Clinical Cancer Research The Science of Cancer Health Disparities
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sheu, B.-S.
Right arrow Articles by Wu, J.-J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sheu, B.-S.
Right arrow Articles by Wu, J.-J.
Clinical Cancer Research Vol. 9, 5245-5251, November 1, 2003
© 2003 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Higher Gastric Cycloxygenase-2 Expression and Precancerous Change in Helicobacter pylori-Infected Relatives of Gastric Cancer Patients

Bor-Shyang Sheu1, Hsiao-Bai Yang, Shew-Meei Sheu, Ay-Huey Huang and Jiunn-Jong Wu

Departments of Internal Medicine [B-S. S.], Pathology [H-B. Y., A-H. H.], and Medical Technology [J-J. W.], and Institute of Basic Science [S-M. S.], Medical College, National Cheng Kung University, Tainan 70428, Taiwan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: This study was conducted to determine whether relatives of gastric cancer patients (GCF) showed greater gastric cycloxygenase-2 (COX-2) expression or a greater incidence of precancerous lesions after Helicobacter pylori infection and whether H. pylori eradication could reduce COX-2 expression.

Experimental Design: Three hundred subjects were enrolled in this study: half were relatives of 50 H. pylori-infected gastric cancer patients, and half were relatives of 50 H. pylori-infected duodenal ulcer (DU) patients (controls). Each relative underwent endoscopy to detect H. pylori infection and related gastric histology. One hundred and twenty GCFs were found to have H. pylori infection. After H. pylori eradication, 90 of the 120 GCFs were followed up with annual endoscopy examinations over the next 2 years. Gastric COX-2 intensity in all of the specimens collected from these patients was immunochemically stained and graded from 0 to 4.

Results: H. pylori infection, gastric atrophy, and intestinal metaplasia (IM) were more prevalent in GCFs than in relatives of H. pylori-infected patients with DUs (P < 0.05). H. pylori-infected GCFs also showed a greater COX-2 intensity than H. pylori-infected relatives of patients with DUs (89.1% versus 62.7%, P < 0.001; relative risk: 4.9; 95% confidence interval: approximately 2.34–10.29). Among the H. pylori-infected GCFs, COX-2 intensity correlated with atrophy and IM (P < 0.001). After H. pylori eradication, gastric COX-2 expression disappeared only in those relatives without IM (P < 0.001).

Conclusions: GCFs are more likely to show greater gastric COX-2 expression and a higher incidence of precancerous lesions after H. pylori infection than the relatives of H. pylori-infected patients with only DUs. H. pylori eradication can reverse gastric COX-2 expression in patients without IM but not in patients with IM.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
H. pylori is now designated as a type I carcinogen by the WHO and recognized as an important pathogen that is closely involved in gastric carcinogenesis (1 , 2) . Despite positive evidence from animal experiments (3 , 4) , the exact role of H. pylori in gastric carcinogenesis in humans remains an urgent issue warranting investigation. Because GCs2 typically exhibit familial clustering (5, 6, 7) , host (or genetic) and environmental risk factors among GC patients and their family members deserve additional study.

H. pylori infection tends to cluster within families and is partially responsible for the familial aggregation of environmental factors associated with stomach cancer (8) . El-Omar et al. (9) additionally extended research on family clustering and GC by showing that H. pylori infection can increase the prevalence of precancerous changes in the GCFs as compared with the relatives of non-GC patients. These findings support the notion that H. pylori infection plays a more aggravating role in gastric carcinogenesis in the first-degree GCFs than in the relatives of H. pylori-infected patients who do not have GC. For this reason, we believe that treatment for H. pylori infection should be provided for the members of families with a history of GC who have premalignant lesions. However, family history should not be the only indication for H. pylori eradication (10) . Molecular evidence (especially the consequences of the host-bacterial interaction) might also reveal subjects with H. pylori infection who are at particular risk of GC. Such an interaction may also explain why H. pylori plays a more pernicious role in GC development in the GCFs as opposed to infected subjects without a family history of GC. Molecular evidence could also explain the family clustering of GC.

Gastric COX-2 expression is now recognized as an early event in gastric carcinogenesis (11) and can be highly up-regulated in the setting of H. pylori-infected premalignant gastric changes (12, 13, 14) . Moreover, gastric COX-2 expression has been proven to positively correlate with the presence of H. pylori infection (14) . Therefore, we presume that the members of GC families are predisposed to greater gastric COX-2 expression and, thus, to more and earlier precancerous lesions after H. pylori infection than the members of families without a history of GC.

