Cancer Epidemiol Biomarkers Prev

Serum autoantibodies recognizing 5-hydroxymethyl-2-deoxyuridine, an oxidized DNA base, as biomarkers of cancer risk in women.

Frenkel K. Karkoszka J. Glassman T. Dubin N. Toniolo P. Taioli E. Mooney LA. Kato I.
Department of Environmental Medicine, and Kaplan Comprehensive Cancer Center, New York University Medical Center, New York 10016, USA. krystyna.frenkel@nyu.edu
Human sera contain anti-5-hydroxymethyl-2'-deoxyuridine (HMdU; an oxidized thymidine) autoantibodies (aAbs), which are significantly higher in chronic inflammatory diseases. The intent of this study was to establish whether anti-HMdU aAbs can serve as predictors of breast and colorectal cancer risk. Sera of 169 women were analyzed by ELISA. Women healthy at blood donation but who were diagnosed 0.5-6 years later with breast or colorectal cancer exhibited significantly increased anti-HMdU aAbs over the age-matched controls (P = 0.028 and P < 0.001, respectively). Subjects diagnosed with rectal cancer had the highest levels of anti-HMdU aAbs (44.80 +/- 11.50; n = 6) in comparison to colon (29.03 +/- 2.49; n = 33) and breast (35.86 +/- 8.55; n = 9) cancers. Individuals with benign breast disease also had elevated anti-HMdU aAb (35.12 +/- 8.77; n = 10), with a borderline statistical significance (P = 0.095), whereas those with benign gastrointestinal tract diseases had those titers (30.95 +/- 3.64; n = 8) significantly increased (P < 0.02). Anti-HMdU aAb levels in subjects with a family history of any cancer (23.57 +/- 2.86; n = 55) did not significantly differ from those of the controls (19.41 +/- 2.90; n = 48), but women with a family history of breast cancer (two primary relatives or one with a bilateral disease) showed increased levels (34.48 +/- 8.16; n = 8; P = 0.024). Ps for linear trend of age-adjusted odds ratios were 0.049 for breast and < 0.001 for colorectal cancers. Anti-HMdU aAb titers showed a remarkable stability over a period of 6 years, with a low (14%) intraindividual variance. Thus, elevated anti-HMdU aAb titers may be an early signal of cancer risk, because they were significantly increased in otherwise healthy women who had a family history of breast cancer; in those who had benign breast disease or benign gastrointestinal tract diseases; and, most importantly, in those who at 0.5-6 years after the initial blood donation developed breast or colorectal cancer.

Quantitative fluorescence image analysis of DNA content and nuclear morphology on esophageal balloon cytology smears and subsequent development of esophageal and gastric cardia cancer in Linxian, China.

Hu N. Taylor PR. Rao JY. Hemstreet GP. Liu SF. Zou XN. Mark SD. Dawsey SM.
National Cancer Institute, Bethesda, Maryland 20892, USA.
The highest incidences of esophageal and gastric cardia cancer in the world occur in northern China. Chinese scientists have developed esophageal balloon cytology screening to detect these cancers, but traditional cytology is sometimes inadequate to find some early, curable lesions. Several studies suggest that quantitative fluorescence image analysis (QFIA) of DNA ploidy and nuclear morphology may be able to improve upon traditional cytology results. In October 1987, esophageal balloon cytology was performed on 1331 adults in Linxian, China, and all samples were evaluated both by traditional cytology and QFIA. From 1987 to May 1991, 62 new squamous esophageal cancers and 44 new adenocarcinomas of the cardia were identified in this cohort. Proportional hazards models were used to evaluate the relationship of cytological diagnoses and six QFIA variables to subsequent cancer risk. These models showed significant trends for increasing esophageal cancer risk, with increasing values in five of the QFIA variables and with increasing severity of the traditional cytological diagnoses. A comparison of models with only cytology variables versus models with both cytology and QFIA variables indicated that the QFIA provided an important additional predictive value. Persons with both cytological dysplasia and high cellular DNA were 8 times more likely to develop esophageal cancer than were individuals with neither of these conditions. For cardia cancer, associations between QFIA variables or cytological diagnoses and later cancer were more limited. This study suggests that the QFIA variables evaluated here are independent predictors of squamous esophageal cancer and that combining QFIA with traditional cytology can improve prediction of esophageal cancer risk.

