09), known to have decreased expression and be associated with lower circulating levels of inflammatory mediators, and tagSNP (rs10116253; CC vs. TT, OR = 3.05, 95% CI: 1.11-8.41), but not haplotypes, were associated with risk. None of the other candidate SNPs or haplotypes was statistically significantly associated with risk., Conclusion: Our prospective study suggests that genetic variation in IL10 and possibly TLR4 is associated with prostate cancer risk. Although none of the SNPs in the obesity genes tested was associated, this does not rule out a complex role of obesity and its metabolic consequences in prostate cancer etiology., (. (c) 2009 Wiley-Liss, Inc.)

Background: Infection with JC virus has been proposed as a risk factor for colorectal cancer. A nested case-control study was conducted to evaluate the association between prediagnostic JC virus antibodies and the risk of incident colorectal cancer and adenomas., Methods: Two research serum banks were established in Washington County, MD in 1974 and 1989, with the collection of blood samples from >45,000 volunteers. Incident colorectal cancer cases diagnosed through 2006 (n = 611) were identified among participants by linkage to population-based cancer registries, contributing 729 pairs of observations. Cases of adenomatous polyps (n = 123) were identified from participants of the 1989 cohort who reported having a colonoscopy-detected adenoma at follow-up through 2000 with histology confirmed through medical record review. One control was matched to each case on age, sex, race, and date of blood draw, and, for adenoma controls, date of endoscopy. IgG antibodies to JC virus were measured using virus-like particle ELISA. Associations between JC virus seropositivity and colorectal cancer and adenomas were estimated using conditional logistic regression., Results: Overall, there was no association between antibodies to JC virus and colorectal cancer [odds ratio (OR), 0.91; 95% confidence interval (95% CI), 0.71-1.17]. However, a statistically significant positive association between JC virus seropositivity and subsequent adenoma diagnosis was observed among males (OR, 2.31; 95% CI, 1.20-4.46), whereas a statistically significant inverse association was observed among females (OR, 0.31; 95% CI, 0.14-0.67; P for interaction = 0.01), after adjustment for baseline smoking and body mass index., Conclusions: Overall, JC virus seropositivity was not associated with colorectal cancer development up to 31 years later. Future studies are needed to confirm the adenoma findings.

Benign breast disease (BBD) is a risk factor for breast cancer and may have a heritable component. Deficient DNA repair has been implicated in breast cancer etiology and may exert its effect before BBD, a known precursor. The association between allelic variants in DNA repair genes and BBD was examined in a cohort of women in Washington County, Maryland. BBD was defined by two criteria: (a) a physician diagnosis of BBD or fibrocystic disease and/or (b) a benign breast biopsy. 3,212 women without BBD at baseline were genotyped for 12 candidate single nucleotide polymorphisms in seven DNA repair genes. Of these women, 482 subsequently reported a diagnosis of BBD. The Cox model was used to calculate hazard ratios (HR). Variant alleles of XRCC1 Arg(194)Trp (rs1799782) and ERCC4 Arg(415)Gln (rs1800067) were significantly associated with BBD [HR, 1.36; 95% confidence interval (95% CI), 1.06-1.74 and HR, 1.39; 95% CI, 1.09-1.76, respectively]. Similar estimates were also observed for each of the BBD criterion used. The BBD association for ERCC4 was even stronger among women with a family history of breast cancer (HR, 2.68; 95% CI, 1.52-4.66; P(interaction) = 0.02). This study suggests that variant alleles in DNA repair genes may modify BBD risk, a potential intermediate marker of breast cancer risk, particularly among high-risk subgroups.

Purpose: To critically assess potentially carcinogenic effects of immunosuppressive therapy in the ocular inflammation setting., Design: Focused evidence assessment., Methods: Relevant publications were identified by MEDLINE and EMBASE queries and reference list searches., Results: Extrapolation from transplant, rheumatology, skin disease, and inflammatory bowel disease cohorts to the ocular inflammation setting suggest that: 1) alkylating agents increase hematologic malignancy risk and cyclophosphamide increases bladder cancer risk, but less so with < or =18 months' duration of therapy and hydration, respectively; 2) calcineurin inhibitors and azathioprine probably do not increase total cancer risk to a detectable degree, except perhaps some other risk factors (uncommon in ocular inflammation patients) might interact with the former to raise risk; 3) tumor necrosis factor (TNF) inhibitors may accelerate diagnosis of cancer in the first six to 12 months, but probably do not increase long-term cancer risk; and 4) changes in risk with methotrexate, mycophenolate mofetil, and daclizumab appear negligible, although nontransplant data are limited for the latter agents. Immunosuppression in general may increase skin cancer risk in a sun exposure-dependent manner., Conclusion: Use of alkylating agents for a limited duration seems justifiable for severe, vision-threatening disease, but otherwise cancer risk may be a relevant constraint on use of this approach. Antimetabolites, daclizumab, TNF inhibitors, and calcineurin inhibitors probably do not increase cancer risk to a degree that outweighs the expected benefits of therapy. Monitoring for skin cancer may be useful for highly sun-exposed patients. Data from ocular inflammation patients are needed to confirm the conclusions made in this analysis by extrapolation.

Background: Individuals with a personal history of nonmelanoma skin cancer (NMSC) may have an increased risk of subsequent noncutaneous malignancies. To test this hypothesis, we carried out a community-based, prospective cohort study., Methods: In the CLUE (Give Us a Clue to Cancer and Heart Disease) II cohort, which was established in Washington County, MD, in 1989, the risk of new malignancies was compared among individuals with (n = 769) and without (n = 18,405) a personal history of NMSC (total n = 19,174) during a 16-year follow-up period. Pathologically confirmed NMSC (and other malignancies) were ascertained from the Washington County Cancer Registry. Cox regression analysis with time-dependent covariates was used to determine the hazard ratios (presented as multivariable-adjusted relative risks [RRs]) and 95% confidence intervals (CIs) of second primary malignancies associated with a previously confirmed NMSC diagnosis. All statistical tests were two-sided., Results: The crude incidence rate (per 10,000 person-years) of subsequent cancers other than NMSC among participants with a positive personal history of NMSC was 293.5 and with a negative history was 77.8. Compared with persons with no personal history of NMSC, those with such a history had a statistically significantly increased risk of being diagnosed with a subsequent cancer other than NMSC (RR = 1.99, 95% CI = 1.70 to 2.33) after adjusting for age, sex, body mass index, smoking status, and educational level. The association was observed for both basal cell carcinoma (multivariable-adjusted RR = 2.03, 95% CI = 1.70 to 2.42) and squamous cell carcinoma (multivariable-adjusted RR = 1.97, 95% CI = 1.50 to 2.59) of the skin. NMSC was a statistically significantly stronger cancer risk factor in younger age groups than in older age groups (P for interaction = .022)., Conclusions: This community-based, prospective cohort study provides evidence for an association between an NMSC diagnosis and an increased risk of subsequent cancer, even after adjusting for individual-level risk factors.