In the present study, we examined whether H. pylori infection is more prevalent in the GCFs and whether it plays a more toxic role in gastric carcinogenesis after host-bacterial interaction than in the relatives of non-GC patients. One part of this study (a large-scale, controlled study) was a prospective 2-year follow-up designed to determine whether H. pylori eradication can reverse gastric COX-2 expression. This study is believed to have the longest follow-up of any study determining whether reducing COX-2 expression by H. pylori eradication can be related to different H. pylori-related histological patterns observed before eradication therapy. We expect that the present study offers promising histological evidence that the cancer risk can be reversed through the eradication of H. pylori infection.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Study Design.
This study consecutively enrolled a total of 300 subjects (181 men and 119 women; mean age, 31.8 years), half of whom were first-degree relatives of 50 H. pylori-infected patients with index cases of GC and half of whom were first-degree relatives of 50 H. pylori-infected patients with DUs. Families were identified through a chart review of the family history of index patients, endoscopic findings, and pathological results. None of the 300 subjects were long-term aspirin or NSAID users. To prevent interference with the tissue immunohistochemical staining results, subjects were asked to refrain from taking aspirin and NSAID medications as early as possible before gastroscopy. Subjects who were not experiencing clinical dyspepsia symptoms were not excluded from the gastroscopy procedure.

After granting informed consent, each subject underwent gastric biopsy via panendoscopy to obtain tissue for histology studies and H. pylori cultures. Five gastric biopsy specimens, two from the antrum, two from the corpus, and one from the cardia, were obtained during the endoscopy (15) . A specimen from each of the three sites was stained with H&E and modified Giemsa stains. In addition, the second specimen from the antrum was stained immunohistochemically to show the intensity of COX-2 expression. The remaining antrum and corpus specimens were used for H. pylori cultures (16) .

Also examined in this study were the GCFs who had been proven to have H. pylori infection (shown by positive culture or histology findings). These subjects then received a 1-week regimen of anti-H. pylori triple therapy (i.e., amoxicillin, 1 g; clarithromycin, 500 mg; and omeprazole, 20 mg twice daily). H. pylori-infected family members with an allergy to penicillin or clarithromycin were not included in the study. Six weeks after the triple therapy, these subjects then underwent a [13C]urea breath test to determine whether the H. pylori infection had been successfully eradicated (17) . In those patients in whom treatment had been successful, endoscopy was repeated annually for the next 2 years to obtain a gastric biopsy specimen for H. pylori-related histology and COX-2 immunohistochemistry studies.

Analysis of H. pylori-Related Histology.
The same pathologist, who was blinded to the endoscopic findings and culture results, examined the gastric histology specimen. The following features were scored using the updated Sydney System: acute inflammation (range, 0–3), chronic inflammation (range, 0–3), atrophic change (absence, 0; presence, 1), and IM (absence, 0; presence, score 1–3; Ref. 18 ). The total acute and chronic inflammation scores were a sum of the scores for the specimens from the three sites and ranged from 0 to 9. AT was defined as the presence of atrophy only in the antrum (score of 1 for atrophy in the antrum but 0 for atrophy in the corpus and cardia). Pangastric atrophy, which was given a score of 1, was defined as atrophy in all three of the sites: the antrum, corpus, and cardia. In this study, if one gastric biopsy specimen with a score of 1 showed metaplastic cells (goblet cells) involving at least 5% of the upper third of the gastric mucosa, this was deemed IM. If two or more biopsy specimens were found to contain goblet cells on <5% of the upper third of the mucosa, the IM was considered global.

