Hostname: page-component-6bf8c574d5-xtvcr Total loading time: 0 Render date: 2025-02-15T09:59:38.292Z Has data issue: false hasContentIssue false
  • English
  • Français

Helicobacter pylori as an oncogenic pathogen, revisited

Published online by Cambridge University Press:  21 March 2017

Muhammad Miftahussurur ,
Yoshio Yamaoka  and
David Y. Graham
Muhammad Miftahussurur
Affiliation:
Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, Texas 77030, USA Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu 879-5593, Japan Gastroentero-Hepatology Division, Department of Internal Medicine, Faculty of Medicine – Dr Soetomo Teaching Hospital – Institute of Tropical Disease, Universitas Airlangga, Surabaya 60115, Indonesia
Yoshio Yamaoka
Affiliation:
Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, Texas 77030, USA Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu 879-5593, Japan
David Y. Graham*
Affiliation:
Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, Texas 77030, USA
*
*Corresponding author: David Y Graham MD, Department of Medicine, Baylor College of Medicine and Michael E DeBakey Veterans Affairs Medical Center, RM 3A-318B (111D), 2002 Holcombe Boulevard, Houston, TX 77030, USA. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Gastric cancer is an inflammation-associated malignancy aetiologically related to infection with the bacterium, Helicobacter pylori, which is considered a necessary but insufficient cause. Unless treated, H. pylori causes life-long acute and chronic gastric inflammation resulting in progressive gastric mucosal damage that may result in gastric cancer. The rate of progression from superficial gastritis, to an atrophic metaplastic mucosa, and ultimately to cancer relates to the virulence of the infecting H. pylori as well as host and environmental factors. H. pylori virulence is a reflection of its propensity to cause severe gastric inflammation. Both mucosal inflammation and H. pylori can cause host genomic instability, including dysregulation of DNA mismatch repair, stimulation of expression of activation-induced cytidine deaminase, abnormal DNA methylation and dysregulation of  micro RNAs, which may result in an accumulation of mutations and loss of normal regulation of cell growth. The difference in cancer risk between the most and least virulent H. pylori strain is only approximately 2-fold. Overall, none of the putative virulence factors identified to date have proved to be disease-specific. The presence, severity, extent and duration of inflammation appear to be the most important factors and current evidence suggests that any host, environmental or bacterial factor that reliably enhances the inflammatory response to the H. pylori infection increases the risk of gastric cancer.

Type
Invited Review
Information
Expert Reviews in Molecular Medicine , Volume 19 , 2017 , e4
Copyright
Copyright © Cambridge University Press 2017 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Faber, K. (1935) Gastritis and its consequences. Paris: Oxford University PressGoogle Scholar
2. Graham, D.Y. (2014) History of Helicobacter pylori, duodenal ulcer, gastric ulcer and gastric cancer. World Journal of Gastroenterology 20, 5191-5204 CrossRefGoogle ScholarPubMed
3. Graham, D.Y. and Asaka, M. (2010) Eradication of gastric cancer and more efficient gastric cancer surveillance in Japan: two peas in a pod. Journal of Gastroenterology 45, 1-8 CrossRefGoogle ScholarPubMed
4. Baron, J.H. and Sonnenberg, A. (2002) Hospital admissions for peptic ulcer and indigestion in London and New York in the 19th and early 20th centuries. Gut 50, 568-570 Google Scholar
5. Marshall, B.J. and Warren, J.R. (1984) Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1, 1311-1315 Google Scholar
6. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, Schistosomes, Liver Flukes and Helicobacter pylori (1994) Infection with Helicobacter pylori. IARC monographs on the evaluation of carcinogenic risks to humans. Vol 61. Lyon, France: International Agency for Research on Cancer, 177-240 Google Scholar