Use of aspirin and other nonsteroidal anti-inflammatory drugs and risk of esophageal and gastric cancer.

Farrow DC. Vaughan TL. Hansten PD. Stanford JL. Risch HA. Gammon MD. Chow WH. Dubrow R. Ahsan H. Mayne ST. Schoenberg JB. West AB. Rotterdam H. Fraumeni JF Jr. Blot WJ.
Fred Hutchinson Cancer Research Center, Program in Epidemiology, Seattle, Washington 98109-1024, USA.
Regular users of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are at reduced risk of colon cancer, but the evidence for protective effects of NSAIDs elsewhere in the digestive tract is scant. We investigated the association between the use of NSAIDs and risk of esophageal and gastric cancer, using data from a large population-based, case-control study. Cases were individuals, ages 30-79 years, diagnosed with esophageal adenocarcinoma (n = 293), esophageal squamous cell carcinoma (n = 221), gastric cardia adenocarcinoma (n = 261), or noncardia gastric adenocarcinoma (n = 368) in three areas with population-based tumor registries. Controls (n = 695) were selected by random digit dialing and through the rosters of the Health Care Financing Administration. After controlling for the major risk factors, we found that current users of aspirin were at decreased risk of esophageal adenocarcinoma [odds ratio (OR), 0.37; 95% confidence interval (CI), 0.24-0.58], esophageal squamous cell carcinoma (OR, 0.49; 95% CI, 0.28-0.87), and noncardia gastric adenocarcinoma (OR, 0.46; 95% CI, 0.31-0.68), but not of gastric cardia adenocarcinoma (OR, 0.80; 95% CI, 0.54-1.19), when compared to never users. Risk was similarly reduced among current users of nonaspirin NSAIDs. The associations with current NSAID use persisted when we excluded use within 2 or 5 years of reference date, which might have been affected by preclinical disease in cases, and when we restricted analyses to subjects reporting no history of chronic gastrointestinal symptoms. Our findings add to the growing evidence that the risk of cancers of the esophagus and stomach is reduced in users of NSAIDs, although whether the association is causal in nature is not clear.

Identifying markers for pancreatic cancer by gene expression analysis.

Zhou W. Sokoll LJ. Bruzek DJ. Zhang L. Velculescu VE. Goldin SB. Hruban RH. Kern SE. Hamilton SR. Chan DW. Vogelstein B. Kinzler KW.
Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
To begin to identify new tumor markers, we recently performed a systematic study of gene expression in cancers of the colon and pancreas. Of the 45,000 genes identified, 183 were found to be expressed at significantly elevated levels in pancreatic cancer. One of the genes was tissue inhibitor of metalloproteinase type I (TIMP-1), which encodes a secreted protein. Analysis of TIMP-1 serum levels revealed significant increases in pancreatic cancer patients, but TIMP-1 by itself was inadequate as a serum marker for cancer. However, a combination of individually suboptimal markers (TIMP-1, CA19-9, and carcinoembryonic antigen) detected 60% of 85 patients with pancreatic cancers in a highly specific manner. These results suggest that a systematic analysis of gene expression can reveal novel serum markers and that individually suboptimal markers can be combined to yield higher sensitivity and specificity.

Psychosocial correlates of healthful diets among male auto workers.

