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Carcinogenesis Advance Access originally published online on March 13, 2008
Carcinogenesis 2008 29(5):1042-1048; doi:10.1093/carcin/bgn072
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Plasma levels of carotenoids, retinol and tocopherol and the risk of gastric cancer in Japan: a nested case–control study

Christina Persson1,2, Shizuka Sasazuki1, Manami Inoue1,*, Norie Kurahashi1, Motoki Iwasaki1, Tsutomu Miura1, Weimin Ye2, Shoichiro Tsugane1 and for the JPHC Study Group

1 Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku 104-0045, Tokyo, Japan
2 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

* To whom correspondence should be addressed. Tel: +81 3 3542 2511 ext. 3389; Fax: +81 3 3547 8578; Email: mnminoue{at}gan2.res.ncc.go.jp


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Funding
 Appendix
 References
 
Fruits and vegetables have been suggested to confer protection against diseases such as cancer through the effects of antioxidants, often represented by carotenoids. We investigated the impact of carotenoids, retinol and tocopherol on gastric cancer development in a large nested case–control study among Japanese with known Helicobacter pylori infection status. A total of 36 745 subjects aged 40–69 in the Japan Public Health Center-based Prospective Study who responded to the baseline questionnaire and provided blood samples in 1990–1995 were followed until 2004. Plasma levels of carotenoids in 511 gastric cancer cases and 511 matched controls were measured by high-performance liquid chromatography. Odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated using conditional logistic regression models. Plasma level of β-carotene was inversely associated with the risk of gastric cancer (compared with the lowest quartile: OR = 0.63, 95% CI = 0.31–0.75; OR = 0.48, 95% CI = 0.31–0.75 and OR = 0.46, 95% CI = 0.28–0.75, for quartile 2, 3 and 4, respectively, Ptrend < 0.01). Inverse associations were evident in men for {alpha}-carotene (Ptrend = 0.04) and β-carotene (Ptrend < 0.01), but not in women, who had relatively higher plasma levels compared with men. We found no statistically significant association between plasma levels of lutein/zeaxanthin, lycopene, retinol, {alpha}- or {gamma}-tocopherol and gastric cancer risk. Our findings suggest that those who have very low plasma levels of {alpha}-carotene and β-carotene are at a higher risk of gastric cancer.

Abbreviations: CI, confidence interval; JPHC study, Japan Public Health Center-based Prospective Study; OR, odds ratio


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Funding
 Appendix
 References
 
According to an estimate of cancer incidence in the year 2002 by the International Agency for Research on Cancer, gastric cancer is one of the most common cancers in the world, following lung, breast and colorectal cancer, and the second most common cause of death from cancer (1). Helicobacter pylori infection is the leading cause of gastric cancer (2), while other suggested risk factors for gastric cancer include diet, smoking, family history of gastric cancer, ethnicity, host genetic polymorphisms in relation to inflammation and hormonal environment (3–6). Previous epidemiological studies have shown that diet plays an important role, and especially fruits and vegetables have been suggested to be protective, owing to the effect of antioxidants (7–10). Studied antioxidants typically include carotenoids, retinol and tocopherol, but results have been conflicting (7,8,11–16). Studies vary by design, for example, with some using food frequency questionnaires whereas others directly measure plasma levels. This variation may result in inconsistent results since food frequency questionnaires represent a subjective measurement over time, which reflects intake of the food or nutrient rather than uptake of the antioxidants. Plasma level is therefore a better reflection of exposure at a specific point in time. Nevertheless, carotenoid level is sensitively reflected by food intake since it is less likely controlled by homeostatic function. Plasma carotenoid level is therefore likely better correlated with estimate from food frequency questionnaires based on long-term rather than short-term food habits. The half-life of carotenoid, which is lipid soluble and thus more easily accumulated in the body, is considered longer than that of other water-soluble polyphenols. The usual half-life period of carotenoid is considered a couple of weeks (17). Confounding from other risk factors may also explain partly conflicting results from previous studies. Lower plasma levels of carotenoids have been reported in smokers suggested to be due to a lower intake of fruit and vegetables and increased metabolic turnover. The metabolic turnover is a result from the degradation of carotenoids by the gas phase of cigarette smoke (18–23). Further, one previous study found differences between those with and without H.pylori infection (24), although another study did not (16).

