Showing papers in "Cancer Epidemiology, Biomarkers & Prevention in 2004"

Etiology of Hormone Receptor–Defined Breast Cancer: A Systematic Review of the Literature

Abstract: Breast cancers classified by estrogen receptor (ER) and/or progesterone receptor (PR) expression have different clinical, pathologic, and molecular features. We examined existing evidence from the epidemiologic literature as to whether breast cancers stratified by hormone receptor status are also etiologically distinct diseases. Despite limited statistical power and nonstandardized receptor assays, in aggregate, the critically evaluated studies ( n = 31) suggest that the etiology of hormone receptor–defined breast cancers may be heterogeneous. Reproduction-related exposures tended to be associated with increased risk of ER-positive but not ER-negative tumors. Nulliparity and delayed childbearing were more consistently associated with increased cancer risk for ER-positive than ER-negative tumors, and early menarche was more consistently associated with ER-positive/PR-positive than ER-negative/PR-negative tumors. Postmenopausal obesity was also more consistently associated with increased risk of hormone receptor–positive than hormone receptor–negative tumors, possibly reflecting increased estrogen synthesis in adipose stores and greater bioavailability. Published data are insufficient to suggest that exogenous estrogen use (oral contraceptives or hormone replacement therapy) increase risk of hormone-sensitive tumors. Risks associated with breast-feeding, alcohol consumption, cigarette smoking, family history of breast cancer, or premenopausal obesity did not differ by receptor status. Large population-based studies of determinants of hormone receptor–defined breast cancers defined using state-of-the-art quantitative immunostaining methods are needed to clarify the role of ER/PR expression in breast cancer etiology.

The Role of Tomato Products and Lycopene in the Prevention of Prostate Cancer: A Meta-Analysis of Observational Studies

Abstract: Purpose: To determine whether intake of tomato products reduces the risk of prostate cancer using a meta-analysis. Methods: We systematically searched MEDLINE and EMBASE and contacted authors to identify potential studies. Log relative risks (RRs) were weighed by the inverse of their variances to obtain a pooled estimate with its 95% confidence interval (CI). Logistic regression and Poisson regression analyses were used to determine the effect produced by a daily intake of one serving of tomato product. Results: Eleven case-control studies and 10 cohort studies or nested case-control studies presented data on the use of tomato, tomato products, or lycopene and met our inclusion criteria. Compared with nonfrequent users of tomato products (1st quartile of intake), the RR of prostate cancer among consumers of high amounts of raw tomato (5th quintile of intake) was 0.89 (95% CI 0.80-1.00). For high intake of cooked tomato products, this RR was 0.81 (95% CI 0.71-0.92). The RR of prostate cancer related to an intake of one serving/day of raw tomato (200 g) was 0.97 (95% CI 0.85-1.10) for the case-control studies and 0.78 (95% CI 0.66-0.92) for cohort studies. Conclusion: Our results show that tomato products may play a role in the prevention of prostate cancer. However, this effect is modest and restricted to high amounts of tomato intake. Further research is needed to determine the type and quantity of tomato products with respect to their role in preventing prostate cancer.

Plasma vitamin D metabolites and risk of colorectal cancer in women.

Abstract: Objective: Experimental evidence suggests that 1,25-dihydroxyvitamin D and its precursor, 25-hydroxyvitamin D [25(OH)D], may aid in the prevention of colorectal cancer. We therefore examined risk in relation to plasma concentrations of these vitamin D metabolites. Methods: In a nested case-control study among women in the Nurses' Health Study, we identified 193 colorectal cancer cases, ages 46 to 78 years, diagnosed up to 11 years after blood collection. Two controls were matched per case on year of birth and month of blood draw. Odds ratios (OR) for risk of colorectal cancer were calculated using conditional logistic regression adjusted for body mass index, physical activity, smoking, family history, use of hormone replacement therapy, aspirin use, and dietary intakes. Results: We found a significant inverse linear association between plasma 25(OH)D and risk of colorectal cancer ( P = 0.02). Among women in the highest quintile, the OR (95% confidence interval) was 0.53 (0.27–1.04). This inverse association remained strong when limited to women ≥60 years at blood collection ( P = 0.006) but was not apparent among the younger women ( P = 0.70). Benefit from higher 25(OH)D concentrations was observed for cancers at the distal colon and rectum ( P = 0.02) but was not evident for those at the proximal colon ( P = 0.81). In contrast to 25(OH)D, we did not observe an association between 1,25-dihydroxyvitamin D and colorectal cancer, although risk was elevated among the women in the highest quintile if they were also in the lower half of the 25(OH)D distribution (OR, 2.52; 95% confidence interval, 1.04–6.11). Conclusion: From these results and supporting evidence from previous studies, we conclude that higher plasma levels of 25(OH)D are associated with a lower risk of colorectal cancer in older women, particularly for cancers at the distal colon and rectum.

Lysophospholipids are potential biomarkers of ovarian cancer.

Abstract: Objective: To determine whether lysophosphatidic acid (LPA) and other lysophospholipids (LPL) are useful markers for diagnosis and/or prognosis of ovarian cancer in a controlled setting. Method: Plasma samples were collected from ovarian cancer patients and healthy control women in Hillsborough and Pinellas counties, Florida, and processed at the University of South Florida H. Lee Moffitt Cancer Center and Research Institute (Moffitt). Case patients with epithelial ovarian cancer ( n = 117) and healthy control subjects ( n = 27) participated in the study. Blinded LPL analysis, including 23 individual LPL species, was performed at the Cleveland Clinic Foundation using an electrospray ionization mass spectrometry–based method. LPL levels were transmitted to Moffitt, where clinical data were reviewed and statistical analyses were performed. Results: There were statistically significant differences between preoperative case samples ( n = 45) and control samples ( n = 27) in the mean levels of total LPA, total lysophosphatidylinositol (LPI), sphingosine-1-phosphate (S1P), and individual LPA species as well as the combination of several LPL species. The combination of 16:0-LPA and 20:4-LPA yielded the best discrimination between preoperative case samples and control samples, with 93.1% correct classification, 91.1% sensitivity, and 96.3% specificity. In 22 cases with both preoperative and postoperative samples, the postoperative levels of several LPL, including S1P, total LPA, and lysophosphatidylcholine (LPC) levels and some individual species of LPA and LPC, were significantly different from preoperative levels. Conclusion: LPA, LPI, LPC, and S1P appear useful as diagnostic and prognostic biomarkers of ovarian cancer.