Glanz K. Kristal AR. Tilley BC. Hirst K.
Cancer Research Center of Hawaii, University of Hawaii, Honolulu 96813, USA. kglanz@hawaii.edu
A better understanding of factors associated with healthful eating practices can improve the design and evaluation of dietary intervention programs. Up to now, little information has been available about these factors in high-risk but healthy populations. This article presents findings of a study of psychosocial factors, including stage of change, and their relationship to patterns of consumption of dietary fat, fiber, and fruits and vegetables in a population of males at increased risk of colorectal cancer. Data are from the baseline survey for the Next Step Trial, a randomized, controlled trial of worksite nutrition and colorectal cancer screening promotion interventions. The respondents (n = 2764) were actively employed or retired auto workers at increased colorectal cancer risk. The psychosocial constructs measured were predisposing factors (benefits, motivation, knowledge; eight items; Cronbach alpha = 0.50), enabling factors (barriers, norms, social support; six items; Cronbach alpha = 0.55), and stages of change for adopting diets lower in fat and higher in fiber/fruits and vegetables. The measures of diet, assessed with a food frequency questionnaire, were intakes of fat, fiber, and servings of fruits and vegetables. There were strong and statistically significant positive associations between both predisposing and enabling scale scores and stages of change for fat and fiber. The percentage of respondents in maintenance stage ranged from 4-80% for fat and 11-81% for fiber, across low to high predisposing scale scores; for enabling scale scores, ranges were 11-71% for fat and 22-81% for fiber. Stage of change was associated with fat, fiber, and fruit and vegetable intake in a stepwise manner, with the greatest change observed between action and maintenance. Correlations with dietary outcomes were significantly greater for predisposing factors (r = -0.30 for fat and 0.36 for fiber) than for enabling factors (r = -0.23 for fat and 0.28 for fiber). Multiple regression models, which included the predisposing and enabling factor scales, stage of change, and covariates related to diet, explained a total of between 16 and 27% of the variance in diet. Predisposing and enabling factors are significantly associated with of stage of change and current diet in this high-risk sample of male auto workers. Stage of change is the strongest correlate examined and seems to serve as a mediating factor for dietary change. Results from the Next Step Trial will provide additional data on whether and how health promotion interventions influence these factors, and whether such changes are associated with dietary change.

Oltipraz chemoprevention trial in Qidong, Peoples Republic of China: modulation of serum aflatoxin albumin adduct biomarkers.

Kensler TW. He X. Otieno M. Egner PA. Jacobson LP. Chen B. Wang JS. Zhu YR. Zhang BC. Wang JB. Wu Y. Zhang QN. Qian GS. Kuang SY. Fang X. Li YF. Yu LY. Prochaska HJ. Davidson NE. Gordon GB. Gorman MB. Zarba A. Enger C. Munoz A. Helzlsouer KJ. et al..
Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland 21205, USA. tkensler@jhsph.edu
In 1995, 234 adults from Qidong, People's Republic of China, were enrolled and followed in a Phase IIa 4-methyl-5-(N-2-pyrazinyl)-1,2-dithiole-3-thione (oltipraz) chemoprevention trial. Residents of this area are at high risk for development of hepatocellular carcinoma, in part due to consumption of aflatoxin-contaminated foods. The intervention was a randomized, placebo-controlled, double-blind study. Elements of the study design and clinical outcomes have been recently published (Jacobson et al, Cancer Epidemiol. Biomark. Prev., 6: 257-265, 1997). The primary objective was to conduct a preliminary assessment of the ability of oltipraz to modulate levels of a validated biomarker of aflatoxin exposure and of the risk of hepatocellular carcinoma by determining levels of aflatoxin-albumin adducts in sera. Healthy eligible individuals were randomized into three arms to receive p.o. 125 mg of oltipraz daily, 500 mg of oltipraz weekly, or placebo for 8 weeks. There were no consistent changes in biomarker levels in the placebo arm over the 16-week observation period, nor was any apparent effect observed in the arm receiving 125 mg of oltipraz each day. However, individuals receiving 500 mg of oltipraz once a week for 8 weeks showed a triphasic response to oltipraz. No effect was observed during the 1st month of the intervention, whereas a significant (P = 0.001) diminution in adduct levels was observed during the 2nd month of active intervention and during the lst month of follow-up. A partial rebound in adduct levels toward baseline values was observed during the 2nd month postintervention. Linear regression models up to week 13 confirmed a significant (P = 0.008) weekly decline of biomarker levels in the group receiving 500 mg of oltipraz once a week. However, despite these effects relative to baseline values within the 500-mg weekly arm, there were no statistically significant differences in biomarker trajectories between treatment arms. The genotype for glutathione S-transferase M1, an oltipraz-inducible isoform involved in the detoxification of aflatoxin B1, did not appear to affect either baseline levels or rates of decline in the biomarker. A follow-up Phase IIb trial with a longer intervention period will be necessary to determine the full extent to which aflatoxin biomarker burden can be reduced and whether diminution of biomarkers can be sustained over the long term.

