Association between aspirin use and the prevalence of nonalcoholic fatty liver disease: a cross-sectional study from the Third National Health and Nutrition Examination Survey.

BACKGROUND: Many basic mechanistic studies found that aspirin inhibited multiple pathways involved in non-alcoholic fatty liver disease (NAFLD) development. AIM: To investigate an association between aspirin use and NAFLD prevalence in the general US population. METHODS: We conducted a cross-sectional analysis of data from the Third National Health and Nutrition Examination Survey (NHANES III). We included 11 416 adults aged 20-74 years who underwent ultrasonography; of those, 2889 were identified as having NAFLD and 8527 as controls. Aspirin use during the month prior to interview was categorised as never use (0 times), occasional use (1-14 times) and regular use (≥15 times). RESULTS: In the multivariate unconditional logistic regression analysis, regular relative to no aspirin use was inversely associated with prevalent NAFLD [odds ratio (OR) = 0.62, 95% confidence interval (CI) 0.51-0.74; P for trend = 0.04], a finding that was primarily limited to men (OR = 0.32, 95% CI 0.23-0.45; P for interaction < 0.01) and those who were older (>60 years) (OR = 0.21, 95% CI 0.14-0.30; P for interaction < 0.01). CONCLUSION: These findings, from the first human study to investigate an association of aspirin use with NAFLD, suggest that regular aspirin use (≥ 15 times per month) may be associated with a lower prevalence of NAFLD, primarily among men and older patients.

Vitamin D receptor polymorphism and the risk of colorectal adenomas: evidence of interaction with dietary vitamin D and calcium.

Laboratory studies and epidemiological investigations suggest that vitamin D plays a role in the etiology of colorectal adenomas, possibly through a mechanism mediated by the vitamin D receptor (VDR). We conducted a clinic-based case-control study to examine the association between VDR polymorphisms and colorectal adenomas. We selectively identified a random subset of 393 cases of colorectal adenomas and 406 colonoscopy-negative controls from a clinic-based case-control study conducted in the metropolitan Minneapolis/St. Paul area during 1991-1994. A self-administered questionnaire was used to collect data on dietary and supplement intake of vitamin D and calcium, as well as on demographics, physical activity, medical information, lifestyle factors, reproductive history, and anthropometry. DNA was extracted from whole blood and assayed for the BsmI VDR polymorphism using an ABI 7700 TaqMan assay. Adjusted odds ratios (OR) and 95% confidence intervals (CIs) were evaluated using logistic regression. Compared with the bb genotype (33% of controls), neither the Bb (48.8% of controls) nor the BB (18.2% of controls) genotypes was strongly associated with risk of colorectal adenomas (OR = 0.86, CI = 0.63-1.19 and OR = 0.77, CI = 0.50-1.18, respectively). However, those with the lowest tertile of vitamin D intake and the BB genotype had a lower risk of colorectal adenoma (OR = 0.24, CI = 0.08-0.76) than those with the highest tertile of intake and the bb genotype. Similarly, those with the lowest tertile of calcium intake and the BB genotype had a reduced risk of colorectal adenoma (OR = 0.34, CI = 0.11-1.06). Although it has generally been shown that higher calcium and vitamin D intake are associated with a modestly reduced risk of colorectal neoplasia, our data suggest that those with the BB BsmI VDR genotype may be at reduced risk of colorectal adenoma in the presence of lower calcium and vitamin D intake.

CYP2C9 and UGT1A6 genotypes modulate the protective effect of aspirin on colon adenoma risk.

Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) has a protective effect on the incidence of colon neoplasia. However, polymorphisms in NSAID-metabolizing enzymes may alter this effect. NSAIDs, particularly aspirin, are glucuronidated by UGT1A6 and some classes of NSAIDs are also metabolized by cytochrome P450 (CYP) 2C9. Both of these enzymes have slow-metabolizing, variant forms. We tested the hypothesis that the slow alleles of these enzymes can modify the inverse association between NSAIDs and colon neoplasia in the Minnesota Cancer Prevention Research Unit (CPRU) adenomatous polyp case-control study. CYP2C9 and UGT1A6 genotypes were determined for 474 adenoma cases and 563 controls. NSAID use was inversely associated with adenoma risk [odds ratio (OR), 0.63; 95% confidence interval (CI), 0.44-0.90 for aspirin; and OR, 0.50; 95% CI, 0.31-0.82 for nonaspirin NSAID]. However, this association was absent in aspirin users who carried the CYP2C9 variant alleles (OR, 0.88; 95% CI, 0.51-1.53) or who were homozygous wild-type UGT1A6 (OR, 0.86; 95% CI, 0.50-1.50). Carriers of both of these alleles who use aspirin were also not at reduced risk of adenomatous polyps (OR, 1.59; 95% CI, 0.68-3.73). The variants of these enzymes did not influence the association between nonaspirin NSAIDs and adenoma risk. These data indicate that the effectiveness of chemopreventive drugs can be modulated by the genotype of metabolizing enzymes.

