Ulcers and gastritis

• Association of autoimmune type atrophic corpus gastritis with Helicobacter pylori infection (Veijola et al., World J Gastroenterol 2010 1)
• Trends and outcomes of hospitalizations for peptic ulcer disease in the United States, 1993 to 2006 (Wang et al., Ann Surg 2010 4)
• The natural course of Helicobacter pylori infection on endoscopic findings in a population during 17 years of follow-up: the Sorreisa gastrointestinal disorder study (Asfeldt et al., Eur J Epidemiol 2009 8)
• Does Helicobacter pylori eradication therapy for peptic ulcer prevent gastric cancer? (Mabe et al., World J Gastroenterol 2009 12)
• Effective reduction of gastric cancer risk with regular use of nonsteroidal anti-inflammatory drugs in Helicobacter pylori-infected patients (Wu et al., J Clin Oncol 2010 17)
• References

Association of autoimmune type atrophic corpus gastritis with Helicobacter pylori infection (Veijola et al., World J Gastroenterol 2010 [1])

It is increasingly recognized that parietal cell antibodies (PCA), previously assumed to be exclusive to autoimmune gastritis, are associated with Helicobacter pylori infection. Veijola et al. reported association of autoimmune-type atrophic corpus gastritis with H. pylori infection [1]. In the study they investigated the signs of previous H. pylori infection in patients with different grades of atrophic gastritis in order to assess the proportion of gastric atrophy not associated with H. pylori infection. In total, 23 patients with different grades of atrophic gastritis were analyzed using enzyme immunoassay-based serology, immunoblot-based serology, and histology to reveal a past or a present H. pylori infection. In addition, serum markers for gastric atrophy (pepsinogen I, pepsinogen I/II, and gastrin) and autoimmunity (PCA and intrinsic factor, antibodies) were determined. Of the 14 patients with severe gastric atrophy, as demonstrated by histology and serum markers, and no evidence for an ongoing H. pylori infection, eight showed H. pylori antibodies by immunoblotting. All eight had elevated PCA, four of whom also had intrinsic factor antibodies. Of the six immunoblot-negative patients with severe corpus atrophy, PCA and intrinsic factor antibodies were detected in four patients. Among the patients with low-to-moderate grade atrophic gastritis (all except one with an ongoing H. pylori infection), serum markers for gastric atrophy and autoimmunity were seldom detected. However, only one H. pylori-negative patient with mild atrophic gastritis had PCA and intrinsic factor antibodies suggestive of a pre-atrophic autoimmune gastritis. They concluded that atrophic corpus gastritis, including autoimmune-type severe atrophy with vitamin B₁₂-malabsorption, is associated with a long-standing H. pylori infection in most cases.

Interestingly, vitamin B₁₂ deficiency, previously associated with autoimmune gastritis, is increasingly described in the elderly, irrespective of H. pylori status. It is difficult to evaluate the role played by genetics, increased use of proton pump inhibitors (PPIs), and H. pylori infection, as current patient work-up does not regularly include screening for PCA and intrinsic factor antibodies. Long-standing H. pylori infection probably plays a role in many patients with pernicious anemia, in whom the active infectious process has been gradually replaced by an autoimmune disease that terminates in a burned-out infection and the irreversible destruction of the gastric body mucosa. In patients with H. pylori infection, superficial gastritis proceeds to atrophic gastritis in about half of the patients. In some patients, antral intestinal metaplasia disappears and PCA appears; thus, the disease resembles classic autoimmune gastritis [2]. Gastric H+/K+-ATPase is also the major autoantigen in chronic H. pylori-induced atrophic gastritis in corpus mucosa [3]. If the classic autoimmune type gastric atrophy is an end-stage of H. pylori-induced gastric autoimmunity with atrophic gastritis, the prevalence of pernicious anemia should decrease with declining prevalence of H. pylori infection. It still remains to be shown whether H. pylori infection is crucial for the development of autoimmune-type atrophic gastritis.