Fear, Anxiety, Worry, and Breast Cancer Screening Behavior: A Critical Review

Abstract: Anxiety, fear, and worry are variously described as facilitators and barriers of breast cancer screening. However, several contradictions are evident in this research. A review article described the literature regarding the relations among fear, anxiety, and worry, along with emotion regulatory styles, and breast cancer screening behaviors before critiquing it in an attempt to uncover preliminary explanations for these discrepancies. Three main conclusions are drawn. First, it is suggested that researchers need to clearly define the components of cancer and the screening process that women are afraid of as each may bear a different relation to screening behavior. Second, greater care needs to be taken to employ psychometrically valid and reliable measures of fear and anxiety. Third, studies need to more systematically test findings across the minority and ethnic groups at greatest risk. A framework is presented and suggestions regarding the continued development of this promising area of research are made.

Folate and DNA Methylation: A Mechanistic Link between Folate Deficiency and Colorectal Cancer?

Abstract: Epidemiological, clinical, and animal studies collectively indicate that dietary folate intake and blood folate levels are inversely associated with colorectal cancer risk. Folate plays an essential role in one-carbon transfer involving remethylation of homocysteine to methionine, which is a precursor of S-adenosylmethionine, the primary methyl group donor for most biological methylations. DNA methylation is an important epigenetic determinant in gene expression, maintenance of DNA integrity and stability, chromosomal modifications, and development of mutations. Dysregulation and aberrant patterns of DNA methylation are generally considered to be mechanistically involved in colorectal carcinogenesis. Aberrant DNA methylation has been considered as a leading mechanism by which folate deficiency enhances colorectal carcinogenesis. However, currently available data pertaining to the effects of folate deficiency on DNA methylation are inconsistent and incomplete. The portfolio of evidence from animal, human, and in vitro studies suggests that the effects of folate deficiency on DNA methylation are highly complex; appear to depend on cell type, target organ, and stage of transformation; and are gene and site specific. In addition, the pattern of site- and gene-specific DNA methylation induced by folate deficiency may not be in concert with the direction of changes in genomic DNA methylation. Collectively, currently available evidence indicates that genomic DNA hypomethylation in the colorectum is not a probable mechanism by which folate deficiency enhances colorectal carcinogenesis. However, there is still a possibility that sequence-specific alterations of DNA methylation in critical cancer-related genes might be mechanistically involved in the folate deficiency-mediated colorectal carcinogenesis.

Diosgenin, a steroid saponin of Trigonella foenum graecum (Fenugreek), inhibits azoxymethane-induced aberrant crypt foci formation in F344 rats and induces apoptosis in HT-29 human colon cancer cells

Abstract: Trigonella foenum graecum (fenugreek) is traditionally used to treat disorders such as diabetes, high cholesterol, wounds, inflammation, and gastrointestinal ailments. Recent studies suggest that fenugreek and its active constituents may possess anticarcinogenic potential. We evaluated the preventive efficacy of dietary fenugreek seed and its major steroidal saponin constituent, diosgenin, on azoxymethane-induced rat colon carcinogenesis during initiation and promotion stages. Preneoplastic colonic lesions or aberrant crypt foci (ACF) were chosen as end points. In addition, we assessed the mechanism of tumor growth inhibition of diosgenin in HT-29 human colon cancer cells. To evaluate the effect of the test agent during the initiation and postinitiation stages, 7-week-old male F344 rats were fed experimental diets containing 0% or 1% fenugreek seed powder (FSP) or 0.05% or 0.1% diosgenin for 1 week and were injected with azoxymethane (15 mg/kg body weight). Effects during the promotional stage were studied by feeding 1% FSP or 0.1% diosgenin 4 weeks after the azoxymethane injections. Rats were sacrificed 8 weeks after azoxymethane injection, and their colons were evaluated for ACF. We found that, by comparison with control, continuous feeding of 1% FSP and 0.05% and 0.1% diosgenin suppressed total colonic ACF up to 32%, 24%, and 42%, respectively (P < or = 0.001 to 0.0001). Dietary FSP at 1% and diosgenin at 0.1% fed only during the promotional stage also inhibited total ACF up to 33% (P < or = 0.001) and 39% (P < or = 0.0001), respectively. Importantly, continuous feeding of 1% FSP or 0.05% or 0.1% diosgenin reduced the number of multicrypt foci by 38%, 20%, and 36% by comparison with the control assay (P < or = 0.001). In addition, 1% FSP or 0.1% diosgenin fed during the promotional stage caused a significant reduction (P < or = 0.001) of multicrypt foci compared with control. Dietary diosgenin at 0.1% and 0.05% inhibited total colonic ACF and multicrypt foci formation in a dose-dependent manner. Results from the in vitro experiments indicated that diosgenin inhibits cell growth and induces apoptosis in the HT-29 human colon cancer cell line in a dose-dependent manner. Furthermore, diosgenin induced apoptosis in HT-29 cells at least in part by inhibition of bcl-2 and by induction of caspase-3 protein expression. On the basis of these findings, the fenugreek constituent diosgenin seems to have potential as a novel colon cancer preventive agent.

Testicular cancer incidence in eight northern European countries: secular and recent trends.

