Helicobacter pylori causes ulcers and stomach cancer

During Feb. 7-9, 1994, the National Institute of Diabetes and Digestive and Kidney Diseases, together with the Office of Medical Applications of Research of the National Institutes of Health, convened a Consensus Development Conference on Helicobacter pylori in Peptic Ulcer Disease, cosponsored by the National Institute of Allergy and Infectious Diseases, admitting that Helicobacter pylori infection is the cause of gastritis and ulcers, and directing that "All patients with gastric or duodenal ulcers who are infected with H. pylori should be treated with antimicrobials regardless of whether they are suffering from the initial presentation of the disease or from a recurrence." (Perhaps not coincidentally, a few weeks later on Feb. 21, 1994, Mary Lasker croaked.) (Helicobacter pylori in peptic ulcer disease. NIH Consens Statement Online 1994 Jan 7-9 [cited 2006-07-29] 12(1):1-23.)

Consensus Statement on Helicobacter pylori / National Institutes of Health

Subsequently, a working group on schistosomes, liver flukes and Helicobacter pylori of the International Agency for Research on Cancer met in Lyon, France, and issued a report concluding that "infections of humans with H. pylori is causally associated with the risk of developing gastric cancer" (Infection with Helicobacter pylori (Group 1). In: Vol. 61, Schistosomes, Liver Flukes and Helicobacter pylori. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 7-14 June 1994).

"5.1 Exposure data ...H. pylori occurs worldwide and causes a chronic infection which rarely resolves spontaneously. Its prevalence is highest in developing countries and increases rapidly during the first two decades of life, such that 80-90% of the population may be infected by early adulthood. In most developed countries, the prevalence of infection is substantially lower at all ages, and especially in childhood. The prevalence increases gradually throughout life up to the age of 70-80 years. The prevalence in both developed and developing countries is higher among people in lower socioeconomic classes and may be associated with crowding in childhood. A progressive reduction in the rate of infection early in life of people in successive birth cohorts has been observed in developed countries."

"H. pylori causes gastritis in all infected people. This is accompanied by a specific, systemic immunoglobulin G response. Nevertheless, many such infections are asymptomatic. In some people, the infection gives rise to duodenal or gastric ulceration. The infection can be eradicated successfully with several regimens in which different drugs are combined. Eradication of H. pylori resolves gastritis, prevents recurrence of peptic ulcer disease and leads to a significant decline in immunoglobulin response within six months."

"5.2 Human carcinogenicity data Six studies in which estimates of prevalence of infection by H. pylori were related to estimates of concurrent or earlier incidence of or mortality from cancer of the stomach in five or fewer populations show no consistent association between these variables. Significantly positive geographical correlations were observed, however, in two larger studies in which the ranges of cancer incidence and mortality were much wider: one in 46 rural populations in China and the other in 17 populations in Europe, Japan and the USA. The populations of certain developing countries, including many in Africa and some in Asia, have low rates of gastric cancer; the prevalence of H. pylori has been studied in some of these populations and is known to be high."

"The association between prior seropositivity for H. pylori and subsequent gastric cancer has been evaluated in three cohort studies, yielding 29-109 cases of gastric cancer. Significant positive associations were observed in all three, with estimated relative risks, based on case-control analyses within the cohorts, varying from 2.8 to 6.0. In a pooled analysis of the three studies, the relative risk was 3.8, which was significant, and there was a significant trend towards increasing estimated relative risks with increasing length of followup... Nine retrospective case-control studies have addressed the association between sero-prevalence for H. pylori infection and incidence of gastric cancer. The estimated relative risks for gastric cancer were evaluated in six studies, ranging from 1.2 to 4.2, and were significant in three studies. In a number of studies, the control series may not have been representative of the population that gave rise to the cases, either because of the method of sampling (e.g. subjects requiring gastrointestinal investigation) or because of exclusions on the basis of a history of gastric symptoms or disease."

"When appropriate stratifications of the results of the prospective and retrospective studies were reported, the association between infection with H. pylori and gastric cancer was stronger in younger patients and for cancers at sites other than the cardia. The association was similarly strong for the intestinal and diffuse histological types of cancer."

"The association between H. pylori infection and gastric lymphoma has been investigated in some studies. In two series of 110 and 178 patients with gastric B-cell mucosa-associated lymphoid tissue lymphomas, 92 and 98%, respectively, had histological evidence of H. pylori infection. In two studies of treatment, five of six patients and 12 of 16 patients showed tumour regression after therapy to eradicate H. pylori. Thirty-three cases of gastric non-Hodgkins lymphoma were observed in a cohort study of patients with H. pylori infection in the USA and Norway, giving a significant estimated relative risk of 6.3."

5.5 Evaluation There is sufficient evidence in humans for the carcinogenicity of infection with Helicobacter pylori.

Overall Evaluation Infection with Helicobacter pylori is carcinogenic to humans (Group 1).

IARC Monograph 61 summary - Helicobacter pylori / IARC (pdf, 12pp)

Helicobacter pylori and ulcers: a paradigm revised. Nancy A. Lynch. Federation of American Societies for Experimental Biology (FASEB), Office of Public Affairs.

Lynch / FASEB (pdf, 9pp)

Helicobacter pylori: epidemiology and routes of transmission. LM Brown [of Biostatistics Branch, Division of Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD]. Epidemiol Rev 2000;22(2):283-297. Review. "Most of the recent studies found no significant association with current smoking or any other measure of tobacco use (52, 55, 60, 66-68), and one recent study from Japan (69) reported a significant negative association with current smoking."

Brown / Epidemiol Rev 2000 full article (pdf, 15pp)

Pathogenesis of Helicobacter pylori infection. JG Kusters, AHM van Vliet, EJ Kuipers. Clin Microbiol Rev 2006 July 1;19(3):449-490. Review.

Kusters / Clin Microbiol Rev 2006 abstract

Global burden of gastric cancer attributable to pylori. M Plummer, S Franceschi, J Vignat, D Forman, C de Martel. Int J Cancer 2015 Jan 15;136(2):487-490. "We previously estimated that 660,000 cases of cancer in the year 2008 were attributable to the bacterium Helicobacter pylori (H. pylori), corresponding to 5.2% of the 12.7 million total cancer cases that occurred worldwide. In recent years, evidence has accumulated that immunoblot (western blot) is more sensitive for detection of anti-H. pylori antibodies than ELISA, the detection method used in our previous analysis... Using the immunoblot-based data, the worldwide AF for H. pylori in [non-cardia gastric cancer] increased from 74.7% to 89.0%. This implies approximately 120,000 additional cases of NCGC attributable to H. pylori infection for a total of around 780,000 cases (6.2% instead of 5.2% of all cancers)."

Plummer - Int J Cancer 2015 abstract / PubMed

Droplet Digital PCR Detects Low-Density Infection in a Significant Proportion of Helicobacter Pylori-Negative Gastric Biopsies of Dyspeptic Patients. MJ Ramírez-Lázaro, S Lario, ME Quílez, A Montserrat, MR Bella, F Junquera, I García-Martínez, À Casalots, T Parra, X Calvet. Clin Transl Gastroenterol 2020 Jun;11(6):e00184. 236 dyspeptic patients. "ddPCR detected low-density "occult" H. pylori infection in a significant proportion (36%) of patients diagnosed as negative by conventional methods."

Ramírez-Lázaro / Clin Transl Gastroenterol 2020 full article

Helicobacter pylori and gastric cancer

Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation. D Forman, DG Newell, F Fullerton, JW Yarnell, AR Stacey, N Wald, F. Sitas. BMJ 1991 Jun 1;302(6788):1302-1305. "20 of the 29 cases (69%) and 54 of the 116 controls (47%) were positive for H pylori specific antibody. The median specific IgG concentration was significantly higher in the cases than controls (90 micrograms/ml v 3.6 micrograms/ml, p less than 0.01). The estimated odds ratio for the risk of gastric cancer in those with a history of infection with H pylori was 2.77 (95% confidence interval 1.04 to 7.97, 2p = 0.039)."

Forman - BMJ 1991 abstract / PubMed

The association of Helicobacter pylori with gastric cancer and preneoplastic gastric lesions in Chiapas, Mexico. J Guarner, A Mohar, J Parsonnet, D Halperin. Cancer 1993 Jan 15;71(2):297-301. In 183 subjects tested by enzyme-linked immunosorbent assay (ELISA) for anti-H. pylori immunoglobulin G, "There was a strong association between H. pylori in the tissue and atrophy (relative risk, 15.0; 95% confidence interval, 4.2-56.6), intestinal metaplasia (relative risk, 5.7; 95% confidence interval, 1.9-16.8), and dysplasia or cancer (relative risk, 4.0; 95% confidence interval, 1.1-14.8)... In this high-risk population, precursor lesions for adenocarcinoma were associated universally with H. pylori infection."

Guarner - Cancer 1993 abstract / PubMed

Helicobacter pylori, pepsinogen, and risk for gastric adenocarcinoma. J Parsonnet, IM Samloff, LM Nelson, N Orentreich, JH Vogelman, GD Friedman. Cancer Epidemiol Biomarkers Prev 1993 Sep-Oct;2(5):461-466. In 136 cases of gastric adenocarcinoma and 136 matched controls without adenocarcinoma from a large cohort that had contributed serum in the 1960's, "By univariate analysis, H. pylori infection [odds ratio (OR), 3.6; P < 0.001] and serum pepsinogen I < 50 ng/ml (OR = 2.9; P = 0.003) were both associated with development of distal cancer. In multivariate analysis, there was interaction between the two variables; H. pylori in the absence of low pepsinogen I was independently associated with cancer (OR, 2.4; P = 0.04) but low pepsinogen I in the absence of H. pylori infection was not associated with cancer (OR, 0.8; P > 0.5). In combination, however, H. pylori infection and a low pepsinogen I were associated with a marked increase in the risk of developing distal malignancy (OR, 10.0; P = 0.08)."

Parsonnet - Cancer Epidemiol Biomarkers Prev 1993 abstract / PubMed

Helicobacter pylori infection: independent risk indicator of gastric adenocarcinoma. LE Hansson, L Engstrand, O Nyren, DJ Evans Jr, A Lindgren, R Bergstrom, B Andersson, L Athlin, O Bendtsen, P Tracz. Gastroenterology 1993 Oct;105(4):1098-1103. In sera from 112 incident gastric cancer patients and 103 control patients with nongastroenterological diseases, "The odds ratio (OR) was 2.60 (95% confidence interval, 1.35-5.02). The increased OR associated with H. pylori infection was confined to tumors with a noncardia location (OR, 3.06) and men (OR, 4.27). OR increased with decreasing age at cancer diagnosis to reach 9.33 in patients < 60 years of age."

Hansson - Gastroenterology 1993 full article / UCSF (pdf, 6 pp)

Helicobacter pylori infection in a randomly selected population, healthy volunteers, and patients with gastric ulcer and gastric adenocarcinoma. A seroprevalence study in Taiwan. JT Lin, JT Wang, TH Wang, MS Wu, TK Lee, CJ Chen. Scand J Gastroenterol 1993 Dec;28(12):1067-72. In serum IgG antibodies of 823 randomly selected subjects, 92 healthy volunteers, 117 patients with gastric ulcer, and 148 with gastric adenocarcinomas, "Gastric ulcer patients had a higher seropositivity (83.8%) than healthy volunteers (62.0%) and gastric adenocarcinoma patients (62.2%) (P < 0.001). Gender difference, blood type, and habit of smoking were not associated with the seroprevalence in any study groups. Gastric ulcer coexistent with duodenal ulcer had a higher seropositivity (94.7%) (P < 0.05). The seropositivity of H. pylori in gastric adenocarcinoma patients was higher than in healthy volunteers only in younger age and was not associated with histologic type, invasion, and location of major tumors."

Lin - Gastroenterol 1993 abstract / PubMed

Serum anti-Helicobacter pylori antibody and gastric carcinoma among young adults. Research Group on Prevention of Gastric Carcinoma among Young Adults. S Kikuchi, O Wada, T Nakajima, T Nishi, O Kobayashi, T Konishi, Y Inaba. Cancer 1995 Jun 15;75(12):2789-2793. For serum IgG to HP in 105 hospitalized patients younger than 40, 102 hospital controls, and 101 screening controls, "The OR (95% confidence interval) was 13.3 (5.3-35.6). For women, the OR was 32.8, whereas for men it was 6.8. The OR for patients with early gastric carcinoma was 20.8, and for patients with advanced disease, it was 10.8. The OR for intestinal-type carcinoma was 18.0, and for diffuse-type carcinoma, it was 12.8. The OR for proximal carcinoma was 11.3, and for distal carcinoma it was 14.8. CONCLUSION: The OR for these young subjects was considerably larger than that for the older subjects in previously published studies."

Kikuchi - Cancer 1995 abstract / PubMed

IgG immune response to Helicobacter pylori antigens in patients with gastric cancer as defined by ELISA and immunoblotting. K Klaamas, M Held, T Wadstrom, A Lipping, O Kurtenkov. Int J Cancer 1996 Jul 3;67(1):1-5. In 182 gastric cancer patients and 306 blood donor controls in Estonia, "A significantly higher H. pylori seroprevalence was found in patients in the early stages of tumor development compared with both advanced cancer patients and controls."

Klaamas - Int J Cancer 1996 abstract / PubMed

Helicobacter pylori in tumor tissues of patients with advanced gastric adenocarcinoma: high prevalence but failure to detect integration. JT Wang, CT Sung, JT Lin, TH Wang. Zhonghua Min Guo Wei Sheng Wu Ji Mian Yi Xue Za Zhi 1996 Aug;29(3):134-142. In 32 patients with gastric adenocarcinoma, "For serum antibody, eighteen (56%) of these patients were positive by ELISA while 24 (75%) were positive by Western blot. For tissue H. pylori genome, 14 were positive by histology while 28 (87%) were positive by PCR."