Trends and outcomes of hospitalizations for peptic ulcer disease in the United States, 1993 to 2006 (Wang et al., Ann Surg 2010 [4])

Medical treatment for peptic ulcer disease (PUD) has changed dramatically since the 1970 s. Advances include the introductions of H₂ receptor antagonists, PPIs, H. pylori eradication therapies, and evolving endoscopic approaches to treat bleeding ulcers. Meanwhile there has clearly been an associated and dramatic decrease in the volume of elective peptic ulcer surgery. Despite progress in diagnosis and treatment, PUD remains a common reason for hospitalization and operation. This is one of a number of recent papers that report trends of PUD [4].

The purpose of the study was to quantify the time trends of hospitalizations and operations for PUD in the USA since 1993. The Healthcare Cost and Utilization Project Nationwide Inpatient Sample is a 20 % stratified sample of all hospitalizations in the USA. It was used to study hospitalizations with PUD as the principal diagnosis during 1993 to 2006, including details on ulcer site, complications, procedures, and mortality. Statistical methods included the chi-squared test and multivariate logistic regression.

The national estimate of hospitalizations for PUD decreased significantly from 222 601 in 1993 to 156 108 in 2006 (–29.9 %), with a larger reduction in duodenal ulcers (95 552 in 1993 vs. 60 029 in 2006; –37.2 %) than gastric ulcers (106 987 in 1993 vs. 86 064 in 2006; –19.6 %). The inpatient mortality rate of PUD decreased from 3.8 % to 2.7 % during 1993 to 2006 (P < 0.001). Hemorrhage remained the most common complication (71.6 % in 1993; 73.3 % in 2006) but perforation had the highest mortality (15.1 % in 1993; 10.6 % in 2006). Compared with 1993, patients hospitalized for PUD in 2006 more frequently underwent endoscopic treatment to control bleeding (12.9 % vs. 22.2 %; P < 0.001), similar use of surgical oversewing of ulcer (7.6 % vs. 7.4 %), less use of gastrectomy (4.4 % vs. 2.1 %; P < 0.001), and less use of vagotomy (5.7 % vs. 1.7 %; P < 0.001). In multivariate logistic regressions, the determinants of mortality were similar in 1993 and 2006.

Hospitalizations for PUD decreased in the USA from 1993 to 2006, suggesting a decrease in the prevalence and/or severity of ulcer complications over this recent period. Despite increased patient age and co-morbidities, there has been a significant decrease in PUD mortality, a significant increase in the use of therapeutic endoscopy for bleeding ulcer, and a significant decrease in the use of definitive surgery (vagotomy or resection) for ulcer complications. This is suggestive of a decrease in the prevalence and/or severity of ulcer complications, reflecting the benefits of outpatient management of PUD, including eradication of H. pylori, avoidance of nonsteroidal anti-inflammatory drugs (NSAIDs), and use of acid suppression medications, especially PPIs. The improved mortality likely reflected the paradigm shift in the inpatient treatment of PUD, including early use of therapeutic endoscopy to control bleeding, benefits of endoscopic retreatment for recurrent bleeding, and decreased definitive operation for PUD in the emergent or urgent setting. The determinants of inpatient mortality for PUD were similar in 1993 and 2006. But, the single most important contributor to inpatient death is perforation, followed by two or more co-morbidities and hemorrhage.

Sadic et al. also reported that in Sweden the incidence rate for bleeding gastric or duodenal ulcers decreased by one half in males and by one-third in females, and that emergency operations and postoperative mortality decreased significantly [5]. Groenen et al. evaluated the trends in incidence and bleeding complications of PUD in The Netherlands [6]. From a computerized endoscopy database of a district hospital, the data of all patients who underwent upper gastrointestinal endoscopy between 1996 and 2005 were analyzed. Duodenal ulcers were diagnosed in 696 cases (3.5 %), with signs of bleeding in 158 (22.7 %). Gastric ulcers were diagnosed in 487 cases (2.4 %), with signs of bleeding in 60 (12.3 %). The incidence of gastric ulcers was stable over time, whereas the incidence of duodenal ulcers declined. Few studies have examined the incidence of uncomplicated PUD or the trends in factors affecting its incidence. Cai et al. estimated the incidence rate of uncomplicated PUD and evaluated temporal trends in demographic characteristics and prescription patterns for various anti-inflammatory and gastroprotective agents [7]. A reduction in H. pylori-related PUD, changing patterns in NSAID use, and increasing PPI use may have contributed to a decline in uncomplicated PUD incidence in the UK.