Abstract: Objective: Striking geographic variation and marked increasing secular trends characterize the incidence of testicular cancer. However, it is not known whether these patterns have attenuated in recent years and whether they are similar for seminomas and nonseminomas, the two main histologic groups of testicular cancer. Method: Cancer registry data, including 27,030 testicular cancer cases, were obtained from Denmark, Estonia, Finland, Latvia, Lithuania, Norway, Poland, and Sweden. Between 57 (Denmark) and 9 (Poland) years of registration were covered. Country-specific temporal trends were estimated, with focus on the last decade and seminomas and nonseminomas. Data from the Nordic countries were further analyzed using an age-period-cohort approach. Results: Age-standardized incidence rates increased annually by 2.6% to 4.9% during the study period, with marginal differences between seminomas and nonseminomas. In the last decade, the increasing trend attenuated only in Denmark (annual change, −0.3%; 95% confidence interval, −1.5 to 0.9). In 1995, the highest and the lowest age-standardized incidence rates (per 105) were 15.2 in Denmark and 2.1 in Lithuania. Incidence rates (i.e., for all cancers and for seminomas and nonseminomas, separately) depended chiefly on birth cohort rather than on calendar period of diagnosis (although both birth cohort and period determined the Danish incidence rates). Conclusions: Testicular cancer incidence is still increasing, with the exception of Denmark, and a large geographic difference exists. The increasing trend is mainly a birth cohort phenomenon also in recent cohorts. Temporal trends for seminomas and nonseminomas are similar, which suggests that they share important causal factors.

Phytoestrogen Concentrations in Serum and Spot Urine as Biomarkers for Dietary Phytoestrogen Intake and Their Relation to Breast Cancer Risk in European Prospective Investigation of Cancer and Nutrition-Norfolk

Abstract: Subjects of this study consisted of 333 women (aged 45-75 years) drawn from a large United Kingdom prospective study of diet and cancer, the European Prospective Investigation of Cancer and Nutrition-Norfolk study. Using newly developed gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry methods incorporating triply (13)C-labeled standards, seven phytoestrogens (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) were measured in 114 spot urines and 97 available serum samples from women who later developed breast cancer. Results were compared with those from 219 urines and 187 serum samples from healthy controls matched by age and date of recruitment. Dietary levels were low, but even so, mean serum levels of phytoestrogens were up to 600 times greater than postmenopausal estradiol levels. Phytoestrogen concentrations in spot urine (adjusted for urinary creatinine) correlated strongly with that in serum, with Pearson correlation coefficients > 0.8. There were significant relationships (P < 0.02) between both urinary and serum concentrations of isoflavones across increasing tertiles of dietary intakes. Urinary enterodiol and enterolactone and serum enterolactone were significantly correlated with dietary fiber intake (r = 0.13-0.29). Exposure to all isoflavones was associated with increased breast cancer risk, significantly so for equol and daidzein. For a doubling of levels, odds ratios increased by 20-45% [log(2) odds ratio = 1.34 (1.06-1.70; P = 0.013) for urine equol, 1.46 (1.05-2.02; P = 0.024) for serum equol, and 1.22 (1.01-1.48; P = 0.044) for serum daidzein]. These estimates of risk are similar to those established for estrogens and androgens in postmenopausal breast cancer but need confirmation in larger studies.

The relative risks of a low-nitrosamine smokeless tobacco product compared with smoking cigarettes: estimates of a panel of experts.

Abstract: A nine-membered panel of experts was asked to determine expert opinions of mortality risks associated with use of low-nitrosamine smokeless tobacco (LN-SLT) marketed for oral use. A modified Delphi approach was employed. For total mortality, the estimated median relative risks for individual users of LN-SLT were 9% and 5% of the risk associated with smoking for those ages 35 to 49 and ≥50 years, respectively. Median mortality risks relative to smoking were estimated to be 2% to 3% for lung cancer, 10% for heart disease, and 15% to 30% for oral cancer. Although individual estimates often varied between 0% and 50%, most panel members were confident or very confident of their estimates by the last round of consultation. In comparison with smoking, experts perceive at least a 90% reduction in the relative risk of LN-SLT use. The risks of using LN-SLT products therefore should not be portrayed as comparable with those of smoking cigarettes as has been the practice of some governmental and public health authorities in the past. Importantly, the overall public health impact of LN-SLT will reflect use patterns, its marketing, and governmental regulation of tobacco products.

Weight Gain, Body Mass Index, Hormone Replacement Therapy, and Postmenopausal Breast Cancer in a Large Prospective Study

Abstract: Excess adiposity and hormone replacement therapy (HRT) are important contributors to postmenopausal breast cancer risk. HRT has been shown to modify the association between body weight and breast cancer risk, although few studies are sufficiently large to examine the risk of breast cancer associated with body mass index (BMI) and weight gain separately among current HRT users and nonusers. This study includes 1,934 incident breast cancer cases occurring among 62,756 postmenopausal women in the Cancer Prevention Study-II Nutrition Cohort. Age-adjusted incidence rates were calculated, and Cox proportional hazards models were used to examine the association of BMI and adult weight gain (since age 18 years) with breast cancer risk stratified by HRT use. Total adult weight gain strongly predicted breast cancer risk among former and never HRT users (P for trend 70 pounds compared with women who maintained their weight within 5 pounds of their weight at age 18. After accounting for weight gain, neither recent BMI nor BMI at age 18 were independent predictors of risk. Among current HRT users, no association was seen between breast cancer and either BMI or weight gain. Adult weight gain is strongly associated with postmenopausal breast cancer only among non-HRT users in this study. These data illustrate the importance of examining breast cancer risk factors separately by HRT use; the effects of other risk factors may be attenuated or obscured among women taking HRT.