Calcium, vitamin D, and colorectal cancer: a review of the epidemiologic evidence.

Martinez ME. Willett WC.
Arizona Cancer Center, University of Arizona Health Sciences Center, Tuscon 85737, USA.
A protective effect of calcium on colorectal cancer, one of the most common malignancies in Western societies, has been supported primarily by results of in vitro animal studies. The present review summarizes the available epidemiological evidence for the association between calcium, vitamin D, and colorectal cancer. The overall results from over 20 published case-control and cohort studies suggest that calcium intake is not associated with a substantially lower risk of colorectal cancer. Findings from large prospective cohort studies, which should be least affected by methodological bias, have been notably consistent in finding weak and nonsignificant inverse associations. Whereas the relation between calcium and colon or colorectal cancer has been studied in numerous epidemiological studies, the role of vitamin D has only been addressed in a few of these investigations. The available results for vitamin D suggest that this micronutrient is inversely associated with risk but, given the scarcity of data, additional studies are needed to investigate this relation in more detail.

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

Year 1998
Zheng W. Anderson KE. Kushi LH. Sellers TA. Greenstein J. Hong CP. Cerhan JR. Bostick RM. Folsom AR.
Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis 55454-1015, USA.
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.

Recent use of hormone replacement therapy and the prevalence of colorectal adenomas.

Year 1998
Chen MJ. Longnecker MP. Morgenstern H. Lee ER. Frankl HD. Haile RW.
Department of Epidemiology, UCLA School of Public Health, Los Angeles, California 90095, USA.
The etiological role of hormone replacement therapy (HRT) (including estrogen only, combined estrogen-progesterone, and progesterone only) in colorectal neoplasia remains unclear. Several large studies have reported a reduced risk of colorectal cancer among HRT users; however, other studies have given inconsistent results. We examined the association between HRT and colorectal adenomatous polyps, precursors of colorectal cancer, among female participants in a case-control study. Subjects were members of a prepaid health plan in Los Angeles who underwent sigmoidoscopy in 1991-1993. Participants received an in-person interview and completed a food frequency questionnaire. A total of 187 histologically confirmed cases and 188 controls, ages 50-75 years, were included in the analysis. Compared with women who did not use HRT during the year before sigmoidoscopy, recent users had an adjusted odds ratio of 0.57 (95% confidence interval, 0.35-0.94). Duration of use was inversely related to the prevalence of colorectal adenomas, with a multivariate-adjusted odds ratio of 0.49 (95% confidence interval, 0.25-0.97) for use of 5 years or more. These results support a protective effect of HRT on colorectal adenomatous polyps.

The epidemiology of cancer of the small bowel.