The natural course of Helicobacter pylori infection on endoscopic findings in a population during 17 years of follow-up: the Sorreisa gastrointestinal disorder study (Asfeldt et al., Eur J Epidemiol 2009 [8])

H. pylori was first described by Marshall and Wallen in 1984 [9]. But the natural course of H. pylori is poorly understood and is not well studied. Asfeldt et al. studied the natural course of H. pylori and its associations to morphological changes of the gastric mucosa, peptic ulcer, and reflux esophagitis in a prospective cohort study of individuals with and without dyspepsia [8]. A total of 361 adults (201 men/160 women, mean age 41/42 years) in the Sorreisa municipality, Norway, who had undergone upper endoscopy and assessment for gastrointestinal symptoms and H. pylori status in 1987 were followed up in 2004. Among the 140 H. pylori-positive individuals in 1987, 39 (28 %) had become negative, and 19 of these had received triple therapy. More interesting is that the remaining 20 subjects (14 %) may have cleared H. pylori spontaneously or by antibiotic treatment not directed at H. pylori eradication. Among 132 H. pylori-negative patients in 1987, 18 (14 %) contracted H. pylori prior to follow-up. In patients persistently positive for H. pylori, signs of inflammation increased significantly, whereas atrophy and intestinal metaplasia did not. These patterns were even more pronounced in patients who contracted H. pylori during follow-up. In those in whom H. pylori was eliminated, signs of inflammation and atrophy decreased, but the grade of intestinal metaplasia increased. Individuals who were persistently negative for H. pylori also developed some degree of intestinal metaplasia, which seems to be part of the normal ageing process. Of further importance is that elimination of H. pylori is associated with regression of most morphological changes except for intestinal metaplasia, supporting the idea of a point of no return in the pathogenesis of H. pylori leading to precancerous lesions [10].

This is the first prospective study of endoscopic findings in individuals without dyspepsia to show that the impact of H. pylori on gastric atrophy is only modest, and that eliminating H. pylori causes regression of signs of inflammation, but does not cause regression of intestinal metaplasia. H. pylori is only a moderate risk factor for PUD, and other explanatory factors deserve more attention in this study; for example, smoking and increasing age are also risk factors for PUD. A recent large US population-based study reports on a number of demographic, behavioral, and chronic medical conditions associated with higher risk of PUD [11]. The overall prevalence of PUD is 8.4 %. A significant increased risk of ulcer history is associated with older age, African-Americans, current and former tobacco use, former alcohol use, obesity, chronic obstructive pulmonary disease, chronic renal insufficiency, coronary heart disease, and three or more doctor visits in a year.

Does Helicobacter pylori eradication therapy for peptic ulcer prevent gastric cancer? (Mabe et al., World J Gastroenterol 2009 [12])

Experimental studies have revealed the primary prevention of gastric cancer by H. pylori eradication, but the effects of cancer prevention in humans have not been determined sufficiently. This report by Mabe et al. describes the results of a multicenter, prospective cohort study that investigated whether H. pylori eradication therapy in patients with PUD, living in an area where the incidence of gastric cancer is especially high, was effective in primary prevention of gastric cancer [12].

A multicenter prospective cohort study was conducted between November 2000 and December 2007 in Yamagata Prefecture, Japan. The study included patients with H pylori-positive PUD who decided themselves whether to receive H pylori eradication (eradication group) or conventional antacid therapy (non-eradication group). Incidence of gastric cancer in the two groups was determined based on the results of annual endoscopy and questionnaire surveys, as well as on Yamagata Prefectural Cancer Registry data, and was compared between the two groups and by results of H pylori therapy. In total, 4133 patients aged between 13 and 91 years (mean 52.9 years) were registered, and 56 cases of gastric cancer were identified over a mean follow-up of 5.6 years. The sex- and age-adjusted incidence ratio of gastric cancer in the eradication group compared with the non-eradication group was 0.58 (95 % confidence interval [CI] 0.28 – 1.19), and ratios by follow-up period (< 1 year, 1 – 3 years, > 3 years) were 1.16 (95 %CI 0.27 – 5.00), 0.50 (95 %CI 0.17 – 1.49), and 0.34 (95 %CI 0.09 – 1.28), respectively. Longer follow-up tended to be associated with better prevention of gastric cancer, although not to a significant extent. No significant difference in incidence of gastric cancer was observed between patients with successful eradication therapy (32 / 2451 patients; 1.31 %) and those with treatment failure (11 / 639 patients; 1.72 %). Among patients with duodenal ulcer, which is known to be more prevalent in younger individuals, the incidence of gastric cancer was significantly less in those with successful eradication therapy (2 / 845 patients; 0.24 %) than in those with treatment failure (3 / 216 patients; 1.39 %). This study concluded that H. pylori eradication therapy for peptic ulcer patients with a mean age of 52.9 years at registration did not significantly decrease the incidence of gastric cancer. But this result did not rule out a role for H. pylori eradication therapy in preventing gastric cancer.