We investigated the impact of plasma levels of selected carotenoids (β-cryptoxanthin, {alpha}- and β-carotene, lutein/zeaxanthin and lycopene), retinol and {alpha}- and {gamma}-tocopherol, on the risk of gastric cancer using a nested case–control study within the Japan Public Health Center-based Prospective Study (JPHC study).


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Funding
 Appendix
 References
 
Study population
The JPHC study was launched in January 1990 for Cohort I (subject age span 40–59 years) and in 1993 for Cohort II (40–69 years) and consisted of 11 public health center areas throughout Japan with a total of 140 420 middle-aged individuals (25–29). One public health area was not included in the present study due to a lack of incidence data. The study was approved by the Institutional Review Board of the National Cancer Center, Tokyo, Japan.

Baseline survey and exposure measurements
A self-administered questionnaire survey was conducted in each cohort at the baseline of the study on various lifestyle factors, including demographic characteristics, personal medical history, family history, smoking and drinking habits, dietary habits, physical activity and other lifestyle factors. A total of 99 808 participants responded, giving an 81% response rate. Respondents were asked to provide a 10 ml blood sample during their health checkup. After exclusion of subjects with self-reported cancer at baseline (n = 2136), non-Japanese race (n = 18) and those who had moved away before baseline (n = 11), 46 803 men and 50 841 women remained eligible. Among these, the study included the 13 467 (29%) men and 23 278 (46%) women who donated blood samples at baseline, collected from 1990 to 1992 in Cohort I and 1993 to 1995 in Cohort II. All centers used the same protocol for specimen collection. The plasma and buffy layer were divided into four tubes, each holding 1.0 ml (three tubes for plasma and one tube for the buffy layer), and then stored at –80°C, as described in an earlier report (27).

Follow-up and case ascertainment
Subjects were followed from 1 January 1990 to 31 December 2004 for Cohort I and from 1 January 1993 to 31 December 2004 for Cohort II. In Japan, residency and death registration are required by law, and the registers are believed to be complete. Residence status and survival were confirmed annually using residential registers kept by each municipality in the study areas. Among study subjects, 10% moved outside the study area and 0.3% was lost to follow-up during the study period. Inspection of the resident register is open to the general public under the resident registration law. Information on the causes of death was obtained by examining death certificates provided by the Ministry of Health, Labor and Welfare with permission from the Ministry of Internal Affairs and Communications.

Incident cancer cases were identified by active patient notification from the local major hospitals in the study area and data linkage with population-based cancer registries. Candidate patients were linked by name, address and date of birth and were entered in the cancer registry for the JPHC study when the date of birth and residence fulfilled cohort inclusion criteria. Death certificate information was used as a supplementary information source. For gastric cancer, the percentage of cases for which information was available from death certificates only was 3.1%, while histological verification of diagnosis was done in 94%. The anatomic site of each case was coded using the International Classification of Diseases for Oncology, Third Edition (30). A tumor located in the lower side of the stomach was classified as distal gastric cancer (non-cardia site) (code C16.2-16.7) and in the upper side of the stomach as proximal gastric cancer (cardia site) (code C16.0-16.1). Tumors that could not be classified because of overlapping lesions (code C16.8) or no information (code C16.9) were categorized as unclassified. Histological classification was based on review of the record from each hospital, as described previously (31) and subdivided as follows: differentiated type [corresponding to intestinal type by Laurén classification (32)] and papillary adenocarcinoma, well-differentiated and moderately differentiated type and undifferentiated type [corresponding to diffuse type by Laurén classification (32)] and poorly differentiated adenocarcinoma. Adenocarcinoma, not otherwise specified, and other types of carcinoma such as adenosquamous carcinoma, squamous cell carcinoma, carcinoid tumor, undifferentiated carcinoma and miscellaneous tumors were considered unclassified types. For each case, we selected one control matched for gender, age (±3 years), study area, blood donation date (±2 months) and time since last meal at blood donation (±5 h). The final analysis included 511 sets of matched cases and controls.