Wang - Zhonghua Min Guo Wei Sheng Wu Ji Mian Yi Xue Za Zhi 1996 abstract / PubMed

Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection. J Parsonnet, GD Friedman, N Orentreich, H Vogelman. Gut 1997 Mar;40(3):297-301. Among 90 cases and 89 controls, all HP-infected, versus 63 uninfected [?] controls, including 13 gastric cancer patients, "Subjects infected with H pylori who had CagA antibodies were 5.8-fold more likely than uninfected subjects to develop gastric cancer (95% confidence interval (95% CI) = 2.6-13.0). This was true for both intestinal (odds ratio (OR) 5.1, 95% CI = 2.1-12.2) and diffuse type (OR 10.1, 95% CI = 2.2-47.4) cancers. By contrast, H pylori infected subjects without CagA antibodies were only slightly, and not significantly, at increased risk for cancer (OR 2.2, 95% CI = 0.9-5.4) and any possible association was restricted to diffuse type carcinoma (OR 9.0, 95% CI = 1.2-65.8)... Educational attainment, cigarette smoking, and ABO blood group were not associated with malignancy."

Parsonnet / Gut 1997 full article (pdf, 6pp)

Association between Helicobacter pylori and gastric carcinoma in the city of Malmo, Sweden. A prospective study. JH Siman, A Forsgren, G Berglund, CH Floren. Scand J Gastroenterol 1997 Dec;32(12):1215-1221. 56 cases of gastric adenocarcinoma and 224 matched controls from a cohort of 32,906 residents recruited from 1974 through 1992. "The overall seropositivity prevalence in gastric cancer cases was 82%, compared with 49% in controls, giving an odds ratio (OR) of 5.0 (95% confidence interval (CI), 2.2-11.5)... Tumours of the cardia were not associated with H. pylori (OR, 0.92; 95% CI, 0.23-3.7), which is in contrast to tumours of the fundus, corpus, and antrum, which were significantly associated (OR, 11.1; 95% CI, 2.4-71.8)."

Siman - Scand J Gastroenterol 1997 abstract / PubMed

Helicobacter pylori infection and gastric neoplasia: correlations with histological gastritis and tumor histology. K Komoto, K Haruma, T Kamada, S Tanaka, M Yoshihara, K Sumii, G Kajiyama, NJ Talley. Am J Gastroenterol 1998 Aug;93(8):1271-1276. "105 patients with gastric carcinoma, 36 patients with gastric adenoma, and 105 age- and sex-matched control subjects were examined for H. pylori infection and histological gastritis. H. pylori status was evaluated by Giemsa staining and IgG serology... H. pylori seroprevalence was higher in patients with gastric carcinoma (98 of 105, 93%) and adenoma (34 of 36, 94%) than in control subjects (82 of 105, 71%, p < 0.05). H. pylori was more prevalent in patients with noncardia (OR, 5.67; 95% CI, 2.25-14.44) than cardia (OR, 5.20; 95% CI, 0.65-41.68) tumors. Histologic types and tumor stage (early; OR, 6.60; 95% CI, 2.23-19.69, advanced; OR, 4.27; 95% CI, 1.21-15.03) showed no difference in H. pylori prevalence." A supposed smoking risk of 3.05 (95% CI, 1.58-5.93).

Komoto - Am J Gastroenterol 1998 abstract / PubMed

Helicobacter pylori infection and risk of cardia cancer and non-cardia gastric cancer. A nested case-control study. S Hansen, KK Melby, S Aase, E Jellum, SE Vollset. Scand J Gastroenterol 1999 Apr;34(4):353-360. 208 gastric adenocarcinoma cases among 101,601 subjects whose serum was collected between 1972 and 1986 in the Norwegian JANUS study: H. pylori infection and non-cardia gastric cancer (odds ratio (OR), 5.15; 95% confidence interval (CI), 2.83-9.37).

Hansen - Scand J Gastroenterol 1999 abstract / PubMed

Helicobacter pylori infection on the risk of stomach cancer and chronic atrophic gastritis. ZF Zhang, RC Kurtz, DS Klimstra, GP Yu, M Sun, S Harlap, JR Marshall. Cancer Detect Prev 1999;23(5):357-367. "This study included 134 patients with adenocarcinoma of the stomach (ACS), 67 patients with chronic atrophic gastritis (CAG), and 65 normal controls recruited at Memorial Sloan-Kettering Cancer Center... H. pylori infection was diagnosed by pathological evaluation... The odds ratio (OR) associated with H. pylori infection was 10.4 [95% confidence interval (CI): 2.6-41.6] for CAG and 11.2 (95% CI: 2.5-50.3) for gastric cancer in comparison with normal controls, with adjustment for pack-years of smoking, alcohol drinking, body mass index, total caloric intake, dietary fat and fiber intake, and Barrett's esophagus."

Zhang - Cancer Detect Prev 1999 abstract / PubMed

Helicobacter pylori infection and risk of gastric cancer in Shanghai, China: updated results based upon a locally developed and validated assay and further follow-up of the cohort. JM Yuan, MC Yu, WW Xu, M Cockburn, YT Gao, RK Ross. Cancer Epidemiol Biomarkers Prev 1999 Jul;8(7):621-624. Their previous study failed to show an association between H. pylori and gastric cancer; "That previous study had a relatively short time period of follow-up and the enzyme-linked immunosorbent assay (ELISA) used was based on strains found in Southern England and without validation among the Chinese... An ELISA developed and validated among Shanghai residents was used in the present study to reexamine specific antibodies to H. pylori in 188 gastric cancer patients and 548 control subjects... Using this alternative assay, combined with increased follow-up, our latest data contradict our earlier findings and show a statistically significant association between H. pylori seropositivity and gastric cancer risk (odds ratio, 1.84; 95% confidence interval, 1.08–3.11). We noted an increasing rate of seropositivity among cases as the time interval between cohort enrollment and cancer diagnosis increased. Among subjects followed for 5 or more years after enrollment, the odds ratio for gastric cancer related to H. pylori seropositivity was 3.74 (95% confidence interval, 1.51–9.30)."

Yuan / Cancer Epidemiol Biomarkers Prev 1999 full article

Association between infections with CagA-positive or -negative strains of Helicobacter pylori and risk for gastric cancer in young adults. Research Group on Prevention of Gastric Carcinoma Among Young Adults. S Kikuchi, JE Crabtree, D Forman, M Kurosawa. Am J Gastroenterol 1999 Dec;94(12):3455-3459. In 103 gastric cancer patients <40 yr of age, 100 inpatients with benign diseases, and 101 screenees younger than age 43 yr: "The overall odds ratios (95% confidence intervals) for gastric cancer in the H. pylori+/CagA- and the H. pylori+/CagA+ groups were 15.0 (6.4, 35.2) and 14.6 (6.7, 31.9), respectively. Between these two groups, no significant difference was observed in risks for intestinal-type, diffuse-type, early, advanced, proximal, or distal gastric cancer."

Kikuchi - Am J Gastroenterol 1999 abstract / PubMed

Assessment of gastric carcinoma risk associated with Helicobacter pylori may vary depending on the antigen used: CagA specific enzyme-linked immunoadsorbent assay (ELISA) versus commercially available H. pylori ELISAs. S Maeda, H Yoshida, K Ogura, Y Yamaji, T Ikenoue, T Mitsushima, H Tagawa, R Kawaguchi, K Mori, K Mafune, T Kawabe, Y Shiratori, M Omata. Cancer 2000 Apr 1;88(7):1530-1535. "Anti-CagA seropositivity differed significantly between gastric carcinoma patients and controls (92.5% vs. 55.0%; P = 0. 0001), showing an odds ratio of 10.4 (95% confidence interval [CI]: 4.23-29.74). The difference was less prominent for the seropositivity of HEL-p (77.5% vs. 58.8%; P = 0.0139; odds ratio: 2. 38; 95% CI: 1.20-4.82) and insignificant for that of HM-CAP (65.0% vs. 57.5%; P = 0.4325; odds ratio: 1.30; 95% CI: 0.68-2.49). CONCLUSIONS: The current study revealed that the antibody assay system used could be one important factor in the assessment of gastric carcinoma risk for patients with H. pylori."

Maeda - Cancer 2000 abstract / PubMed

Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Helicobacter and Cancer Collaborative Group. Gut 2001 Sep;49(3):347-353. "Twelve studies with 1228 gastric cancer cases were considered. The association with H pylori was restricted to non-cardia cancers (OR 3.0; 95% CI 2.3-3.8) and was stronger when blood samples for H pylori serology were collected 10+ years before cancer diagnosis (5.9; 3.4-10.3). H pylori infection was not associated with an altered overall risk of cardia cancer (1.0; 0.7-1.4). CONCLUSIONS: These results suggest that 5.9 is the best estimate of the relative risk of non-cardia cancer associated with H pylori infection and that H pylori does not increase the risk of cardia cancer. They also support the idea that when H pylori status is assessed close to cancer diagnosis, the magnitude of the non-cardia association may be underestimated [emphasis added]." "Assuming an average prevalence of H pylori of 35% in developed countries and 85% in developing countries, an OR of 5.9 suggests that between about 65% and 80%, respectively, of non-cardia gastric cancers are attributable to H pylori infection and therefore potentially preventable by control of the infection."

Helicobacter and Cancer Collaborative Group - Gut 2001 full article / PubMed Central

Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection. AM Ekstrom, M Held, LE Hansson, L Engstrand, O Nyren. Gastroenterology 2001 Oct;121(4):784-791. HP infection may disappear spontaneously during progression to gastric cancer, so antibodies that persist longer after eradication were used. "RESULTS: Using IgG ELISA only, the adjusted OR for noncardia gastric cancer among H. pylori-positive subjects was 2.2 (95% confidence interval [CI], 1.4-3.6). When ELISA-/CagA+ subjects (odds ratio [OR], 68.0) were removed from the reference, the OR rose to 21.0 (95% CI, 8.3-53.4) and the previous effect modification by age disappeared. ELISA+/CagA- subjects had an OR of 5.0 (95% CI, 1.1-23.6). There were no associations with cardia cancer. CONCLUSIONS: The weaker H. pylori-cancer relationships in studies based on IgG ELISA rather than CagA may be caused by misclassification of relevant exposure. A much stronger relationship emerges with more accurate exposure classification. In the general Swedish population, 71% of noncardia adenocarcinomas were attributable to H. pylori."

Ekstrom - Gastroenterology 2001 abstract / PubMed

Helicobacter pylori CagA seropositivity and gastric carcinoma risk in a Japanese American population. AM Nomura, J Lee, GN Stemmermann, RY Nomura, GI Perez-Perez, MJ Blaser. J Infect Dis 2002 Oct 15;186(8):1138-1144. 261 incident cases of gastric carcinoma of the distal stomach among 9963 Japanese American men recruited between 1967 and 1977: "Compared with H. pylori-negative, CagA-negative men, H. pylori-positive, CagA-negative men had an odds ratio (OR) of 2.7 (95% confidence interval [CI], 1.3-5.6) for intestinal gastric carcinoma. Men seropositive for both H. pylori and CagA had an OR of 4.1 (95% CI, 2.2-7.7)."

Nomura - J Infect Dis 2002 abstract / PubMed

Serum Helicobacter pylori IgG and IgA levels in patients with gastric cancer. C Atalay, G Atalay, M Altinok. Neoplasma 2003;50(3):185-190. "Serological tests revealed IgA and IgG positivity as 53.9% and 50.9%, respectively, while 74.5% had positive results for either IgA or IgG. Serum IgA positivity was significantly higher in gastric cancer group compared to control group (p=0.02). In contrast, serum IgG positivity did not show a significant difference in both groups and either IgG or IgA seropositivity was significantly higher in patients with gastric cancer compared to control patients (p=0.04). This study revealed a higher seroprevalence of Helicobacter pylori in gastric cancer patients and IgA was a better predictor of Helicobacter pylori seropositivity in gastric cancer patients" [emphasis added].

Atalay - Neoplasma 2003 abstract / PubMed

Is Helicobacter pylori infection a necessary condition for noncardia gastric cancer? H Brenner, V Arndt, C Stegmaier, H Ziegler, D Rothenbacher. Am J Epidemiol 2004 Feb 1;159(3):252-258. "Although the association between Helicobacter pylori infection and gastric cancer is well established, this association might have been underestimated in epidemiologic studies because of possible clearance of the infection in the course of disease development [emphasis added]. The authors addressed this hypothesis in a case-control study from Saarland, Germany (68 cases first diagnosed between 1996 and 1998 and 360 controls), with serologic assessment of H. pylori infection in which various exclusion criteria were used to minimize potential bias from this source. Joint application of three such exclusion criteria (blood sample taken more than 90 days after gastrectomy, advanced (T4) gastric cancer, and CagA positivity in Western blot analysis despite a negative result in anti-H. pylori immunoglobulin G enzyme-linked immunosorbent assay) increased the odds ratio of noncardia gastric cancer from 3.7 (95% confidence interval (CI): 1.7, 7.9) to 18.3 (95% CI: 2.4, 136.7) for any H. pylori infection and from 5.7 (95% CI: 2.6, 12.8) to 28.4 (95% CI: 3.7, 217.1) for CagA-positive H. pylori infections. Furthermore, there was no single H. pylori-negative patient out of 32 patients with noncardia gastric cancer left after additional exclusion of subjects with borderline levels in immunoglobulin G enzyme-linked immunosorbent assay. The H. pylori-gastric cancer relation may be much stronger than previously thought, and H. pylori infection may even be a (close to) necessary condition for development of noncardia gastric cancer."