No significant reduction in the incidence of gastric cancer by H. pylori eradication therapy was observed in a meta-analysis in 2007 [13]. But, in a randomized clinical study on the effects of eradication of H. pylori after endoscopic mucosal resection of early gastric cancer, Fukase et al. have recently reported a significant decrease in the incidence of secondary gastric carcinoma during a 3-year follow-up period [14]. A large-scale randomized controlled study in China did not support that H. pylori eradication therapy prevents the development of gastric cancer [15]. But, a sub-population analysis of patients who did not have precancerous change at the time of eradication therapy has suggested gastric cancer-preventing effects of H. pylori eradication therapy. And the nationwide cohort study in Taiwan revealed that early H. pylori eradication (hazard ratio [HR], 0.77) and frequent aspirin or NSAID use (HR, 0.65) were independent protective factors for gastric cancer in patients with PUD [16]. The precancerous state may represent the point of no return at which development of gastric cancer can no longer be prevented by H. pylori eradication. Evidence of early eradication in preventing gastric cancer needs to be obtained.

Effective reduction of gastric cancer risk with regular use of nonsteroidal anti-inflammatory drugs in Helicobacter pylori-infected patients (Wu et al., J Clin Oncol 2010 [17])

Previous studies have provided important evidence of the protective roles of NSAIDs in gastric carcinogenesis; however, the interaction between NSAID use and H. pylori infection and the subpopulation for which benefits of chemoprevention outweigh the risks of gastrointestinal bleeding and the number needed to treat (NTT) remains unclear.

Wu et al. conducted a nationwide retrospective cohort study based on data from the Taiwan National Health Insurance Database [17]. Hospitalized patients with a primary diagnosis of PUD were selected. Overall, 52 161 patients were divided into non-NSAID user and regular NSAID user cohorts. Standardized incidence ratios (SIRs), cumulative incidences, and hazard ratios were calculated. Patients with peptic ulcers who never used NSAIDs had higher risk of gastric cancer compared with the general population (SIR 2.11; 95 %CI 2.07 – 2.15), but regular NSAID use was associated with lower risk (SIR 0.79; 95 %CI 0.77 – 0.81). The protective role of NSAID use was observed in patients with gastric ulcer, but not in patients with non-H. pylori-associated duodenal ulcer. On stratified analysis, they observed the protective role of NSAIDs in gastric cancer in patients with gastric ulcer (cumulative incidence in 7 years: 11.6 % for non-NSAID users vs. 6.2 % for regular NSAID users; P < 0.001), but not in patients with duodenal ulcer. Among patients with gastric ulcers, the NNT to prevent a gastric cancer was 186. Also among patients with gastric ulcers, regular NSAID use had stronger prophylactic effect against gastric cancer development in H. pylori-associated patients (cumulative incidence in 7 years: 25.2 % for non-NSAID users vs. 5.0 % for regular NSAID users; P < 0.001) than in non-H. pylori-associated patients (8.7 % for non-NSAID users vs. 6.7 % for regular NSAID users; P = 0.0169). For H. pylori-associated and noninfected gastric ulcer patients the NNTs to prevent a gastric cancer were 50 and 500, respectively. On Cox multivariate proportional hazards analysis, older age (HR 1.03 for each incremental year; P < 0.01), gastric ulcer (HR 2.85; P < 0.001), and H. pylori-associated peptic ulcer (HR 1.93; P < 0.001) were independent risk factors for gastric cancer development. Regular NSAID use was an independent protective factor for gastric cancer development (HR 0.79 for each incremental year; P < 0.005). Patients with both regular NSAID use (each incremental year) and positive H. pylori status were associated with significantly lower risk for gastric cancer (HR 0.69; P < 0.001). Among H. pylori-associated patients, regular NSAID use was associated with significantly lower risk of gastric cancer (HR 0.52 for each incremental year; P < 0.001). For those never receiving H. pylori eradication therapy, regular NSAID use was also associated with reduced risk of gastric cancer (HR 0.80 for each incremental year; P < 0.001).