Association of menstrual and reproductive factors with breast cancer risk: results from the Shanghai Breast Cancer Study.

The incidence of breast cancer among women in Shanghai, a traditionally low-risk population, has increased substantially over the past 20 years. To evaluate the association of menstrual and reproductive factors with breast cancer risk and the influence of these factors on the temporal trend of breast cancer incidence, we analyzed data from the Shanghai Breast Cancer Study, a population-based case-control study of breast cancer recently completed among Chinese women in urban Shanghai. In-person interviews were completed for 1,459 women newly diagnosed with breast cancer between ages 25 and 64 and for 1,556 controls frequency-matched to cases by age. Unconditional logistic regression was employed to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) related to menstrual and reproductive factors. Earlier menarcheal age, nulliparity, and later age at first live birth were associated with increased risk of breast cancer among both pre- and post-menopausal women, while never having breast-fed and later age at menopause were associated with elevated risk only among post-menopausal women. Among controls, 32% of younger women (40 years) reported starting menarche at age of 13 or younger, and this factor contributed to 44% of cases diagnosed among younger women and 26% to 28% of cases in older women. Older age at first live birth or at menopause explained a considerable portion of cases diagnosed in older, but not younger, women. Our study suggests that the changes in menstrual and reproductive patterns among women in Shanghai have contributed to the recent increase in breast cancer incidence, particularly among younger women.

Effect of calcium supplementation on serum cholesterol and blood pressure. A randomized, double-blind, placebo-controlled, clinical trial.

OBJECTIVE: To test the effect of daily supplemental calcium on serum total and high-density lipoprotein cholesterol (HDL-C) levels and blood pressure in adults. DESIGN: Randomized, double-blind, placebo-controlled clinical trial; adjunct study to a trial of calcium and colon cell proliferation in patients with sporadic adenoma. SETTING: Outpatient clinic. PATIENTS: A total of 193 men and women, aged 30 to 74 years. INTERVENTION: Treatment with 1.0 and 2.0 g/d of elemental calcium vs placebo over a 4-month period for cholesterol determinations and 6 months for blood pressure. MAIN OUTCOME MEASURES: Serum total cholesterol and HDL-C levels, systolic and diastolic blood pressure. RESULTS: Because there were no apparent differences in responses between the 1.0-g and 2.0-g calcium groups, their data were combined and compared with those of the placebo group. Among all participants, the mean total cholesterol level dropped 0.07 mmol/L (2.9 mg/dL) (1.3%) (P = .43) more, and the mean HDL-C level dropped 0.01 mmol/L (0.4 mg/dL) (1.1%) (P = .71) less in the calcium group than in the placebo group. Among participants without a history of hypercholesterolemia, the mean total cholesterol level dropped 0.18 mmol/L (6.8 mg/dL) (3.3%) (P = .10) and the HDL-C level dropped 0.02 mmol/L (0.6 mg/dL) (1.5%) (P = .61) more in the calcium group than in the placebo group. Among all participants, there was no apparent change in blood pressure until 6 months, when the mean systolic blood pressure dropped 0.8 mm Hg (0.6%) (P = .85) and the mean diastolic blood pressure dropped 0.4 mm Hg (0.5%) (P = .80) more in the calcium group than in the placebo group. CONCLUSIONS: There were no substantial or statistically significant effects of calcium supplementation on total cholesterol or HDL-C levels or on blood pressure. There was a suggestion (not statistically significant) of a 0.07 to 0.18 mmol/L (3-7 mg/dL) or 2% to 4% drop in the total cholesterol level, a finding similar to that reported in other studies, which indicates the need for further study.

Vitamin D receptor polymorphisms and prostate cancer.