7. Yamaoka, Y. (2010) Mechanisms of disease: Helicobacter pylori virulence factors. Nature Reviews Gastroenterology & Hepatology 7, 629-641 Google Scholar
8. Graham, D.Y. (2015) Helicobacter pylori update: gastric cancer, reliable therapy, and possible benefits. Gastroenterology 148, 719-731 e713CrossRefGoogle ScholarPubMed
9. Kamada, T. et al. (2015) Time trends in Helicobacter pylori infection and atrophic gastritis over 40 years in Japan. Helicobacter 20, 192-198 Google Scholar
10. Wang, C., Weber, A. and Graham, D.Y. (2015) Age, period, and cohort effects on gastric cancer mortality. Digestive Diseases and Sciences 60, 514-523 Google Scholar
11. Yamaoka, Y. and Graham, D.Y. (2014) Helicobacter pylori virulence and cancer pathogenesis. Future Oncology 10, 1487-1500 Google Scholar
12. Correa, P. (1984) Chronic gastritis as a cancer precursor. Scandinavian Journal of Gastroenterology. Supplement 104, 131-136 Google Scholar
13. Ruddell, W.S. et al. (1976) Gastric-juice nitrite. A risk factor for cancer in the hypochlorhydric stomach? Lancet 2, 1037-1039 Google Scholar
14. Lee, Y.C. et al. (2016) Association between Helicobacter pylori eradication and gastric cancer incidence: a systematic review and meta-analysis. Gastroenterology 150, 1113-1124 e1115Google Scholar
15. Lee, Y.C. et al. (2016) Mass eradication of Helicobacter pylori to prevent gastric cancer: theoretical and practical considerations. Gut and Liver 10, 12-26 CrossRefGoogle ScholarPubMed
16. Graham, D.Y. and Shiotani, A. (2005) The time to eradicate gastric cancer is now. Gut 54, 735-738 CrossRefGoogle ScholarPubMed
17. Hanada, K. and Graham, D.Y. (2014) Helicobacter pylori and the molecular pathogenesis of intestinal-type gastric carcinoma. Expert Review of Anticancer Therapy 14, 947-954 Google Scholar
18. Xue, H. et al. (2010) Interleukin-1B and interleukin-1 RN polymorphisms and gastric carcinoma risk: a meta-analysis. Journal of Gastroenterology and Hepatology 25, 1604-1617 Google Scholar
19. Figueiredo, C. et al. (2002) Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. Journal of the National Cancer Institute 94, 1680-1687 Google Scholar
20. Sgouros, S.N. and Bergele, C. (2006) Clinical outcome of patients with Helicobacter pylori infection: the bug, the host, or the environment? Postgraduate Medical Journal 82, 338-342 Google Scholar
21. Lu, H., Yamaoka, Y. and Graham, D.Y. (2005) Helicobacter pylori virulence factors: facts and fantasies. Current Opinion in Gastroenterology 21, 653-659 Google Scholar
22. Censini, S. et al. (1996) cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proceedings of the National Academy of Sciences of the United States of America 93, 14648-14653 Google Scholar
23. Asahi, M. et al. (2000) Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells. Journal of Experimental Medicine 191, 593-602 Google Scholar
24. van Doorn, L.J. et al. (1998) Clinical relevance of the cagA, vacA, and iceA status of Helicobacter pylori . Gastroenterology 115, 58-66 Google Scholar
25. Huang, J.Q. et al. (2003) Meta-analysis of the relationship between cagA seropositivity and gastric cancer. Gastroenterology 125, 1636-1644 Google Scholar
26. Parsonnet, J. et al. (1997) Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection. Gut 40, 297-301 Google Scholar
27. Brandt, S. et al. (2005) NF-kappaB activation and potentiation of proinflammatory responses by the Helicobacter pylori CagA protein. Proceedings of the National Academy of Sciences of the United States of America 102, 9300-9305 Google Scholar
28. Crabtree, J.E. et al. (1995) Helicobacter pylori induced interleukin-8 expression in gastric epithelial cells is associated with CagA positive phenotype. Journal of Clinical Pathology 48, 41-45 Google Scholar
29. Yamaoka, Y. et al. (1996) Helicobacter pylori cagA gene and expression of cytokine messenger RNA in gastric mucosa. Gastroenterology 110, 1744-1752 Google Scholar
30. Backert, S. et al. (2001) Phosphorylation of tyrosine 972 of the Helicobacter pylori CagA protein is essential for induction of a scattering phenotype in gastric epithelial cells. Molecular Microbiology 42, 631-644 Google Scholar