Year 1998
Neugut AI. Jacobson JS. Suh S. Mukherjee R. Arber N.
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Despite its anatomical location between two regions of high cancer risk, the small bowel rarely develops a malignant tumor. However, in recent years, small bowel cancer incidence rates have begun to rise. The purpose of this review is to explore the descriptive and analytic epidemiology of small bowel cancer for those factors that protect this organ and those factors associated with loss of this protection. Within the small intestine, the sites at the highest risk are the duodenum, for adenocarcinomas, and the ileum, for carcinoids and lymphomas. In industrialized countries, small bowel cancers are predominantly adenocarcinomas; in developing countries, lymphomas are much more common. The incidence of small bowel cancer rises with age and has generally been higher among males than among females. The risk factors for small bowel cancer include dietary factors similar to those implicated in large bowel cancer, cigarette smoking, alcohol intake, and other medical conditions, including Crohn's disease, familial adenomatous polyposis, cholecystectomy, peptic ulcer disease, and cystic fibrosis. The protective factors may include rapid cell turnover, a general absence of bacteria, an alkaline environment, and low levels of activating enzymes of precarcinogens. Adenocarcinomas of the small and large bowel are similar in risk factors and geographic distribution but not in recent time trends; colorectal cancer incidence rates in the United States have been falling since the mid-1980s. Small bowel lymphoma may be associated with infectious agents, such as HIV. Given the differences in anatomic and geographic location among histological subtypes, much may be learned from well-designed, histology-specific epidemiological and genetic studies of cancer of the small bowel.

Agreement of endoscopic findings and serum pepsinogen levels as an indicator of atrophic gastritis.

Year 1998
Inoue M. Kobayashi S. Matsuura A. Hamajima N. Tajima K. Tominaga S.
Division of Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan. minoue@aichi-cc.pref.aichi.jp
Serum pepsinogen I and II levels have recently become popular as indicators of atrophic gastritis in epidemiological studies. Previous studies show a significant association between serum pepsinogen levels and endoscopically diagnosed atrophic gastritis. This study assesses the level of agreement between the degree of atrophic gastritis as assessed by endoscopic examination and by serum pepsinogen assays. Study subjects were 200 outpatients at Aichi Cancer Center Hospital, Nagoya, Japan, who were endoscoped between February and August 1995. Agreement of the degree of atrophic gastritis was assessed by endoscopic examination and by serum pepsinogen levels. Agreement in assessing the extent of atrophic gastritis between the two methods was 57%, and the presence of atrophic gastritis was 79%. Serum pepsinogen assays identify the majority of patients with atrophic gastritis, although they are less useful in assessing the degree of atrophy in detail.

Long-term cancer patient survival in the United States.

Year 1998
Wingo PA. Ries LA. Parker SL. Heath CW Jr.
Epidemiology and Surveillance Research Department, American Cancer Society, Atlanta, Georgia 30329-4251, USA.
Although survival rates are useful for monitoring progress in the early detection and treatment of cancer and are of particular interest to patients with new diagnoses, there are limited population-based estimates of long-term survival rates. We used data collected by the Surveillance, Epidemiology, and End Results Program for cases diagnosed during 1974-1991 and followed through 1992 to estimate relative survival at 5, 10, and 15 years after diagnosis of cancer of the breast, prostate, colon and rectum, and lung. Relative survival after diagnosis of breast and prostate cancer continued to decline up through 15 years after diagnosis, whereas survival after diagnosis of lung and colon or rectal cancer remained approximately constant after 5 and 10 years, respectively. Age-specific patterns of survival varied by site, stage, and demographics. Among patients with localized breast and prostate cancer, women who were younger than age 45 at breast cancer diagnosis and men who were 75 years and older at prostate cancer diagnosis had the poorest relative survival. Relative survival among lung cancer patients decreased with age at diagnosis, regardless of stage or demographics, and age-specific patterns of relative survival for patients with cancer of the colon and rectum differed according to race. Among white patients diagnosed with cancers of the colon and rectum, relative survival did not vary by age at diagnosis; among black patients older than 45 at diagnosis, relative survival decreased with age. This study provides population-based estimates of long-term survival and confirms black/white, male/female, and stage- and age-specific differences for the major cancers.