C-reactive protein is a sensitive but nonspecific systemic marker of inflammation. Several prospective studies have investigated the association of prediagnostic circulating C-reactive protein concentrations with the development of colorectal cancer, but the results have been inconsistent. We performed a systematic review of prospective studies of the association between prediagnostic measurements of circulating high-sensitivity C-reactive protein and development of invasive colorectal cancer. Authors of original studies were contacted to acquire uniform data. We combined relative risks (RR) for colorectal cancer associated with a one unit change in natural logarithm-transformed high-sensitivity C-reactive protein using inverse variance weighted random effects models. We identified eight eligible studies, which included 1,159 colorectal cancer cases and 37,986 controls. The summary RR per one unit change in natural log-transformed high-sensitivity C-reactive protein was 1.12 (95% confidence intervals [CI], 1.01-1.25) for colorectal cancer, 1.13 (95% CI, 1.00-1.27) for colon cancer, and 1.06 (95% CI, 0.86-1.30) for rectal cancer. The association was stronger in men (RR, 1.18; 95% CI, 1.04-1.34) compared to women (RR, 1.09; 95% CI, 0.93-1.27) but this difference was sensitive to the findings from a single study. Prediagnostic high-sensitivity C-reactive protein concentrations were weakly associated with an increased risk for colorectal cancer. More work is needed to understand the extent to which circulating high-sensitivity C-reactive protein or other blood inflammatory markers are related to colonic inflammation.

Objective: Circulating C-reactive protein concentration has been associated with colorectal cancer in some studies. Whether C-reactive protein is associated with earlier steps in the natural history of this cancer has not been published (aside from an abstract). Thus, we evaluated the association between plasma C-reactive protein concentration and development of colorectal adenoma in a nested case-control study., Methods: Colorectal adenoma cases (n = 135) and matched controls (n = 269) who had a negative sigmoidoscopy or colonoscopy were identified between baseline in 1989 and 2000 from among participants in the CLUE II cohort of Washington County, Maryland. Cases were confirmed by medical record review. Controls were matched with cases on age, sex, race, date of blood draw, time since last meal, and type of endoscopy. The odds ratio (OR) of adenoma was estimated from conditional logistic regression models., Results: C-reactive protein concentrations were similar between colorectal adenoma cases and controls (median C-reactive protein, 1.31 vs. 1.38 mg/l; p = 0.13). The OR of colorectal adenoma among those in the highest fourth (>2.95 mg/l) of C-reactive protein concentration compared with the lowest fourth (<0.65 mg/l) was 0.61 (95% confidence interval, 0.29-1.25; p for trend = 0.25)., Conclusions: Pre-diagnostic plasma C-reactive protein concentration was not associated with an increased risk of colorectal adenoma. More work is needed to determine whether C-reactive protein is a valid marker of intra-colonic inflammation, and whether such inflammation contributes to the etiology of colorectal neoplasia.

Objective: Cigarette smoking behavior may be influenced by catechol-O-methlyltransferase (COMT), dopamine beta-hydroxylase (DBH), and monamine oxidase-A (MAO-A), genes that play roles in dopamine metabolism. The association between common polymorphisms of these genes and smoking behavior was assessed among 10,059 Caucasian volunteers in Washington County, MD in 1989., Methods: Age-adjusted logistic regression was used to measure the association between variants of these single nucleotide polymorphisms and smoking initiation and persistent smoking., Results: Overall, no association was seen between each genotype and smoking behavior. However, among younger (<54 years) women, the COMT GG genotype was positively associated with smoking initiation (OR=1.3; 95% CI: 1.0 1.5), and the MAO-A TT genotype was inversely associated with persistent smoking (OR=0.7; 95% CI: 0.4, 1.0). Men who smoked fewer than 10 cigarettes per day were more likely to be persistent smokers if they had the COMT GG (OR=1.7; 95% CI: 1.0, 2.9) or the DBH GG (OR=1.6; 95% CI: 1.0, 2.5) genotypes., Conclusion: Overall the results of this large community-based study do not provide evidence to support the presence of important associations between variants of COMT, DBH, or MAO-A and smoking initiation or persistent smoking.

Objective: To investigate the hypothesis that pelvic floor disorders are associated with female sexual problems, independently of other related factors., Methods: The study population included 301 adult women seeking outpatient gynecologic and urogynecologic care. Pelvic floor disorders were assessed with the Pelvic Floor Disorders Inventory-20 (PFDI-20) and the pelvic organ prolapse quantification examination. Sexual function was assessed with the Personal Experiences Questionnaire. Using ordinal regression analysis, we identified characteristics and conditions associated with decreased libido, infrequent orgasm, decreased arousal, and dyspareunia., Results: Sexual function was poorer among 78 women (26%) without a current sexual partner than among 223 with a partner (P<.01). Among the 223 with a current partner, women with a high Pelvic Floor Disorders Inventory score were significantly more likely to report decreased arousal (P<.01), infrequent orgasm (P<.01), and increased dyspareunia (P<.01). A similar pattern was observed for the urinary, colorectal-anal, and prolapse scales of the Pelvic Floor Disorders Inventory, although some associations were marginally significant. Stage III-IV prolapse was significantly associated with infrequent orgasm (P=.02), but other sexual complaints were not more common with increasing prolapse stage., Conclusion: Pelvic floor symptoms are significantly associated with reduced sexual arousal, infrequent orgasm, and dyspareunia. We conclude that sexual function is worse in women with symptomatic prolapse but not in women with asymptomatic prolapse., Level of Evidence: II.