31. Franco, A.T. et al. (2008) Regulation of gastric carcinogenesis by Helicobacter pylori virulence factors. Cancer Research 68, 379-387 Google Scholar
32. Watanabe, T. et al. (1998) Helicobacter pylori infection induces gastric cancer in mongolian gerbils. Gastroenterology 115, 642-648 Google Scholar
33. Franco, A.T. et al. (2005) Activation of beta-catenin by carcinogenic Helicobacter pylori . Proceedings of the National Academy of Sciences of the United States of America 102, 10646-10651 CrossRefGoogle ScholarPubMed
34. Sugimoto, M. et al. (2009) Gastric mucosal interleukin-17 and -18 mRNA expression in Helicobacter pylori-induced Mongolian gerbils. Cancer Science 100, 2152-2159 Google Scholar
35. Sugimoto, M. et al. (2011) Helicobacter pylori outer membrane proteins on gastric mucosal interleukin 6 and 11 expression in Mongolian gerbils. Journal of Gastroenterology and Hepatology 26, 1677-1684 Google Scholar
36. Nozaki, K. et al. (2002) Reversibility of heterotopic proliferative glands in glandular stomach of Helicobacter pylori-infected Mongolian gerbils on eradication. Japanese Journal of Cancer Research 93, 374-381 Google Scholar
37. Cao, X. et al. (2004) Eradication of Helicobacter pylori induces apoptosis and inhibits proliferation of heterotopic proliferative glands in infected Mongolian gerbils. Cancer Science 95, 872-877 Google Scholar
38. Shimizu, N. et al. (2000) Eradication diminishes enhancing effects of Helicobacter pylori infection on glandular stomach carcinogenesis in Mongolian gerbils. Cancer Research 60, 1512-1514 Google Scholar
39. Cai, X. et al. (2005) Helicobacter felis eradication restores normal architecture and inhibits gastric cancer progression in C57BL/6 mice. Gastroenterology 128, 1937-1952 Google Scholar
40. Tsukamoto, T. et al. (2013) Helicobacter pylori infection and gastric carcinogenesis in rodent models. Seminars in Immunopathology 35, 177-190 Google Scholar
41. Freedberg, D.E., Abrams, J.A. and Wang, T.C. (2014) Prevention of gastric cancer with antibiotics: can it be done without eradicating Helicobacter pylori? Journal of the National Cancer Institute 106, dju148Google Scholar
42. Cao, X. et al. (2002) Earlier Helicobacter pylori infection increases the risk for the N-methyl-N-nitrosourea-induced stomach carcinogenesis in Mongolian gerbils. Japanese Journal of Cancer Research 93, 1293-1298 Google Scholar
43. Nozaki, K. et al. (2003) Effect of early eradication on Helicobacter pylori-related gastric carcinogenesis in Mongolian gerbils. Cancer Science 94, 235-239 Google Scholar
44. Ohnishi, N. et al. (2008) Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proceedings of the National Academy of Sciences of the United States of America 105, 1003-1008 Google Scholar
45. Hayakawa, Y. et al. (2013) Mouse models of gastric cancer. Cancers (Basel) 5, 92-130 Google Scholar
46. Zhang, W., Lu, H. and Graham, D.Y. (2014) An Update on Helicobacter pylori as the cause of Gastric Cancer. Gastrointestinal Tumors 1, 155-165 Google Scholar
47. Hatakeyama, M. (2004) Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nature Reviews. Cancer 4, 688-694 Google Scholar
48. Higashi, H. et al. (2002) Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites. Proceedings of the National Academy of Sciences of the United States of America 99, 14428-14433 Google Scholar
49. Satomi, S. et al. (2006) Relationship between the diversity of the cagA gene of Helicobacter pylori and gastric cancer in Okinawa, Japan. Journal of Gastroenterology 41, 668-673 Google Scholar
50. Abe, T. et al. (2011) Impact of Helicobacter pylori CagA diversity on gastric mucosal damage: an immunohistochemical study of East-Asian-type CagA. Journal of Gastroenterology and Hepatology 26, 688-693 Google Scholar
51. Matsunari, O. et al. (2012) Association between Helicobacter pylori virulence factors and gastroduodenal diseases in Okinawa, Japan. Journal of Clinical Microbiology 50, 876-883 Google Scholar
52. Vilaichone, R.K. et al. (2004) Molecular epidemiology and outcome of Helicobacter pylori infection in Thailand: a cultural cross roads. Helicobacter 9, 453-459 Google Scholar