Brenner - Am J Epidemiol 2004 abstract / PubMed

Is the association between Helicobacter pylori and gastric cancer confined to CagA-positive strains? M Held, L Engstrand, LE Hansson, R Bergstrom, T Wadstrom, O Nyren. Helicobacter 2004 Jun;9(3):271-277. "100 case patients with a newly diagnosed gastric adenocarcinoma and 96 control patients with diseases unrelated to H. pylori status. Antibodies to H. pylori were analyzed by enzyme-linked immunosorbent assay (ELISA), and antibodies to CagA were detected by immunoblot... ELISA positivity was associated with an increased risk of gastric adenocarcinoma compared to ELISA negativity (OR for gastric cancer regardless of site 3.9, 95% CI 1.9-8.2). The OR was 7.4 (95% CI 3.3-16.6) for CagA-positive relative to CagA-negative subjects. Among ELISA-positive subjects the presence of CagA antibodies increased the risk 3.6 times (95% CI 1.2-11.1). ELISA-positive CagA-negative infections were associated with a fourfold increased risk (OR = 4.2, 95% CI 1.0-17.0) compared to no infection (ELISA-negative and CagA-negative)."

Held - Helicobacter 2004 abstract / PubMed

Association of Helicobacter pylori infection and environmental factors in non-cardia gastric cancer in Japan. A Machida-Montani, S Sasazuki, M Inoue, S Natsukawa, K Shaura, Y Koizumi, Y Kasuga, T Hanaoka, S Tsugane. Gastric Cancer 2004;7(1):46-53. "H. pylori infection was strongly associated with non-cardia gastric cancer after adjustment for possible confounding factors (odds ratio [OR], 8.2; 95% confidence interval [CI], 3.7-18.2)." They claim an OR of 2.8 for smoking, which is likely due to false HP-negatives, because the cases were newly diagnosed.

Machida-Montani - Gastric Cancer 2004 abstract / PubMed

Relationship between Helicobacter pylori infection and the prevalence, site and histological type of gastric cancer. M Kato, M Asaka, Y Shimizu, A Nobuta, H Takeda, T Sugiyama; Multi-Centre Study Group. Aliment Pharmacol Ther 2004 Jul;20 Suppl 1:85-89. "The prevalence of H. pylori infection in gastric cancer patients was markedly high in all age groups. In contrast, the rate increased with age among control subjects. The overall prevalence of H. pylori infection in control subjects was 50.2% (3300/6578) vs. 82.8% in gastric cancer patients (2072/2503) (OR = 2.47; 95% CI: 2.19-2.79). The prevalence of H. pylori in early gastric cancer was significantly higher than that in advanced gastric cancer (86.5% vs. 75.7%; OR = 2.06; 95% CI: 1.66-2.55)."

Kato - Aliment Pharmacol Ther 2004 abstract / PubMed

Association of Helicobacter pylori IgA antibodies with the risk of peptic ulcer disease and gastric cancer. TU Kosunen, K Seppala, S Sarna, A Aromaa, P Knekt, J Virtamo, A Salomaa-Rasanen, H Rautelin. World J Gastroenterol 2005 Nov 21;11(43):6871-6874. Versus controls with chronic gastritis, IgA antibodies to H. pylori were more strongly associated with gastric cancer and gastric ulcers than were IgG antibodies. "Severe atrophic gastritis may progress to a disease stage when Helicobacters first gradually decrease in number, then disappear and finally also Helicobacter antibodies, the longest lasting indicators of the infection, fall to a normal level. In particular, in elderly subjects with non-cardia cancer, there may be several individuals who at the time of diagnosis may have lost all direct indicators of their burnt out Helicobacter infection" [emphasis added].

Kosunen / World J Gastroenterol 2005 full article

Effect of Helicobacter pylori infection combined with CagA and pepsinogen status on gastric cancer development among Japanese men and women: a nested case-control study. S Sasazuki, M Inoue, M Iwasaki, T Otani, S Yamamoto, S Ikeda, T Hanaoka, S Tsugane; Japan Public Health Center Study Group. Cancer Epidemiol Biomarkers Prev 2006 Jul;15(7):1341-1347. 511 gastric cancer cases matched to 511 controls from a cohort of 123,576. "The adjusted odds ratio (95% confidence interval) of gastric cancer associated with H. pylori infection was 5.1 (3.2-8.0). Assuming all CagA-positive subjects are true H. pylori positives doubled this risk. Atrophic gastritis was also associated with an elevated risk of gastric cancer and the risk increased further with pepsinogen levels."

Sasazuki - Cancer Epidemiol Biomarkers Prev 2006 abstract / PubMed

Serum antibody positivity for distinct Helicobacter pylori antigens in benign and malignant gastroduodenal disease. C Schumann, K Triantafilou, FM Rasche, A Möricke, K Vogt, M Triantafilou, P Hahn, EM Schneider, PM Lepper. Int J Med Microbiol 2006 Aug;296(4-5):223-228. "Serum samples were taken from 285 patients who underwent gastroscopy. H. pylori infection was diagnosed by histology, culture or rapid urease test (RUT). Serum IgG reactivity against H. pylori-specific antigens was studied by Western blot. There was a significant association between the diagnosis of gastric cancer and the presence of IgG antibodies against the 19.5, 33 and 136 kDa (CagA) antigens. Comparing all H. pylori-positive patients with the gastric cancer group for the presence of the 19.5, 33 and 136 kDa (CagA) antigens, the results were as follows: chi2: 17.482, p < 0.001, power P = 0.994, odds ratio (OR) for the presence of gastric cancer: 19.5 (95% confidence interval (CI): 4.11-92.56). Antibodies against CagA alone or other bands (except 33 and 19.5 kDa antigens), as well as the age of patients were not related to a diagnosis of gastric cancer."

Schumann - Int J Med Microbiol 2006 abstract / PubMed

Age and severity of mucosal lesions influence the performance of serologic markers in Helicobacter pylori-associated gastroduodenal pathologies. M Camorlinga-Ponce, L Flores-Luna, E Lazcano-Ponce, R Herrero, F Bernal-Sahagún, JM Abdo-Francis, J Aguirre-García, N Muñoz, J Torres. Cancer Epidemiol Biomarkers Prev 2008 Sep;17(9):2498-2504. 368 patients with non–atrophic gastritis, 126 with precancerous lesions, 65 with gastric cancer, and 59 with duodenal ulcer. "Detection of infection and IgG against CagA had a significant increase from non–atrophic gastritis to mild and up to advanced stages of metaplasia (P < 0.05), followed by decreased infection and IgG to CagA in patients with gastric cancer (P < 0.05). However, infection and CagA antibodies were associated with young gastric cancer cases. Duodenal ulcer showed a significant association with infection detected by histology and serology, particularly among women, and a trend to associate with IgG to CagA." "H. pylori is able to colonize only normal gastric epithelia and when it is altered because of mucosal damage, such as during the appearance of preneoplastic lesions, the infection tends to disappear. Fading of the infection would alter diagnostic tests, and those documenting active infection such as culture or histology become negative, whereas those testing the memory of infection, such as humoral immune response, decline more gradually."

Camorlinga-Ponce / Cancer Epidemiol Biomarkers Prev 2008 full article

Factors contributing to the underestimation of Helicobacter pylori-associated gastric cancer risk in a high-prevalence population. B Peleteiro, N Lunet, R Barros, C La Vecchia, H Barros. Cancer Causes Control 2010 Aug;21(8):1257-1264. 420 non-cardia gastric cancer patients and 1389 population controls. "When assessing infection by ELISA, the OR for its association with gastric cancer decreases and reverts as IgG titers increased, from 1.96 (95% CI: 1.09-3.54) for borderline positive results (16.0-21.9 RU/ml) to 0.52 (95% CI: 0.36-0.74) for the highest IgG levels (> or = 102.0 RU/ml)... The presence of CagA (Western Blot) was associated with an increased risk of gastric cancer (OR = 11.32; 95% CI: 5.64-22.73). CONCLUSION: The use of methods with low sensitivity to detect past infection leads to a substantial underestimation of gastric cancer risk in high-prevalence settings."

Peleteiro - Cancer Causes Control 2010 abstract / PubMed

A CagA-independent cluster of antigens related to the risk of non-cardia gastric cancer: Associations between helicobacter pylori antibodies and gastric adenocarcinoma explored by multiplex serology. H Song, A Michel, O Nyrén, AM Ekström, M Pawlita, W Ye. Int J Cancer 2014 Jun 15;134(12):2942-2950. Point estimates for all antibodies were above unity, 15 significant with top three being CagA (OR=9.2), GroEL (6.6), HyuA (3.6). ORs were substantially attenuated in individuals with chronic atrophic gastritis. Principal component analysis identified two significant factors: a CagA-dominant factor (antibodies against CagA, VacA, and Omp as prominent markers), and a non-CagA factor (antibodies against NapA and Catalase as prominent markers). Both factors showed dose-dependent associations with non-cardia GAC risk (CagA-dominant factor, highest vs. lowest quartiles, OR=16.2 [95% CI 4.8-54.9]; non-CagA factor OR=5.3 [95%CI 2.1-13.3])."

Song - Int J Cancer 2014 abstract / PubMed

Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial. RM Mera, LE Bravo, MC Camargo, JC Bravo, AG Delgado, J Romero-Gallo, MC Yepez, JL Realpe, BG Schneider, DR Morgan, RM Peek Jr, P Correa, KT Wilson, MB Piazuelo. Gut 2018 Jul;67(7):1239-1246. 795 patients. "Incomplete-type IM was associated with higher risk of progression to cancer than complete-type (OR, 11.3; 95% CI 1.4 to 91.4)."

Mera - Gut 2018 abstract / PubMed

Multiple infections by EBV, HCMV and Helicobacter pylori are highly frequent in patients with chronic gastritis and gastric cancer from Southwest Mexico: An observational study. O Del Moral-Hernández, CA Castañón-Sánchez, S Reyes-Navarrete, DN Martínez-Carrillo, R Betancourt-Linares, H Jiménez-Wences, S de la Peña, A Román-Román, D Hernández-Sotelo, G Fernández-Tilapa. Medicine (Baltimore) 2019 Jan;98(3):e14124. 106 chronic gastritis, 32 gastric cancer patients. " In chronic gastritis and gastric cancer EBV was found in 69.8% and 87.5%, HCMV in 52.8% and 53.1%, and H. pylori in 48.1% and 40.6%, respectively. In chronic gastritis, 53% of H. pylori patients were EBV and 33% were both EBV/HCMV; in gastric cancer, 92.3% of H. pylori-infected individuals were EBV and 46.1% were EVB/HCMV."

Del Moral-Hernández - Medicine (Baltimore) 2019 abstract / PubMed

Helicobacter pylori infection, chronic atrophic gastritis and risk of stomach and esophagus cancer: Results from the prospective population-based ESTHER cohort study. B Holleczek, B Schöttker, H Brenner. Int J Cancer 2020 May 15;146(10):2773-2783. 30 noncardia gastric cancers and 33 esophageal cancers. "Infection by H. pylori without and with expression of CagA was associated with a 5.2-fold (95% confidence interval 1.00-27.1) and an 18.2-fold (4.3-77.4) increase of noncardia gastric cancer incidence. A 0.65-fold decreased risk of esophageal adenocarcinomas (HR 0.35, 0.12-0.97) was observed among H. pylori-infected individuals. In participants infected with CagA expressed H. pylori, the presence of mild/moderate and severe CAG was associated with a 6.4-fold (1.3-31.0) and an 11.8-fold (3.1-45.4) increase of gastric cancer incidence, respectively."

Holleczek - Int J Cancer 2020 abstract / PubMed

[Note: Epstein-Barr virus is also involved in gastric carcinoma.]

Helicobacter pylori and lymphomas

Helicobacter pylori infection and gastric lymphoma. J Parsonnet, S Hansen, L Rodriguez, AB Gelb, RA Warnke, E Jellum, N Orentreich, JH Vogelman, GD Friedman. N Engl J Med 1994 May 5;330(18):1267-1271. 33 patients with gastric non-Hodgkin's lymphoma, 31 patients with nongastric non-Hodgkin's lymphoma, 132 controls. For gastric NHL and previous H. pylori infection: matched odds ratio, 6.3; 95 percent confidence interval, 2.0 to 19.9.

Parsonnet - N Engl J Med 1994 abstract / PubMed

A comparison of Helicobacter pylori and H. heilmannii gastritis. A matched control study involving 404 patients. M Stolte, G Kroher, A Meining, A Morgner, E Bayerdorffer, B Bethke. Scand J Gastroenterol 1997 Jan;32(1):28-33. 202 patients with H. heilmannii gastritis and 202 matched control patients with H. pylori gastritis and duodenal ulcer. "In a single case of H. heilmannii gastritis a concurrent gastric carcinoma and in seven cases a low-grade gastric MALT lymphoma were found... Whether the observed relatively frequent association of H. heilmannii infection and gastric MALT lymphoma is coincidental, and whether H. heilmannii gastritis is more commonly associated with MALT lymphoma than is H. pylori gastritis must be investigated in further studies."