The purpose of this study was to examine the associations between single nucleotide polymorphisms (SNPs) in genes controlling inflammatory processes and mortality. Data were analyzed from 9,933 individuals who participated in two large community-based cohort studies conducted in Washington County, Maryland, in 1974 and 1989, designated "CLUE I" and "CLUE II," respectively. DNA from blood collected in 1989 was genotyped for 47 SNPs in 23 inflammation-related genes, including interferon-gamma (IFNgamma), lymphotoxin-alpha (LTalpha), tumor necrosis factor-alpha (TNFalpha), C-reactive protein (CRP), peroxisome proliferator-activated receptor (PPAR), and the human endothelial nitric oxide synthase (eNOS). All participants were followed from 1989 to the date of death or to June 20, 2005. The results showed no observable patterns of association for the SNPs and the all-cause and cause-specific mortality outcomes, although statistically significant associations were observed between at least one mortality outcome and SNPs in eNOS (reference SNP (rs) 1799983), PPARG (rs4684847), CRP (rs2794521), IFNgamma (rs2069705), TNFalpha (rs1799964), and LTalpha (rs2229094). Additionally, three of the four examined CRP SNPs were strongly associated with CRP serum concentration among those with CRP measurements. The authors' findings from this community-based prospective cohort study suggest that the selected SNPs are not associated with overall or cause-specific death, although CRP genotypes may be associated with systemic inflammation.

Introduction: This study was conducted in an ongoing community-based cohort study to examine the prevalence of non-cancer adverse health conditions among cancer survivors and the association of these conditions with self-rated health and functional status., Methods: Data were analyzed from CLUE II, a community-based cohort study in Washington County, Maryland that began in 1989. Cross-sectional comparisons were made between 1,261 cancer survivors and 1,261 age- and gender-matched individuals without a history of cancer. Information on non-cancer adverse health conditions, self-rated health, and activities of daily living was based on self-report., Results: Compared to individuals without a history of cancer, cancer survivors were significantly more likely to report a diagnosis of cardiovascular disease (33.8% versus 29.8%; p = 0.009) and endocrine disease (other than diabetes) (17.0% versus 14.3%; p = 0.02). Further, cancer survivors reporting two or more non-cancer adverse health conditions had a greater likelihood of reporting fair or poor self-rated health (odds ratio (OR) 4.11; 95% confidence interval (95% CI) 3.06, 5.54), and difficulty with at least one activity of daily living (OR 6.03; 95% CI 4.01, 9.05) compared to cancer survivors who did not report other adverse health conditions., Discussions/conclusions: Findings from this cross-sectional data analysis indicate that cancer survivors are at increased risk for non-cancer adverse health conditions, which are associated with poorer self-rated health, more interference with normal activities, and functional limitations., Implications for Cancer Survivors: Increased attention must be given to the preventive care and treatment of non-cancer adverse health conditions among cancer survivors to decrease non-cancer morbidity and mortality and to maintain and improve quality of life.

Purpose: To evaluate potential epidemiologic methods for studying long-term effects of immunosuppression on the risk of mortality and fatal malignancy, and present the methodological details of the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study., Methods: Advantages and disadvantages of potential study designs for evaluating rare, late-occurring events are reviewed, and the SITE Cohort Study approach is presented., Results: The randomized, controlled trial is the most robust method for evaluating treatment effects, but long study duration, high costs, and ethical concerns when studying toxicity limit its use in this setting. Retrospective cohort studies are potentially more cost-effective and timely, if records exist providing the desired information over sufficient follow-up time in the past. Case-control methods require extremely large sample sizes to evaluate risk associated with rare exposures, and recall bias is problematic when studying mortality. The SITE Cohort Study is a retrospective cohort study. Past use of antimetabolites, T-cell inhibitors, alkylating agents, and other immunosuppressives is ascertained from medical records of approximately 9,250 ocular inflammation patients at five tertiary centers over up to 30 years. Mortality and cause-specific mortality outcomes over approximately 100,000 person-years are ascertained using the National Death Index. Immunosuppressed and non-immunosuppressed groups of patients are compared with each other and general population mortality rates from US vital statistics. Calculated detectable differences for mortality/fatal malignancy with respect to the general population are 22%/49% for antimetabolites, 28%/62% for T-cell inhibitors, and 36%/81% for alkylating agents., Conclusions: Information from the SITE Cohort Study should clarify whether use of these immunosuppressive drugs for ocular inflammation increases the risk of mortality and fatal cancer. This epidemiologic approach may be useful for evaluating long-term risks of systemic therapies for other ocular diseases.

The primary aim of this study was to examine prospectively the associations between 5 peroxisome proliferator-activated receptor (PPAR) single nucleotide polymorphisms (SNPs) and cardiovascular morbidity and mortality in a community-based cohort study in Washington County, Maryland. Data were analyzed from 9,364 Caucasian men and women participating in CLUE-II. Genotyping on 5 PPAR polymorphisms was conducted using peripheral DNA samples collected in 1989. The followup period was from 1989 to 2003. The results showed that there were no statistically significant associations between the PPAR SNPs and cardiovascular deaths or events. In contrast, statistically significant age-adjusted associations were observed for PPARG rs4684847 with both baseline body mass and blood pressure, and for PPARG rs709158, PPARG rs1175543, and PPARD rs2016520 with baseline cholesterol levels. Future studies should be conducted to confirm these findings and to explore the associations in populations with greater racial and ethnic diversity.

The objective of this study was to examine the association between nonsteroidal anti-inflammatory drug (NSAID) use and the development of breast cancer, and to assess whether this association differed by estrogen receptor (ER) subtype. Data were analyzed from 15,651 women participating in CLUE II, a cohort study initiated in 1989 in Washington County, MD. Medication data were collected at baseline in 1989 and in 1996. Incident cases of invasive breast cancer occurring from baseline to March 27, 2006 were identified through linkage of cohort participants with the Washington County Cancer Registry and the Maryland State Cancer Registry. Cox proportional hazards modeling was used to calculate the risk ratios (RR) and 95% confidence intervals (95% CI) for breast cancer associated with medication use. Among women in the CLUE II cohort, 418 invasive breast cancer cases were identified during the follow-up period. The results showed that self-reported use of NSAIDs in both 1989 and in 1996 was associated with a 50% reduction in the risk of developing invasive breast cancer compared with no NSAID use in either 1989 or 1996 (RR = 0.50; 95% CI 0.28, 0.91). The protective association between NSAID use and the risk of developing breast cancer was consistent among ER-positive and ER-negative breast cancers, although only the RR for ER-positive breast cancer was statistically significant. Overall, findings from this study indicate that NSAID use is associated with a decrease in breast cancer risk and that the reduction in risk is similar for ER-positive and ER-negative tumors.