Prostate cancer is a common disease, yet determinants of prostate cancer risk remain largely unidentified. Low circulating levels of 1, 25-dihydroxy vitamin D (1,25-D) have been implicated as a risk factor for prostate cancer. In addition, 1,25-D exhibits significant antineoplastic properties both in vitro and in vivo, and these antiproliferative effects appear to be mediated through the vitamin D receptor (VDR). The VDR has a number of common polymorphisms, including a TaqI restriction fragment length polymorphism in exon 9 and a poly(A) length polymorphism in the 3'-untranslated region. Previous studies have found an association between the TaqI T allele or poly(A) L allele and prostate cancer. To further investigate the putative link between VDR polymorphisms and prostate cancer, we conducted a case-control study of prostate cancer patients from the Piedmont region of North Carolina. Using polymerase chain reaction-based techniques on DNA extracted from peripheral blood, we genotyped 77 cases (70 white, seven black) and 183 controls (169 white, 14 black) for the TaqI and poly(A) alleles. We report here an overall lack of association between either the TaqI or poly(A) genotype and prostate cancer odds ratio (OR)=1.4, 95% confidence interval (CI)=0.7-2.8; and OR=1.2, 95% CI=0.6-2.5, respectively). Using a case-case analysis, we tested whether these polymorphisms might be associated with more advanced disease but found no statistically significant association for the TaqI T or poly(A) L allele (OR=2.5, 95% CI=0.3-21.7; OR=2.8, 95% CI=0.3-23.8, respectively). We report strong evidence of linkage disequilibrium between the TaqI and poly(A) polymorphisms (P < 0.0001), with whites demonstrating stronger linkage disequilibrium than blacks (D=0.24 vs. D=0.18).

Colorectal adenomatous and hyperplastic polyps: smoking and N-acetyltransferase 2 polymorphisms.

Arylamine N-acetyltransferase 2 (NAT2) is involved in both the detoxification and bioactivation of carcinogenic arylamines and other mutagens. This enzyme is polymorphic, and the fast and slow phenotypes are thought to be risk factors for colon and bladder cancer, respectively. Here, we report on a case-control study of adenomatous and hyperplastic polyps, with particular attention to tobacco smoking, a known risk factor for adenomas, and polymorphisms of NAT2. All participants underwent complete colonoscopy and were subsequently divided into case and control groups on the basis of pathology. Cases were diagnosed with confirmed adenomas (n = 527) or hyperplastic polyps (n = 200); controls (n = 633) had no history of colonic neoplasia and no polyps at colonoscopy. NAT2 genotype was determined using an oligonucleotide ligation assay and fast, intermediate, or slow phenotype imputed. Multivariate-adjusted odds ratios (ORs) and 95% confidence intervals were computed using logistic regression adjusting for age, sex, nonsteroidal anti-inflammatory drug use, and hormone replacement therapy use. Smoking was associated with an increased risk of adenomas [current versus never smoking OR = 2.0 (95% confidence interval, 1.4-2.9)] and hyperplastic polyps [current versus never smoking OR = 4.1 (2.6-6.5)]. NAT2 status among adenomatous polyp patients and hyperplastic polyp patients, respectively, showed ORs of 1.1 (0.8-1.4) and 1.2 (0.8-1.6; intermediate versus slow) and 1.1 (0.6-1.9) and 0.9 (0.4-1.9; fast versus slow). There were no differences in risk when adenoma patients were stratified on multiplicity, size, or histopathological subtype of polyps. Never-smokers showed no variation in risk across acetylator status for either species of polyp, whereas current smokers showed ORs of 2.0 (1.2-3.2) and 2.3 (1.4-3.9) for adenomas and 3.9 (2.1-7.1) and 4.9 (2.6-9.4) for hyperplastic polyps for slow and intermediate/fast NAT2, respectively, compared with slow-NAT2 never-smokers. Risks of both multiple [OR = 4.3 (2.1-8.8)] and large [OR = 3.8 (1.9-7.5)] adenomas were somewhat elevated in current smokers with an intermediate/fast phenotype compared with smokers with a slow NAT2 phenotype, but the interaction was not statistically significant. Risk of hyperplastic polyps and adenomatous polyps is strongly related to smoking. There is little suggestion of interaction between NAT2 status and smoking and no relationship with NAT2 genotype alone.

Relation of calcium, vitamin D, and dairy food intake to ischemic heart disease mortality among postmenopausal women.