Stolte - Scand J Gastroenterol 1997 abstract / PubMed

Blood groups Lewis(b) and ABH expression in gastric mucosa: lack of inter-relation with Helicobacter pylori colonisation and occurrence of gastric MALT lymphoma. G Oberhuber, A Kranz, C Dejaco, B Dragosics, I Mosberger, W Mayr, T Radaszkiewicz. Gut 1997 Jul;41(1):37-42. "Colonisation with H pylori was found in 134 (72·8%) patients, including 55 (61·1%) of MALT lymphoma negative and 79 (84%) of MALT lymphoma positive cases. In two cases H pylori status remained unclear. The occurrence of MALT lymphomas was highly significantly associated with H pylori colonisation (p<0·0003)."

Oberhuber / Gut 1997 full article (pdf, 7pp)

Helicobacter pylori and non-Helicobacter pylori bacterial flora in gastric mucosal and tumour specimens of patients with primary gastric lymphoma. D Jonkers, I Gisbertz, A de Bruine, F Bot, JW Arends, E Stobberingh, H Schouten, R Stockbrugger. Eur J Clin Invest 1997 Nov;27(11):885-892. "In total, 32 (61.5%) patients were H. pylori positive using IMM [specific immunohistochemical stain for H. pylori] and 34 (65.4%) were non-H. pylori positive using MG [modified Giemsa stain]. In 24 out of the 34 patients, the non-H. pylori flora consisted mainly of cocci in combination with rods in 15 patients, mostly in minor quantities; in another 10 patients, high numbers of both cocci and different types of rods were present. Most non-H. pylori bacteria were localized superficially, although in 22 patients minor quantities of non-H. pylori were also seen in the glandular lumina."

Jonkers - Eur J Clin Invest 1997 abstract / PubMed

Hematopoietic cancer and peptic ulcer: a multicenter case-control study. P Vineis, P Crosignani, C Sacerdote, A Fontana, G Masala, L Miligi, O Nanni, V Ramazzotti, S Rodella, E Stagnaro, R Tumino, C Vigano, C Vindigni, AS Costantini. Carcinogenesis 1999 Aug;20(8):1459-1463. 2671 cases and 1718 controls. "Subjects who reported a diagnosis of peptic ulcer had a relative risk of 5.6 [95% confidence interval (CI) 3.8–8.0] for gastric NHL, whereas the estimate for non-gastric NHL was 1.3 (1.0–1.6)... We found a strong effect modification by educational level, with ORs for ulcer more elevated in higher social groups. Gender was an effect modifier (OR = 4.1 in males, 9.2 in females; P = 0.03 for heterogeneity)... Almost all gastric lymphomas were B-cell NHLs of intermediate grade according to the working formulation; the majority belonged to the mucosa-associated lymphoid tissue (MALT) type." Non-Hodgkin's lymphomas have been increasing by 3-4% a year in Western countries.

Vineis - Carcinogenesis 1999 abstract / PubMed
Vineis / Carcinogenesis 1999 full article

Helicobacter pylori and gastric lymphoma: high seroprevalence of CagA in diffuse large B-cell lymphoma but not in low-grade lymphoma of mucosa-associated lymphoid tissue type. JC Delchier, D Lamarque, M Levy, EM Tkoub, C Copie-Bergman, L Deforges, MT Chaumette, C Haioun. Am J Gastroenterol 2001 Aug;96(8):2324-2328. 45/53 (85%) gastric lymphoma patients were positive for H. pylori (78% (29/37) in LGLM and 100% (16/16) in DLBCL).

Delchier - Am J Gastroenterol 2001 abstract / PubMed

Helicobacter pylori and malignant lymphoma in Spain. S de Sanjose, A Dickie, T Alvaro, V Romagosa, M Garcia Villanueva, E Domingo-Domenech, A Fernandez de Sevilla, E El-Omar. Cancer Epidemiol Biomarkers Prev 2004 Jun;13(6):944-948. 536 cases. "H. pylori infection was not associated with an overall increased risk of lymphoma. Within all lymphoma categories, H. pylori was associated with an almost 4-fold increased risk of splenic MZL (OR = 3.97, 95% CI = 0.92-17.16, P value = 0.065). Of 26 patients with splenic MZL, 24 had detectable antibodies against H. pylori... H. pylori was not associated with an overall increased risk of extranodal lymphomas (OR = 0.73, 95% CI = 0.44-1.22). However, when specific sites were explored, all 10 lymphomas localized primarily in the stomach were H. pylori seropositive. No other lymphoma category shown in Table 3 showed an association with H. pylori." HP infection was not related to smoking.

de Sanjose / Cancer Epidemiol Biomarkers Prev 2004 full article

A past history of gastric ulcers and Helicobacter pylori infection increase the risk of gastric malignant lymphoma. T. Suzuki, K Matsuo, H Ito, K Hirose, K Wakai, T Saito, S Sato, Y Morishima, S Nakamura, R Ueda, K Tajima. Carcinogenesis 2006 Jul;27(7):1391-1397. 645 cases, 3445 controls. "An association with a history of gastric, but not duodenal ulcers was found for gastric lymphoma [odds ratio (OR) = 5.41, 95% confidence interval (CI): 3.12-9.39]. In the examination according to histological subtype, the OR was high for both gastric mucous-associated lymphoid tissue (MALT) lymphoma (OR = 5.54, 95% CI: 2.56-12.01) and diffuse large B-cell lymphoma (DLBCL) (OR = 7.23, 95% CI: 2.62-19.90). In the analysis of H. pylori antibody, the risk of total gastric lymphoma was associated with H. pylori infection (OR = 5.34, 95% CI: 1.42-20.05). A high prevalence of H. pylori infection was also found for both gastric MALT lymphoma (8 out of 10: 80.0%) and DLBCL (8 out of 9: 88.9%)."

Suzuki - Carcinogenesis 2006 abstract / PubMed

Helicobacter pylori infection and the risk of gastric malignancy. PI Hsu, KH Lai, PN Hsu, GH Lo, HC Yu, WC Chen, FW Tsay, HC Lin, HH Tseng, LP Ger, HC Chen. Am J Gastroenterol 2007 Apr;102(4):725-730. 1,225 patients with nonulcer dyspepsia, gastric ulcers, or duodenal ulcers. "During a mean follow-up of 6.3 yr, gastric adenocarcinoma developed in 7 of the 618 H. pylori-infected patients, but in none of the 607 uninfected patients (1.1%vs 0.0%, P= 0.015). The incidence of gastric lymphoma was 0.2% (1/618) and 0% in H. pylori-infected and uninfected patients. Taken together, the development rate of gastric malignancy in H. pylori-infected patients was significantly higher than that in uninfected patients (1.3%vs 0%, P= 0.007). Among H. pylori-infected subjects, the incidence of gastric malignancy was similar between those receiving and not receiving eradication therapy (1.4%vs 1.2%). Multivariate analysis showed that intestinal metaplasia was the only independent factor predicting subsequent development of gastric malignancy in H. pylori-infected subjects with an odds ratio of 4.5 (95% CI 1.1-19.1)."

Hsu - Am J Gastroenterol 2007 abstract / PubMed

The association between conjunctival MALT lymphoma and Helicobacter pylori. SB Lee, JW Yang, CS Kim. Br J Ophthalmol 2008 Apr;92(4):534-536. "H pylori DNA was identified in all 15 specimens of conjunctival MALT lymphomas and none of the controls. Of these 15 H pylori positive lymphoma specimens, the vacA s1 and vacA m2 alleles were detected in two, and only vacA s1 allele was detected in 11."

Lee - Br J Ophthalmol 2008 abstract / PubMed

Primary low-grade and high-grade gastric MALT-lymphoma presentation. A Zullo, C Hassan, A Andriani, F Cristofari, V Cardinale, GP Spinelli, S Tomao, S Morini. J Clin Gastroenterol 2010 May-Jun;44(5):340-344. Review of 2000 patients. "Helicobacter pylori infection was present in 88.8% of considered patients. At endoscopy, the ulcerative type was the most frequent presentation, although low-grade lymphoma was diagnosed on normal/hyperemic gastric mucosa in 9% of cases. Patients with high-grade lymphoma presented alarm symptoms (anemia and/or melena and/or hemorrhage, persistent vomiting, weight loss), an exophytic or ulcerative lesion, a stage III-IV, and a H. pylori negative status more frequently than low-grade lymphoma cases."

Zullo - J Clin Gastroenterol 2010 abstract / PubMed

Repeating gastric biopsy for accuracy of gastric lymphoma diagnosis. W Xu, C Zhou, G Zhang, H Wang, L Wang, J Guo. Gastroenterol Nurs 2010 Jul-Aug;33(4):313-317. 70.4% of 54 cases of gastric lymphoma were positive for H. pylori. "Of these, 13 cases were diffuse large B-cell lymphoma and 41 cases were marginal zone B-cell lymphoma."

Xu - Gastroenterol Nurs 2010 abstract / PubMed

Ocular adnexal lymphoma and Helicobacter pylori gastric infection. D Decaudin, A Ferroni, A Vincent-Salomon, K Beldjord, P Validire, P de Cremoux, P Validire, C Plancher, C Mathiot, E Macintyre, B Asselain, J Girodet, F Mal, N Brousse, JL Beretti, R Dendale, L Lumbroso-Le Rouic, O Hermine, M Lecuit. Am J Hematol 2010 Sep;85(9):645-649. 83 patients with OAL, 101 with extraophthalmologic extragastric lymphoma, and 156 controls. "We found gastric Hp infection in 37 OAL patients (45%), in 25 extraophthalmologic extragastric lymphoma cases (25%), and in 18 controls individuals (12%) (P < 0.0001 OAL/C and P < 0.01 OAL/extra-OAL cases)... Gastric Hp infection only correlated with MALT/LPL lymphoma (P = 0.03). There is a significant association between gastric Hp infection and MALT/LPL OAL."

Decaudin - Am J Hematol 2010 abstract / PubMed

Helicobacter pylori and gastric mucosa-associated lymphoid tissue lymphoma: Recent progress in pathogenesis and management. S Nakamura, T Matsumoto. World J Gastroenterol 2013 Dec 7;19(45):8181-8187. Review. In approximately 90% of cases, Helicobacter pylori (H. pylori) infection plays the causative role in the pathogenesis, and H. pylori eradication is nowadays the first-line treatment for this disease, which leads to complete disease remission in 50%-90% of cases. In H. pylori-dependent cases, microbe-generated immune responses, including interaction between B and T cells involving CD40 and CD40L co-stimulatory molecules, are considered to induce the development of MALT lymphoma. In H. pylori-independent cases, activation of the nuclear factor-κB pathway by oncogenic products of specific chromosomal translocations such as t(11;18)/API2-MALT1, or inactivation of tumor necrosis factor alpha-induced protein 3 (A20) are considered to contribute to the lymphomagenesis."

Nakamura - World J Gastroenterol 2013 full article / PubMed
Nakamura / World J Gastroenterol 2013 full article

Helicobacter pylori (HP) infection alone, but not HP-induced atrophic gastritis, increases the risk of gastric lymphoma: a case-control study in Japan. N Ishikura, Y Usui, H Ito, Y Kasugai, I Oze, S Kato, Y Yatabe, S Nakamura, K Matsuo. Ann Hematol 2019 Aug;98(8):1981-1987. 86 patients with gastric lymphoma, 1720 controls. "A consistent association was observed for MALT lymphoma, DLBCL, and other lymphomas with ORs of 1.96 (1.00-3.86), 1.92 (0.74-4.95), and 5.80 (1.12-30.12), respectively."

Ishikura - Ann Hematol 2019 abstract / PubMed

Antibiotic treatment of gastric lymphomas

[Treatment of low-grade gastric MALT lymphoma with Helicobacter pylori eradication. Follow-up of the histological and molecular response]. C Montalban, A Manzanal, D Boixeda, C Redondo, I Alvarez, B Frutos, JL Calleja, P Sanchez-Godoy, C Bellas. Med Clin (Barc) 1998 Jan 24;110(2):41-44. After HP eradication, lymphomas regressed in 10/11 patients. Nine were still in remission 18 months later.

Montalban - Med Clin (Barc) 1998 abstract / PubMed

Treatment of low grade gastric mucosa-associated lymphoid tissue lymphoma in stage I with Helicobacter pylori eradication. Long-term results after sequential histologic and molecular follow-up. C Montalban, A Santon, D Boixeda, C Redondo, I Alvarez, JL Calleja, CM de Argila, C Bellas. Haematologica 2001 Jun;86(6):609-617. Regression in 18 of 19 consecutive patients with stage I gastric low grade MALT lymphoma; 15 remaining patients are still in histologic remission after a mean period of 43 months.

Montalban / Haematologica 2001 full article (pdf, 9pp)

Changes in pattern of immunoglobulin heavy chain gene rearrangement and MIB-1 staining before and after eradication of Helicobacter pylori in gastric mucosa-associated lymphoid tissue (MALT) lymphoma. M Kanda, J Suzumiya, K Ohshima, M Okada, K Tamura, M Kikuchi. Leuk Lymphoma 2001 Aug;42(4):639-647. 9/12 gastric MALT lymphomas regressed completely after HP eradication.

Kanda - Leuk Lymphoma 2001 abstract / PubMed

Regression of low-grade gastric mucosa-associated lymphoid tissue lymphoma after eradication of Helicobacter pylori: possible association with p16 hypermethylation. YS Kim, JS Kim, HC Jung, CH Lee, CW Kim, IS Song, CY Kim. J Gastroenterol 2002 Jan;37(1):17-22. "Eighteen patients (90%) achieved complete remission, with a median duration of 15.7 months. The initial detection rate of p16 hypermethylation was 58% (7 of the 12 patients in whom p16 hypermethylation was evaluated successfully). In a serial investigation, 3 patients who were followed-up for a median 28 months showed that the p16 hypermethylation had disappeared."