Bowel Inflammation as Measured by Fecal Calprotectin A Link between Lifestyle Factors and Colorectal Cancer Risk

Abstract: The mechanisms by which the lifestyle risk factors obesity, physical inactivity, and low fiber intake predispose to colorectal cancer (CRC) are unclear. Chronic bowel inflammation predisposes to malignancy in cases of inflammatory bowel disease. Many lifestyle risk factors for CRC are associated with evidence of systemic inflammation as indicated by circulating levels of C-reactive protein (CRP), but it is unknown how this relates to inflammation at tissue level. Little is known about the degree of bowel inflammation in general population and the factors that affect it. Therefore, we aimed to assess the relation of levels of bowel inflammation in the general population and lifestyle risk factors for CRC, and to additionally assess whether these associations, if present, were attenuated by controlling for evidence of systemic inflammation. Average CRC risk subjects (320) of either sex aged 50-70 were recruited in South London. A stool sample was provided for calprotectin measurement (a marker of bowel inflammation), serum for CRP, and a detailed dietary and lifestyle questionnaire completed. There was a significant positive relationship between fecal calprotectin and increasing age (P = 0.002), obesity (P = 0.04), physical inactivity (P = 0.01), and an inverse relationship with fiber intake (P = 0.02) and vegetable consumption (P = 0.04). The relationship with obesity was attenuated by controlling for serum CRP. Fecal calprotectin levels are associated with lifestyle risk factors for colorectal cancer. Low-level asymptomatic bowel inflammation may be the link between lifestyle and the pathogenesis of CRC, and circulating proinflammatory cytokines may be part of the mechanism for this link.

Seroreactivity to human papillomavirus (HPV) types 16, 18, or 31 and risk of subsequent HPV infection: results from a population-based study in Costa Rica

Abstract: Whether antibodies to human papillomavirus (HPV) capsids, elicited by natural infection, are protective is unknown. This question was addressed in a population-based cohort of 7046 women in Costa Rica by examining the association between baseline seroreactivity to HPV-16, HPV-18, or HPV-31 virus-like particles and the risk of subsequent HPV infection at a follow-up visit 5-7 years after enrollment. Seropositivity to HPV-16, HPV-18, or HPV-31 was not associated with a statistically significant decreased risk of infection with the homologous HPV type [relative risk (RR) and [95% confidence interval (CI)], 0.74 (0.45-1.2), 1.5 (0.83-2.7), and 0.94 (0.48-1.8), respectively]. Seropositivity to HPV-16 or HPV-31 was not associated with a decreased risk of infection with HPV-16 or its genetically related types [RR (95% CI), 0.82 (0.61-1.1) and 0.93 (0.68-1.2), respectively]. Seropositivity to HPV-18 was not associated with a decreased risk of infection with HPV-18 or its genetically related types (RR 1.3; 95% CI 1.0-1.8). Thus, we did not observe immunity, although a protective effect from natural infection cannot be excluded because of the limits of available assays and study designs.

Natural history of human papillomavirus type 16 virus-like particle antibodies in young women.

Abstract: Immunization with a vaccine of human papillomavirus (HPV) type 16 virus-like particles (VLPs) can reduce incidence of HPV-16 infection and its related cervical intraepithelial neoplasia. However, development of detectable antibodies to VLPs does not always occur after natural HPV infection. This study examined prospectively for seroconversion and duration of antibodies to HPV-16 VLPs and their associated host and viral factors. Six-hundred eight subjects were tested for HPV DNA biannually and for IgG and IgA antibodies to HPV-16 VLPs annually for 3 years. Both IgG and IgA antibodies to HPV-16 VLPs were predominantly type specific. Women with cervicovaginal HPV-16 infection were 8-10 times more likely to seroconvert than those with infection of HPV-16-related types. Among subjects who had an incident infection with HPV-16, a maximum of 56.7% became seropositive for IgG within 8.3 months and 37.0% had IgA within 14 months. Detectable seroconversion was a slow process that required sufficient antigenic exposure associated with either a high viral load (relative risk = 5.7 for IgG) or persistent infection of HPV-16 (relative risk = 3.4 for IgA). The median duration for both types of antibodies was approximately 36 months. Antibodies could persist for a long period of time if the initial antibody levels were high or if there was continued antigenic exposure.

Plasma and Dietary Carotenoids, and the Risk of Prostate Cancer: A Nested Case-Control Study

Abstract: The association between plasma carotenoids and prostate cancer risk was investigated in a case-control study nested within the prospective Health Professionals Follow-up Study. We matched 450 incident prostate cancer cases diagnosed from 1993-1998 to 450 controls by age, time, month, and year of blood donation. Modest inverse, but not statistically significant, associations were observed among plasma alpha-carotene, beta-carotene, and lycopene concentrations, and overall risk of prostate cancer diagnosis [odds ratio (highest versus lowest quintile; OR), alpha-carotene: OR, 0.67 [95% confidence interval (CI), -0.40-1.09]; beta-carotene: OR, 0.78 (95% CI, 0.48-1.25); lycopene: OR, 0.66 (95% CI, 0.38-1.13)]. The inverse association between plasma lycopene concentrations and prostate cancer risk was limited to participants who were 65 years or older (OR, 0.47; 95% CI, 0.23-0.98) and without a family history of prostate cancer (OR, 0.48; 95% CI, 0.26-0.89). Combining, older age and a negative family history provided similar results (OR, 0.43; 95% CI, 0.18-1.02). Inverse associations between beta-carotene and prostate cancer risk were also found among younger participants (<65 years of age; OR, 0.36; 95% CI, 0.14-0.91; P(trend) = 0.03). Combining dietary intake and plasma data confirmed our results. We found a statistically significant inverse association between higher plasma lycopene concentrations and lower risk of prostate cancer, which was restricted to older participants and those without a family history of prostate cancer. This observation suggests that tomato products may exhibit more potent protection against sporadic prostate cancer rather than those with a stronger familial or hereditary component. In addition, our findings also suggest that among younger men, diets rich in beta-carotene may also play a protective role in prostate carcinogenesis.