To investigate whether greater intakes of calcium, vitamin D, or milk products may protect against ischemic heart disease mortality, the authors analyzed data from a prospective cohort study of 34,486 postmenopausal Iowa women 55-69 years old and without a history of ischemic heart disease who completed a dietary questionnaire in 1986. Through 1994, 387 deaths due to ischemic heart disease were documented (International Classification of Diseases, Ninth Revision, codes 410-414, 429.2). The multivariate-adjusted relative risks for the highest versus the lowest quartiles of total calcium, vitamin D, and milk product intakes were as follows: 0.67 (95% confidence interval (CI) 0.47-0.94; p for trend = 0.09) for calcium, 1.41 (95% CI 0.93-2.15; p for trend = 0.12) for vitamin D, and 0.94 (95% CI 0.66-1.35; p for trend = 0.68) for milk products. The relative risk was 0.63 (95% CI 0.40-0.98) for high dietary calcium but no supplemental calcium intake and 0.66 (95% CI 0.36-1.23) for high supplemental calcium but low dietary calcium intake. These results suggest that a higher intake of calcium, but not of vitamin D or milk products, is associated with reduced ischemic heart disease mortality in postmenopausal women, and reduced risk may be achievable whether the higher intake of calcium is attained by diet, supplements, or both.

Diet and risk of colon cancer in a large prospective study of older women: an analysis stratified on family history (Iowa, United States).

OBJECTIVE: The purpose was to investigate whether dietary associations with risk of colon cancer in women differ by family history of the disease. METHODS: Data were analyzed from a prospective cohort study of 35,216 Iowa (United States) women aged 55 to 69 years at baseline. Through 31 December 1995, 241 colon cancers were identified through record linkage with the State Health Registry. The cohort was stratified on family history of colon cancer in first-degree relatives; nutrient intakes were divided into tertiles. RESULTS: Analyses using Cox regression revealed that the association of most dietary components with colon cancer incidence were similar for individuals with and without a family history. However, total calcium intake was associated inversely with colon cancer among women with a negative family history (relative risk [RR] = 0.50 for upper cf lower tertile, P < 0.001), but was unrelated to incidence for women with a positive family history (RR = 1.1 for upper cf lower tertile, P = 0.69). Similarly, total vitamin E intake was associated with lower risk among women with a negative family history (RR = 0.67 for upper cf lower tertile, P = 0.04), but not among women with a positive family history (RR = 0.87 for upper cf lower tertile, P = 0.67). High intakes of fiber, fruits, and vegetables were each weakly inversely associated with risk among family-history negative women, but not among family-history positive women. CONCLUSIONS: These data, if corroborated, suggest that dietary factors typically associated with lower risk may be less effective risk-reduction interventions against colon cancer for individuals with a family history of colon cancer.

A prospective cohort study of intake of calcium, vitamin D, and other micronutrients in relation to incidence of rectal cancer among postmenopausal women.

To investigate whether high intakes of calcium and other micronutrients (carotene, retinol, and vitamins C, D, and E) are related to reduced risks of rectal cancer, we analyzed data from a large cohort study of postmenopausal Iowa women who responded to a mailed survey in 1986. After 9 years of follow-up, 144 incident rectal cancer cases were ascertained among the 34,702 women at risk. Intake levels of micronutrients at baseline were derived from self-reported data on vitamin supplements and dietary intake of 127 foods included in a semiquantitative food frequency questionnaire. After adjustment for total energy intake and other potential confounding factors, a dose-response inverse association was observed between total calcium intake and the risk of rectal cancer: adjusted relative risks (RRs) were 1.00, 0.90, and 0.59 (trend test, P = 0.02) from the lowest to the highest calcium intake tertiles. High intakes of dietary and supplement calcium were both related to a slightly reduced risk of rectal cancer, but neither of the trend tests was statistically significant. Reduced risks of rectal cancer were also observed for high intake of carotene and vitamins A, C, and D, although none of the associations were statistically significant. For vitamin D, the adjusted RRs were 1.00, 0.71, and 0.76 (trend test, P = 0.20) for increasing intake tertiles. Compared with women who consumed low levels of both total calcium and vitamin D, those in the highest intake group of both nutrients were at a 45% reduced risk of rectal cancer (RR, 0.55; 95% confidence interval, 0.32-0.93). This study supports the hypothesis that high intake of calcium and possibly other micronutrients may be beneficial in the prevention of rectal cancer.