Kim - J Gastroenterol 2002 abstract / PubMed

Long-term persistence of molecular disease after histological remission in low-grade gastric MALT lymphoma treated with H. pylori eradication. Lack of association with translocation t(11;18): a 10-year updated follow-up of a prospective study. C Montalban, S Santon, C Redondo, M Garcia-Cosio, D Boixeda, E Vazquez-Sequeiros, F Norman, CM de Argila, I Alvarez, V Abraira, C Bellas. Ann Oncol 2005 Sep;16(9):1539-1544. "Twenty-two of the 24 patients (91%) achieved disappearance of the lymphoma. Eighteen (82%) of the 22 histologically cured patients and 16 of the 19 (84%) with long follow-up had monoclonality," but "Only one patient (6%) with persistent monoclonality relapsed."

Montalban - Ann Oncol 2005 abstract / PubMed

HLA-DQA1*0103-DQB1*0601 haplotype and Helicobacter pylori-positive gastric mucosa-associated lymphoid tissue lymphoma. Y Kawahara, M Mizuno, T Yoshino, K Yokota, K Oguma, H Okada, S Fujiki, Y Shiratori. Clin Gastroenterol Hepatol 2005 Sep;3(9):865-868. "After H pylori eradication, the lymphomas regressed completely in all 10 patients who possessed the DQA1*0103-DQB1*0601 haplotype but in only 4 of the 8 without this haplotype (P = .023)."

Kawahara - Clin Gastroenterol Hepatol 2005 abstract / PubMed

Long-term results of anti-Helicobacter pylori therapy in early-stage gastric high-grade transformed MALT lymphoma. LT Chen, JT Lin, JJ Tai, GH Chen, HZ Yeh, SS Yang, HP Wang, SH Kuo, BS Sheu, CM Jan, WM Wang, TE Wang, CW Wu, CL Chen, IJ Su, J Whang-Peng, AL Cheng. J Natl Cancer Inst 2005 Sep 21;97(18):1345-1353. "H. pylori was eradicated in 97% (30 of 31) of evaluable H. pylori-positive low-grade patients and in 92% (22 of 24) of high-grade patients, which led to CR in 80% (24 of 30, 95% confidence interval [CI] = 65% to 95%) and 64% (14 of 22, 95% CI = 42% to 86%) of patients, respectively. None of the five patients who were either initially H. pylori negative or had persistent H. pylori infection after antibiotics achieved CR. After median follow-up of more than 5 years in complete responders, tumor recurrence was observed in three (13%) low-grade patients but not in high-grade patients."

Chen - J Natl Cancer Inst 2005 abstract / PubMed

Comparison of localized gastric mucosa-associated lymphoid tissue (MALT) lymphoma with and without Helicobacter pylori infection. T Akamatsu, T Mochizuki, Y Okiyama, A Matsumoto, H Miyabayashi, H Ota. Helicobacter 2006 Apr;11(2):86-95. "Complete regression was achieved with antibiotic therapy against H. pylori-negative gastric MALT lymphoma in one of nine patients (11.1%), compared to 28 of 38 patients (73.7%) with H. pylori-positive gastric MALT lymphoma (p < .001)... Two of 16 patients (12.5%) with H. pylori-negative gastric MALT lymphoma died because of the transformation of the disease into diffuse large B-cell lymphoma."

Akamatsu - Helicobacter 2006 abstract / PubMed

Successful antibiotic treatment of Helicobacter pylori negative gastric mucosa associated lymphoid tissue lymphomas. M Raderer, B Streubel, S Wohrer, M Hafner, A Chott. Gut 2006 May;55(5):616-618. In six patients with MALT lymphoma of the stomach, "H pylori infection was ruled out by histology, urease breath test, serology, and stool antigen testing." After antibiotic treatment, lymphomas regressed completely in four patients and partially in one.

Raderer - Gut 2006 abstract / PubMed

Gastric MALT lymphoma: epidemiology and high adenocarcinoma risk in a nation-wide study. LG Capelle, AC de Vries, CW Looman, MK Casparie, H Boot, GA Meijer, EJ Kuipers. Eur J Cancer 2008 Nov;44(16):2470-2476. "1419 patients were newly diagnosed with gMALT, compatible with an incidence of 0.41/100,000/year. GC was diagnosed in 34 (2.4%) patients of the cohort. Patients with gMALT had a sixfold increased risk for GC in comparison with the general population (p<0.001). This risk was 16.6 times higher in gMALT patients aged between 45 and 59 years than in the Dutch population (p<0.001)."

Capelle - Eur J Cancer 2008 abstract / PubMed

Effects of Helicobacter pylori eradication on early stage gastric mucosa-associated lymphoid tissue lymphoma. A Zullo, C Hassan, F Cristofari, A Andriani, V De Francesco, E Ierardi, S Tomao, M Stolte, S Morini, D Vaira. Clin Gastroenterol Hepatol 2010 Feb;8(2):105-110. Review of 32 studies, with 1408 patients treated only by H pylori eradication. "The MALT lymphoma remission rate was 77.5% (95% confidence interval, 75.3-79.7), and was significantly higher in patients with stage I than stage II(1) lymphoma (78.4% vs 55.6%; P = .0003) and in Asian than in Western groups (84.1% vs 73.8%; P = .0001)... In an analysis of data from 994 patients, 7.2% experienced lymphoma relapse during 3253 patient-years of follow-up evaluation, with a yearly recurrence rate of 2.2%. Infection and lymphoma were cured by additional eradication therapy in all patients with H pylori recurrence (16.7%)."

Zullo - Clin Gastroenterol Hepatol 2010 abstract / PubMed

Decreasing incidence of gastric MALT lymphomas in the era of anti-Helicobacter pylori interventions: results from a population-based study on extranodal marginal zone lymphomas. S Luminari, M Cesaretti, L Marcheselli, I Rashid, S Madrigali, A Maiorana, M Federico. Ann Oncol 2010 Apr;21(4):855-859. 165 cases from the Modena Cancer Registry. "[T]he incidence of gastric mucosa-associated lymphoid tissue (g-MALT) lymphomas (N = 51) markedly declined during the study period, dropping from 1.4 in 1997 to 0.2 in 2002 and then remaining stable until 2007; the calculated annual percent change for g-MALT was -17.0% (95% confidence interval -26.6% to -6.2%). We also observed a significant decrease in the rate of g-MALT associated with Helicobacter pylori (HP) infection from 61% to 17% of patients diagnosed before and after 2002 (P = 0.007; P for trend = 0.016)."

Luminari - Ann Oncol 2010 abstract / PubMed

Gastric MALT lymphoma: old and new insights. A Zullo, C Hassan, L Ridola, A Repici, R Manta, A Andriani. Ann Gastroenterol 2014;27(1):27-33. Review.

Zullo - Ann Gastroenterol 2014 full article / PubMed Central

Helicobacter pylori Eradication Therapy Is Effective as the Initial Treatment for Patients with H. pylori -Negative and Disseminated Gastric Mucosa-Associated Lymphoid Tissue Lymphoma. EJ Gong, JY Ahn, HY Jung, H Park, YB Ko, HK Na, KW Jung, DH Kim, JH Lee, KD Choi, HJ Song, GH Lee, JH Kim. Gut Liver 2016 Sep 15;10(5):706-713. 345 gastric MALT lymphoma patients. "H. pylori infection was detected in 317 patients (91.9%). The complete remission (CR) rate after eradication therapy was 82.3%, which was higher in H. pylori -positive patients than in H. pylori-negative patients (84.5% vs 57.1%, p=0.001)."

Gong - Gut Liver 2016 abstract / PubMed
Gong / Gut Liver 2016 full article landing

Helicobacter pylori and ulcers

Smoking does not contribute to duodenal ulcer relapse after Helicobacter pylori eradication. TJ Borody, LL George, S Brandl, P Andrews, E Jankiewicz, N Ostapowicz. Am J Gastroenterol 1992 Oct;87(10):1390-1393. 80 smokers and 117 nonsmokers: "In the 197 patients with eradicated H. pylori and cured DU, there has been no recurrence of ulcer, regardless of smoking status. We conclude that in patients with DU in whom H. pylori infection is eradicated, ulcer disease does not recur, as observed for up to 6 yr. Furthermore, cigarette smoking is not a risk factor for DU recurrence, provided H. pylori is eradicated."

Borody - Am J Gastroenterol 1992 full article / UCSF (pdf, 4 pp)

Helicobacter pylori infection, cigarette smoking and alcohol consumption. A histological and clinical study on 286 subjects. G Battaglia, F Di Mario, M Pasini, PM Donisi, P Dotto, ME Benvenuti, V Stracca-Pansa, M Pasquino. Ital J Gastroenterol 1993 Oct;25(8):419-424. "Hp infection was found to be significantly correlated with presence of ulcer symptoms, gastritis, lymphoid follicles and, among DU patients, with active DU. The other parameters considered did not influence Hp infection. In conclusion smoking habits and alcohol consumption do not affect Hp infection of the stomach."

Battaglia - Ital J Gastroenterol 1993 full article / UCSF (pdf, 6 pp)

Helicobacter pylori infection and the risk for duodenal and gastric ulceration. A Nomura, GN Stemmermann, PH Chyou, GI Perez-Perez, MJ Blaser. Ann Intern Med 1994 Jun 15;120(12):977-981. 150 gastric ulcer and 65 duodenal ulcer patients from Honolulu Heart Program prospective study. "Ninety-three percent (139 of 150) of the patients with gastric ulcer and 78% (117 of 150) of the matched controls had a positive H. pylori-specific IgG antibody level, yielding an odds ratio of 3.2 (P = 0.001). (The odds ratio is determined by dividing 32 ± pairs by 10 -/+ pairs.) Ninety-two percent of the case-patients with duodenal ulcer and 78% of the matched controls had a positive test result, yielding an odds ratio of 4.0 (P = 0.03)."

Nomura / Ann Intern Med 1994 full article

Helicobacter pylori infection, anti-cagA antibodies and peptic ulcer: a case-control study in Italy. D Palli, M Menegatti, G Masala, C Ricci, C Saieva, J Holton, L Gatta, M Miglioli, D Vaira. Aliment Pharmacol Ther 2002 May;16(5):1015-1020. 275 duodenal and 71 gastric ulcer patient cases, with 1280 non-ulcer dyspepsia controls.

Palli - Aliment Pharmacol Ther 2002 abstract / PubMed

Relation between Helicobacter pylori cagA status and risk of peptic ulcer disease. AM Nomura, GI Perez-Perez, J Lee, G Stemmermann, MJ Blaser. Am J Epidemiol 2002 Jun 1;155(11):1054-1059. 229 cases tested for IgG to H. pylori and CagA. "Persons with H. pylori positivity had an odds ratio of 4.0 (95% confidence interval (CI): 1.9, 8.5) for gastric ulcer and 2.5 (95% CI: 0.8, 7.4) for duodenal ulcer. For CagA positivity, the odds ratios were 1.4 (95% CI: 0.9, 2.4) for gastric ulcer and 2.6 (95% CI: 1.1, 5.8) for duodenal ulcer. Subjects who were seropositive for both H. pylori and CagA had an odds ratio of 4.4 (95% CI: 1.8, 10.5) for gastric ulcer and 5.8 (95% CI: 1.1, 30.0) for duodenal ulcer." [The study claimed an association with smoking, which could disappear if IgA positivity was determined as well -cast]

Nomura / Am J Epidemiol 2002 full article

The prevalence of peptic ulcer not related to Helicobacter pylori or non-steroidal anti-inflammatory drug use is negligible in southern Europe. MT Arroyo, M Forne, CM de Argila, F Feu, J Arenas, J de la Vega, V Garrigues, F Mora M Castro, L Bujanda, A Cosme, A Castiella, JP Gisbert, A Hervas, A Lanas. Helicobacter 2004 Jun;9(3):249-254. "Of the 472 patients who had duodenal ulcers, 95.7% (n = 452) were H. pylori-positive and only 1.69% (n = 8) were negative for both H. pylori infection and NSAID use; 193 patients had benign gastric ulcers and 87% (n = 168) of them were infected by H. pylori (p <.001 vs. duodenal ulcers)."

Arroyo - Helicobacter 2004 abstract / PubMed


Helicobacter pylori and methylation of the p16 gene

Helicobacter pylori membrane protein 1: a new carcinogenic factor of helicobacter pylori. M Suganuma, M Kurusu, S Okabe, N Sueoka, M Yoshida, Y Wakatsuki, H Fujiki. Cancer Res 2001 Sep 1;61(17):6356-6359. "Two cell lines, BALB/3T3 cells as control and v-Ha-ras-transfected BALB/3T3 cells (Bhas 42 cells) as putative initiated cells, were each transfected with HP-MP1, urease B genes, or vector alone. All of the Bhas/mpl clones showed strong expression of tumor necrosis factor-α gene and produced tumors in 100% of nude mice. Two Bhas/ure clones showed weak tumorigenicity; the other Bhas and BALB clones showed none. Results indicate strong carcinogenic activity of HP-MP1 in cooperation with viral Ras protein and weak activity of urease B."

