Abraham M. Y. Nomura

Helicobacter pylori Infection and Gastric Carcinoma among Japanese Americans in Hawaii

BACKGROUND Helicobacter pylori are gram-negative spiral bacteria that are associated with chronic gastritis, a known precursor of gastric carcinoma. Persons at high risk for gastric carcinoma have been shown to have a high prevalence of H. pylori infection. METHODS We studied the relation of H. pylori infection and gastric carcinoma in a cohort of Japanese American men living in Hawaii. The 5908 men were enrolled and examined from 1967 to 1970. By 1989, 109 cases of pathologically confirmed gastric carcinoma had been identified. The store serum of each patient with gastric carcinoma and of each matched control subject were tested for the presence of serum IgG antibody to H. pylori. RESULTS Ninety-four percent of the men with gastric carcinoma and 76 percent of the matched control subjects had a positive test for H. pylori antibodies, for an odds ratio of 6.0 (95 percent confidence interval, 2.1 to 17.3). As the level of antibody to H. pylori increased, there was a progressive increase in the risk of gastric carcinoma (P for trend = 0.0009). The association was strong even for men in whom the diagnosis was made 10 or more years after the serum sample was obtained (odds ratio, 10.5; 95 percent confidence interval, 2.5 to 44.8). CONCLUSIONS Infection with H. pylori is strongly associated with an increased risk of gastric carcinoma. However, most persons infected with H. pylori will never have gastric carcinoma. Therefore, other factors that increase the risk of gastric carcinoma among persons infected with H. pylori need to be identified.