Methodological findings and considerations in measuring colorectal epithelial cell proliferation in humans.

The methodological issues for measuring colorectal epithelial cell proliferation, an intermediate end point for studies of colon neoplasia, in epidemiological studies are deceptively numerous and complex, with few methodological data available. Accordingly, during our experience with measuring colorectal epithelial cell proliferation from nearly 500 participants attending over 1300 study visits over a 6-year period, we recorded data on a variety of measurement variations. Methods investigated included rectal biopsy technique, general histological and labeling procedures [including the tritiated thymidine, 5-bromodeoxyuridine (BrdUrd), and the proliferating cell nuclear antigen (PCNA) immunohistochemical techniques used to label S-phase cells in colonic crypts in rectal biopsy specimens], biopsy scoring procedures, and summary scoring methods. Findings include that the PCNA technique was the simplest, most economical, and least time-consuming. The BrdUrd labeling failure rate was 15% versus < 1% for PCNA. The percentage of labeled cells (labeling index) was highest using PCNA in biopsies processed without prior incubation, intermediate using PCNA in biopsies processed with prior incubation as for BrdUrd, and lowest using BrdUrd. The percentage of labeled cells that were in the upper 40% of the crypt (phi h) was higher using BrdUrd than PCNA; visit-to-visit correlations were higher using PCNA (r = 0.51 versus 0.35), and visit-to-visit variability was lower and between-person variability was higher using PCNA. Intra- and inter-rater reliabilities for the techniques were comparable (PCNA intra-rater r = 0.93, inter-rater r = 0.92). The PCNA technique, compared to the BrdUrd technique, is more feasible and reliable, provides a more accurate estimate of the labeling index, and cell proliferation measures determined with PCNA have statistical properties that are generally more favorable for detecting differences in clinical trials. Thus, the PCNA technique may be preferable to techniques requiring incubation of biopsies. Other methodological findings lead us to recommend that, for larger studies measuring colorectal epithelial cell proliferation on outpatient rectal biopsies, biopsies should be taken 10 cm above the anus using a flexible, preferably jumbo cup, endoscopic forceps through a rigid sigmoidoscope, and histological sections should be 3 microns thick taken 50 microns apart.

Human studies of calcium supplementation and colorectal epithelial cell proliferation.

The kinetics of colorectal epithelial cell proliferation (CECP) have been found to be altered in patients at increased risk for colon cancer. Altered CECP kinetics include an increase within the colon crypts of the overall proportion of proliferating cells (labeling index; LI) and the proportion of proliferating cells that are in the upper 40% of the crypts (phi h). Use of CECP as a biomarker to measure effects of calcium interventions on the colon has been reported in five small uncontrolled clinical trials, nine small randomized placebo-controlled trials, and three full-scale randomized placebo-controlled trials. All five uncontrolled trials indicated substantial and significant decreases in proliferation. Of the nine small controlled trials, three found statistically significant decreases in the LI, and the remainder were inconclusive because of insufficient sample size. Of the three full-scale trials, one found a decrease in, or normalization of, the phi h but no effect on the LI; a second found an increase in the phi h but no effect on the LI; and the third, which did not measure the phi h, also found no effect on the LI. Differences between the two full-scale trials that measured the phi h were that the negative trial was multicentered, used multiple types of bowel-cleansing preparations, had no baseline measurements of CECP, and had low intrareader reliability for CECP scoring. The positive trial was single centered, used no bowel-cleansing preparations, measured CECP prior to, and at three precise intervals after, randomization, and had high intrareader reliability for CECP scoring. The current literature indicates that in humans, it is unlikely that calcium supplementation can substantially lower CECP rates, but it may normalize the distribution of proliferating cells within colon crypts.

Surrogate end-point biomarkers as measures of colon cancer risk and their use in cancer chemoprevention trials.