53. Matsuhisa, T. et al. (2015) Gastric mucosa in Mongolian and Japanese patients with gastric cancer and Helicobacter pylori infection. World Journal of Gastroenterology 21, 8408-8417 Google Scholar
54. Xia, Y. et al. (2009) A comprehensive sequence and disease correlation analyses for the C-terminal region of CagA protein of Helicobacter pylori . PLoS ONE 4, e7736 Google Scholar
55. Yamaoka, Y. et al. (1998) Variants of the 3’ region of the cagA gene in Helicobacter pylori isolates from patients with different H. pylori-associated diseases. Journal of Clinical Microbiology 36, 2258-2263 Google Scholar
56. Yamaoka, Y. et al. (1999) Relationship between the cagA 3′ repeat region of Helicobacter pylori, gastric histology, and susceptibility to low pH. Gastroenterology 117, 342-349 Google Scholar
57. Argent, R. et al. (2004) Determinants and consequences of different levels of CagA phosphorylation for clinical isolates of Helicobacter pylori . Gastroenterology 127, 514-523 Google Scholar
58. Azuma, T. et al. (2002) Correlation between variation of the 3’ region of the cagA gene in Helicobacter pylori and disease outcome in Japan. Journal of Infectious Diseases 186, 1621-1630 Google Scholar
59. Naito, M. et al. (2006) Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA. Gastroenterology 130, 1181-1190 Google Scholar
60. Nagase, L. et al. (2015) Dramatic increase in SHP2 binding activity of Helicobacter pylori Western CagA by EPIYA-C duplication: its implications in gastric carcinogenesis. Scientific Reports 5, 15749 Google Scholar
61. Yamaoka, Y., Reddy, R. and Graham, D.Y. (2010) Helicobacter pylori virulence factor genotypes in children in the United States: clues about genotype and outcome relationships. Journal of Clinical Microbiology 48, 2550-2551 Google Scholar
62. Atherton, J.C. et al. (1995) Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. Journal of Biological Chemistry 270, 17771-17777 Google Scholar
63. Cover, T.L. et al. (1994) Divergence of genetic sequences for the vacuolating cytotoxin among Helicobacter pylori strains. Journal of Biological Chemistry 269, 10566-10573 CrossRefGoogle ScholarPubMed
64. McClain, M.S. et al. (2001) A 12-amino-acid segment, present in type s2 but not type s1 Helicobacter pylori VacA proteins, abolishes cytotoxin activity and alters membrane channel formation. Journal of Bacteriology 183, 6499-6508 Google Scholar
65. Cover, T.L. and Blanke, S.R. (2005) Helicobacter pylori VacA, a paradigm for toxin multifunctionality. Nature Reviews. Microbiology 3, 320-332 Google Scholar
66. Radin, J.N. et al. (2014) Role of connexin 43 in Helicobacter pylori VacA-induced cell death. Infection and Immunity 82, 423-432 Google Scholar
67. Memon, A.A. et al. (2014) Vacuolating cytotoxin genotypes are strong markers of gastric cancer and duodenal ulcer-associated Helicobacter pylori strains: a matched case-control study. Journal of Clinical Microbiology 52, 2984-2989 Google Scholar
68. Saxena, A. et al. (2011) Virulence attributes of Helicobacter pylori isolates & their association with gastroduodenal disease. Indian Journal of Medical Research 133, 514-520 Google Scholar
69. Chomvarin, C. et al. (2008) Prevalence of Helicobacter pylori vacA, cagA, cagE, iceA and babA2 genotypes in Thai dyspeptic patients. International Journal of Infectious Diseases 12, 30-36 Google Scholar
70. Sugimoto, M. and Yamaoka, Y. (2009) The association of vacA genotype and Helicobacter pylori-related disease in Latin American and African populations. Clinical Microbiology and Infection 15, 835-842 Google Scholar
71. González, C.A. et al. (2011) Helicobacter pylori cagA and vacA genotypes as predictors of progression of gastric preneoplastic lesions: a long-term follow-up in a high-risk area in Spain. American Journal of Gastroenterology 106, 867-874 CrossRefGoogle Scholar
72. Rhead, J.L. et al. (2007) A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer. Gastroenterology 133, 926-936 Google Scholar