Objective: Men tend to report higher health-related quality of life (HRQOL) than women of the same age, despite higher mortality rates and lower life expectancy. Social support is one factor related to HRQOL that may contribute to the observed gender difference. The purpose of this study was to determine the factors associated with HRQOL, especially levels of social support, and variation by gender., Methods: Multivariable logistic regression was used to analyze data from 4,498 men and 6,948 women participating in an ongoing community-based cohort study in Washington County, Maryland (CLUE-II)., Results: The results showed that men reported significantly better HRQOL than women. Men reported having higher levels of social support than women, but the magnitude of the association with HRQOL was similar. Having two or less close friends was associated with a statistically significant increase in the odds of reporting poorer HRQOL compared to having 10 or more close friends among both genders (men: OR = 1.49; women: OR = 1.53). Differences in the level of social support did not explain the gender difference in HRQOL., Conclusions: Our findings show that social support is an important correlate of HRQOL for both men and women. However, the gender differences in HRQOL are not explained by social support or the other factors examined.

Purpose: Ductal lavage, a technique used to sample epithelial cells from breast ducts, has potential use in risk assessment and biomarker evaluation among women at increased risk for breast cancer. However, little is known about the reliability of the procedure., Methods: We evaluated the reliability of nipple aspirate (NAF) and ductal lavage at two time points 6 months apart in women at increased risk for breast cancer. Eligible women had a 5-year Gail risk >or=1.66% or lifetime risk of >20%, and/or a family history or personal history of breast cancer. All ducts that produced NAF were cannulated. The kappa statistic was used to evaluate reliability of NAF production, cellular yield, and cytologic diagnosis., Results: Sixty-nine women (mean age, 47 years) were enrolled over 35 months. Forty-seven returned for a second visit. At baseline, 65% of premenopausal and 41% of postmenopausal women produced NAF (P = 0.05), of which 72% underwent successful lavage of at least one duct. Samples of inadequate cellular material for diagnosis were significantly more likely in postmenopausal women than in premenopausal women (P = 0.04). Of the women who returned for a second visit, 18 of 24 who produced NAF had at least one duct successfully cannulated. Twenty-four ducts in 14 women were lavaged twice. Among these ducts, cellular yield for the two time points was inconsistent (kappa = 0.33 +/- 0.13), and only fair cytologic agreement was observed (kappa = 0.32 +/- 0.15). Ductal lavage was associated with moderate discomfort., Conclusion: Currently, the use of ductal lavage is limited by technical challenges in duct cannulation, inconsistent NAF production, a high rate of inadequate cellular material for diagnosis, fair cytologic reproducibility, and low participant return rates.

Objectives: To examine the association of cigarette smoking with subsequent fatal prostate cancer., Methods: Two private censuses were conducted in Washington County, Maryland, in which 26,810 adult men in 1963 and 28,292 in 1975 provided smoking information. Prostate cancer deaths through 2000 (1963 cohort, 240 deaths; and 1975 cohort, 184 deaths) were ascertained by review of the death certificates. Poisson regression analysis was used to estimate the rate ratio of prostate cancer death adjusted for age., Results: Overall, cigarette smokers in the 1963 census cohort were not more likely to die of prostate cancer than those who had never smoked cigarettes, pipes, or cigars when considering the total follow-up period. However, current smokers of 20 or more cigarettes per day (rate ratio 2.38; 95% confidence interval 0.94 to 5.99) and former smokers (rate ratio 2.75; 95% confidence interval 1.13 to 6.74) had a greater risk of death from prostate cancer during the first 10 years of follow-up. Weaker positive associations of prostate cancer death with current and former cigarette smoking were seen during the first 10 years of follow-up in the 1975 census cohort. Current cigarette smoking at baseline was not associated with the prostate cancer incidence., Conclusions: The lack of an association between cigarette smoking and prostate cancer incidence, but the tendency of greater prostate cancer mortality in former and current cigarette smokers earlier in the follow-up period is consistent with other studies in which smoking was assessed once at baseline.

Rare germline variants in mismatch repair genes have been linked to hereditary nonpolyposis colorectal cancer; however, it is unknown whether common polymorphisms in these genes alter the risk of colorectal cancer. To examine the association between common variants in mismatch repair genes and colorectal cancer, we conducted a case-cohort study within the CLUE II cohort. Four single nucleotide polymorphisms in 3 mismatch repair genes (MSH3 R940Q, MSH3 T1036A, MSH6 G39E and MLH1 I219V) were genotyped in 237 colorectal cancer cases and a subcohort of 2,189 participants. Incidence rate ratios (RRs) and 95% confidence intervals (95% CIs) for each polymorphism were estimated. The MSH3 1036A variant was found to be associated with an increased risk of colorectal cancer (RR=1.28, 95% CI: 0.94-1.74 and RR=1.65, 95% CI: 1.01-2.70 for the AT and TT genotypes, respectively, with p(trend)=0.02), particularly proximal colon cancer. Although the MSH3 940Q variant was only weakly associated with colorectal cancer overall (p(trend)=0.07), it was associated with a significant increased risk of proximal colon cancer (RR=1.69, 95% CI: 1.10-2.61 and RR=2.68, 95% CI: 0.96-7.47 for the RQ and QQ genotypes, respectively with p(trend)=0.005). Processed meat intake appeared to modify the association between the MSH3 polymorphisms and colorectal cancer (p(interaction) < 0.10 for both). No association was observed with the MSH6 and MLH1 polymorphisms overall. This study suggests that common polymorphisms in the mismatch repair gene, MSH3, may increase the risk of colorectal cancer, especially proximal colon cancer., ((c) 2006 Wiley-Liss, Inc.)