Surrogate end-point biomarkers (SEBs) have become widely used in short-term cancer chemoprevention trials in place of cancer end points. This paper discusses criteria relevant to the selection and validation of SEBs for colon cancer risk and the use of SEBs in colon cancer chemoprevention trials. As with a number of other cancers, colon carcinogenesis is the result of a multistep process in which an increasing number of alterations, including specific gene mutations, occur as cells progress from normal to precancerous states of increasing size and dysplasia to cancer and finally to metastatic disease. Ideally, a SEB would show differential expression between the various phases of colon carcinogenesis (i.e., normal, premalignant, and malignant tissues) and be associated with risk of colon cancer. Some SEBs that do not meet these criteria may still be useful for demonstrating the effect of a particular agent. It is also necessary that a SEB be measured in tissues (or other sample material) accessible for multiple and sequential sampling and allow for development of appropriate quality control procedures. Some SEBs must have the potential for modulation by chemopreventive agents. Validation of SEBs for use in chemoprevention studies requires that a relationship between the marker and subsequent risk of cancer be established. Also, the assay reliability and accuracy for each SEB must be determined adequately in well-designed prospective studies.

Vitamin E and breast cancer: a review.

Breast cancer is a major health problem in America, accounting for almost one-third of cancer-related deaths in women. The prevention of breast cancer through dietary modification is an active area of clinical and epidemiologic research. It has been proposed that the dietary supplementation of vitamin E, a lipid-soluble antioxidant, may reduce a woman's risk of developing breast cancer. In animal models, vitamin E has decreased the incidence of carcinogen-induced mammary tumors. Intake and serum levels of vitamin E and their relation to breast cancer have been evaluated in epidemiologic studies. Results of epidemiologic studies, however, have been conflicting. In this review, we examine the evidence that is available pertaining to the relationship between vitamin E and breast cancer. Although epidemiologic study results have been inconsistent, further study of this nontoxic vitamin is warranted. Particular attention should be paid to the interactions of other antioxidants with vitamin E and to the duration and timing (pre- vs. postmenopausal) of vitamin E use in determining its preventive utility in breast cancer.

Colorectal epithelial cell proliferative kinetics and risk factors for colon cancer in sporadic adenoma patients.

Colorectal epithelial cell proliferative kinetics are altered in patients at increased risk for colon cancer: proliferation rates [labeling index (LI)] are higher and there is a shift of the proliferative zone from one confined to the lower 60% of the colonic crypt to one that includes the entire crypt (higher phi(h)). To assess factors associated with LI and phi(h), we performed a cross-sectional analysis using baseline rectal mucosal biopsies from sporadic adenoma patients participating in a chemoprevention trial. Biopsies (taken without preparatory cleansing) were taken 10 cm above the level of the anus, and proliferation was assessed by detection of endogenous S-phase-associated proliferating cell nuclear antigen by immunohistochemical methods. High-quality, scorable biopsies were obtained for 115 patients, and using analysis of covariance and multiple linear regression, the LI and phi(h) were evaluated in relation to diet and other lifestyle factors, demographics, anthropometrics, family history of colon cancer, and polyp history. Statistically significant findings included the following: (a) The LI for those in the upper versus the lowest tertile of vegetable and fruit consumption was, proportionately, 35% lower (3.4% versus 5.3%; P < 0.001); for vitamin supplement users versus nonusers, it was 36% lower (3.3 versus 5.2%; P < 0.001); for recurrent versus incident polyp patients, it was 36% higher (6.2 versus 4.0%; P < 0.001); and for those with rectal polyps only versus those with colon polyps only, it was 28% higher (6.0 versus 4.3%; P = 0.05); and (b) the phi(h) for those in the upper versus the lowest tertile of sucrose consumption was, proportionately, 48% higher (7.1% versus 3.7%; P = 0.01). These results indicate that (a) colorectal epithelial cell proliferation rates are higher in recurrent adenoma patients than in incident adenoma patients and in patients with rectal adenomas only versus those with colon adenomas only, but they are lower in patients with higher intakes of vegetables and fruit and in those who take vitamin/mineral supplements, and (b) the distribution of proliferating cells is shifted toward more inclusion of the upper 40% of the crypt in patients with higher intakes of sucrose. The pattern of positive, negative, and null associations of potential risk factors with cell proliferation is similar to that commonly found with colonic neoplasms.

Calcium and colorectal epithelial cell proliferation in ulcerative colitis.