Dietary carotenoids and risk of lung cancer in a pooled analysis of seven cohort studies

Abstract: Intervention trials with supplemental beta-carotene have observed either no effect or a harmful effect on lung cancer risk. Because food composition databases for specific carotenoids have only become available recently, epidemiological evidence relating usual dietary levels of these carotenoids with lung cancer risk is limited. We analyzed the association between lung cancer risk and intakes of specific carotenoids using the primary data from seven cohort studies in North America and Europe. Carotenoid intakes were estimated from dietary questionnaires administered at baseline in each study. We calculated study-specific multivariate relative risks (RRs) and combined these using a random-effects model. The multivariate models included smoking history and other potential risk factors. During follow-up of up to 7-16 years across studies, 3,155 incident lung cancer cases were diagnosed among 399,765 participants. beta-Carotene intake was not associated with lung cancer risk (pooled multivariate RR = 0.98; 95% confidence interval, 0.87-1.11; highest versus lowest quintile). The RRs for alpha-carotene, lutein/zeaxanthin, and lycopene were also close to unity. beta-Cryptoxanthin intake was inversely associated with lung cancer risk (RR = 0.76; 95% confidence interval, 0.67-0.86; highest versus lowest quintile). These results did not change after adjustment for intakes of vitamin C (with or without supplements), folate (with or without supplements), and other carotenoids and multivitamin use. The associations generally were similar among never, past, or current smokers and by histological type. Although smoking is the strongest risk factor for lung cancer, greater intake of foods high in beta-cryptoxanthin, such as citrus fruit, may modestly lower the risk.

Evaluation of Osteopontin as Biomarker for Pancreatic Adenocarcinoma

Abstract: Objective: Pancreatic adenocarcinoma is a deadly disease with an overall 5-year patient survival of less than 5%. This dismal prognosis of pancreatic cancer is largely due to the advanced stage of the disease at presentation. If pancreatic cancer could be diagnosed more readily and accurately using serum markers, patient survival could theoretically be improved by enabling more patients to avail of surgical resection. One candidate tumor marker recently identified by global gene expression analysis of pancreatic cancer is the secreted glycophosphoprotein osteopontin (OPN). In this study, we evaluate OPN as a serum marker of pancreatic adenocarcinoma. Methods: In situ hybridization for OPN was performed on a pancreatic adenocarcinoma tissue microarray. Serum OPN levels were determined in preoperative sera from 50 patients with pancreatic cancer and 22 healthy control individuals by competitive ELISA. Results: In situ hybridization for OPN performed on a tissue microarray revealed strong OPN mRNA signal in tumor-infiltrating macrophages in 8 of 14 pancreatic adenocarcinomas. In contrast, OPN expression was not seen in the pancreatic cancer cells themselves, nor was it seen in normal pancreatic tissue or in the macrophages distant from the infiltrating cancer. Serum OPN levels, as measured by ELISA, were elevated in the sera of 50 patients with resectable pancreatic adenocarcinoma compared to 22 healthy control individuals (mean ± SD for OPN was 482 ± 170 ng/ml and 204 ± 65 ng/ml, respectively; P < 0.001). Using a cutoff level of 2 SD above the mean for healthy individuals, elevated OPN had sensitivity of 80% and specificity of 97% for pancreatic cancer. In contrast, only 62% of these patients with resectable pancreatic cancer had elevated CA19-9. Conclusion: Serum OPN may have utility as a diagnostic marker in patients with pancreatic cancer.

Red Meat, Chicken, and Fish Consumption and Risk of Colorectal Cancer

Abstract: Background: Red meat and processed meat consumption have been associated with increased risk of colorectal cancer in some, but not all, relevant cohort studies. Evidence on the relationship between risk of colorectal cancer and poultry and fish consumption is inconsistent. Methods: We conducted a prospective cohort study of 37,112 residents of Melbourne, Australia recruited from 1990 to 1994. Diet was measured with a food frequency questionnaire. We categorized the frequency of fresh red meat, processed meat, chicken, and fish consumption into approximate quartiles. Adenocarcinomas of the colon or rectum were ascertained via the Victorian Cancer Registry. Results: We identified 283 colon cancers and 169 rectal cancers in an average of 9 years of follow-up. For rectal cancer, the hazard ratios [95% confidence intervals (95% CI)] in the highest quartile of consumption of fresh red meat and processed meat were 2.3 (1.2–4.2; P for trend = 0.07) and 2.0 (1.1–3.4; P for trend = 0.09), respectively. The corresponding hazard ratios (95% CIs) for colon cancer were 1.1 (0.7–1.6; P for trend = 0.9) and 1.3 (0.9–1.9; P for trend = 0.06). However, for neither type of meat was the heterogeneity between subsites significant. Chicken consumption was weakly negatively associated with colorectal cancer (hazard ratio highest quartile, 0.7; 95% CI, 0.6–1.0; P for trend = 0.03), whereas hazard ratios for fish consumption were close to unity. Conclusion: Consumption of fresh red meat and processed meat seemed to be associated with an increased risk of rectal cancer. Consumption of chicken and fish did not increase risk.

Selenium and Lung Cancer: A Quantitative Analysis of Heterogeneity in the Current Epidemiological Literature

Abstract: While numerous laboratory investigations have shown that selenium may have anticarcinogenic activity, the epidemiological data have been inconsistent. In this report, meta-analysis was used to quantitatively summarize the existing epidemiological evidence on selenium and lung cancer and identify sources of heterogeneity among studies. When all studies were combined, the summary relative risk (RR) for subjects with higher selenium exposures was 0.74 [95% confidence interval (CI) 0.57-0.97]. In subgroup analyses based on the average selenium level in the study population, the summary RR for areas where selenium levels were low was 0.72 (95% CI 0.45-1.16), while the RR for areas where selenium levels were higher was 0.86 (95% CI 0.61-1.22). In both studies in high selenium areas where RRs were markedly below 1.0, protective effects were only found when subjects in the lowest category of selenium exposure were used as referents. No clear protective effects were seen when highly exposed subjects were compared with those in the middle exposure categories. The summary RR was lower in studies assessing selenium exposure using toenails (RR 0.46, 95% CI 0.24-0.87) than in studies using serum selenium (RR 0.80, 95% CI 0.58-1.10) or studies assessing dietary intake (RR 1.00, 95% CI 0.77-1.30). Overall, these results suggest that selenium may have some protective effect against lung cancer in populations where average selenium levels are low. The evidence for these findings is greater in studies of toenail selenium than in studies involving other measures of exposure.