Immunohistochemistry Studies for the Gastric Expression of COX-2.
Tissue immunohistochemical staining was performed using monoclonal antibodies with COX-2 (Cayman Chemical Company, Ann Arbor, MI) and the DAKO-labeled streptavidin-biotin 2 system, peroxidase complex kit (LSAB 2KIT/horseradish peroxidase RB/BO, 3-amino-9-ethylcarbazole; Dako, Carpinteria, CA). Resected gastric tissues were fixed in 10% buffered formalin. Specimens were embedded in paraffin, serially sectioned at a thickness of 4 µm, placed onto microscope slides, and then deparaffinized. The slides were immersed for 10 min in 0.3% peroxide in methanol to stop the endogenous peroxidase activity. Nonspecific binding sites were saturated with 0.3% BSA. Tissue sections were treated with primary antibody against COX-2 at a dilution of 1:100 and then incubated in a humidified chamber at room temperature for 1 h. The DAKO-labeled streptavidin-biotin 2 system, peroxidase complex kit was adapted for blocking, linkage, and labeling for staining according to the manufacturer’s instructions. 3-Amino-9-ethylcarbazole was selected as the chromogen. Sections were then counterstained with hematoxylin. For a negative control, nonimmune rabbit {gamma} immunoglobulin was substituted for the primary antibody. The intensity of gastric COX-2 expression was graded in the epithelial cells of the mucosa as follows: 0 (negative), 1 (<5% cells showing positive staining), 2 (5–30% cells showing positive staining), 3 (30–60% cells showing positive staining), or 4 (>60% cells showing positive staining; Ref. 14 ). The other investigator, who was blinded to the severity of H. pylori-related histology findings and the study group of the subject the specimen came from, scored the intensity of COX-2 expression.

COX-2 staining was confirmed in 30 randomly selected tissues by Western blotting. In this analysis, each tissue was first homogenized in an ice-cold radioimmunoprecipitation buffer (11) . The mixture was then centrifuged (13,000 rpm for 10 min at 4°C) to produce a supernatant, which was then used to measure the protein concentration, done with a Bio-Rad Protein Assay kit (Bio-Rad Laboratories, Hercules, CA). Using 8% SDS-PAGE, 30 µg of COX-2 protein was extracted and transferred to a nitrocellulose membrane. The membrane was then immersed in 0.5% skim milk to block the reaction, and then incubated with rabbit polyclonal IgG specific for human COX-2 (Santa Cruz Biotechnology) for 1 h and with peroxidase-labeled goat antirabbit IgG (1:2,000) for an additional 1 h at 25°C. The reaction band was visualized by the enhanced chemiluminescence system (11) .

Statistics.
Student’s t test and paired t test were applied where appropriate to determine parametric differences. Pearson’s {chi}2 test was used for assessing nonparametric proportions. The relative risk and 95% CI were also tested in the different study groups. The correlation coefficients were calculated using the nonparametric Spearman rank test. All of the tests were two-tailed, with a P < 0.05 taken as significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Prevalence of H. pylori Infection and Related Histology Before Treatment.
The prevalence rate of H. pylori infection was significantly higher in GCFs than in controls (80% versus 50%; P < 0.001). The demographic characteristics, endoscopic diagnosis, and pretreatment histological features of the 300 enrolled relatives are shown in Table 1Citation . The prevalence rates of both AT and IM were higher in the H. pylori-infected GCFs than in the H. pylori-infected relatives of patients with DUs (AT: 70.8% versus 40%, P < 0.01; IM: 55% versus 26.6%, P < 0.05).


View this table:
[in this window]
[in a new window]
  		Table 1 Clinicohistological features of the relatives from gastric cancer and non-gastric cancer families

 
Gastric COX-2 Expression in the GCFs and Non-Cancer Families.
Table 1Citation shows that the mean gastric COX-2 intensity was higher in those infected with H. pylori than in those not infected, regardless of the group (P < 0.001). However, as shown in Fig. 1Citation , there was a higher proportion of H. pylori-infected GCFs than of H. pylori-infected relatives of non-GC families showing strong COX-2 intensity (grades 2–4; 89.1% versus 62.7%; P < 0.001). In addition, the risk for strong gastric COX-2 intensity was greater in the H. pylori-infected GCFs (4.9; 95% CI, approximately 2.34–10.29) than in the H. pylori-infected and noninfected relatives of the non-GC families (115.2; 95% CI, approximately 39.35–337.46).



View larger version (69K):
[in this window]
[in a new window]
  		Fig. 1. The prevalence rate of a strong COX-2 expression (grades: 2–4) was significantly higher in the H. pylori-infected relatives of GC patients than in relatives of the noncancer patients (89.1% versus 62.7%; P < 0.0001). For those relatives without H. pylori infection, the strong gastric COX-2 expression was seen only in 20% and 3.3% of those from GC and non-GC families, respectively. HP (+), presence of H. pylori infection; HP (-), absence of H. pylori infection. GCF (+), GCF; GCF (-):, relatives of non-GC patients.