In persons at higher risk for colon cancer (e.g., those with sporadic adenoma or ulcerative colitis), compared to those at lower risk, colonic epithelial cell proliferation kinetics are altered. We have shown previously that calcium supplementation appears to normalize the distribution of proliferating cells without affecting the proliferation rate in the colorectal mucosa of sporadic adenoma patients. In a pilot randomized, double-blind, placebo-controlled, clinical trial conducted concurrently with our previously published sporadic adenoma trial, we tested whether calcium supplementation can also modulate cell proliferation kinetics in patients with ulcerative colitis. Ulcerative colitis patients (n = 31) were randomized to placebo or 2.0 g of supplemental calcium daily. Colorectal epithelial cell proliferation was determined by immunohistochemical detection of proliferating cell nuclear antigen labeling of cells in "nonprep" rectal biopsies taken at randomization and after 2 months treatment. All biopsies were scored by one reviewer. Differences in mean follow-up minus baseline labeling index (LI; the proportion of colon crypt epithelial cells that were labeled) and in the phi(h) (proportion of labeled cells that were in the upper 40% of the crypts) were compared with analysis of covariance. Pill-taking adherence was 97%. Biopsy-scoring reliability was high (r = 0.89). The pooled baseline LI and phi(h) were 6.3% and 5.6%, respectively. The LI in the calcium group decreased by 0.5% (proportionately, 3%) more than in the placebo group (P = 0.91). Similarly, the phi(h) in the calcium group decreased by 0.3% (proportionately, 10%) more than in the placebo group (P = 0.85). This pilot study does not suggest that 2.0 g of calcium as calcium carbonate daily can substantially normalize either the rate or distribution of proliferating cells over a 2-month period in the colon crypts of patients with ulcerative colitis; a more definitive answer to the question of whether calcium may be effective would require a study with a larger sample size and/or other study design modifications.

Hormone replacement therapy is associated with lower risk of adenomatous polyps of the large bowel: the Minnesota Cancer Prevention Research Unit Case-Control Study.

Evidence of a role for steroid hormones and reproduction in colon neoplasia remains tantalizing but unclear. Hormone replacement therapy (HRT) has been reported in a number of recent studies to be associated with a reduced risk of colon cancer. A case-control study was undertaken to establish whether HRT is associated with lower risk of adenomatous polyps. This case-control study was undertaken as a project of the Minnesota Cancer Prevention Research Unit. Cases (n = 219) were women, ages 30-74 years with colonoscopy-proven, pathology-confirmed, adenomatous polyps of colon and rectum recruited at Digestive Healthcare PA (Minneapolis, MN). Two control groups were selected: women without polyps at colonoscopy (n = 438) at Digestive Healthcare and age- and zip code-matched women selected from the general community (n = 247). Response rates were 68% among those colonoscoped and 65% among community controls. Parity, age at first live birth, and oral contraceptive use did not distinguish cases from either control group. Multivariate adjusted odds ratios and 95% confidence limits for use of HRT for less than 5 years (compared with never use) among postmenopausal women were 0.52 (0.32-0.85) versus colonoscopy-negative controls and 0.74 (0.44-1.26) versus community controls. For 5 years of use or greater, the corresponding figures were 0.39 (0.23-0.67) and 0.61 (0.34-1.07). These results were not materially different when stratified on body mass index, oophorectomy, hysterectomy, aspirin use, or family history. There is no marked increase in risk even 5 years after cessation of HRT use. HRT appears to lower risk of colorectal adenomatous polyps, suggesting that it acts quite early in the neoplastic process. Mechanisms remain unclear. Reduction of risk of colorectal neoplasia is an additional benefit of postmenopausal HRT.

Reproductive factors and risk of endometrial cancer. The Iowa Women's Health Study.

Gravidity and parity have strong inverse relations with endometrial cancer occurrence. To determine whether gravidity masks an association with other reproductive factors, the authors analyzed data from a cohort study of 24,848 postmenopausal Iowa women aged 55-69 years who were cancer free at baseline in 1986 and who had not had a hysterectomy. During 5 years of follow-up, 167 incident endometrial cancer cases were documented. As expected, the mean gravidity of cases was lower than that of noncases (2.6 vs. 3.5, p < 0.0001). Endometrial cancer occurrence was associated positively with early age at menarche, late age at natural menopause, and total length of ovulation span, but history of infertility and ages at first and last pregnancy were unrelated to risk after adjustment for gravidity. Two additional factors remained statistically significant independent of gravidity: a history of ever (vs. never) having had an induced abortion (relative risk = 2.5, 95% confidence interval 1.1-5.7) and timing of spontaneous abortions (miscarriages). Results suggest that a miscarriage late in reproductive life, followed by lack of a subsequent full-term pregnancy, may be a marker for progesterone deficiency. If so, the findings support the "unopposed" estrogen hypothesis for the etiology of endometrial cancer.