73. Ogiwara, H. et al. (2009) Role of deletion located between the intermediate and middle regions of the Helicobacter pylori vacA gene in cases of gastroduodenal diseases. Journal of Clinical Microbiology 47, 3493-3500 Google Scholar
74. Bakhti, S.Z. et al. (2016) Relevance of Helicobacter pylori vacA 3′-end region polymorphism to gastric cancer. Helicobacter 21, 305-316 Google Scholar
75. Hussein, N.R. et al. (2008) Differences in virulence markers between Helicobacter pylori strains from Iraq and those from Iran: potential importance of regional differences in H. pylori-associated disease. Journal of Clinical Microbiology 46, 1774-1779 Google Scholar
76. Basso, D. et al. (2008) Clinical relevance of Helicobacter pylori cagA and vacA gene polymorphisms. Gastroenterology 135, 91-99 Google Scholar
77. Yordanov, D. et al. (2012) Significance of Helicobacter pylori vacA intermediate region genotyping – a Bulgarian study. Diagnostic Microbiology and Infectious Disease 74, 253-257 Google Scholar
78. Ogiwara, H., Graham, D.Y. and Yamaoka, Y. (2008) vacA i-region subtyping. Gastroenterology 134, 1267; author reply 1268Google Scholar
79. Yamaoka, Y. et al. (1998) Relationship of vacA genotypes of Helicobacter pylori to cagA status, cytotoxin production, and clinical outcome. Helicobacter 3, 241-253 Google Scholar
80. Backert, S., Clyne, M. and Tegtmeyer, N. (2011) Molecular mechanisms of gastric epithelial cell adhesion and injection of CagA by Helicobacter pylori . Cell Communication and Signaling 9, 28 Google Scholar
81. Yamaoka, Y. et al. (2002) Importance of Helicobacter pylori oipA in clinical presentation, gastric inflammation, and mucosal interleukin 8 production. Gastroenterology 123, 414-424 Google Scholar
82. Yamaoka, Y. et al. (2006) Helicobacter pylori outer membrane proteins and gastroduodenal disease. Gut 55, 775-781 Google Scholar
83. Liu, J. et al. (2013) Association of presence/absence and on/off patterns of Helicobacter pylori oipA gene with peptic ulcer disease and gastric cancer risks: a meta-analysis. BMC Infectious Diseases 13, 555 Google Scholar
84. Sheu, B.S. et al. (2003) Host gastric Lewis expression determines the bacterial density of Helicobacter pylori in babA2 genopositive infection. Gut 52, 927-932 Google Scholar
85. Moonens, K. et al. (2016) Structural insights into polymorphic ABO glycan binding by Helicobacter pylori . Cell Host & Microbe 19, 55-66 Google Scholar
86. Rad, R. et al. (2002) The Helicobacter pylori blood group antigen-binding adhesin facilitates bacterial colonization and augments a nonspecific immune response. Journal of Immunology 168, 3033-3041 Google Scholar
87. Hill, A.B. (1965) The environment and disease: association or causation? Proceedings of the Royal Society of Medicine 58, 295-300 Google Scholar
88. Kikuchi, S. (2002) Epidemiology of Helicobacter pylori and gastric cancer. Gastric Cancer 5, 6-15 Google Scholar
89. Hanada, K. et al. (2014) Helicobacter pylori infection introduces DNA double-strand breaks in host cells. Infection and Immunity 82, 4182-4189 Google Scholar
90. Shiotani, A., Cen, P. and Graham, D.Y. (2013) Eradication of gastric cancer is now both possible and practical. Seminars in Cancer Biology 23, 492-501 Google Scholar
91. Okazaki, I.M. et al. (2003) Constitutive expression of AID leads to tumorigenesis. Journal of Experimental Medicine 197, 1173-1181 Google Scholar
92. Shimizu, T. et al. (2015) Molecular pathogenesis of Helicobacter pylori-related gastric cancer. Gastroenterology Clinics of North America 44, 625-638 Google Scholar
93. Hollstein, M. et al. (1991) p53 mutations in human cancers. Science 253, 49-53 Google Scholar
94. Matsumoto, Y. et al. (2007) Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Natural Medicines 13, 470-476 Google Scholar
95. Toller, I.M. et al. (2011) Carcinogenic bacterial pathogen Helicobacter pylori triggers DNA double-strand breaks and a DNA damage response in its host cells. Proceedings of the National Academy of Sciences of the United States of America 108, 14944-14949 Google Scholar
96. Xu, Y. and Price, B.D. (2011) Chromatin dynamics and the repair of DNA double strand breaks. Cell Cycle 10, 261-267 CrossRefGoogle ScholarPubMed