 
Factors Determining COX-2 Expression in Stomach.
Table 2Citation shows that the gastric COX-2 intensity was correlated positively with the presence of H. pylori infection, AT, and IM in the relatives of both GC and non-GC families (P < 0.001). However, the correlation coefficient (r value) indicated that gastric COX-2 expression was more closely correlated with the presence of H. pylori infection than with either AT or IM. Fig. 2Citation also shows that only among the H. pylori-infected GCFs were the prevalence rates of both AT and IM higher in those with strong COX-2 expression (grades 2–4) than in those with weak or no (grades 0–1) COX-2 expression (AT: 67.3% versus 15.4%, P < 0.001; IM: 50.5% versus 7.7%, P < 0.001). Multivariate logistic regression analysis confirmed that H. pylori infection and a family history of GC were the only two independent factors that correlated with the gastric intensity of COX-2 expression (Table 3)Citation .


View this table:
[in this window]
[in a new window]
  		Table 2 Correlation of COX-2 expression with antral atrophy, intestinal metaplasia, and H. pylori infection in the relatives of gastric cancer and nongastric cancer patients

 


View larger version (23K):
[in this window]
[in a new window]
  		Fig. 2. The prevalence rates of antral atrophy (AT) and IM were compared in H. pylori-infected relatives with strong COX-2 intensity (grades: 2–4) and those with weak or none (grades: 0–1) COX-2 intensity in the stomach. Controls, relatives of non-GC patients. *, indicated significant difference with a P < 0.05 by {chi}2 test.

 

View this table:
[in this window]
[in a new window]
  		Table 3 Multivariate logistic regression for the independent factors relevant to the COX-2 expression in stomach

 
Longitudinal Follow-Up of COX-2 Intensity After H. pylori Eradication.
As Fig. 3Citation shows, 108 of the 120 H. pylori-infected GCFs were given anti-H. pylori therapy. Ninety of these 108 patients completed the 2-year follow-up and achieved successful H. pylori eradication. As shown in Table 4Citation , the mean COX-2 intensity in the 60 patients without IM decreased 1 year after anti-H. pylori therapy (P < 0.001, paired t test). A closer look at Table 4Citation reveals that gastric COX-2 expression decreased in the patients without IM in the first year after therapy followed by a more substantial decrease in the second year after therapy (P < 0.05, McNemar test).



View larger version (23K):
[in this window]
[in a new window]
  		Fig. 3. Schematic flow chart of the study design and patient numbers during the follow-up study. Controls, relatives of non-GC patients. HP (+) and (-) indicated the presence and absence of H. pylori infection, respectively.

 

View this table:
[in this window]
[in a new window]
  		Table 4 Improvements of gastric intensity of COX-2 after H. pylori eradication for gastric cancer relatives with and without IM in gastric histology

 
In contrast, COX-2 intensity in the 30 patients with IM persisted during the first year after therapy (P > 0.05), but the median COX-2 intensity decreased from 3 to 2 during the second year. However, gastric COX-2 expression did not disappear in any patients with IM who underwent H. pylori treatment (Table 4)Citation .


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, we demonstrated that the prevalence rate of H. pylori infection was higher in GCFs than in relatives of non-GC patients (80% versus 50%; P < 0.001). These findings indicate that H. pylori infection tends to cluster within families, particularly in GC families. Of particular importance is the fact that our findings supported the hypothesis that H. pylori infection is an important environmental factor associated with the familial aggregation of GC (8) .

Gastric tissue is predisposed to atrophy and IM after H. pylori infection (18) . Indeed, Table 1Citation shows that in the relatives of both GC and non-GC families in our study, the prevalence rates of AT and IM were significantly higher in H. pylori-infected relatives than in relatives without H. pylori infection (P < 0.05). In addition, among the relatives with H. pylori infection, the prevalence rates of AT and IM were higher in those from GC families than in those from the non-GC families (AT: 70.8% versus 40%, P < 0.01; IM: 55% versus 26.6%, P < 0.05). These findings confirm that H. pylori infection could predispose to the development of AT and IM. Moreover, the likelihood of H. pylori infection inducing AT and IM was significantly different between the age-matched H. pylori-infected GCFs and those from non-GC families.

Our findings are compatible with those of El-Omar et al. (9) who found that GCFs were at higher risk for precancerous changes after H. pylori infection. However, the exact reason why H. pylori infection plays different roles in GCFs and non-GC patients warrants additional molecular studies that focus on the specific interaction between host and bacterial virulence factors.