Laboratory analysis
Plasma levels of the carotenoids (β-cryptoxanthin, {alpha}- and β-carotene, lutein/zeaxanthin and lycopene), retinol and {alpha}- and {gamma}-tocopherol were determined by reverse-phase high-performance liquid chromatography with a photodiode array detector (33). In order to correct for recoveries, internal standards were run with each sample. Standard curves for β-cryptoxanthin, {alpha}- and β-carotene, lutein/zeaxanthin, lycopene, retinol, {alpha}- and {gamma}-tocopherol displayed linearity from 0 to 6.2, 0 to 5.9, 0 to 6.2, 0 to 4.4, 0 to 16.7, 0 to 16.5, 0 to 108.7 and 0 to 140.1 µg/dl, respectively, and correlation coefficients were 1.000, 1.000, 0.999, 0.985, 0.983, 0.995, 0.997 and 0.998, respectively. The detection limits were 0.1 µg/dl for β-cryptoxanthin, 0.1 µg/dl {alpha}- and β-carotene, 1.1 µg/dl for lutein/zeaxanthin, 0.5 µg/dl for lycopene, 1.4 µg/dl for retinol, 18.8 and 2.6 µg/dl for {alpha}- and {gamma}-tocopherol, respectively, among the plasma samples. The coefficients of variation were <5%, and sample recovery rate was 96.3, 77.6, 91.0, 96.7, 93.5, 83.5, 95.1 and 99.5% for β-cryptoxanthin, {alpha}- and β-carotene, lutein/zeaxanthin, lycopene, retinol, {alpha}- and {gamma}-tocopherol, respectively.

Serum IgG antibodies against whole H.pylori and CagA were measured with an ELISA kit (E Plate ‘Eiken’ H.pylori Antibody, Eiken Kagaku Co. Ltd, Tokyo, Japan) as described previously (34). The investigators were blinded during all analyses.

Statistical analysis
Matched odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable conditional logistic regression models, adjusted for potential confounding factors such as a family history of gastric cancer, smoking status, H.pylori infection, salt intake, consumption of highly salted foods (salted fish guts and roe) and body mass index (kg/m2). Further adjustments for serum levels of cholesterol were considered for {alpha}- and {gamma}-tocopherol. Smoking status was divided into never, past, current ≤20 cigarettes per day and current ≥21 cigarettes per day. Body mass index was divided into ≤19.9, 20–24.9 and ≥25 kg/m2. Family history was considered positive if at least one parent or sibling had had gastric cancer. Helicobacter pylori infection was regarded as positive if the individual tested positive for antibodies against either whole H.pylori or CagA. Plasma levels of β-cryptoxanthin, {alpha}- and β-carotene, lutein, lycopene, retinol, {alpha}- and {gamma}-tocopherol were divided into quartiles according to plasma levels in the controls over all or by gender. Tests for trend were done by including semicontinuous variables in the conditional logistic regression models. Ptrend<0.05 were considered statistically significant. All statistical analyses were performed using Stata/SE 9.2 (StataCorp, College Station, TX, USA).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Funding
 Appendix
 References
 
Baseline characteristics of the case and control group are shown in Table I. As expected, H.pylori infection and family history of gastric cancer were more common in patients with gastric cancer than in controls. Cholesterol levels were higher in the control group than in the gastric cancer cases. Table II shows ORs and 95% CIs for the associations between plasma levels of lutein/zeaxanthin, β-cryptoxanthin, {alpha}- and β-carotene, lycopene, retinol, {alpha}- and {gamma}-tocopherol and risk of gastric cancer, by comparison with the lowest quartile. We found a statistically significant inverse association for {alpha}-carotene (OR = 0.66, 95% CI = 0.44–0.98 for second quartile and OR = 0.65, 95% CI = 0.42–1.00 for third quartile) and β-carotene (OR = 0.63, 95% CI = 0.31–0.75; OR = 0.48, 95% CI = 0.31–0.75 and OR = 0.46, 95% CI = 0.28–0.75, for quartiles 2, 3 and 4, respectively; Ptrend < 0.01). We found no statistically significant association for lutein/zeaxanthin, lycopene, retinol, {alpha}- or {gamma}-tocopherol and gastric cancer risk.