Suganuma / Cancer Res 2001 full article

Helicobacter pylori infection affects the expression of PCNA, p53, c-erbB-2 and Bcl-2 in the human gastric mucosa. O Jorge, FD Cuello Carrion, A Jorge, DR Ciocca. Rev Esp Enferm Dig 2003 Feb;95(2):97-104, 89-96. 57 biopsies of patients with chronic gastritis and gastric cancer. "PCNA [Proliferating Cell Nuclear Antigen] content of epithelial cells was significantly higher in H. pylori infected biopsies. Treatment aimed to eradicate H. pylori decreased the level of PCNA-positive cells in the group of patients that became H. pylori-negative as well as in H. pylori-positive patients. Nuclear p53 expression (used here as a surrogate marker for p53 mutation/inactivation) and c-erbB-2 expression were observed only in the group of patients that remained with the bacteria after treatment. A higher bcl-2 expression in lymphoid cells was observed in H. pylori-positive biopsies, and treatment did not change the expression of this protein. No significant expression of p21 H-ras was observed in the studied biopsies."

Jorge - Rev Esp Enferm Dig 2003 abstract / PubMed

New tumor necrosis factor-alpha-inducing protein released from Helicobacter pylori for gastric cancer progression. M Suganuma, M Kurusu, K Suzuki, A Nishizono, K Murakami, T Fujioka, H Fujiki. J Cancer Res Clin Oncol 2005 May;131(5):305-313. "rTipalpha significantly induced TNF-alpha gene expression and NF-kappaB activation in both Bhas 42 cells and MGT-40, and induced in vitro transformation of Bhas 42 cells. However, rdel-Tipalpha did not."

Suganuma - J Cancer Res Clin Oncol 2005 abstract / PubMed

CDH1 gene promoter hypermethylation in gastric cancer: relationship to Goseki grading, microsatellite instability status, and EBV invasion. M Zazula, AM Ferreira, JP Czopek, P Kolodziejczyk, A Sinczak-Kuta, A Klimkowska, P Wojcik, K Okon, M Bialas, J Kulig, J Stachura. Diagn Mol Pathol 2006 Mar;15(1):24-29. "All cases with the MSI-high phenotype revealed CDH1 promoter hypermethylation. In MSI-low and MSS gastric cancers, this percentage was lower, reaching 71% and 41%, respectively. Moreover, the methylation status was correlated with the LOH phenotype. We detected CDH1 promoter hypermethylation in all EBV-positive gastric cancers (5/5), whereas methylation in the EBV-negative group occurred in 58% of cases."

Zazula - Diagn Mol Pathol 2006 abstract / PubMed

Risk prediction of gastric cancer by analysis of aberrant DNA methylation in non-neoplastic gastric epithelium. T Tahara, T Arisawa, T Shibata, FY Wang, M Nakamura, M Sakata, M Nagasaka, T Takagi, Y Kamiya, H Fujita, M Nakamura, S Hasegawa, M Iwata, K Takahama, M Watanabe, I Hirata, H Nakano. Digestion 2007;75(1):54-61. 43 cases with gastric cancer, versus 46 without (11 peptic ulcer, 35 gastritis). "In all 89 subjects, CpG island methylation was found in 25.8% for p14, 52.8% for p16, 1.1% for p21. Among non-cancer patients, the methylation frequency of the p14 gene was significantly higher in H. pylori-positive than in H. pylori-negative patients (38.5 vs. 10.0%, p = 0.03). The mean (+/- SD) methylation levels of the p16 gene in non-neoplastic gastric epithelium was significantly higher in gastric cancer cases both in all patients and in H. pylori-positive patients (0.45 +/- 0.31 vs. 0.20 +/- 0.17; p = 0.019, 0.45 +/- 0.31 vs. 0.20 +/- 0.17; p = 0.016, respectively). The methylation level of the p16 gene was also associated with the presence of intestinal-type gastric cancer (p = 0.017). The methylation level of the p16 gene was significantly higher in patients with intestinal metaplasia (IM) than those without (p = 0.04). Furthermore, the methylation level of the p16 gene was correlated with lower PG l/ll ratio (p = 0.04). The methylation of the p21gene was found in only 1 patient with gastric cancer."

Tahara - Digestion 2007 abstract / PubMed

Chromosomal instability in gastric mucosa-associated lymphoid tissue lymphomas: a fluorescent in situ hybridization study using a tissue microarray approach. B Bernasconi, E Karamitopoulou-Diamantis, L Tornillo, A Lugli, D Di Vizio, S Dirnhofer, S Wengmann, K Glatz-Krieger, F Fend, C Capella, L Insabato, LM Terracciano. Hum Pathol 2008 Apr;39(4):536-542. 115 cases of MALT lymphomas, 88 cases of diffuse large B-cell lymphomas (DLBCLs, 75 with an associated MALT lymphoma, so-called ex-MALT DLBCL, and 13 de novo), and 54 controls cases of Helicobacter pylori-associated chronic gastritis. "Trisomies 1, 3, 12, and 18 were detected in 3.3%, 44.4%, 12.3%, and 19.2% of MALT lymphomas and in 11.1%, 42.2%, 26.5%, and 22.0% of ex-MALT DLBCLs, respectively. In addition, we found gains of the X chromosome in 36.4% of MALT lymphomas, in 34.5% of ex-MALT DLBCLs, and in 36.4% of de novo DLBCLs. Structural and/or numeric abnormalities of the MALT1 gene were observed in 37.0% of MALT lymphomas and in 22.2% of ex-MALT DLBCLs. In de novo DLBCL, trisomies for chromosomes 3, 12, 18, and X were found in 42.9%, 10.0%, 11.1%, and 36.4%, respectively, whereas alterations of MALT1 (namely, translocations) were found in 20.0% of the cases. An unexpected high and previously unreported gain of chromosome X in gastric MALT lymphomas was found."

Bernasconi - Hum Pathol 2008 abstract / PubMed

Accumulation of aberrant CpG hypermethylation by Helicobacter pylori infection promotes development and progression of gastric MALT lymphoma. T Kondo, T Oka, H Sato, Y Shinnou, K Washio, M Takano, T Morito, K Takata, N Ohara, M Ouchida, K Shimizu, T Yoshino. Int J Oncol 2009 Sep;35(3):547-557. 21 specimens of MALT lymphoma, 5 specimens of MALT lymphoma with large cell component (high-grade MALT lymphoma), 15 specimens of diffuse large B-cell lymphoma (DLBCL), 8 specimens of complete remission of MALT lymphoma after eradication therapy, 5 specimens with no evidence of malignancy and PBMCs from 10 healthy donors. "The average number of methylated genes was significantly greater in gastric lymphomas as compared to normal controls (P<0.001). The CpG island methylator phenotype (CIMP) was observed in 93.3% (14/15) of DLBCLs, 100% (5/5) of high-grade MALT lymphomas and 61.9% (13/21) of MALT lymphomas; in contrast, CIMP was not found in the control group (0%). The average number of methylated genes and the CIMP incidence significantly increased with H. pylori infection. Furthermore, aberrant CpG methylation of specific genes, such as p16, MGMT and MINT31, was consistently associated with H. pylori infection."

Kondo / Int J Oncol 2009 abstract & link to full article

Helicobacter pylori and EBV in gastric carcinomas: methylation status and microsatellite instability. AC Ferrasi, NA Pinheiro, SH Rabenhorst, OL Caballero, MA Rodrigues, F de Carvalho, CV Leite, MV Ferreira, MA Barros, MI Pardini. World J Gastroenterol 2010 Jan 21;16(3):312-319. "The most frequent hypermethylated gene was COX-2 (63.5%) followed by DAPK (55.7%), CDH1 (51%), CDKN2A (36%) and hMLH1 (30.3%). Intestinal and diffuse adenocarcinomas showed different methylation profiles and there was an association between methylation of E-CDH1 and H. pylori-cagA(+) in the intestinal adenocarcinoma type. MSI was correlated with hMLH1 methylation. There was an inverse correlation between DAPK hypermethylation and MSI." 5 (9.3%) of specimens were EBV-positive. "The EBV+ cases were found to be associated with H. pylori, but only one was H. pylori-cagA+. Although the number of EBV+ cases was small, most of them displayed DAPK, COX2 and CDKN2A methylation."

Ferrasi - World J Gastroenterol 2010 full article / PubMed Central
Ferrasi / World J Gastroenterol 2010 full article

Translocation of Helicobacter pylori CagA into Human B lymphocytes, the origin of mucosa-associated lymphoid tissue lymphoma. WC Lin, HF Tsai, SH Kuo, MS Wu, CW Lin, PI Hsu, AL Cheng, PN Hsu. Cancer Res 2010 Jul 15;70(14):5740-5748. "In this work, we showed that CagA can be directly translocated into human B lymphoid cells by H. pylori, and the translocated CagA undergoes tyrosine phosphorylation and binds to intracellular SH-2. Meanwhile, the translocated CagA induces activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase in human B lymphoid cells, and upregulates the expressions of Bcl-2 and Bcl-X(L), which prevents apoptosis. These results provide the first direct evidence for the role of CagA as a bacterium-derived oncoprotein that acts in human B cells, and further implies that CagA is directly delivered into B cells by H. pylori and is associated with the development of MALT lymphomas."

Lin - Cancer Res 2010 abstract / PubMed

MGMT and MLH1 methylation in Helicobacter pylori-infected children and adults. MC Alvarez, JC Santos, N Maniezzo, MS Ladeira, AL da Silva, IC Scaletsky, J Pedrazzoli Jr, ML Ribeiro. World J Gastroenterol 2013 May 28;19(20):3043-3051. 50 H. pylori-infected children, 97 adults with chronic gastritis, and 92 adults with gastric cancer. "Methylation was not detected in the promoter regions of MLH1 and MGMT in gastric biopsy samples from children, regardless of H. pylori infection status. The MGMT promoter was methylated in 51% of chronic gastritis adult patients and was associated with H. pylori infection (P < 0.05); this region was methylated in 66% of gastric cancer patients, and the difference in the percentage of methylated samples between these patients and those from H. pylori-infected chronic gastritis patients was statistically significant (P < 0.05). MLH1 methylation frequencies among H. pylori-infected and non-infected chronic gastritis adult patients were 13% and 7%, respectively. We observed methylation of the MLH1 promoter (39%) and increased MSI levels (68%) in samples from gastric cancer patients in comparison to samples from H. pylori-infected adult chronic gastritis patients (P < 0.001 and P < 0.01, respectively)."

Alvarez - World J Gastroenterol 2013 full article / PubMed Central
Alvarez - World J Gastroenterol 2013 full article

Virulence of infecting Helicobacter pylori strains and intensity of mononuclear cell infiltration are associated with levels of DNA hypermethylation in gastric mucosae. BG Schneider, MB Piazuelo, LA Sicinschi, R Mera, DF Peng, JC Roa, J Romero-Gallo, AG Delgado, T de Sablet, LE Bravo, KT Wilson, W El-Rifai, RM Peek Jr, P Correa. Epigenetics 2013 Nov;8(11):1153-1161. "Among Colombian subjects at high and low risk for gastric cancer, biopsies from subjects from the high-risk region had significantly higher levels of methylation at these 5 genes than samples from subjects in the low risk region (p ≤ 0.003). When results were stratified by Helicobacter pylori infection status, infection with a cagA positive, vacA s1m1 strain was significantly associated with highest methylation levels, compared with other strains (p = 0.024 to 0.001). More severe gastric inflammation and more advanced precancerous lesions were also associated with higher levels of DNA methylation (p ≤ 0.001)... High levels of mononuclear cell infiltration were significantly related to methylation in PCDH10, RSPO2, and ZIC1 genes."

Schneider - Epigenetics 2013 abstract / PubMed

DNA methylation in gastric cancer, related to Helicobacter pylori and Epstein-Barr virus. K Matsusaka, S Funata, M Fukayama, A Kaneda. World J Gastroenterol 2014 Apr 14;20(14):3916-3926. Review.

Matsusaka - World J Gastroenterol 2014 full article / PubMed Central
Matsusaka / World J Gastroenterol 2014 full article

Helicobacter pylori-infection introduces DNA double-strand breaks in host cells. K Hanada, T Uchida, Y Tsukamoto, M Watada, N Yamaguchi, K Yamamoto, S Shiota, M Moriyama, DY Graham, Y Yamaoka. Infect Immun 2014 Oct;82(10):4182-4189. "We found upregulation of ATM expression in vivo in gastric mucosal cells infected with H. pylori. Using gastric cancer cell lines, we confirmed that the H. pylori-related ATM activation was due to the accumulation of DNA double-stranded breaks (DSBs). DSBs were observed following infection with both cag pathogenicity island (PAI)-positive and -negative strains, but the effect was more robust with cag PAI-positive strains. These results are consistent with the fact that both cag PAI-positive and -negative infections are associated with gastric carcinogenesis but the risk is higher in individuals infected with cag PAI-positive strains."

Hanada - Infect Immun 2014 abstract / PubMed

Helicobacter pylori Infection Causes Characteristic DNA Damage Patterns in Human Cells. M Koeppel, F Garcia-Alcalde, F Glowinski, P Schlaermann, TF Meyer. Cell Rep 2015 Jun;11(11):1703-1713. "Infection impaired several DNA repair factors, the extent of which depends on a functional cagPAI. This leads to accumulation of a unique DNA damage pattern, preferentially in transcribed regions and proximal to telomeres, in both gastric cell lines and primary gastric epithelial cells. The observed pattern correlates with focal amplifications in adenocarcinomas of the stomach and partly overlaps with known cancer genes."

Koeppel / Cell Rep 2015 full article

Epigenetic regulation of DNA repair machinery in Helicobacter pylori-induced gastric carcinogenesis. JC Santos, ML Ribeiro. World J Gastroenterol 2015 Aug 14;21(30):9021-9037. Review.