Active cigarette smoking is a major risk factor for bladder cancer. Secondhand exposure to cigarette smoke may also contribute to bladder carcinogenesis. The authors conducted a prospective cohort study to examine the influence of both active smoking and household exposure to secondhand smoke (SHS) on subsequent bladder cancer risk. The study population included persons from two cohorts established from private censuses conducted in Washington County, Maryland, in 1963 (n = 45,749; 93 cases) and 1975 (n = 48,172; 172 cases). Poisson regression models were fitted to estimate the relative risk of bladder cancer associated with active and passive smoke exposure in the two cohorts (referent category: never smokers who did not live with any smokers). Current smokers had an elevated risk of bladder cancer in both the 1963 cohort (relative risk (RR) = 2.7, 95% confidence limits (CL): 1.6, 4.7) and the 1975 cohort (RR = 2.6, 95% CL: 1.7, 3.9) after adjustment for age, education, and marital status. Among nonsmoking women, current household SHS exposure was associated with bladder cancer risk in the 1963 cohort (RR = 2.3, 95% CL: 1.0, 5.4) but not in the 1975 cohort (RR = 0.9, 95% CL: 0.4, 2.3). This study further solidifies the evidence that active smoking is causally associated with bladder cancer. Additional studies are needed to determine whether passive smoking is a risk factor for bladder cancer.

Background: Allele frequencies reported from public databases or articles are mostly based on small sample sizes. Differences in genotype frequencies by age, race and sex have implications for studies designed to examine genetic susceptibility to disease. In a community-based cohort of 9,960 individuals, we compared the allele frequencies of 49 single nucleotide polymorphisms (SNPs) of genes involved in inflammatory pathways to the frequencies reported on public databases, and examined the genotypes frequencies by age and sex. The genes in which SNPs were analyzed include CCR2, CCR5, COX1, COX2, CRP, CSF1, CSF2, IFNG, IL1A, IL1B, IL2, IL4, IL6, IL8, IL10, IL13, IL18, LTA, MPO, NOS2A, NOS3, PPARD, PPARG, PPARGC1 and TNF., Results: Mean(SD) age was 53.2(15.5); 98% were Caucasians and 62% were women. Only 1 out of 33 SNPs differed from the SNP500Cancer database in allele frequency by >10% in Caucasians (n = 9,831), whereas 12 SNPs differed by >10% (up to 50%) in African Americans (n = 105). Two out of 15 SNPs differed from the dbSNP database in allele frequencies by >10% in Caucasians, and 5 out of 15 SNPs differed by >10% in African Americans. Age was similar across most genotype groups. Genotype frequencies did not differ by sex except for TNF(rs1799724), IL2(rs2069762), IL10(rs1800890), PPARG(rs1801282), and CRP(rs1800947) with differences of less than 4%., Conclusion: When estimating the size of samples needed for a study, particularly if a reference sample is used, one should take into consideration the size and ethnicity of the reference sample. Larger sample size is needed for public databases that report allele frequencies in non-Caucasian populations.

Background: In vitro, human isoenzymes encoded by genes homozygous for the ADH1C*1 or ADH1B*2 alleles metabolize ethanol to acetaldehyde at a faster rate than those homozygous for the ADH1C*2 or ADH1B*1 allele. Because alcohol is a known risk factor for breast cancer, we evaluated the joint association of genetic variants in ADH and alcohol consumption in relation to breast cancer., Methods: A nested case-control study of 321 cases and matched controls was conducted. Five single nucleotide polymorphisms (SNPs) in the ADH1C and ADH1B genes were genotyped. Logistic regression was used to assess odds ratios (ORs) and 95% confidence limits (CIs) for each SNP. Haplotype analysis of all 5 SNPs was also undertaken., Results: Among drinkers, the median intake of total alcohol was 13 g/wk (10th-90th percentiles; 4.5-135.9) in cases and 18 g/wk (10th-90th percentiles; 4.5-104.1) in controls. Women who drank alcohol tended to be at an increased risk of developing breast cancer compared with those who did not drink (OR=1.40%, 95% CI 0.97-2.03), particularly those who were premenopausal at the time of breast cancer diagnosis (OR=2.69%, 95% CI: 1.00-7.26). Of the known functional alleles, breast cancer risk was not significantly increased among carriers of at least 1 ADH1C*1 or ADH1B*2 allele, when compared with those homozygous for the genotype at each locus. However, breast cancer risk tended to be lower among women who inherited the G allele at ADH1B IVS1+896A>G (OR=0.62, 95% CI 0.37-1.04). Overall haplotype frequencies were not significantly different between cases and controls., Conclusions: In this study low levels of alcohol are associated with a modest increase in breast cancer risk that is not altered by known functional allelic variants of the ADH1B and 1C gene. The protective association conferred by the G allele at ADH1B IVS1+896A>G needs further evaluation.

Objective: To evaluate the association of meat and dairy food consumption with subsequent risk of prostate cancer., Methods: In 1989, 3,892 men 35+ years old, who participated in CLUE II study of Washington County, MD, completed an abbreviated Block food frequency questionnaire. Intake of meat and dairy related foods was calculated using consumption frequency and portion size. Incident prostate cancer cases (n = 199) were ascertained through October 2004. Cox proportional hazards regression was used to calculate hazard ratios (HR) of total and advanced (SEER states three and four; n = 54) prostate cancer and 95% confidence intervals (CI) adjusted for age, BMI at age 21, and intake of energy, saturated fat, and tomato products., Results: Intakes of total mean (HR = 0.90, 95% CI 0.60-1.33, comparing highest to lowest tertile) and red meat (HR = 0.87, 95% CI 0.59-1.32) were not statistically significantly associated with prostate cancer. However, processed meat consumption was associated with a non-statistically significant higher risk of total (5+ vs. < or =1 servings/week: HR = 2.24; 95% CI 0.90-5.59) prostate cancer. There was no association across tertiles of dairy or calcium with total prostate cancer, although compared tp < or =1 servings/week consumption of 5+ servings/week of dairy foods was associated with an increased risk of prostate cancer (HR = 1.65, 98% CI 1.02-2.66)., Conclusion: Overall, consumption of processed meat, but not total meat or red meat, was associated with a possible increased risk of total prostate cancer in this prospective study. Higher intake of dairy foods but not calcium was positively associated with prostate cancer. Further investigation into the mechanisms by which processed meat and dairy consumption might increase the risk of prostate cancer is suggested.