Helicobacter pylori Infection and the Risk for Duodenal and Gastric Ulceration

Infection with Helicobacter pylori probably increases the risk for developing duodenal and gastric ulcer disease. Previous studies have shown that 75% to 100% of patients with duodenal ulcer and 35% to 86% of patients with gastric ulcer have evidence of an H. pylori infection [1]. The finding that eradication of H. pylori in patients with duodenal ulcer is associated with a statistically significant decrease in the recurrence rate of the disease further supports the association [2-5]. However, these observations may just reflect the frequent coexistence of duodenal ulcer with antral gastritis [6], which has been shown to be caused by H. pylori [7, 8]. Wormsley [9] has noted that the Henle-Koch postulates have not been satisfied for causation of duodenal ulcer by H. pylori because the organism has not been shown to produce the disease. The evidence is weaker that H. pylori causes gastric ulcer because only a single study with 26 patients has shown that antimicrobial therapy directed against H. pylori decreased the gastric ulcer recurrence rate [5]. None of the previous studies evaluated patients with duodenal or gastric ulcers before they were diagnosed or hospitalized with their disease. The usual temporal sequence is that patients with peptic ulcer disease are examined to detect H. pylori infection at the time the diagnosis is made or after they have had treatment to eradicate the organism. Consequently, peptic ulceration could possibly predispose persons to colonization by H. pylori [9]. We did a prospective study in a large population-based cohort using serum specimens that were obtained from study participants before they were diagnosed with peptic ulcer. We tried to determine whether H. pylori infection, as shown by the presence of specific IgG antibodies, is a risk factor for the subsequent development of either duodenal or gastric ulceration. Methods Study Population Japanese-American men born from 1900 to 1919, who were identified by the Honolulu Heart Program in 1965 by using the comprehensive 1942 Selective Service draft registration files [10], composed the study population. Of 11 148 eligible men, 8006 (72%) were interviewed and examined from 1965 to 1968, 180 (2%) died before they could be examined, and 2962 (26%) did not participate in the program. Study participants ranged in age from 45 to 68 years. The data collected included birthplace, marital status, history of alcohol use, blood pressure, and body mass index (the weight in kilograms divided by the square of the height in meters). Serum cholesterol values were determined by the Auto Analyzer N-24A method, and serum glucose values were determined by the Auto Analyzer N-2B method 1 hour after a 50-g glucose load had been given [11]. A total of 7498 (94%) men returned for a second examination between 1967 and 1970, and a serum specimen was obtained at this time. Serum specimens for a 20% random sample of the men were sent to the U.S. Public Health Service Hospital in San Francisco, whereas specimens for the remaining 5924 men were stored at 20C at the study site. Four hundred eighty-one patients with previous gastrectomy or a previous diagnosis of peptic ulcer disease were excluded from the study. The average age of the remaining 5443 patients at the time of their second examination was 56.6 years. Surveillance Methods Surveillance of the cohort to identify incident patients with peptic ulcer was done by a continuous review of discharge records of all general hospitals on Oahu. Based on a 19-year follow-up survey of the study patients from the time of their examination in 1965 to 1968, only 1.3% of the men could not be located on Oahu. Thus, surveillance was nearly complete. Two hundred fifty-eight patients were hospitalized with peptic ulcer disease from 1968 to 1989. One hundred sixty (62%) patients had their diagnosis confirmed by examination of tissue obtained by either surgery or biopsy, 36 (14%) were diagnosed by radiologic examination, and 62 (24%) were clinically diagnosed based on the endoscopic or surgical report of the presence of an ulcer. One hundred sixty-nine incident patients had gastric ulcer, 73 had duodenal ulcer, and 16 had gastric and duodenal ulcers. Seventeen of the 169 patients with gastric ulcer, 6 of the 73 patients with duodenal ulcer, and 2 of the 16 patients with gastric and duodenal ulcers were removed from study because they had an insufficient amount of serum in the freezer repository. Selection of Controls Each of the remaining patients was matched with one control from the study cohort based on age at examination (47 to 70 years) and date of serum collection. If a potential control had a diagnosis of gastric cancer before or after the serum was obtained, he was excluded from the study. As a consequence, 160 patients (3.1%) were removed from the control pool of 5185 men because of the reported association between H. pylori infection and gastric cancer [12, 13]. Of the