Dietary and supplemental calcium and the recurrence of colorectal adenomas.

Year 1998
Hyman J. Baron JA. Dain BJ. Sandler RS. Haile RW. Mandel JS. Mott LA. Greenberg ER.
Dartmouth Medical School, Hanover, New Hampshire 03755-3861, USA.
The association between calcium intake and the risk of colorectal neoplasia remains controversial. This analysis prospectively investigated the association between dietary and supplemental calcium intake and recurrent colorectal adenomas. Participants were part of a multicenter, randomized clinical trial of antioxidant vitamins. The study endpoints were adenomas detected between surveillance colonoscopies conducted at approximately 1 year and 4 years after study entry. Baseline intake of energy-adjusted calcium derived from a food frequency questionnaire was used as the main exposure of interest. Calcium supplement use was assessed by semiannual questionnaires. Logistic regression was used to compute odds ratios and 95% confidence limits, and Poisson regression was used to estimate rate ratios. Subjects in the fifth quintile of dietary calcium had an adjusted odds ratio of 0.72 (95% confidence interval, 0.43-1.22) compared to those in the lowest quintile. Investigation of the numbers of adenomas yielded stronger findings: the rate ratio for the fifth quintile versus the first was 0.63 (95% confidence interval, 0.39-1.02). Dietary calcium seemed to have a greater effect among individuals with a high-fat diet than among those with a low-fat diet; however, the interaction was not statistically significant. Use of calcium supplements was not related to adenoma recurrence. These results suggest that a high calcium intake may be associated with a reduction in risk of recurrent adenomas, especially among individuals on a high-fat diet.

Mutations of p53 in gallbladder carcinomas in high-incidence areas of Japan and Chile.

Year 1998
Yokoyama N. Hitomi J. Watanabe H. Ajioka Y. Pruyas M. Serra I. Shirai Y. Hatakeyama K.
First Department of Pathology, School of Medicine, Niigata University, Japan.
Gallbladder adenocarcinomas from patients in two high-prevalence areas, Niigata (Japan) and Santiago (Chile), were analyzed for acquired mutations in exons 5-8 of the p53 tumor suppressor gene, and the characteristics of p53 alterations in the two groups were compared. Of 42 tumors, 22 (52.4%) harbored 25 alterations identified by PCR amplification and direct sequencing (13 of 22 tumors from Niigata and 12 of 20 tumors from Santiago). All alterations were single base pair substitutions, 20 (80%) leading to an amino acid substitution or a chain-termination signal, and 5 (20%) were silent. Immunohistochemically, 55 of 84 cases (65.5%) showed overexpression of p53 protein, with no significant difference in frequency between the two areas. Missense mutations correlated highly with overexpression of the p53 protein (93.4%). Mutations of p53 occurred in all four exons examined, most commonly in exon 5, but in no particular "hot spot." In base-change spectra, all 12 mutations from Santiago showed transitions, with 4 arising at the CpG dinucleotide (33.3%). In contrast, no such transition was found at CpG sites in Niigata, and 4 of 13 mutations (30.8%) were transversions. The data indicated that p53 mutations are highly important in carcinogenesis in the gallbladder. In addition, the difference in p53 mutational spectra in Niigata and Santiago indicate a likely regional difference in mutagenesis.

Hormone replacement therapy and risk of colon and rectal cancer.