Base excision repair (BER) corrects DNA damage caused by oxidative stress and low folate intake, which are putative risk factors for colorectal neoplasia. To examine the relationship between genetic variation in BER genes and colorectal adenoma risk, we conducted a case-control study of 767 cases of advanced colorectal adenoma and 773 controls from the baseline screening exam of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cases included participants diagnosed with advanced left-sided adenoma, and controls were subjects without evidence of a left-sided polyp by sigmoidoscopy, frequency-matched to cases on race and gender. Twenty single nucleotide polymorphisms were genotyped in four BER genes (APEX1, PARP1, POLB, and XRCC1), and conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association with colorectal adenoma. Two variants with possible functional significance were associated with risk. The APEX1 51H variant was associated with a borderline significant decreased risk of colorectal adenoma (OR, 0.66; 95% CI, 0.44-1.00), and the XRCC1 399Q variant was inversely associated with risk among Caucasians (OR, 0.80; 95% CI, 0.64-0.99). Homozygotes at two PARP1 loci (A284A and IVS13+118G>A) were also associated with a decreased risk of colorectal adenoma compared with wild-type carriers (OR, 0.70; 95% CI, 0.49-0.98 for both), which was restricted to advanced adenomas displaying histologically aggressive characteristics (OR, 0.51; 95% CI, 0.33-0.78, P = 0.002 for PARP1 A284A). This study suggests that polymorphisms in APEX1, XRCC1, and PARP1 may be associated with advanced colorectal adenoma.

Background: A cohort study was conducted among post-menopausal women to determine whether genetic polymorphisms in selected obesity-related genes (PPARG, LPL, LEPR, PON1, PON2, TNF-alpha) were associated with the progression of benign breast disease (BBD) to breast cancer and whether the selected polymorphisms modified the association between body mass and breast cancer among women with BBD., Methods: Among participants in an ongoing cohort study, 994 Caucasian post-menopausal women had a breast biopsy for BBD. Of these women, 61 subsequently developed breast cancer. A short questionnaire was administered at baseline in 1989. Genotypes were determined using DNA extracted from blood collected in 1989., Results: In this cohort, body mass index (BMI) was positively associated with the risk of developing breast cancer. In contrast, polymorphisms in PON1 (Gln192Arg) and LEPR (IVS2+6920) were associated with a decreased risk of developing invasive breast cancer. No statistically significant associations were observed for polymorphisms in PPARG, PON2, LPL, or TNF and breast cancer risk or for interactions between the polymorphisms and BMI and breast cancer risk., Conclusions: The findings suggest that specific polymorphisms in the PON1 and LEPR genes may play a role in progression of BBD to breast cancer among post-menopausal Caucasian women.

Obesity results from a complex interaction between diet, physical activity, and the environment. The built environment encompasses a range of physical and social elements that make up the structure of a community and may influence obesity. This review summarizes existing empirical research relating the built environment to obesity. The Medline, PsychInfo, and Web of Science databases were searched using the keywords "obesity" or "overweight" and "neighborhood" or "built environment" or "environment." The search was restricted to English-language articles conducted in human populations between 1966 and 2007. To meet inclusion criteria, articles had to 1) have a direct measure of body weight and 2) have an objective measure of the built environment. A total of 1,506 abstracts were obtained, and 20 articles met the inclusion criteria. Most articles (84%) reported a statistically significant positive association between some aspect of the built environment and obesity. Several methodological issues were of concern, including the inconsistency of measurements of the built environment across studies, the cross-sectional design of most investigations, and the focus on aspects of either diet or physical activity but not both. Given the importance of the physical and social contexts of individual behavior and the limited success of individual-based interventions in long-term obesity prevention, more research on the impact of the built environment on obesity is needed.

Background: The genes mutated in the cancer-prone syndrome, xeroderma pigmentosum (XP genes), have been well studied both biochemically and mechanistically. These genes are important components of the DNA nucleotide excision repair (NER) pathway, which protects against environmentally-induced cancers. XP genes are also downstream of the hereditary breast cancer syndrome gene, BRCA1, suggesting that XP genes may be important to hereditary forms of breast cancer as well. Although mutated XP genes are rare, polymorphic forms with potential functional deficiencies are common, and could pose a significant cancer risk in the general population., Hypothesis: This study tested the hypothesis that common polymorphic variants of XP genes were associated with the risk of breast cancer among a population of women in Washington County, Maryland., Methods: Five single nucleotide polymorphisms (SNPs) among four XP genes (XPC, XPD, XPF and XPG) were genotyped from DNA samples collected at baseline, and then analyzed by conditional logistic regression for association with the incidence of breast cancer. 321 cases were individually matched to 321 controls, by age and menopausal status., Results: No significant associations were found between breast cancer risk and any of the XP genotypes. Odds ratios for all genotypes ranged from 0.61 to 1.14, and none were statistically significant. Adjustment and stratification for family history of breast cancer did not alter the findings., Conclusion: These results suggest that polymorphisms of XP genes are not likely to be significant risk factors for women within the general population. This study did not address, however, risks for subpopulations of women with high exposures to DNA damaging agents.

The reproducibility of a test result is a critical component of its clinical utility. Little information is available concerning the intrarater reproducibility of cytologic assessments. This study evaluated the reproducibility of cytologic interpretation of epithelial cells obtained from ductal lavage (DL), a minimally invasive method used to obtain sample cells from breast tissue. Two cytospin slides were made for each duct sampled. Slides with <10 cells were considered inadequate to make a diagnosis; the remaining slides were classified into mildly atypical, markedly atypical, and malignant cells. Each pair of slides were classified by the more serious diagnosis. DL samples from 100 ducts were independently blind-reviewed by two experienced cytopathologists. All abnormal slides and a random sample of normal slides and slides identified as inadequate for diagnosis (n = 43) were re-reviewed. The kappa for intrarater agreement was 0.59 +/- 0.10 for cytopathologist 1 and 0.33 +/- 0.08 for cytopathologist 2. The kappa for interrater agreement of slides from 100 ducts was 0.46 +/- 0.07. The interrater agreement of the slides that were re-reviewed was kappa = 0.27 +/- 0.09. Fair to moderate intrarater and interrater agreement of DL cytology was observed. Low intrarater and interrater cytologic consistency may compromise the interpretation of clinical studies of DL.