CagA of H. pylori is a well-known virulence factor of H. pylori that has shown close links to GC (2 , 10) . Nevertheless, in Taiwan, the prevalence of CagA-positive H. pylori infection is extremely high, approaching 100% (16) . Therefore, the exposure to such a virulence factor existed equally for the relatives of both GC and non-GC families. Therefore, it is possible that, in addition to the bacterial virulence factor, there are also host factors in H. pylori-infected GCFs that predispose them to the development of precancerous lesions.

One possible host factor might be the IL-1 ß gene, which could be highly up-regulated by H. pylori infection (8 , 19) . IL-1 polymorphisms have also been significantly related to a risk of GCs (20) . In addition, besides IL-1ß, several proinflammatory genotypes of tumor necrosis factor {alpha} and IL-10 of the H. pylori-infected host could also serve as host factors that increase the risk for distal GC (21) . Barrios-Rodiles et al. (22) have also proposed that certain bacterial lipopolysaccharides, IL-10, tumor necrosis factor {alpha}, and IL-1ß, could all significantly enhance COX-2 expression. Therefore, it would be interesting to determine whether these host factors induce precancerous lesions and increase the rate of GC after H. pylori infection caused by higher COX-2 expression in the stomach.

Our findings revealed that the GCFs, who showed a higher GC clustering risk, were significantly more likely (4.9-fold) to have a strong gastric COX-2 intensity after H. pylori infection (Fig. 1)Citation . Table 2Citation shows that such gastric COX-2 expression was correlated significantly with the presence of H. pylori infection, AT, and IM (P < 0.001). Taken together, our findings appear to show a positive molecular linkage that explains why the so-called host factors can increase the risk of GC after H. pylori infection.

Nevertheless, gastric COX-2 expression can be found in patients with and without precancerous lesions after H. pylori infection, without their being at particular risk for GC (11, 12, 13, 14) . This suggests that gastric COX-2 expression serves only as an early event in gastric carcinogenesis (11) . Again, it will be interesting to determine whether higher COX-2 expression in the H. pylori-infected GCFs really accounts for the higher prevalence rate of precancerous lesions, such as AT and IM. Fig. 2Citation shows that the prevalence rates of AT and IM were higher in the H. pylori-infected GCFs showing strong COX-2 expression than in those showing weak COX-2 expression or no COX-2 impression (P < 0.001). Because this finding was not observed in the relatives of non-GC families, certain host factors likely exist that enhance gastric COX-2 expression in these individuals. In turn, the higher gastric COX-2 intensity enhances the development of AT and IM in these patients, and places them at a higher risk for cancer after H. pylori infection. Therefore, a longitudinal therapeutic study would be valuable in clarifying whether higher gastric COX-2 expression could be reversed by anti-H. pylori therapy in the relatives of cancer families, who genetically should have exerted the clustering of poor host factors to yield a higher COX-2 intensity to induce more precancerous lesions.

Fig. 3Citation shows 90 GCFs who have completed the 2-year follow-up after H. pylori eradication. The mean gastric COX-2 intensity of these 90 patients in the first year (1.34) and the second year (1.01) after H. pylori eradication was significantly lower than the intensity before therapy (2.51; P < 0.001, paired t test). We believe that these data constitute an initial rationale for beginning anti-H. pylori therapy to produce COX-2 regression in the H. pylori-infected GCFs at high risk for GC. Indeed, our study confirmed that anti-H. pylori therapy could significantly decrease gastric COX-2 expression in relatives with a high GC risk. However, because the mean COX-2 intensity in the second year remained ~1.01, some patients might have had persistent COX-2 expression despite the success of H. pylori eradication. In our view, an appropriate next step would be to determine whether the different histological backgrounds surveyed in this study could have a bearing on the persistence of COX-2 expression in the stomach.

As shown in Table 4Citation , anti-H. pylori therapy can decrease gastric COX-2 intensity at the end of the second year but cannot completely reverse gastric COX-2 expression in patients with IM. The data from our large-scale study with a 2-year follow-up are compatible with the data from the study of Sung et al. (14 , 23) , who conducted a 1-year follow-up and found that anti-H. pylori therapy could not reverse COX-2 expression in the presence of IM (14 , 23) . Because anti-H. pylori therapy cannot reverse COX-2 expression in these individuals, there is a need for an additional intervention such as the COX-2 inhibitor to reduce the cancer risk in those with precancerous lesions. Similarly, Table 3Citation shows that COX-2 expression declined significantly in 40% and 66.7% of patients without IM during the first and second year after therapy, respectively (McNemar test, P < 0.05). These positive data support the initiation of anti-H. pylori therapy as early as possible to abolish the GC risk in patients without IM.