In a meta-analysis of the results of clinical studies, NSAID use was found to be associated with a reduced risk of gastric cancer, with similar magnitudes of risk reduction for aspirin and nonaspirin NSAID users [18]. Another meta-analysis also reports similar protective effects of NSAIDs in gastric cancer [19]. Gastric carcinogenesis is a multifactorial process, involving complex interactions between host and environmental factors. Elucidation of inflammation-based carcinogenesis offers new opportunities for gastric cancer chemoprevention. Aspirin and NSAIDs have been suggested to prevent gastric cancer by inhibiting production of cyclooxygenase (COX)-1 and COX-2 through both pepsinogen-dependent and -independent pathways. A recent study investigated the preventive effects of etodolac, a selective COX-2 inhibitor, on metachronous cancer development after endoscopic resection of early gastric cancer [20]. Long-term etodolac treatment did not influence the extent of metaplastic gastritis as revealed by endoscopic findings or by serum pepsinogen levels, but effectively reduced metachronous cancer development in patients with extensive metaplastic gastritis. NSAIDs attenuate COX-2 expression and pepsinogen synthesis stimulated by H. pylori infection thus reducing the risk of H. pylori-related gastric cancer.

Competing interests: None

References

• 1 Veijola L I, Oksanen A M, Sipponen P I et al. Association of autoimmune type atrophic corpus gastritis with Helicobacter pylori infection.  World J Gastroenterol. 2010;  16 83-88
  PubMedSearch in Google Scholar
• 2 Valle J, Kekki M, Sipponen P et al. Long-term course and consequences of Helicobacter pylori gastritis. Results of 32-years follow-up study.  Scand J Gastroenterol. 1996;  31 546-550
  CrossrefPubMedSearch in Google Scholar
• 3 Claeys D, Faller G, Appermelk B J et al. The gastric H+, K+-ATPase is a major autoantigen in chronic Helicobacter pylori gastritis with body mucosa atrophy.  Gastroenterology. 1998;  115 340-347
  CrossrefPubMedSearch in Google Scholar
• 4 Wang Y R, Richter J E, Dempsey D T. Trends and outcomes of hospitalizations for peptic ulcer disease in the United States, 1993 to 2006.  Ann Surg. 2010;  251 51-58
  CrossrefPubMedSearch in Google Scholar
• 5 Sadic J, Borgstrom A, Manjer J et al. Bleeding peptic ulcer – time trends in incidence, treatment and mortality in Sweden.  Aliment Pharmacol Ther. 2009;  30 392-398
  CrossrefPubMedSearch in Google Scholar
• 6 Groenen M J, Kuipers E J, Hansen B E et al. Incidence of duodenal ulcers and gastric ulcers in a Western population: back to where it started.  Can J Gastroenterol. 2009;  23 604-608
  PubMedSearch in Google Scholar