Santos & Ribeiro - World J Gastroenterol 2015 full article / PubMed Central
Santos & Ribeiro / World J Gastroenterol 2015 full article

HP strains have differing pathogenic effects

Mechanism of action of low recurrence of gastritis caused by Helicobacter pylori with the type II urease B gene. M Badruzzaman, H Matsui, SM Fazle Akbar, B Matsuura, M Onji. Helicobacter 2004 Apr;9(2):173-180. 45 patients with H. pylori. "The capacity of different strains of H. pylori to induce IL-8 mRNA and IL-8 from a human gastric cancer cell line and human peripheral blood mononuclear cells was evaluated... These results indicate that both the lower level of urease activity and the low IL-8-inducing capacity of type II H. pylori might underlie the lower recurrence rate of gastritis caused by type II H. pylori."

Badruzzaman - Helicobacter 2004 abstract / PubMed

Comparative genomics of Helicobacter pylori isolates recovered from ulcer disease patients in England. F Kauser, MA Hussain, I Ahmed, S Srinivas, SM Devi, AA Majeed, KR Rao, AA Khan, LA Sechi, N Ahmed. BMC Microbiology 2005 May 25;5(1):32. "The cag PAI is a major virulence determinant in H. pylori and strains lacking this island are akin to commensals rather than pathogens. Reports suggest that the presence of a complete set of genes within the cag PAI ensures a 5-fold increased severity of disease outcome than the intermediate PAI. We have earlier showed that a higher number of strains from Japan had an intact cag PAI, hence it may be thought as an important factor influencing the outcome of the infection as a higher rate of gastric cancers was observed in the Japanese patients... English strains mainly showed a higher number of the toxigenic s1 type of vacA allele... Although no association between iceA subtypes and clinical outcome has been reported, strains carrying iceA1 produce higher levels of IL-8 in the gastric mucosa and are more often associated with DU in the North America and Dutch people than strains carrying iceA2."

Kauser - BMC Microbiology 2005 full article / BMC
Kauser - BMC Microbiology 2005 full article / PubMed Central

Distinct diversity of vacA, cagA, and cagE genes of Helicobacter pylori associated with peptic ulcer in Japan. S Yamazaki, A Yamakawa, T Okuda, M Ohtani, H Suto, Y Ito, Y Yamazaki, Y Keida, H Higashi, M Hatakeyama, T Azuma. J Clin Microbiol 2005 Aug;43(8):3906-3916. "[T]he prevalence of infection with the Western group strain was significantly higher in patients with peptic ulcer (90.0%, 9/10) than in patients with chronic gastritis (22.7%, 5/22) (x2 = 12.64, P = 0.00057)."

Yamazaki / J Clin Microbiol 2005 abstract

Polymorphism in the CagA EPIYA Motif Impacts Development of Gastric Cancer. KR Jones, YM Joo, S Jang, YJ Yoo, HS Lee, IS Chung, CH Olsen, JM Whitmire, DS Merrell, JH Cha. J Clin Microbiol 2009 Apr;47(4):959-968. "We conducted a large-scale molecular epidemiologic analysis of South Korean strains, and herein report a statistical link between the East Asian CagA, EPIYA-ABD genotype and development of gastric cancer. Characterization of a subset of the Korean isolates showed that all strains from cancer patients expressed and delivered phosphorylateable CagA to host cells, whereas the presence of the cagA gene did not strictly correlate to expression and delivery of CagA in all non-cancer strains."

Jones - J Clin Microbiol 2009 abstract / PubMed

Gastric helicobacters in domestic animals and nonhuman primates and their significance for human health. F Haesebrouck, F Pasmans, B Flahou, K Chiers, M Baele, T Meyns, A Decostere, R Ducatelle. Clin Microbiol Rev 2009 Apr;22(2):202-223. "H. suis, which has been isolated from the stomachs of pigs, is the most prevalent gastric non-H. pylori Helicobacter species in humans. Other gastric non-H. pylori helicobacters colonizing the human stomach are H. felis, H. salomonis, H. bizzozeronii, and the still-uncultivable "Candidatus Helicobacter heilmannii." These microorganisms are often detected in the stomachs of dogs and cats."

Haesebrouck / Clin Microbiol Rev 2009 full article
Haesebrouck - Clin Microbiol Rev 2009 full article / PubMed Central

Differences in the genome content between H. pylori isolates from gastritis, duodenal ulcer or gastric cancer reveal novel disease associated genes. C Romo-González, NR Salama, J Burgeño-Ferreira, V Ponce-Castañeda, E Lazcano-Ponce, M Camorlinga-Ponce, J Torres. Infect Immun 2009 May;77(5):2201-2211. "The overall number of variable genes present in a given isolate was significantly lower for gastric cancer isolates. Thirty genes were significantly associated with nonatrophic gastritis, duodenal ulcer, or gastric cancer, 14 (46.6%) of which were within PZs [plasticity zones] and the cag PAI. Two genes (HP0674 and JHP0940) were absent in all gastric cancer isolates. Many of the disease-associated genes outside the PZs formed clusters, and some of these genes are regulated in response to acid or other environmental conditions."

Romo-González - Infect Immun 2009 abstract / PubMed

Diversity of VacA intermediate region among Helicobacter pylori strains from several regions of the world. C Chung, A Olivares, E Torres, O Yilmaz, H Cohen, G Perez-Perez. J Clin Microbiol 2010 Mar;48(3):690-696. "120 strains were analyzed: 30 Chinese isolates, 35 Turkish isolates, 30 Uruguayan isolates, and 25 African-American isolates... There was a strong correlation among CagA+, s1, and i1 in Chinese, African-American, and Uruguayan isolates, but less correlation among these markers in Turkish isolates. A new intermediate variant (i3) was identified in 25.7% of Turkish strains and 3.3% of the Chinese strains. In summary, the distribution of CagA+ and s1 correlated with the i1 in the three populations, except in the Turkish population, which showed a disproportionate representation of the i3 allele."

Chung - J Clin Microbiol 2010 abstract / PubMed

From array-based hybridization of Helicobacter pylori isolates to the complete genome sequence of an isolate associated with MALT lymphoma. JM Thiberge, C Boursaux-Eude, P Lehours, MA Dillies, S Creno, JY Coppée, Z Rouy, A Lajus, L Ma, C Burucoa, A Ruskoné-Foumestraux, A Courillon-Mallet, H De Reuse, IG Boneca, D Lamarque, F Mégraud, JC Delchier, C Médigue, C Bouchier, A Labigne, J Raymond. BMC Genomics 2010 Jun 10;11:368. "B38 has the smallest H. pylori genome described thus far (1,576,758 base pairs containing 1,528 CDSs); it contains the vacAs2m2 allele and lacks the genes encoding the major virulence factors (absence of cagPAI, babB, babC, sabB, and homB)."

Thiberge / BMC Genomics 2010 full article

CagA and VacA polymorphisms are associated with distinct pathological features in H. pylori-infected adults with peptic and non-peptic ulcer disease. EG Panayotopoulou, DN Sgouras, KS Papadakos, K Petraki, S Breurec, S Michopoulos, G Mantzaris, G Papatheodoridis, A Mentis, A Archimandritis. J Clin Microbiol 2010 Jun;48(6):2237-2239. "Polymorphic variability in H. pylori factors CagA and VacA contributes to bacterial virulence. Presence of one CagA-EPIYA-C site is an independent risk factor for gastroduodenal ulceration (OR: 4.647, 95% CI: 2.037-10.602), while VacAi1 allele for increased activity (OR: 5.310, 95% CI: 2.295-12.287) and severity of gastritis (OR: 3.862, 95% CI: 1.728-8.632)."

Panayotopoulou - J Clin Microbiol 2010 abstract / PubMed

Attenuated CagA oncoprotein in Helicobacter pylori from Amerindians in Peruvian Amazon. M Suzuki, K Kiga, D Kersulyte, J Cok, CC Hooper, H Mimuro, T Sanada, S Suzuki, M Oyama, H Kozuka-Hata, S Kamiya, QM Zou, RH Gilman, DE Berg, C Sasakawa. J Biol Chem 2011 Aug 26;286(34):29964-29972. "Amerindian CagA proteins induced less production of IL-8 and cancer-associated Mucin 2 than did those of prototype Western or East Asian strains, and behaved as dominant negative inhibitors of action of prototype CagA during mixed infection of Mongolian gerbils."

Suzuki - J Biol Chem 2011 abstract / PubMed

Characterization of Helicobacter pylori cagA and vacA genotypes among Alaskans and their correlation with clinical disease. K Miernyk, J Morris, D Bruden, B McMahon, D Hurlburt, F Sacco, A Parkinson, T Hennessy, M Bruce. J Clin Microbiol 2011 Sep;49(9):3114-3121. 515 H. pylori samples from 220 Native and 66 non-Native Alaskans. "After removing mixed infections (n=17), 83% of H. pylori had either the vacA s1m1 (120/269) or s2m2 (103/269) genotypes. 66% (68/103) of H. pylori with the vacA s2m2 genotype also contained the cagA gene. Infection with H. pylori having the cagA gene or vacA s1m1 genotype (compared with s1m2 and s2m2) was associated with a decreased risk of esophagitis (p=0.003 and 0.0003, respectively). Infection with H. pylori having vacA s1m1 genotype (compared with s1m2 and s2m2) was associated with an increased risk of PUD (p=0.003)."

Miernyk - J Clin Microbiol 2011 abstract / PubMed

Helicobacter pylori homB, but not cagA, is Associated with Gastric Cancer in Iran. A Talebi Bezmin Abadi, A Rafiei, A Ajami, V Hosseini, T Taghvai, KR Jones, DS Merrell. J Clin Microbiol 2011 Sep;49(9):3191-3197. 35 gastritis patients, 62 peptic ulcer patients, and 41 gastric cancer patients. "The frequency of homB was statistically higher in gastric cancer patients (78%) than in patients suffering from peptic ulcers (20%) or gastritis (43%, P<0.0001). The presence of homB was also associated with the presence of cagA (r=0.243)."

Talebi Bezmin Abadi - J Clin Microbiol 2011 abstract / PubMed

Association between Helicobacter pylori virulence factors and gastroduodenal diseases in Okinawa, southwestern island of Japan. O Matsunari, S Shiota, R Suzuki, M Watada, N Kinjo, K Murakami, T Fujioka, F Kinjo, Y Yamaoka. J Clin Microbiol 2012 Mar;50(3):876-883. "Overall, 86.4% of strains possessed cagA: 70.3 % were East-Asian-type and 16.0 % were Western-type. After adjustment by age and sex, the presence of East-Asian-type cagA/vacA s1m1 genotypes was significantly associated with gastric cancer compared with gastritis (Odds Ratio = 6.68, 95 % Confidence Interval = 1.73-25.8). The structure of Western-type CagA in Okinawa was different from that of typical Western-type CagA found in Western countries. Intriguingly, MLST analysis revealed that the majority of Western-type cagA strains formed individual clusters but not hpEurope. Overall, low prevalence of gastric cancer in Okinawa may result from the high prevalence of non East-Asian-type cagA strains. The origin of Western-type cagA strains in Okinawa can be different from those of Western countries."

Matsunari - J Clin Microbiol 2012 full article / PubMed Central
Matsunari / J Clin Microbiol 2012 full article

Age of the Association between Helicobacter pylori and Man. Y Moodley, B Linz, RP Bond, M Nieuwoudt, H Soodyall, CM Schlebusch, S Bernhöft, J Hale, S Suerbaum, L Mugisha, SW van der Merwe, M Achtman. PLoS Pathogens 2012;8(5): e1002693. "Three distinct H. pylori populations are native to Africa: hpNEAfrica in Afro-Asiatic and Nilo-Saharan speakers, hpAfrica1 in Niger-Congo speakers and hpAfrica2 in South Africa. Rather than representing a sustained co-evolution over millions of years, we find that the coalescent for all H. pylori plus its closest relative H. acinonychis dates to 88–116 kya... We also find evidence for a second Out of Africa migration in the last 52,000 years, because hpEurope is a hybrid population between hpAsia2 and hpNEAfrica, the latter of which arose in northeast Africa 36–52 kya, after the Out of Africa migrations around 60 kya."

Moodley / PLoS Pathogens 2012 full article

Phylogeographic Origin of Helicobacter pylori Determines Host-Adaptive Responses upon Coculture with Gastric Epithelial Cells. A Sheh, R Chaturvedi, DS Merrell, P Correa, KT Wilson, JG Fox. Infect Immun 2013 Jul;81(7):2468-2477. "To investigate the role of bacterial factors in H. pylori pathogenesis, global gene expression of six H. pylori isolates was analyzed during coculture with gastric epithelial cells. Clustering analysis of six Colombian clinical isolates from a region with low gastric cancer risk and a region with high gastric cancer risk segregated strains based on their phylogeographic origin. One hundred forty-six genes had increased expression in European strains, while 350 genes had increased expression in African strains. Differential expression was observed in genes associated with motility, pathogenicity, and other adaptations to the host environment. European strains had greater expression of the virulence factors cagA, vacA, and babB and were associated with increased gastric histologic lesions in patients. In AGS cells, European strains promoted significantly higher interleukin-8 (IL-8) expression than did African strains. African strains significantly induced apoptosis, whereas only one European strain significantly induced apoptosis."

Sheh - Infect Immun 2013 abstract / PubMed

Reduced genome size of Helicobacter pylori originating from East Asia. QJ Dong, LL Wang, ZB Tian, XJ Yu, SJ Jia, SY Xuan. World J Gastroenterol 2014 May 21;20(19):5666-5671. "Comparative analysis of strains from different H. pylori populations revealed that the genome size of strains from East Asia decreased to 1.60 Mbp, which is significantly smaller than that from Europe or Africa. In parallel with the genome reduction, the number of protein coding genes was decreased, and the guanine-cytosine content was lowered to 38.9%."