remaining 5025 men, 336 (6.7%) were excluded because they previously had cardiovascular disease or other cancer, and 1532 (30.5%) were excluded because they were diagnosed with cardiovascular disease or other cancer after their serum collection. This exclusion was done because the serum specimens from these patients are going to be used for other studies. A total of 3157 patients remained in the pool of controls from which 233 (7.4%) were matched to incident case-patients with peptic ulcer. Each control participant was alive at the time of hospitalization of the matched case-patient, so that death was not a competing factor. Serologic Testing The presence of serum IgG antibodies to H. pylori was determined by enzyme-linked immunosorbent assay (ELISA), using the Pyloristat kit (Whittaker Bioproducts, Inc., Walkersville, Maryland). As validated by the manufacturer, the results of this assay closely mirror those of a previously described IgG ELISA [13-18]. In brief, serum specimens from patients were diluted 1:20 for use in the kit, and IgG levels of sera were determined according to the manufacturers instructions. The serum specimens were coded so that the laboratory technician could not distinguish case-patients from controls. A ratio of 1.00 or greater was considered positive, a ratio of less than 0.80 was considered negative, and a ratio of 0.80 to 0.99 was considered equivocal, as calibrated in the kit. Two patients with gastric ulcer and two patients with duodenal ulcer or their controls had equivocal values, so they were excluded from the study. Statistical Analysis A matched casecontrol study design was used to identify the patients and controls for serum tests. As a result, odds ratios, based on the results of the H. pylori IgG antibody test, were determined using conditional logistic regression methods [19]. When odds ratios were indeterminable, approximate confidence intervals (CIs) were determined by the method of Breslow and Day [19]. Tests for trend in the logit of risk were derived from conditional logistic regression models by using grouped H. pylori test results (coded as 1, 2, 3, and 4). All conditional logistic regression models were fitted using iterative maximum likelihood methods and a special application of the proportional hazards regression model [20]. Results The characteristics of the 229 patients with peptic ulcer and of their matched controls are presented in Table 1. The two groups of men were similar with respect to demographic characteristics and laboratory values. Table 1. Characteristics of Patients with Peptic Ulcer and of Controls The mean age at diagnosis was 67.5 years (range, 52.7 to 87.2 years) for the 150 patients with gastric ulcer, 64.5 years (49.4 to 80.0 years) for the 65 patients with duodenal ulcer, and 63.5 years (52.4 to 83.1 years) for the 14 patients with gastric and duodenal ulcers. Table 2 shows the association between the H. pylori test result and peptic ulcer by specific type. Ninety-three percent (139 of 150) of the patients with gastric ulcer and 78% (117 of 150) of the matched controls had a positive H. pylori-specific IgG antibody level, yielding an odds ratio of 3.2 (P = 0.001). (The odds ratio is determined by dividing 32 pairs by 10 -/+ pairs.) Ninety-two percent of the case-patients with duodenal ulcer and 78% of the matched controls had a positive test result, yielding an odds ratio of 4.0 (P = 0.03). If a patient had either a gastric or duodenal ulcer, then the odds ratio was 3.4 (P = 0.0001). Only 14 patients had both gastric and duodenal ulcers. The odds ratio was 1.3 (P > 0.2), based on these patients. Table 2. Odds Ratio for the Association between Helicobacter pylori Seropositivity and Type of Peptic Ulcer Because some of the hospitalized patients with peptic ulcer may have developed their ulcers after the use of adrenocorticosteroids or nonsteroidal anti-inflammatory drugs, we systematically reviewed the hospital records of the patients. A similar review could not be done for the controls because they were not hospitalized. We found that 18 of the 150 patients with gastric ulcer and 9 of the 65 patients with duodenal ulcer had taken these medications at the time of hospitalization. If these patients and their matched controls were excluded, the odds ratio would have been 3.3 (95% CI, 1.6 to 7.0) for gastric ulcer, 3.3 (CI, 0.9 to 12.1) for duodenal ulcer, and 3.3 (CI, 1.7 to 6.4) for either gastric or duodenal ulcer. Of the 215 patients with either gastric or duodenal ulcer, 100 also had a hospital-based diagnosis of cardiovascular disease or cancer. If these patients were excluded from the study, as were controls with these diseases, 115 patients with gastric or duodenal ulcer would have remained in the study. Ninety-four percent of these case-patients and 77% of their controls had a positive test result for H. pylori antibody. The odds ratio for peptic ulcer was 4.3 (CI, 1.8 to 10.5) in this group of patients. When the patients with gastric ulcer who had positive antibody resu