• 7 Cai S, Garcia Rodriguez L A, Masso-Gonzalez E L et al. Uncomplicated peptic ulcer in the UK: trends from 1997 to 2005.  Aliment Pharmacol Ther. 2009;  30 1039-1048
  CrossrefPubMedSearch in Google Scholar
• 8 Asfeldt A M, Steigen S E, Lochen M L et al. The natural course of Helicobacter pylori infection on endoscopic findings in a population during 17 years of follow-up: the Sorreisa gastrointestinal disorder study.  Eur J Epidemiol. 2009;  24 649-658
  CrossrefPubMedSearch in Google Scholar
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  PubMedSearch in Google Scholar
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  PubMedSearch in Google Scholar
• 11 Garrow D, Delegge M H. Risk factors for gastrointestinal ulcer disease in the US population.  Dig Dis Sci. 2010;  55 66-72
  CrossrefPubMedSearch in Google Scholar
• 12 Mabe K, Takahashi M, Oizumi H et al. Does Helicobacter pylori eradication therapy for peptic ulcer prevent gastric cancer?.  World J Gastroenterol. 2009;  15 4290-4297
  CrossrefPubMedSearch in Google Scholar
• 13 Fuccio L, Zagari R M, Minardi M E et al. Systematic review: Helicobacter pylori eradication for the prevention of gastric cancer.  Aliment Pharmacol Ther. 2007;  25 133-141
  CrossrefPubMedSearch in Google Scholar
• 14 Fukase K, Kato S, Kikuchi S et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial.  Lancet. 2008;  372 392-397
  CrossrefPubMedSearch in Google Scholar
• 15 Wong B C, Lam S K, Wong W M et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial.  JAMA. 2004;  291 187-194
  CrossrefPubMedSearch in Google Scholar
• 16 Wu C Y, Kuo K N, Wu M S et al. Early Helicobacter pylori eradication decreases risk of gastric cancer in patients with peptic ulcer disease.  Gastroenterology. 2009;  137 1641-1648
  CrossrefPubMedSearch in Google Scholar
• 17 Wu C Y, Wu M S, Kuo K N et al. Effective reduction of gastric cancer risk with regular use of nonsteroidal anti-inflammatory drugs in Helicobacter pylori-infected patients.  J Clin Oncol. 2010;  28 2952-2957
  CrossrefPubMedSearch in Google Scholar
• 18 Wang W H, Huang J Q, Zheng G F et al. Non-steroidal anti-inflammatory drug use and the risk of gastric cancer: a systematic review and meta-analysis.  J Natl Cancer Inst. 2003;  95 1784-1791
  CrossrefPubMedSearch in Google Scholar
• 19 Conzales-Perez A, Garcia Rodriguez L A, Lopez-Ridaura R. Effects of non-steroidal anti-inflammatory drugs on cancer sites other than the colon and rectum: a meta-analysis.  BMC Cancer. 2003;  3 28-39
  CrossrefPubMedSearch in Google Scholar
• 20 Yanaoka K, Oka M, Yoshimura N et al. Preventive effects of etodolac, a selective cyclooxygenase-2 inhibitor, on cancer development in extensive metaplastic gastritis, a Helicobacter pylori-negative precancerous lesion.  Int J Cancer. 2010;  126 1467-1473
  PubMedSearch in Google Scholar