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  		Table I. Baseline characteristics of the study population

 


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  		Table II. Plasma levels of carotenoids, retinol and tocopherol and their associations with the risk of gastric cancer, a case–control study nested within the JPHC study

 
Because plasma carotenoid levels varied by gender, further stratified analyses by gender were performed using specific quartiles for β-cryptoxanthin, {alpha}- and β-carotene (Table III). In men, an increased level of {alpha}- and β-carotene was associated with a reduced risk of gastric cancer (OR = 0.60, 95% CI = 0.36–1.00, Ptrend = 0.04 and OR = 0.47, 95% CI = 0.27–0.81, Ptrend < 0.01, for the highest compared with the lowest quartile of {alpha}- and β-carotene, respectively), whereas no statistically significant association was found in women. Further, no statistically significant association for β-cryptoxanthin plasma levels was found in men or women, although plasma levels were more than twice as high in women, as were those of {alpha}- and β-carotene. Table IV shows results for men stratified by smoking status, revealing a decreased risk with a statistically significant trend for β-carotene in both smokers and non-smokers as well as for β-cryptoxanthin in non-smokers.


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  		Table III. Plasma levels of selected carotenoids and their associations with the risk of gastric cancer among men and women, a case–control study nested within the JPHC study

 


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  		Table IV. Plasma levels of selected carotenoids and their associations with the risk of gastric cancer among male smokers and non-smokers, a case–control study nested within the JPHC study

 
We found no statistically significant associations in stratified analyses by anatomic site or histological type, except that, in men, {alpha}-carotene and β-cryptoxanthin seemed to confer a protective effect on distal differentiated gastric cancer (Ptrend = 0.06 and <0.01, respectively), whereas high β-carotene level was associated with a decreased risk of distal undifferentiated gastric cancer (Ptrend < 0.01). We found no statistically significant association for lutein/zeaxanthin, lycopene, retinol, {alpha}- or {gamma}-tocopherol and gastric cancer subtypes by anatomic subsite or histological type.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Funding
 Appendix
 References
 
We have previously reported that the intake of fruits and yellow (such as carrot and pumpkin) and white (such as pickled vegetables, Chinese cabbage, radish, tomato and cucumber) vegetables was inversely related to gastric cancer incidence in the JPHC study (29). The underlying mechanism of this protective effect is not fully understood but is suggested to be via antioxidants (8). The effect of carotenoids on gastric cancer development has been studied using both plasma levels (13,15,16,35–38) and food frequency questionnaires (11,12,14,39–42) with varying results.

Here, we found that some carotenoids may have a protective effect against gastric cancer development. Consistent with some earlier studies (14,15,40) but inconsistent with others (16,35,36), higher levels of {alpha}- and β-carotene were protective against gastric cancer development. We conclude from our results that a clearly deficient or very low intake of β-carotene confers an increased risk of gastric cancer. We also suggest that subjects with sufficient levels receive no benefit from further supplement, which is consistent with previous intervention trials in China (Linxian study) (43,44), Finland (the alpha-tocopherol, beta-carotene cancer prevention study) (45) and the USA [the beta carotene and retinol efficacy trial (46) and the physician's health study (47)]. Subjects from Linxian with low β-carotene plasma levels showed a decrease in risk of gastric cancer when intake was increased (44). In contrast, no decrease in risk was seen in patients with sufficient β-carotene levels (46,47), while another study conversely showed that a high dose increased the risk of cancer development (45). In addition, the sources of {alpha}-carotene in Japan are carrots, tomatoes and leaf mustard (48), but worldwide the main sources are carrots, red palm oil and mangoes (49). This can possibly contribute to the different uptake as well as the inconsistent study results. Furthermore, plasma levels of {alpha}-carotene appear to be extremely low in this population, especially in men, compared with those in Europe (16). Thus, it is conceivable that we could detect a high risk of gastric cancer associated with deficient {alpha}-carotene because this study contained a group of men who had very low plasma levels of {alpha}-carotene.