Prospective study of alcohol consumption and cancer.

The relation between alcohol consumption and the subsequent occurrence of the five most frequent cancers in Japanese men in Hawaii (cancer of the stomach, colon, rectum, lung, and prostate) was analyzed in a prospective study of 8006 subjects. Information on alcohol consumption was obtained through interviews in the mid-1960s, and the cohort has been followed since then. The analysis, which was adjusted for the effects of age and cigarette smoking, revealed a positive association between consumption of alcohol and rectal cancer, accounted for primarily by an increased risk in men whose usual monthly consumption of beer was 500 oz (15 liters) or more (relative risk, 3.05; P less than 0.01, as compared with those who did not drink beer). A significant positive relation between alcohol consumption and lung-cancer incidence was also found, accounted for primarily by an increased risk among subjects who consumed larger amounts of wine or whiskey, as compared with the risks among nonconsumers of these beverages (relative risk, 2.19, [P = 0.03] and 2.62 [P less than 0.01], respectively). No significant relation between alcohol consumption and the incidence of the other three cancers was found.

Serum vitamin D metabolite levels and the subsequent development of prostate cancer (Hawaii, United States)

Objectives: Because several serum studies of vitamin D metabolites have produced equivocal results on their relation to prostate cancer risk, the purpose of this study is to evaluate this association further.Methods: A nested case-control study in a cohort of 3,737 Japanese-American men examined from 1967 to 1970 was conducted in Hawaii (United States). At the time of examination, a single blood specimen was obtained, and the serum was frozen. After a surveillance period of over 23 years, 136 tissue-confirmed incident cases of prostate cancer were identified. Their stored sera and those of 136 matched controls were measured for the following: 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, calcium, phosphorus, and parathyroid hormone.Results: There were no notable differences between cases and controls in their median serum levels of the five laboratory measurements. Odds ratios (OR) for prostate cancer, based on the quartiles of serum levels in controls, were also determined. The ORs for the highest quartiles relative to the lowest were 0.8 (95 percent confidence interval [CI] = 0.4-1.8) for 25-hydroxyvitamin D and 1.0 (CI = 0.5-2.1) for 1,25-dihydroxyvitamin D.Conclusion: It is possible that the lack of sufficient numbers of study subjects with low vitamin D levels affected the results. Nonetheless, the findings suggest that there is a lack of a strong association between vitamin D and prostate cancer.

Black tea consumption and cancer risk: A prospective study

In a prospective cohort study, men of Japanese ancestry were clinically examined from 1965 to 1968. For 7,833 of these men, data on black tea consumption habits were recorded. Since 1965, newly diagnosed cancer incidence cases have been identified: 152 colon, 151 lung, 149 prostate, 136 stomach, 76 rectum, 57 bladder, 30 pancreas, 25 liver, 12 kidney and 163 at other (miscellaneous) sites. Compared to almost-never drinkers, men habitually drinking black tea more than once/day had an increased relative risk (RR) for rectal cancer (RR = 4.2). This positive association (P = 0.0007) could not be accounted for by age or alcohol intake. We also observed a weaker but significant negative association of black tea intake and prostate cancer incidence (P = 0.020). There were no significant associations between black tea consumption and cancer at any other site.

Childhood Soy Intake and Breast Cancer Risk in Asian American Women

Introduction: Historically, breast cancer incidence has been substantially higher in the United States than in Asia. When Asian women migrate to the United States, their breast cancer risk increases over several generations and approaches that for U.S. Whites. Thus, modifiable factors, such as diet, may be responsible. Methods: In this population-based case-control study of breast cancer among women of Chinese, Japanese, and Filipino descent, ages 20 to 55 years, and living in San Francisco-Oakland (California), Los Angeles (California) and Oahu (Hawaii), we interviewed 597 cases (70% of those eligible) and 966 controls (75%) about adolescent and adult diet and cultural practices. For subjects with mothers living in the United States (39% of participants), we interviewed mothers of 99 cases (43% of eligible) and 156 controls (40%) about the daughters childhood exposures. Seventy-three percent of study participants were premenopausal at diagnosis. Results: Comparing highest with lowest tertiles, the multivariate relative risks (95% confidence interval) for childhood, adolescent, and adult soy intake were 0.40 (0.18-0.83; Ptrend = 0.03), 0.80 (0.59-1.08; Ptrend = 0.12), and 0.76 (0.56-1.02; Ptrend = 0.04), respectively. Inverse associations with childhood intake were noted in all three races, all three study sites, and women born in Asia and the United States. Adjustment for measures of westernization attenuated the associations with adolescent and adult soy intake but did not affect the inverse relationship with childhood soy intake. Discussion: Soy intake during childhood, adolescence, and adult life was associated with decreased breast cancer risk, with the strongest, most consistent effect for childhood intake. Soy may be a hormonally related, early-life exposure that influences breast cancer incidence. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1050–9)