H. KashiwagiMD 

Department of Surgery
Jikei University School of Medicine

3-25-8, Nishishinbashi
Minato-ku, Tokyo, Japan 105-8461

Fax: +81-3-5472-4120

Email: hkashiwagi.surg@jikei.ac.jp

References

• 1 Veijola L I, Oksanen A M, Sipponen P I et al. Association of autoimmune type atrophic corpus gastritis with Helicobacter pylori infection.  World J Gastroenterol. 2010;  16 83-88
  PubMedSearch in Google Scholar
• 2 Valle J, Kekki M, Sipponen P et al. Long-term course and consequences of Helicobacter pylori gastritis. Results of 32-years follow-up study.  Scand J Gastroenterol. 1996;  31 546-550
  CrossrefPubMedSearch in Google Scholar
• 3 Claeys D, Faller G, Appermelk B J et al. The gastric H+, K+-ATPase is a major autoantigen in chronic Helicobacter pylori gastritis with body mucosa atrophy.  Gastroenterology. 1998;  115 340-347
  CrossrefPubMedSearch in Google Scholar
• 4 Wang Y R, Richter J E, Dempsey D T. Trends and outcomes of hospitalizations for peptic ulcer disease in the United States, 1993 to 2006.  Ann Surg. 2010;  251 51-58
  CrossrefPubMedSearch in Google Scholar
• 5 Sadic J, Borgstrom A, Manjer J et al. Bleeding peptic ulcer – time trends in incidence, treatment and mortality in Sweden.  Aliment Pharmacol Ther. 2009;  30 392-398
  CrossrefPubMedSearch in Google Scholar
• 6 Groenen M J, Kuipers E J, Hansen B E et al. Incidence of duodenal ulcers and gastric ulcers in a Western population: back to where it started.  Can J Gastroenterol. 2009;  23 604-608
  PubMedSearch in Google Scholar
• 7 Cai S, Garcia Rodriguez L A, Masso-Gonzalez E L et al. Uncomplicated peptic ulcer in the UK: trends from 1997 to 2005.  Aliment Pharmacol Ther. 2009;  30 1039-1048
  CrossrefPubMedSearch in Google Scholar
• 8 Asfeldt A M, Steigen S E, Lochen M L et al. The natural course of Helicobacter pylori infection on endoscopic findings in a population during 17 years of follow-up: the Sorreisa gastrointestinal disorder study.  Eur J Epidemiol. 2009;  24 649-658
  CrossrefPubMedSearch in Google Scholar
• 9 Marshall B J, Warren J R. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration.  Lancet. 1984;  1 1311-1315
  PubMedSearch in Google Scholar
• 10 Axon A T. Relationship between Helicobacter pylori gastritis, gastric cancer and gastric acid secretion.  Adv Med Sci. 2007;  52 55-60
  PubMedSearch in Google Scholar
• 11 Garrow D, Delegge M H. Risk factors for gastrointestinal ulcer disease in the US population.  Dig Dis Sci. 2010;  55 66-72
  CrossrefPubMedSearch in Google Scholar
• 12 Mabe K, Takahashi M, Oizumi H et al. Does Helicobacter pylori eradication therapy for peptic ulcer prevent gastric cancer?.  World J Gastroenterol. 2009;  15 4290-4297
  CrossrefPubMedSearch in Google Scholar
• 13 Fuccio L, Zagari R M, Minardi M E et al. Systematic review: Helicobacter pylori eradication for the prevention of gastric cancer.  Aliment Pharmacol Ther. 2007;  25 133-141
  CrossrefPubMedSearch in Google Scholar
• 14 Fukase K, Kato S, Kikuchi S et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial.  Lancet. 2008;  372 392-397
  CrossrefPubMedSearch in Google Scholar
• 15 Wong B C, Lam S K, Wong W M et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial.  JAMA. 2004;  291 187-194
  CrossrefPubMedSearch in Google Scholar
• 16 Wu C Y, Kuo K N, Wu M S et al. Early Helicobacter pylori eradication decreases risk of gastric cancer in patients with peptic ulcer disease.  Gastroenterology. 2009;  137 1641-1648
  CrossrefPubMedSearch in Google Scholar
• 17 Wu C Y, Wu M S, Kuo K N et al. Effective reduction of gastric cancer risk with regular use of nonsteroidal anti-inflammatory drugs in Helicobacter pylori-infected patients.  J Clin Oncol. 2010;  28 2952-2957
  CrossrefPubMedSearch in Google Scholar
• 18 Wang W H, Huang J Q, Zheng G F et al. Non-steroidal anti-inflammatory drug use and the risk of gastric cancer: a systematic review and meta-analysis.  J Natl Cancer Inst. 2003;  95 1784-1791
  CrossrefPubMedSearch in Google Scholar
• 19 Conzales-Perez A, Garcia Rodriguez L A, Lopez-Ridaura R. Effects of non-steroidal anti-inflammatory drugs on cancer sites other than the colon and rectum: a meta-analysis.  BMC Cancer. 2003;  3 28-39
  CrossrefPubMedSearch in Google Scholar
• 20 Yanaoka K, Oka M, Yoshimura N et al. Preventive effects of etodolac, a selective cyclooxygenase-2 inhibitor, on cancer development in extensive metaplastic gastritis, a Helicobacter pylori-negative precancerous lesion.  Int J Cancer. 2010;  126 1467-1473
  PubMedSearch in Google Scholar

H. KashiwagiMD 

Department of Surgery
Jikei University School of Medicine

3-25-8, Nishishinbashi
Minato-ku, Tokyo, Japan 105-8461

Fax: +81-3-5472-4120

Email: hkashiwagi.surg@jikei.ac.jp