Our findings may be due to residual confounding by smoking. An earlier study reported that smoking decreased the levels of carotenoids in blood even when intake was high (21,46). Plasma concentration discrepancies between smokers and non-smokers have been reported, suggesting the inhibition of carotenoid uptake by cigarette smoke (7,19,20,50–52). We also found that levels of plasma carotenoids in smokers were lower than in never smokers. The difference was clearer when smokers were further separated by the amount of daily cigarette consumption. However, smoking is only moderately associated with an increased risk of gastric cancer, and the inverse association with gastric cancer remained clear after adjustment for smoking. Given findings that alcohol intake also lowered the amount of carotenoids in the blood (53), we further compared carotenoid levels among non-drinkers with regular drinkers (≥3 times/week). Results showed that carotenoid levels were lower among regular drinkers. However, alcohol intake was not associated with gastric cancer risk, thus alcohol is unlikely to be a confounder for the observed inverse associations. Helicobacter pylori infection was also considered a potential confounder due to its role as the leading cause of gastric cancer (2,54), and H.pylori infection has been found to decrease the absorption of many nutrients. In H.pylori-infected individuals, the concentration of β-carotene is reduced in the gastric juice but not in the plasma, and {alpha}-tocopherol level is reduced in the corpus when H.pylori is present in the antrum (24). In our study, we also found that plasma levels of β-cryptoxanthin, {alpha}- and β-carotene and lycopene were lower in H.pylori-positive controls (37, 23 and 16% lower than those in the non-infected, respectively). However, the results remained almost unchanged after adjustment for H.pylori infection status, although we cannot rule out the possibility of residual confounding. Finally, although we controlled for major potential confounders, it is likely that the results were also affected by unmeasured or unidentified ones.

The inverse association between plasma carotenoids and gastric cancer was found only in men. This gender discrepancy can be explained by the different intake of carotenoids and also by the minute influence of smoking and alcohol in Japanese women. Smoking was uncommon among women (<3%), whereas almost 50% of all men smoked. Alcohol intake was also low among women, with ~16% drinking alcohol, whereas >65% of the men consumed alcohol at least three times a week.

In our study, we found no statistically significant effect of lutein/zeaxanthin, β-cryptoxanthin, lycopene or retinol, in agreement with earlier reports (12,15,36,41,42), notwithstanding that high levels of lutein/zeaxanthin and low levels of retinol increased the risk of gastric cancer in one study (13) and that high {alpha}-tocopherol levels decreased it (13,35). The reason we saw no effect of plasma levels of lutein/zeaxanthin, β-cryptoxanthin, lycopene or retinol on gastric cancer might be that the individuals in our study had sufficient levels, therefore obviating the detection of any effect.

The strength of this study includes its relatively large sample size and almost complete follow-up as the quality of our cancer registry system during the study period was satisfactory. The prospective study design ensured that blood sample was collected before any diagnosis of gastric cancer, diminishing the probability of reversal causality. Direct measurement of plasma levels is also better than using food frequency questionnaire, which might often be subject to recall bias. Samples were also matched for blood donation date to rule out seasonal variation in diet and for fasting time to rule out differences during the day. However, although our measurement of actual plasma levels rather than estimated levels based on questionnaires can be seen as an advantage, measurement at a single point might possibly not reflect habitual intake over time. Our study subjects were restricted to those who participated in the baseline health checkup survey. Among 97 644 eligible subjects of the JPHC study, only 36 745 (35%) men and women participated and provided blood samples. As reported earlier, compared with non-participants, participants in the health checkup survey, especially women, had a different socioeconomic status and more favorable lifestyle profile, such as less smoking, more frequent participating in physical exercise and higher consumption of green vegetables and fruits (55). Caution is thus required in generalizing or interpreting these results. Our small sample size might limit the ability to detect any small effects in stratified analysis by anatomic site or histological type.

In conclusion, our findings suggest that very low plasma levels of {alpha}-carotene and β-carotene may increase the risk of gastric cancer. We found no effect in women in this study, implying that their plasma carotenoid levels are sufficient. Confirmation of these results in other prospective settings would be valuable.


   Funding
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
Appendix
 References
 
A Grant-in-Aid for Cancer Research (19shi-2) and by the Third-Term Comprehensive Control Research for Cancer (H18-3jigan-ippan-001) from the Ministry of Health, Labour and Welfare, Japan; The Scandinavian-Japan Sasakawa Foundation, Sweden; Erik and Edit Fernströms Foundation, Sweden.