A prospective study of diet, smoking, and lower urinary tract cancer☆

The association of diet and smoking with bladder cancer was investigated in a cohort study conducted in Hawaii. The study included 7995 Japanese-American men who were born between 1900 and 1919, and were examined from 1965 to 1968. After 22 years of follow-up, 96 incident cases of bladder cancer were diagnosed. Current cigarette smokers had a 2.9-fold risk of bladder cancer, compared with nonsmokers. A direct dose-response relation was observed, based on pack-years of cigarette smoking. Consumption of fruit was inversely associated with the risk of bladder cancer (P = 0.038). The relative risk was 0.6 among subjects who had the most frequent (> or = 5 times/wk) intake of fruits compared to those with the least intake (< or = 1 time/wk). A weaker inverse association with milk intake was also observed (P = 0.07). Frequent consumption of fried vegetables, pickles, or coffee increased the risk of bladder cancer, but none of these foods showed a significant dose-response relationship. There was no association of other selected foods, alcohol, total calories, protein, fat, or carbohydrates with bladder cancer risk.

A prospective study of colon and rectal cancer among Hawaii Japanese men

The goals of this study were to assess the association of diet, alcohol, smoking, and other life-style factors with the risk of colon and rectal cancer and to examine the differences in the risk factors associated with each cancer site. Information on diet, alcohol, smoking, and other life-style factors was obtained from 7945 Japanese-American men who were living in Hawaii and examined from 1965 through 1968. After 174,514 person-years of observation, 330 incident cases of colon cancer and 123 incident cases of rectal cancer were diagnosed by histology. The risk of both colon and rectal cancer increased with age, alcohol intake, and pack-years of cigarette smoking. For colon cancer, there was also a direct association with body mass index and heart rate, while an inverse association was observed with serum cholesterol, intake of monounsaturated fatty acid, and percentage of calories from fat. For rectal cancer, the risk decreased with an increase in the intake of carbohydrates as percentage of calories. These findings suggest that some of the risk factors for colon cancer are different from those for rectal cancer.

Liquid chromatographic-photodiode array mass spectrometric analysis of dietary phytoestrogens from human urine and blood.

Dietary phytoestrogens have been implicated in the prevention of chronic diseases. However, it is uncertain whether the phytoestrogens or the foods associated with phytoestrogens account for the observed effects. We report here a new liquid chromatography photodiode array mass spectrometry (LC-PDA-MS) assay for the determination of nanomolar amounts of the most prominent dietary phytoestrogens (genistein, dihydrogenistein, daidzein, dihydrodaidzein, glycitein, O-desmethylangolensin, hesperetin, naringenin, quercetin, enterodiol, enterolactone) in human plasma or serum and urine. This assay was found to be suitable for the assessment of quercetin exposure in an onion intervention study by measuring urinary quercetin levels. Other successful applications of this assay in clinical and epidemiologic studies validated the developed method and confirmed previous results on the negative association between urinary isoflavone excretion and breast cancer risk.

Helicobacter pylori CagA Seropositivity and Gastric Carcinoma Risk in a Japanese American Population

Helicobacter pylori colonization is associated with gastric cancer, but whether and to what extent the risk is greater for strains with the cagA gene than for those without needs to be determined. Between 1967 and 1977, 9963 Japanese American men were recruited and examined. By 1996, incident cases of gastric carcinoma of the distal stomach had been diagnosed in 261 men. Stored serum samples from these case patients and 261 age-matched control subjects were tested for immunoglobulin G antibodies to H. pylori and to the CagA product of H. pylori, using antibody-specific enzyme-linked immunosorbent assays. Compared with H. pylori-negative, CagA-negative men, H. pylori-positive, CagA-negative men had an odds ratio (OR) of 2.7 (95% confidence interval [CI], 1.3-5.6) for intestinal gastric carcinoma. Men seropositive for both H. pylori and CagA had an OR of 4.1 (95% CI, 2.2-7.7). This suggests that colonization by an H. pylori strain with the cagA gene is associated with a greater risk of intestinal gastric carcinoma.