In summary, the GCFs are predisposed to higher gastric COX-2 expression and the development of precancerous lesions after H. pylori infection than nongastric patients. Although eradication of H. pylori infection may significantly reverse gastric COX-2 expression in such patients without IM, the possibility of this is still limited for patients with IM. Additional clinical trials of the COX-2 inhibitor to reverse COX-2 expression are called for in patients with IM in the stomach.


   ACKNOWLEDGMENTS
 
We thank Hunt-Wen Wu for assistance.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This work was supported by Grant NSC91-2314-B-006-001 from the National Science Council, Taiwan.

1 To whom requests for reprints should be addressed, at Department of Internal Medicine, National Cheng Kung University Hospital, 138 Sheng Li Road, Tainan, Taiwan 70428. Phone: 886-6-2353535, extension 5368; Fax: 886-6-2370941; E-mail: sheubs{at}mail.ncku.edu.tw Back

2 The abbreviations used are: GC, gastric cancer; COX, cyclooxygenase; IM, intestinal metaplasia; AT, gastric atrophy; DU, duodenal ulcer; GCF, relatives or family members of gastric cancer patients; CI, confidence interval; IL, interleukin. Back

Received 1/28/03; revised 4/17/03; accepted 4/22/03.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Parsonnet J., Friedman G. D., Vandersteen D. P., Chang Y., Vogelman J. H., Orentreich N., Sibley R. K. Helicobacter pylori infection and the risk of gastric carcinoma. N. Engl. J. Med., 325: 1127-1131, 1991.[Abstract]
  2. Asaka M., Takeda H., Sugiyama T., Kato M. What role does. Helicobacter pylori play in gastric cancer?. Gastroenterology, 113: S56-S60, 1997.[Medline]
  3. Watanabe T., Tada M., Nagai H., Sasaki S., Nakao M. Helicobacter pylori infection induces gastric cancer in Mongoliam gerbils. Gastroenterology, 115: 642-648, 1998.[CrossRef][Medline]
  4. Honda S., Fujioka T., Tokieda M., Satoh R., Nishizono A., Nasu M. Development of Helicobacter pylori-induced gastric carcinoma in Mongolian gerbils. Cancer Res., 58: 4255-4259, 1998.[Abstract/Free Full Text]
  5. Brenner H., Bode G., Boeing H. Helicobacter pylori infection among the offspring of patients with stomach cancer. Gastroenterology, 118: 31-35, 2000.[CrossRef][Medline]
  6. La Vecchia C., Negri E., Franceschi S., Gentile A. Family history and the risk of stomach and colorectal cancer. Cancer (Phila.), 70: 50-55, 1992.
  7. Huang J. G., Sridhar S., Chen Y., Hunt R. H. Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology, 114: 1169-1179, 1998.[CrossRef][Medline]
  8. El-Omar E. M., Chow W. H., Rabkin C. M. Gastric cancer and H. pylori: Host genetics open the way. Gastroenterology, 121: 1002-1004, 2001.[Medline]
  9. El-Omar E. M., Oien K., Murray L. S., El-Nujumi A., Wirz A., Gillen D., Williams C., Fullarton G., McColl K. E. Increased prevalence of precancerous changes in relatives of gastric cancer patients: critical role of H. pylori. Gastroenterology, 118: 22-30, 2000.[CrossRef][Medline]
  10. Parsonnet J. When heredity is infectious. Gastroenterology, 18: 222-224, 2000.
  11. Lim H. Y., Joo H. J., Choi J. H., Yi J. W., Yang M. S., Cho D. Y., Kim H. S., Nam D. K., Lee K. B., Kim H. C. Increased expression of cyclooxygenase-2 protein in human gastric carcinoma. Clin. Cancer Res., 6: 519-525, 2000.[Abstract/Free Full Text]
  12. Jackson L. M., Wu K. C., Mahida Y. R., Jenkins D., Hawkey C. J. Cyclooxygenase (COX) 1 and 2 in normal, inflamed, and ulcerated human gastric mucosa. Gut, 47: 762-770, 2000.[Abstract/Free Full Text]