   Appendix
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
 Appendix
References
 
Members of the JPHC study (principal investigator: S.T.) group are S.T., M.I., T.Sobue and T.Hanaoka, National Cancer Center, Tokyo; J.Ogata, S.Baba, T.Mannami, A.Okayama and Y.Kokubo, National Cardiovascular Center, Osaka; K.Miyakawa, F.Saito, A.Koizumi, Y.Sano, I.Hashimoto and T.Ikuta, Iwate Prefectural Ninohe Public Health Center, Iwate; Y.Miyajima, N.Suzuki, S.Nagasawa, Y.Furusugi and N.Nagai, Akita Prefectural Yokote Public Health Center, Akita; H.Sanada, Y.Hatayama, F.Kobayashi, H.Uchino, Y.Shirai, T.Kondo, R.Sasaki, Y.Watanabe, Y.Miyagawa and Y.Kobayashi, Nagano Prefectural Saku Public Health Center, Nagano; Y.Kishimoto, E.Takara, T.Fukuyama, M.Kinjo, M.Irei and H.Sakiyama, Okinawa Prefectural Chubu Public Health Center, Okinawa; K.Imoto, H.Yazawa, T.Seo, A.Seiko, F.Ito and F.Shoji, Katsushika Public Health Center, Tokyo; A.Murata, K.Minato, K.Motegi and T.Fujieda, Ibaraki Prefectural Mito Public Health Center, Ibaraki; K.Matsui, T.Abe, M.Katagiri and M.Suzuki, Niigata Prefectural Kashiwazaki and Nagaoka Public Health Center, Niigata; M.Doi, A.Terao, Y.Ishikawa and T.Tagami, Kochi Prefectural Chuo-higashi Public Health Center, Kochi; H.Sueta, H.Doi, M.Urata, N.Okamoto and F.Ide, Nagasaki Prefectural Kamigoto Public Health Center, Nagasaki; H.Sakiyama, N.Onga, H.Takaesu and M.Uehara, Okinawa Prefectural Miyako Public Health Center, Okinawa; F.Horii, I.Asano, H.Yamaguchi, K.Aoki, S.Maruyama, M.Ichii and M.Takano, Osaka Prefectural Suita Public Health Center, Osaka; Y.Tsubono, Tohoku University, Miyagi; K.Suzuki, Research Institute for Brain and Blood Vessels Akita, Akita; Y.Honda, K.Yamagishi and S.Sakurai, Tsukuba University, Ibaraki; M.Kabuto, National Institute for Environmental Studies, Ibaraki; M.Yamaguchi, Y.Matsumura, S.Sasaki and S.Watanabe, National Institute of Health and Nutrition, Tokyo; M.Akabane, Tokyo University of Agriculture, Tokyo; T.Kadowaki, Tokyo University, Tokyo; M.Noda, International Medical Center of Japan, Tokyo; Y.Kawaguchi, Tokyo Medical and Dental University, Tokyo; Y.Takashima, Kyorin University, Tokyo; K.Nakamura, Niigata University, Niigata; S.Matsushima and S.Natsukawa, Saku General Hospital, Nagano; H.Shimizu, Sakihae Institute, Gifu; H.Sugimura, Hamamatsu University, Shizuoka; S.Tominaga, Aichi Cancer Center Research Institute, Aichi; H.Iso, Osaka University, Osaka; M.Iida, W.Ajiki and A.Ioka, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka; S.Sato, Osaka Medical Center for Health Science and Promotion, Osaka; E.Maruyama, Kobe University, Hyogo; M.Konishi, K.Okada and I.Saito, Ehime University, Ehime; N.Yasuda, Kochi University, Kochi and S.Kono, Kyushu University, Fukuoka.


   Acknowledgments
 
We are indebted to the Iwate, Ibaraki, Niigata, Osaka, Kochi, Nagasaki and Okinawa Cancer Registries for providing their incidence data.

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
 Appendix
 References
 

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Received December 3, 2007; revised February 26, 2008; accepted March 5, 2008.


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C. Pelucchi, I. Tramacere, P. Bertuccio, A. Tavani, E. Negri, and C. La Vecchia
Dietary intake of selected micronutrients and gastric cancer risk: an Italian case-control study
Ann. Onc., January 1, 2009; 20(1): 160 - 165.
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