Nucleotide excision repair (NER) enzymes are critical for the removal of bulky DNA adducts caused by environmental carcinogens, such as heterocyclic amines and polycyclic aromatic hydrocarbons, which are found in two putative risk factors for colorectal cancer, tobacco smoke and meat cooked at high temperature. To examine the association between common genetic variants in NER genes and the risk of colorectal cancer, we conducted a case-cohort study within the CLUE II cohort. Twenty-two single nucleotide polymorphisms in 11 NER genes were genotyped in 250 colorectal cancer cases and a subcohort of 2,224 participants. Incidence rate ratios (RR) and 95% confidence intervals (95% CI) were estimated using a modified Cox regression model and robust variance estimate. The ERCC6 1213G variant, which is thought to reduce NER capacity, was associated with an increased risk of colorectal cancer compared with the homozygous wild type (RR, 1.36; 95% CI, 1.00-1.86 and RR, 2.64; 95% CI, 1.53-4.58 for the RG and GG genotypes respectively with P(trend) = 0.0006). Having at least one XPC 492H allele was also associated with an increased risk of colorectal cancer (RR, 1.75; 95% CI, 1.20-2.57). When the combined effects of ERCC6 R1213G and XPC R492H were examined, the risk of colorectal cancer significantly increased with increasing number of variant alleles (P(trend) = 0.00003). Our study suggests that genetic polymorphisms in the NER genes, ERCC6 and XPC, may be associated with an increased risk of colorectal cancer.

Hair dyes are widely used, and permanent hair dye is the most commonly used type of product. Permanent hair dye colors are formed by an oxidative process involving arylamines, giving rise to concerns about the potential adverse health effects of long-term exposure, especially cancer. A 1993 International Agency for Cancer Research (IARC) review concluded that evidence was inadequate to evaluate the carcinogenicity of personal hair dye use. This systematic review synthesizes the results from studies of personal hair dye use and cancer published since 1993, taking into consideration the quality of exposure assessment. Thirty-one English-language articles published in January 1992-February 2005 that investigated the association between personal hair dye use and cancer were identified through the PubMed search engine. Quality of exposure assessment was rated between 1+ (lowest quality: assessed ever use of hair dyes) and 4+ (highest quality: assessed dye type [permanent/nonpermanent], dye color/shade, frequency and duration of use). Because of the heterogeneity of the exposure assessment across the studies, a formal meta-analysis was not conducted. Associations between personal hair dye use and non-Hodgkin's lymphoma, multiple myeloma, acute leukemia, and bladder cancer were observed in at least one well-designed study with detailed exposure assessment (rated 3+ or 4+), but were not consistently observed across studies. Results for bladder cancer studies suggest that subsets of the population may be genetically susceptible to hair dye exposures, but these findings are based on small subgroups in one well-designed case-control study. Replication of these findings is needed to determine whether the reported associations are real or spurious.

Purpose: The objective of this study was to examine the association between flame-broiled food consumption, a source of heterocyclic amine exposure, and the development of breast cancer among cohort of women with benign breast disease (BBD). The variation of the association by acetylation phenotype, as determined by the genotypes of selected N-acetyltransferase 2 (NAT2) enzymes, was also examined., Methods: Among participants in an ongoing cohort study, 1187 women reported having a breast biopsy for BBD and completed a food frequency questionnaire. NAT2 G857A, NAT2 T341C, and NAT2 G590A genotypes were determined using DNA extracted from blood specimens collected in 1989. Incident cases of breast cancer were identified through linkage of the cohort participants with the Washington County Cancer Registry and the Maryland State Cancer Registry. Follow-up for the BBD cohort began at study entry in 1989 and ended on April 28, 2003., Results: Of the women in this study, 77 subsequently developed breast cancer. Results showed that, among rapid acetylators, flame-broiled food intake was associated with a statistically significant increase in the risk of breast cancer (odds ratio (OR) 2.62; 95% confidence interval (CI) 1.06, 6.46). No association was observed between flame-broiled food intake and breast cancer among slow acetylators (OR 0.75; 95% CI 0.39, 1.43)., Conclusions: These findings suggest that flame-broiled food may be a modifiable risk factor for the progression of BBD to invasive breast cancer among women who have genotypes consistent with rapid acetylation.

Background: A cohort study was conducted to examine the role of genetic polymorphisms in three estrogen metabolizing enzymes (COMT, CYP1A1, CYP1B1) and the two estrogen receptors (ESR1, ESR2) in the progression of benign breast disease (BBD) to breast cancer., Methods: Among participants in an ongoing cohort study, 1438 Caucasian women had a breast biopsy for BBD and were successfully genotyped for at least one of the polymorphisms examined in this study. Genotypes were determined using DNA extracted from blood specimens collected in 1989. Incident cases of breast cancer occurring subsequent to BBD diagnosis up to 2003 were identified through cancer registries., Results: Among all participants, the ESR2 *5772G allele was associated with a significant decrease in the risk of breast cancer among women with BBD (Odds Ratio (OR) 0.38; 95% Confidence Interval (CI) 0.15, 0.96). Compared to the reference wild-type genotypes, marginally significant associations with the development of breast cancer were observed between carriers of the variant ESR1 - 104062T allele (OR 0.70, 95% CI 0.45, 1.09), the variant ESR2 *38A allele (OR 1.40; 95% CI 0.88, 2.25), and the variant CYP1B1 453Ser allele (OR 1.48, 95% CI 0.95, 2.32)., Conclusion: The results indicate that specific polymorphisms in the CYP1B1, ESR1, and ESR2 genes may play a role in progression of BBD to breast cancer among Caucasian women. Although additional studies are needed to confirm or refute our findings, these results suggest that genetic markers may aid in the identification of women who are at risk for progression of BBD to cancer.