Metabolic syndrome and the risk of prostate cancer in Finnish men: a population-based study.

Abstract: Objective: Individual components of metabolic syndrome have been linked to an increased risk for prostate cancers. We hypothesized that metabolic syndrome itself could confer an increased risk for incident prostate cancer. Methods: The participants were a population-based sample of 1,880 men from eastern Finland without history of cancer or diabetes mellitus at baseline. Results: The metabolic syndrome (WHO criteria) was present in 357 (19%) of subjects. During an average follow-up of 13 years, a total of 183 cancers occurred, of which 56 were due to prostate cancer. The metabolic syndrome at baseline was related to a 1.9-fold (95% confidence interval, 1.1-3.5) risk of prostate cancer after adjustment for age, alcohol consumption, physical fitness, and energy, fat, fiber, calcium, vitamin E, and α-linolenic acid intake. The association between metabolic syndrome and risk of prostate cancer was stronger among overweight and obese men with a body mass index ≥27 kg/m 2 (adjusted relative risk, 3.0; 95% confidence interval, 1.2-7.3) than in lighter men (relative risk, 1.8; 95% confidence interval, 0.7-4.7). Conclusions: Middle-aged men with the metabolic syndrome were more likely to develop prostate cancer in this prospective population-based study. This finding suggests that efforts to curb the epidemic of overweight and sedentary lifestyle and the accompanying metabolic syndrome may decrease the risk for prostate cancer.

Identifying and Characterizing Adolescent Smoking Trajectories

Abstract: Our understanding of longitudinal patterns of adolescent smoking development and the determinants of these patterns is limited. The present study evaluated adolescent smoking trajectories and characterized these trajectories with social, psychological, and behavioral factors in a cohort of adolescents assessed annually from grades 9 to 12. Complete data (smoking practices, novelty seeking, academic performance, substance use, peer smoking, physical activity and sports participation, and tobacco ad receptivity) were available on 968 participants; data were analyzed using latent class growth modeling. Four adolescent smoking trajectories emerged: never smokers, experimenters, earlier/faster smoking adopters, and later/slower smoking adopters. Early adopters were characterized by their high novelty seeking personality, depressive symptoms, poorer academic performance, and receptivity to tobacco advertising, as well as their exposure to other smokers, and use of other substances. Later adopters were characterized quite similarly to the early adopters, although they tended to perform better in school and to be more involved in sports. Experimenters also shared many of these same risk characteristics but to a lesser degree. Overall, never smokers were the most conventional in their profile. These data suggest that there is significant heterogeneity in the timing, rate, and intensity of smoking progression. Adolescent smoking prevention and intervention programs will need to consider this heterogeneity and tailor or enhance attention to risk and protective factors depending on the subpopulation.

Common gene polymorphisms in the metabolic folate and methylation pathway and the risk of acute lymphoblastic leukemia and non-Hodgkin's lymphoma in adults

Abstract: Folate and methionine metabolism is involved in DNA synthesis and methylation processes. Polymorphisms in the genes of folate metabolism enzymes have been associated with some forms of cancer. In a case-control study, we evaluated whether four common polymorphisms in methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MS A2756G), and methionine synthase reductase (MTRR A66G) genes may have a role in altering susceptibility to adult acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). We analyzed DNA of 120 adult ALL, 200 NHL, and 257 healthy control subjects. Individual carrying the MTHFR 677TT genotype showed a 3.6-fold decreased ALL risk [odds ratio (OR) 0.28, 95% confidence interval (95% CI) 0.12-0.72] than wild-types. Similarly, MS 2756GG individuals showed a 5.0-fold decreased ALL risk (OR 0.20, 95% CI 0.02-1.45) than wild-types. In combined results, subjects with the MTHFR 677CT/TT and MS 2756AG/GG genotypes revealed a 3.6-fold ALL risk reduction (OR 0.28, 95% CI 0.14-0.58) and those with the MTHFR 677TT and MTRR 66AG genotypes revealed a 4.2-fold ALL risk reduction (OR 0.24, 95% CI 0.06-0.81). Finally, those with the MS 2756AG/GG and MTRR 66AG/GG genotypes revealed a 2.2-fold ALL risk reduction (OR 0.45, 95% CI 0.10-0.85). Single analysis for NHL did not show any significant difference for all the polymorphisms investigated, but in the low-grade NHL subgroup, we found a 2.0-fold risk reduction for the MTRR 66GG homozygous genotype (OR 0.50, 95% CI 0.25-0.99), which was higher (OR 0.37, 95% CI 0.14-0.85) when analyzed in combination with MS 2756AA genotype. These data are in accordance with the hypothesis that polymorphisms in the genes for folate and methionine metabolism might play a greater role in the occurrence of ALL than NHL by influencing DNA synthesis and/or DNA methylation.

Preliminary communication: glycated hemoglobin, diabetes, and incident colorectal cancer in men and women: a prospective analysis from the European prospective investigation into cancer-Norfolk study.