Year 1998
Fernandez E. La Vecchia C. Braga C. Talamini R. Negri E. Parazzini F. Franceschi S.
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. efernandez@bell.ub.es
The hypothesis that sex hormones may influence colorectal cancer risk was formulated in the early 1980s, but epidemiological studies on a relationship between colorectal cancer risk and hormone replacement therapy (HRT) have only accumulated over the last few years. To investigate the relationship between HRT and colon and rectal cancer and the role of other covariates that might modify it, we analyzed combined data from two case-control studies conducted in Italy between 1985 and 1996, including 994 women with incident colon cancer, 542 with rectal cancer, and 3110 controls with acute, non-neoplastic, nondigestive, non-hormone-related disorders. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived from unconditional multiple logistic regression equations including terms for age, center/study period, education, family history of colorectal cancer, status and age at menopause, parity, use of oral contraceptives, total energy intake, and body mass index. Ever use of HRT was inversely associated with cancer of the colon (OR = 0.64, 95% CI = 0.46-0.88) and of the rectum (OR = 0.46, 95% CI = 0.29-0.72). Increasing duration of use of HRT was related to decreasing risk for colon and rectal cancers (P for trend < 0.01). No interaction emerged, and the inverse association persisted across separate strata of other risk factors. This study, one of the largest case-control investigations on exogenous female hormones and colorectal cancer thus far, provides further evidence that women who have ever used HRT are at lower risk of colon and rectal cancer. Because colorectal cancer is the second most common neoplasm and cause of death among nonsmoking women in developed countries, these results may have a major public health impact.

Lipid peroxidation-induced etheno-DNA adducts in the liver of patients with the genetic metal storage disorders Wilsons disease and primary hemochromatosis.

Year 1998
Nair J. Carmichael PL. Fernando RC. Phillips DH. Strain AJ. Bartsch H.
Division of Toxicology and Cancer Risk Factors, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
To assess DNA damage caused by lipid peroxidation due to copper and iron storage disorders in the human liver, the formation of the etheno adducts 1,N6-ethenodeoxyadenosine (epsilon dA) and 3,N4-ethenodeoxycytine (epsilon dC) was measured in liver DNA from normal subjects and from patients with Wilson's disease (WD) and primary hemochromatosis. The mean epsilon dA and epsilon dC levels per 10(9) parent nucleotides in normal liver were 19.3 +/- 4.9 and 27.5 +/- 10.0, respectively. The mean epsilon dA and epsilon dC levels per 10(9) parent nucleotides in WD were 61.03 +/- 7.95 and 91.50 +/- 36.02, and in primary hemochromatosis, they were 46.62 +/- 32.83 and 64.32 +/- 11.55, respectively, two to three times higher than those in the normal liver. The etheno adduct levels were highly correlated with the copper content of the liver in the normal and WD samples. This study demonstrates for the first time the formation of promutagenic etheno adducts in humans in association with copper and iron storage-induced lipid peroxidation. Thus, the etheno adducts are implicated as initiating DNA damage in copper/iron-induced carcinogenesis in humans and should also be explored as biomarkers in disease progression and prevention trials.

Epstein-Barr virus involvement in gastric cancer: biomarker for lymph node metastasis.

Year 1998
Tokunaga M. Land CE.
Department of Public Health, Kagoshima University School of Medicine, Sakuragaoka, Japan.
EBV involvement in gastric cancer is characterized by episomal monoclonality, high antibody titers, EBV encoded small RNA and EBV nuclear antigen 1 expression in all tumor cells, and in the intramucosal stage, by a unique morphology. EBV involvement varies by population (approximately 7% of gastric cancers in Japan and >15% in Western countries), sex, histological type, and tumor location. The present study compares frequency of lymph node metastasis (LNM) between 170 EBV-positive and 1590 EBV-negative gastric cancer cases in Japan by level of invasiveness. Frequency of LNM increased with increasing depth of invasiveness but was consistently and significantly greater for EBV-negative cases (P = 0.0018). In particular, there were no instances of LNM among 75 EBV-positive cases as compared with 53 among 562 EBV-negative cases restricted to the mucosa and submucosa (odds ratio, 0; 95% confidence limits, 0-0.20). The finding suggests that genetic control of metastasis may differ between EBV-related and other gastric cancers. Also, the possibility that EBV-positive, noninvasive gastric cancers may not require lymph node dissection suggests that routine assay of biopsy specimens for EBV involvement could be important in populations, like that of Japan, where early gastric cancers are seen frequently.