Background: Biopsy-proven benign breast disease (BBD) is a risk factor for developing breast carcinoma; however, to the authors' knowledge, little is known regarding factors related to progression to carcinoma. A cohort study was conducted to examine the role of cyclooxygenase (COX) polymorphisms and nonsteroidal anti-inflammatory drugs (NSAIDs) in the progression of BBD to breast carcinoma., Methods: Among participants in an ongoing cohort study, 1467 women underwent a breast biopsy for BBD. Of these women, 91 subsequently developed breast carcinoma. Medication data were collected in 1989 and in 1996. COX genotypes were determined using DNA extracted from blood specimens collected in 1989., Results: A decrease in breast carcinoma risk was observed among women who reported using aspirin in 1989 (odds ratio [OR] of .46; 95% confidence interval [95% CI], .22-.98) and in 1996 (OR of .47, 95% CI, .18-1.21). Furthermore, a higher frequency, dose, and longer duration of aspirin use were associated with a decrease in the odds of developing breast carcinoma. Overall, no association was observed between COX genotypes and the subsequent development of breast carcinoma. However, among women not using NSAIDs, one COX-2 polymorphism (rs2143416) was found to be significantly associated with the development of breast carcinoma., Conclusions: Findings from the current study suggest that inflammation through COX-2 pathways may play a role in the progression of BBD to breast carcinoma and that aspirin may help to lower the risk of progression to breast carcinoma among women with BBD., (Copyright 2006 American Cancer Society.)

Chronic inflammation has been implicated in the pathogenesis of many common chronic diseases, including cancer. C-reactive protein (CRP) concentration is a non-specific serum marker of inflammation, and higher levels have been observed among individuals who go on to develop cardiovascular disease. Nested case-control studies were conducted within the CLUE II study, a community-based cohort, to examine the association between CRP concentrations and subsequent development of colorectal or prostate cancer. CRP concentrations were higher among individuals who went on to develop colon cancer, but not rectal or prostate cancer, compared with controls. The association between CRP concentrations and development of colon cancer is consistent with other evidence suggesting a role of inflammation and cancer. Preventive interventions that decrease systemic chronic inflammation have the potential to reduce certain types of cancer as well as cardiovascular disease. However, the potential benefits of anti-inflammatory chemopreventive agents must be weighed against their adverse effects before widespread use is recommended.

Introduction and Objective: Manganese superoxide dismutase (MnSOD), an enzyme that catalyzes superoxide radical quenching, is hypothesized to protect against premature aging. A C47T transition in the MnSOD gene may affect the enzyme's distribution to the mitochondrion, a site of high oxidative stress. We examined the association between this polymorphism and survival., Methods: Individuals who donated a blood sample to the CLUE I and II campaigns in 1974 and 1989, respectively, and completed a food frequency questionnaire in 1989 (N=6151) were included in the analysis. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated by Cox proportional hazards models. Mortality follow-up extended from 1989 to 2002., Results: MnSOD genotype distributions were 27% CC (wildtype homozygotes), 50% CT (heterozygotes) and 23% TT (variant homozygotes). TT and CT genotypes compared to the CC genotype were not associated with all-cause or cardiovascular disease mortality. A slight, but non-statistically significant higher risk of cancer mortality was observed for the CT (HR=1.13, 95% CI: 0.86-1.49) and TT (HR=1.24, 95% CI: 0.90-1.70) genotypes compared to CC genotype (p-trend=0.19)., Conclusion: We did not observe an association between the C47T polymorphism in the MnSOD gene and survival. These null associations were not modified by fruit and vegetable intake, cigarette smoking status, or body mass index.

Objective: The objective of this study was to examine the association between active cigarette smoking, household passive smoke exposure, and pancreatic cancer risk using a prospective cohort design., Methods: Two cohorts were established in Washington County, Maryland in 1963 (n = 45,749) and 1975 (n = 48,172). The Washington County Cancer Registry was used to ascertain the occurrence of pancreatic cancer in the 1963 cohort from 1963-1978 and in the 1975 cohort from 1975-1994. Poisson regression was used to analyze the associations between active smoking and household passive smoke exposure and pancreatic cancer risk., Results: Current active smoking was associated with a two-fold increased risk of pancreatic cancer in both cohorts. Among never-smokers in each cohort, exposure to household passive smoke was not associated with an increased risk of pancreatic cancer, although the confidence limits were wide due to a small number of cases., Conclusions: This study further documents the approximate doubling of pancreatic cancer risk in current active smokers. Our results also indicate that household passive smoke exposure is not associated with pancreatic cancer risk, although our risk estimates lacked precision.

Increased levels of insulin-like growth factor I (IGF-I) may directly stimulate breast cell proliferation and promote growth and survival of transformed cells. Higher levels of IGF-I have been associated with increased risk of premenopausal breast cancer but not postmenopausal breast cancer. We investigated whether circulating levels of IGF-I prior to menopause are associated with breast cancer diagnosed after menopause in a population-based nested case-control study. Female cohort participants were enrolled in 1974 (n = 15,192) and 1989 (n = 18,724) and blood was drawn. Cases were women diagnosed with primary breast cancer at ages > or =50, of whom 152 were premenopausal at blood draw. One control was matched to each case on cohort participation, age, ethnic group, menopausal status and date of blood draw. Levels of IGF-I and IGF binding protein 3 (IGFBP-3) were measured using enzyme-linked immunoabsorbent assays. The association between IGF-I and breast cancer was determined using conditional logistic regression, adjusting for IGFBP-3. IGF-I levels decreased with age (p = 0.0001). Prior to age-stratification, IGF-I levels neither measured before nor after menopause were associated with postmenopausal breast cancer. After age-stratification, associations were suggested in the youngest premenopausal age group (upper vs. lowest third: odds ratio (OR) = 5.31, 95% confidence intervals (CI) = 0.85-33.13; p trend = 0.06) and oldest postmenopausal age group (upper vs. lowest third: OR = 3.41, 95% CI = 0.66-17.71; p trend = 0.13). The association between circulating levels of IGF-I and postmenopausal breast cancer risk may be modified by age. Increased levels of circulating IGF-I may be of particular interest in the younger premenopausal women and older postmenopausal women. Age-stratification should be undertaken in larger investigations of IGF-I levels as predictors of postmenopausal breast cancer., ((c) 2005 Wiley-Liss, Inc.)