Abstract: Background: Increasing evidence suggests that abnormal glucose metabolism may be associated with increased risk of colorectal cancer. Methods: We examined the relationship between known diabetes and glycated hemoglobin (HbA1c) concentrations measured in 1995 to 1997 and subsequent incident colorectal cancer after 6 years follow-up in 9,605 men and women ages 45 to 79 years in the European Prospective Investigation into Cancer–Norfolk Study. Results: Among individuals not known to have cancer at the baseline survey, there were 67 incident colorectal cancers. HbA1c concentration appeared continuously related to incident colorectal cancer risk, with lowest rates observed in those with HbA1c below 5%. Known diabetes was also associated with incident colorectal cancer, with relative risk (RR) 3.18 and 95% confidence interval (CI) 1.36-7.40 ( P < 0.01) adjusting for age and sex and RR 2.78 and 95% CI 1.10-7.00 ( P = 0.03) adjusting for age, sex, body mass index, and smoking compared with those without known diabetes. The RR (95% CI) of incident colorectal cancer per 1% absolute increase in HbA1c was 1.34 (1.12-1.59; P < 0.001). HbA1c concentrations appeared to explain the increased colorectal cancer risk associated with diabetes in multivariate models. Conclusions: Known diabetes was associated with ∼3-fold risk of colorectal cancer in this analysis; this increased risk was largely explained by HbA1c concentrations, which appears continuously related to colorectal cancer risk across the population distribution.

Dietary Patterns and Risk of Breast Cancer in the ORDET Cohort

Abstract: The aim of this study was to evaluate the association between dietary patterns and risk of developing breast cancer in an Italian cohort. Women volunteers were recruited from 1987 to 1992 from residents in Varese province, northern Italy, an area covered by a cancer registry. Participants completed a semiquantitative food frequency questionnaire, and anthropometric and other data were collected systematically. Using nutritional data from 8984 women with an average follow up of 9.5 years and 207 incident cases of breast cancer, we conducted an exploratory factor analysis to identify major dietary patterns. Four dietary patterns, which explained 30% of the variance, emerged: salad vegetables (mainly consisting of raw vegetables and olive oil); western (mainly consisting of potatoes, red meat, eggs and butter); canteen (pasta and tomato sauce); and prudent (cooked vegetables, pulses, and fish, with negative loading on wines and spirits). After adjustment for potential confounders, only the salad vegetables pattern was associated with significantly lower (34-35%) breast cancer incidence (RR = 0.66, CI(95%) = 0.47+/-0.95 comparing highest with lowest tertile) with a significant linear trend (P = 0.016). Women with body mass index 50% less risk than the lowest tertile, RR = 0.39, CI(95%) = 0.22-0.69) with a significant trend (P = 0.001); whereas women with body mass index > or =25 had no protective effect for the consumption of salad vegetables. These findings suggest that a diet rich in raw vegetables and olive oil protects against breast cancer.

Meta-Analysis of the Efficacy of Tobacco Counseling by Health Care Providers

Abstract: Given the proportion of American adults who smoke, even if health professionals only have a small effect on quit rates, the public health impact of this change could potentially be enormous. Yet, health care providers may differ in their cessation efficacy. The purpose of this study was to evaluate recent rigorous trials of smoking cessation counseling among physicians, nurses, dentists, and teams of providers: (1) to compare providers on the efficacy of cessation and (2)to determine which intervention and study characteristics explain variations in intervention effects. Thirty-seven randomized clinical trials or quasi-experiments (with control groups) of health care provider-delivered smoking cessation interventions, out of over 200 articles that were published between 1990 and 2004 were collected through searches of Medline, CINAHL, PSYCINFO, and dissertation abstracts, as well as hand searches. The outcome modeled was the mean difference between intervention and control groups in the cessation rates using Hedges g. The univariate results revealed that receiving advice from any health care professional produced increases in quit rates. Multivariate analyses of intervention effects on cessation revealed that physicians were most effective, followed by multiprovider teams, dentists, and nurses. The findings suggest that contact with a health care professional will increase cessation; however, additional training in tobacco control for nurses is warranted. Longer-term studies of smoking cessation, particularly among dentists, are necessary.

MTHFR polymorphisms, dietary folate intake, and breast cancer risk: results from the Shanghai Breast Cancer Study

Abstract: Folate plays an important role in DNA methylation, synthesis, and repair; intake has been associated with breast cancer. The folate-metabolizing enzyme, methylenetetrahydrofolate reductase (MTHFR) is polymorphic at nucleotides 677 (C-->T) and 1298 (A-->C), resulting in allozymes with decreased activity. We evaluated these two common polymorphisms and their effects on the folate intake and breast cancer risk association in a population-based case-control study of 1144 breast cancer cases and 1236 controls using a PCR-RFLP-based assay. All subjects completed in-person interviews, which included a food frequency questionnaire. Unconditional logistic regression models were used to calculate odds ratios and their 95% confidence intervals, after adjusting for potential confounding factors. Cases and controls were similar in the distribution of MTHFR polymorphisms at codons 677 (41.4% cases and 41.8% controls carried the T allele) and 1298 (17.6% cases and 17.5% controls carried the C allele). An inverse association of breast cancer risk with folate intake was observed in all genotype groups, particularly among subjects with the 677TT genotype. Compared with those with the 677CC genotype and high folate, the adjusted odds ratios (95% confidence intervals) associated with low folate intake were 1.94 (1.15-3.26), 2.17 (1.34-3.51), and 2.51 (1.37-4.60) for subjects who had CC, CT, and TT genotypes (p for interaction, 0.05). No modifying effect of A1298C genotypes on the association of folate intake with breast cancer risk was observed. Results of this study suggest that the MTHFR C677T polymorphisms may modify the association between dietary folate intake and breast cancer risk.