  13. Tatsuguchi A., Sakamoto C., Wada K., Akamatsu T., Tsukui T., Miyake K., Futagami S., Kishida T., Fukuda Y., Yamanaka N., Kobayashi M. Localisation of cyclooxygenase 1 and cyclooxygenase 2 in Helicobacter pylori related gastritis and gastric ulcer tissues in humans. Gut, 46: 782-789, 2000.[Abstract/Free Full Text]
  14. Sung J. J., Leung W. K., Go M. Y., To K. F., Cheng A. S., Ng E. K., Chan F. K. Cyclooxygenase-2 expression in Helicobacter pylori-associated premalignant and malignant gastric lesions. Am. J. Pathol., 157: 729-735, 2000.[Abstract/Free Full Text]
  15. Yang S. B., Sheu B. S., Su I. J., Chien C. H., Lin X. Z. Clinical application of gastric histology to monitor treatment of dual therapy in H. pylori eradication. Dig. Dis. Sci., 42: 1835-1840, 1997.[CrossRef][Medline]
  16. Sheu S. M., Sheu B. S., Yang H. B., Lai C., Chu T. C., Wu J. J. The presence of iceA1 but not cagA, cagC, cagE, cagF, cagN, cagT, or orf13 genes of Helicobacter pylori is associated with a more severe gastric inflammation in Taiwanese. J. Formos. Med. Assoc., 101: 18-23, 2002.[Medline]
  17. Sheu B. S., Lee S. C., Yang H. B., Kuo A. W., Wang Y. L., Shiesh S. C., Wu J. J., Lin X. Z. Selection of a lower cut-off value for the 13C-urea breath test is mandatory to detect H. pylori infection in patients after proton pump inhibitor-based triple therapy. Dig. Dis. Sci., 45: 1330-1336, 2000.[Medline]
  18. Dixon M. F., Genta R. M., Yardley J. H., Correa P. Classification and grading of gastritis: the updated Sydney system. International Workshop on the Histology of Gastritis, Houston. Am. J. Surg. Pathol., 20: 1161-1181, 1994.
  19. El-Omar E. M. The importance of interleukin-1 ß in Helicobacter pylori-associated disease. Gut, 48: 743-747, 2001.[Free Full Text]
  20. El-Omar E. M., Chow W. H., Gammon M. D., Vaughan T. L., Risch H. A., Fraumeni J. F., Jr. Proinflammatory genotypes of IL-1ß, TNF-a and IL-10 increase risk of distal gastric cancer but not of cardia or esophageal carcinoma. Gastroenterology, 120 (Suppl. 1): A86 2001.
  21. El-Omar E. M., Carrington M., Chow W. H., McColl K. E., Bream J. H., Young H. A., Herrera J., Lissowska J., Yuan C. C., Rothman N., Lanyon G., Martin M., Fraumeni J. F., Jr., Rabkin C. S. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature (Lond.), 404: 398-402, 2000.[CrossRef][Medline]
  22. Barrios-Rodiles M., Tiraloche G., Chadee K. Lipopolysaccharide modulates cyclooxygenase-2 transcriptionally and posttranscriptionally in human macrophages independently from endogenous IL-1 ß and TNF-{alpha}. J. Immunol., 163: 963-969, 1999.[Abstract/Free Full Text]
  23. Sung J. J., Lin S. R., Ching J. Y., Zhou L. Y., To K. F., Wang R. T., Leung W. K., Ng E. K., Lau J. Y., Lee Y. T., Yeung C. K., Chao W., Chung S. C. Atrophy and intestinal metaplasia one year after cure of H. pylori infection: a prospective, randomized study. Gastroenterology, 119: 7-14, 2000.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Am. J. Clin. Nutr.Home page
B.-S. Sheu, H.-C. Cheng, A.-W. Kao, S.-T. Wang, Y.-J. Yang, H.-B. Yang, and J.-J. Wu
Pretreatment with Lactobacillus- and Bifidobacterium-containing yogurt can improve the efficacy of quadruple therapy in eradicating residual Helicobacter pylori infection after failed triple therapy.
Am. J. Clinical Nutrition, April 1, 2006; 83(4): 864 - 869.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sheu, B.-S.
Right arrow Articles by Wu, J.-J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sheu, B.-S.
Right arrow Articles by Wu, J.-J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online