97. Mantovani, A. (2010) Molecular pathways linking inflammation and cancer. Current Molecular Medicine 10, 369-373 Google Scholar
98. Nardone, G. et al. (2007) Helicobacter pylori and epigenetic mechanisms underlying gastric carcinogenesis. Digestive Diseases 25, 225-229 Google Scholar
99. Maekita, T. et al. (2006) High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk. Clinical Cancer Research 12, 989-995 Google Scholar
100. Fischle, W., Wang, Y. and Allis, C.D. (2003) Histone and chromatin cross-talk. Current Opinion in Cell Biology 15, 172-183 Google Scholar
101. Barbarotto, E., Schmittgen, T.D. and Calin, G.A. (2008) MicroRNAs and cancer: profile, profile, profile. International Journal of Cancer 122, 969-977 Google Scholar
102. Zhang, Z. et al. (2008) miR-21 plays a pivotal role in gastric cancer pathogenesis and progression. Laboratory Investigation 88, 1358-1366 Google Scholar
103. Petrocca, F. et al. (2008) E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell 13, 272-286 Google Scholar
104. Nagata, N. et al. (2014) Enhanced expression of activation-induced cytidine deaminase in human gastric mucosa infected by Helicobacter pylori and its decrease following eradication. Journal of Gastroenterology 49, 427-435 Google Scholar
105. Shiotani, A. et al. (2012) Eradication of H. pylori did not improve abnormal sonic hedgehog expression in the high risk group for gastric cancer. Digestive Diseases and Sciences 57, 643-649 Google Scholar
106. Shiotani, A. et al. (2012) H. pylori eradication did not improve dysregulation of specific oncogenic miRNAs in intestinal metaplastic glands. Journal of Gastroenterology 47, 988-998 Google Scholar
107. Take, S. et al. (2007) Baseline gastric mucosal atrophy is a risk factor associated with the development of gastric cancer after Helicobacter pylori eradication therapy in patients with peptic ulcer diseases. Journal of Gastroenterology 42 (Suppl 17), 21-27 Google Scholar
108. Shiotani, A., Haruma, K. and Graham, D.Y. (2014) Metachronous gastric cancer after successful Helicobacter pylori eradication. World Journal of Gastroenterology 20, 11552-11559 Google Scholar
109. Graham, D.Y. (2014) Helicobacter pylori eradication and metachronous gastric cancer. Clinical Gastroenterology and Hepatology 12, 801-803 Google Scholar
110. Shiotani, A., Matsueda, A. and Graham, D.Y. (2015) Changing the natural history of metachronous gastric cancer after H. pylori eradication. Japanese Journal of Helicobacter Research 16, 52-60 Google Scholar
111. Yoon, S.B. et al. (2014) Effect of Helicobacter pylori eradication on metachronous gastric cancer after endoscopic resection of gastric tumors: a meta-analysis. Helicobacter 19, 243-248 Google Scholar
112. Comfort, M.W. (1951) Gastric acidity before and after development of gastric cancer: its etiologic, diagnostic and prognostic significance. Annals of Internal Medicine 34, 1331-1348 Google Scholar
113. Forsythe, S.J. et al. (1988) Nitrate- and nitrite-reducing bacteria in the achlorhydric stomach. Journal of Medical Microbiology 25, 253-259 Google Scholar
114. Osato, M.S. et al. (1998) Microflora of gastric biopsies from patients with duodenal ulcer and gastric cancer: a comparative study of patients from Korea, Colombia, and the United States. Digestive Diseases and Sciences 43, 2291-2295 Google Scholar
115. Rugge, M. et al. (2012) Autoimmune gastritis: histology phenotype and OLGA staging. Alimentary Pharmacology & Therapeutics 35, 1460-1466 Google Scholar
116. Gaddy, J.A. et al. (2013) High dietary salt intake exacerbates Helicobacter pylori-induced gastric carcinogenesis. Infection and Immunity 81, 2258-2267 CrossRefGoogle ScholarPubMed
117. Graham, D.Y., Shiotani, A. and El-Zimaity, H.M. (2006) Chromoendoscopy points the way to understanding recovery of gastric function after Helicobacter pylori eradication. Gastrointestinal Endoscopy 64, 686-690 Google Scholar
118. Chang, W.J. et al. (2014) Inflammation-related factors predicting prognosis of gastric cancer. World Journal of Gastroenterology 20, 4586-4596 Google Scholar