Diet and Melanoma in a Case-Control Study

Abstract: Background: Malignant melanoma has been one of the most rapidly increasing cancers within the United States with few modifiable risk factors. This study investigates risk related to dietary factors, which are potentially modifiable. Methods: Newly diagnosed patients with melanoma (n = 502) were recruited from pigment lesion clinics and controls (n = 565) were recruited from outpatient clinics. To investigate the relationship between melanoma and dietary factors in this case-control study, study subjects were requested to complete a food frequency questionnaire, which assessed diet over the previous year. Using logistic regression, odds ratios (ORs) for melanoma were computed for nutrient and alcohol intake. Results: Persons in high versus low quintiles of energy-adjusted vitamin D, a-carotene, b-carotene, cryptoxanthin, lutein, and lycopene had significantly reduced risk for melanoma (ORs V 0.67), which remained after adjustment for presence of dysplastic nevi, education, and skin response to repeated sun exposure. Addition of micronutrients from supplements did not add an additional reduction in risk. High alcohol consumption was associated with an increased risk for melanoma, which remained after adjustment for confounders [OR (95% confidence interval) in highest versus lowest quintiles, 1.65 (1.09-2.49)]. Conclusions: Diets consisting of foods rich in vitamin D and carotenoids and low in alcohol may be associated with a reduction in risk for melanoma. These analyses should be repeated in large, prospective studies. (Cancer Epidemiol Biomarkers Prev 2004;13(6):1042 – 51)

Amount, Type, and Timing of Recreational Physical Activity in Relation to Colon and Rectal Cancer in Older Adults: the Cancer Prevention Study II Nutrition Cohort

Abstract: Physical activity has consistently been associated with lower risk of colon cancer, but information is limited on the amount, type, and timing of activities. The relationship between physical activity and rectal cancer is unclear. We examined characteristics of recreational physical activity in relation to colon and rectal cancer in the Cancer Prevention Study II Nutrition Cohort of 70,403 men and 80,771 women (median age, 63 years); 940 colon and 390 rectal cancers were identified from enrollment in 1992 to 1993 through August 1999. The multivariate-adjusted rate ratios (95% confidence intervals) associated with any recreational physical activity compared with none were 0.87 (0.71-1.06) for colon cancer and 0.70 (0.53-0.93) for rectal cancer. Colon cancer risk decreased significantly with increasing total hours ( P for trend without reference group = 0.007) and metabolic equivalent hours ( P for trend = 0.006) per week of activities. No clear decrease in rectal cancer risk was seen with increasing hours per week of physical activity. Rate ratios (95% confidence intervals) were 0.72 (0.52-0.98) for <2 hours, 0.68 (0.47-0.97) for 2 to 3 hours, 0.59 (0.41-0.83) for 4 to 6 hours, and 0.83 (0.59-1.16) for ≥7 hours per week of physical activity compared with none. Past exercise, as reported in 1982, was not associated with risk of either colon or rectal cancer. We conclude that increasing amounts of time spent at recreational physical activity are associated with substantially lower risk of colon cancer and that recreational physical activity is associated with lower risk of rectal cancer in older men and women.

Body Mass Index, Leptin and Leptin Receptor Polymorphisms, and Non-Hodgkin Lymphoma

Abstract: In a population-based case-control study, obesity was associated with elevated odds ratios (ORs) for non-Hodgkin lymphoma (NHL), and the two major subtypes, diffuse large cell (DLCL) and follicular lymphoma (FL). Those who were obese (body mass index ≥ 30) were up to three times more likely to develop NHL or its major subtypes than persons with body mass index of 20 to <25. Obesity-related genetic factors including common polymorphisms in the leptin gene ( LEP A19G and G-2548A) and its receptor ( LEPR Q223R) were investigated in DNA available for 376 patients and 805 controls. Leptin is an adipocyte-derived hormone that regulates food intake and modulates immune and inflammatory responses through its receptor. Among those with the LEP 19G allele, an increased risk estimate was found for all NHL [OR = 1.6, confidence interval (CI) 1.1–2.3], DLCL (OR = 1.6, CI 0.86–3.0), and FL lymphoma (OR = 1.9, CI 0.98–3.6). Gene-gene interaction existed between the −G2548A and LEPR Q223R polymorphisms. Specifically, among those with LEPR 223RR, the risk estimate for NHL was increased in LEP −2548GA (OR = 1.7, CI 0.88–3.1) and LEP −2548AA (OR = 2.3,CI 1.1–4.6) relative to LEP −2548GG genotypes. These results suggest that genetic interactions between leptin and its receptor may promote immune dysfunction associated with obesity and NHL and that the emerging obesity epidemic is consistent with the increasing incidence of NHL in developed countries.

Body size and composition and colon cancer risk in men

Abstract: Background: Several studies of male colon cancer have found positive associations with body size and composition. It is uncertain whether this relationship is due to non-adipose mass, adipose mass, distribution of adipose mass such as central adiposity, or all three. Methods: In a prospective cohort study of men aged 27–75 at recruitment in 1990–1994, body measurements were taken by interviewers. Fat mass and fat-free mass (FFM) were estimated from bioelectrical impedance analysis. Waist circumference and waist-to-hips ratio (WHR) estimated central adiposity. Incident colon cancers were ascertained via the population cancer registry. Altogether, 16,556 men contributed 145,433 person-years and 153 colon cancers. Results: Rate ratios (RRs) comparing men in the fourth quartile with those in the first quartile were as follows: FFM 2.3 [95% confidence interval (CI) 1.4–3.7]; height 1.9 (95% CI 1.1–3.1); waist circumference 2.1 (95% CI 1.3–3.5); WHR 2.1 (95% CI 1.3–3.4); fat mass 1.8 (95% CI 1.1–3.0); and body mass index 1.7 (95% CI 1.1–2.8). When continuous measures of FFM and WHR were modeled together, the RR for FFM per 10 kg was 1.37 (95% CI 1.04–1.80) and the RR for WHR per 0.1 unit was 1.65 (95% CI 1.28–2.13). After adjustment for FFM and WHR, the RRs for fat mass and body mass index were no longer statistically significant. Conclusion: Male colon cancer appears to be related to body size and composition by two different pathways, via central adiposity and via non-adipose mass.