Dong - World J Gastroenterol 2014 full article / PubMed Central
Dong / World J Gastroenterol 2014 full article

Differential Mechanisms for SHP2 Binding and Activation Are Exploited by Geographically Distinct Helicobacter pylori CagA Oncoproteins. T Hayashi, M Senda, N Suzuki, H Nishikawa, C Ben, C Tang, L Nagase, K Inoue, T Senda, M Hatakeyama. Cell Rep 2017 Sep 19;20(12):2876-2890. "Here we show that, upon tyrosine phosphorylation, the East Asian CagA-specific EPIYA-D segment binds to the N-SH2 domain of pro-oncogenic SHP2 phosphatase two orders of magnitude greater than Western CagA-specific EPIYA-C."

Hayashi - Cell Rep 2017 abstract / PubMed

A 500-year tale of co-evolution, adaptation, and virulence: Helicobacter pylori in the Americas. ZY Muñoz-Ramirez, B Pascoe, A Mendez-Tenorio, E Mourkas, S Sandoval-Motta, G Perez-Perez, DR Morgan, RL Dominguez, D Ortiz-Princz, ME Cavazza, G Rocha, DMM Queiroz, M Catalano, GZ Palma, CG Goldman, A Venegas, T Alarcon, M Oleastro, FF Vale, KJ Goodman, RC Torres, E Berthenet, MD Hitchings, MJ Blaser, SK Sheppard, K Thorell, J Torres. ISME J 2020 Sep 2 Epub ahead of print.

Muñoz-Ramirez - ISME J 2020 abstract / PubMed
Muñoz-Ramirez / ISME J 2020 full article

Helicobacter pylori and social class

Epidemiology of, and risk factors for, Helicobacter pylori infection among 3194 asymptomatic subjects in 17 populations. The EUROGAST Study Group. D Forman for the EUROGAST Study Group. Gut 1993 Dec;34(12):1672-1676. "The cross sectional study describes the prevalence of infection with Helicobacter pylori as determined by a serodiagnostic assay in over 3000 asymptomatic subjects, in two age groups 25-34 years and 55-64 years, from 17 geographically defined populations in Europe, North Africa, North America, and Japan, using a common protocol for blood collection and serological testing. In all populations combined, the prevalence of infection was higher in the older age group (62.4%) than in the younger age group (34.9%). There was no difference in prevalence of infection between men and women. Subjects with higher education had considerably lower levels of infection (34.1%) compared with subjects with education up to secondary level (46.9%) or those with primary education only (61.6%). This trend was confined to the older of the two age groups. In contrast a trend of increasing prevalence of infection with increasing body mass index was confined to the younger of the two age groups. There was no effect of smoking or alcohol consumption on the prevalence of infection after adjusting for the other risk factors. There was considerable variation in the prevalence of infection between the 17 populations but, within populations, low education standard was consistently and positively associated with the prevalence of infection."

Forman - Gut 1993 full article / PubMed Central

Importance of childhood socioeconomic status on the current prevalence of Helicobacter pylori infection. HM Malaty, DY Graham. Gut 1994 Jun;35(6):742-745. Anti-H pylori IgG in 150 healthy black and Hispanic people aged between 19 and 49 years. "The H pylori prevalence was inversely related to the social class during childhood. It was 85% for class I, 52% for combined classes II and III, and 11% for classes IV and V combined. The inverse correlation remained after adjustments were made for the present social class and age. H pylori infection was also related to crowded living conditions (odds ratio 4.5: 95% confidence interval 3.3, 5.7) for those who had had the most crowded living conditions during childhood)."

Malaty - Gut 1994 full article / PubMed Central

Relation of adult lifestyle and socioeconomic factors to the prevalence of Helicobacter pylori infection. P Moayyedi, ATR Axon, R Feltbower, S Duffett, W Crocombe, D Braunholtz, IDG Richards, AC Dowell, D Forman, for the Leeds HELP Study Group. International Journal of Epidemiology 2002;31(3):624-631. "The prevalence of H. pylori infection had a statistically significant association with present social class in an unadjusted analysis. Present social class is correlated with childhood social class (Pearson's correlation coefficient = 0.22, P < 0.0001) and the unadjusted results of present social class could be confounded by childhood socioeconomic conditions. However, the prevalence of H. pylori infection increased with decreasing social class even within levels of childhood social class." "The proportion of subjects infected increased with increasing numbers of cigarettes smoked (Table 4) but when adjusted for childhood and adult socioeconomic status the 95% CI for the OR did not include unity only in those that smoked >35 cigarettes/day."

Moayyedi / Int J Epidemiol 2002 full article

The Prevalence of Helicobacter pylori Remains High in African American and Hispanic Veterans. T Nguyen, D Ramsey, D Graham, Y Shaib, S Shiota, M Velez, R Cole, B Anand, M Vela, HB El-Serag. Helicobacter 2015 Aug;20(4):305-315. 1200 veterans age 40-80. "H. pylori was positive in 347 (28.9%) and was highest among black males aged 50-59 (53.3%; 44.0-62.4%), followed by Hispanic males aged 60-69 (48.1%; 34.2-62.2%), and lowest in non-Hispanic white males aged 40-49 (8.2%; 2.7-20.5%)... Irrespective of age group, patients born during 1960-1969 had a lower risk of H. pylori (adjusted OR, 0.45; 95% CI, 0.22-0.96) compared to those born in 1930-1939. Those with some college education were less likely to have H. pylori compared to those with no college education (adjusted OR 0.51; 95% CI, 0.37-0.69)."

Nguyen - Helicobacter 2015 abstract / PubMed


The Helicobacter Pylori Foundation

The Helicobacter Pylori Foundation

"A study of 90 pregnant women in Puerto Rico found that those who experienced severe nausea and vomiting were 10 times more likely to have the Helicobacter pylori bacterium in their stomachs than women who did not feel sick... 'We found H pylori in 83% of the women with morning sickness, but only 7% of the controls were positive," said Dr Nilda Santiago, who conducted the study with colleagues at the Ponce School of Medicine in Puerto Rico. (Morning sickness linked to ulcer bug. BBC News, Oct. 21, 2000.)

Morning Sickness linked to ulcer bug, Oct. 21, 2000 / BBC News

Helicobacter pylori is not the cause of sudden infant death syndrome (SIDS). GY Ho, HM Windsor, B Snowball, BJ Marshall. Am J Gastroenterol 2001 Dec;96(12):3288-3294. HP in 53% (9/17) SIDS samples vs. 57% (4/7) non-SIDS samples.

Ho - Am J Gastroenterol 2001 abstract / PubMed


A Hall of Fame and Shame of Quotes Concerning Helicobacter pylori

"Since at least 1906, doctors had reported seeing curved bacteria in the stomach of patients who died with ulcers but less often in people without them. Still, doctors paid little attention to the observation in the belief that bacteria could not thrive in the acid-filled stomach. Doctors assumed that the bacteria appeared after death... Dr. Freedberg examined pieces of stomach removed during operations for ulcers and other ailments. Using a silver chemical stain, he identified the bacteria in more than a third of ulcer patients, but his colleagues’ efforts to culture them failed. In a 2005 interview with The New York Times, Dr. Freedberg said he was “very upset” when others did not confirm the findings he published because it implied that his work was wrong. Even his boss, Dr. Herrman Blumgart, suggested that he had erred and discouraged him from continuing the research. Other doctors tried and failed to find the evidence until 1983, when two Australians, Dr. Barry J. Marshall and Dr. J. Robin Warren, identified the bacteria, now known as Helicobacter pylori, among ulcer patients. In 2005, the two Australians received Nobel Prizes in medicine for that work. The two later met. In an interview in The Times in 2005, Dr. Marshall said that if Dr. Freedberg had been able to pursue his ulcer research, researchers would have developed treatments for ulcers decades earlier. 'They would have won the Nobel Prize about 1951, as I was getting born,' Dr. Marshall said." (A. Stone Freedberg, Pioneer in Study of Ulcers, Dies at 101. By Lawrence K. Altman. New York Times, Aug. 23, 2009.)

A. Stone Freedberg, Pioneer in Study of Ulcers, Dies at 101 / New York Times

Ulcers were proposed to be an infectious disease in 1914: "Two important announcements were made to the members of the International Surgical Association at yesterday morning's session of the fourth congress, which is meeting at the Hotel Astor, during a discussion of ulcers of the stomach and duodenum. The first tended to show that these ulcers, which are comparatively common in persons of middle age, belong to the category of infectious diseases... Dr. Arthur D. Bevan, Professor of Surgery at the University of Chicago, made the announcement relative to the origin of gastric and duodenal ulcers. He said that his colleague, Dr. Edward C. Rosenau, who occupies the Chair of Pathology at the Chicago University and has a wide reputation as a research worker, has demonstrated that these ulcers could be caused by the injection of bacteria taken from other ulcers. The injections were made intravenously, that is, directly into the blood, whereupon the disease made its appearance at the usual sites of ulceration, both in the stomach and intestines of animals... Dr. H. Hartmann and Dr. P. Lecène of Paris presented a joint paper in which they asserted that duodenal ulcer was more frequent than supposed several years ago. In their opinion, however, its frequency has been exaggerated. They have found one ulcer of the duodenum to eight or ten of the stomach. They also found that about one-fifth of these cases of the callous ulcers of the stomach degenerate into cancer." (Say Gastric Ulcers May Be Infectious. New York Times, Apr. 15, 1914.) In 1916, Dr. Francis Carter Wood, the president of the American Society for the Control of Cancer and later one of the original members of the National Advisory Cancer Council of the National Cancer Institute, proclaimed that 'cancer was not a germ disease nor in any way allied to germ diseases.'

See how the quacks continue to spew the discredited lie that smoking causes ulcers! "There are other causes of peptic ulcer that are unrelated to H. pylori infection, but these are less common. In particular, the chronic use of non steroidal antiinflammatory drugs (NSAIDs) and cigarette smoking can be causes of both ulcer formation and failure of treatment." (What causes ulcers. By Melissa Stoppler, Barbara K. Hecht. MedicineNet.com Feb. 10, 2005.) Oh, and by the way, in light of the billions of dollars of "damages" that US corporations have shoveled out to the health fascist parasites for their pretended crimes against public health - HOW MUCH MONEY HAVE THE HEALTH FASCIST LICE BEEN FORCED TO PAY OUT FOR THEIR DECADES-LONG SUPPRESSION OF THE TRUTH THAT HELICOBACTER PYLORI IS THE REAL CAUSE OF ULCERS? They have not paid one cent, and there's not even the rumor of a lawsuit; nor have they even been subjected to a single word of reproach from their fawning mass media toadies.

What Causes Ulcers / Medicine.Net

"It is amazing that this major problem of mankind was largely defined and solved by clinical gastroenterologists essentially without support from the biomedical research establishment... It is time that our biomedical research establishment tempers its traditional focus on molecular mechanisms of disease and addresses questions that appear 'clinical' and 'should be funded by drug companies.'" And, "...many of these same skeptics helped perform the needed scientific studies (unfunded by traditional sources) to validate the fact that peptic ulcers are one manifestation of an infectious disease... We can no longer ignore the evidence that peptic ulcers are caused by H pylori and that they can be cured." Peura DA, Graham DY. Editorial. Helicobacter pylori: Consensus Reached: Peptic ulcer is on the way to becoming an historic disease. Am J Gastroenterol 1994 Aug;89(8):1137. National Institutes of Health, Helicobacter pylori Consensus Development Conference, Feb. 7-9, 1994.

Let us remember: While the clinical gastroenterologists were investigating and solving this problem, all by themselves, the health establishment was pouring money into studies on acid secretion, gastrin, catecholamines, epidermal growth factors, prostaglandins, bile acids, pepsinogen, thromboxane, gastric emptying time, and everything else they could think of, for the sole purpose of trying to find some mechanism whereby they could claim that smoking causes ulcers. (They had, of course, long before declared that smoking causes ulcers without having such a mechanism; they merely bluffed the public that they did: McCarthy DM. Editorial re Sontag: "Smoking and Ulcers -- Time to Quit." New England Journal of Medicine 1984 Sep. 13;311(11):726-727).

McCarthy - NEJM 1984 / UCSF (pdf, 3 pp)

If it were up to the establishment, ulcers would still be a lifelong affliction, treated with H2 blockers and proton pump inhibitors and drivelous rhetoric about smoking, diet and stress, while they pat themselves on the back for the imagined sophistication of their intervention in the molecular bases of the disease.

"The natural history of gastric and duodenal ulcers is to recur at a rate of 50 to 90% in the year following the ulcer healing... Although all the answers are not yet in, at least a hundred clinical trials have now been completed and the results have been consistent. Cure of H. pylori infection results in virtual elimination of ulcer recurrence... Factors previously used to predict ulcer recurrence such as smoking... are no longer important. The new dictum is 'no H pylori, no ulcer.'" "The discovery that H pylori was a cause of gastritis elicited major international interest and clinical studies have been done in all parts of the world; probably the fewest number of investigations have come from the United States." Graham DY. Review. Benefits from elimination of Helicobacter pylori infection include major reduction in the incidence of peptic ulcer disease, gastric cancer, and primary gastric lymphoma. Prev Med 1994 Sep;23(5):712-716).

Helicobacter pylori also causes stomach cancer. Interestingly, Mr. Mary Lasker (Albert) died of stomach cancer in 1952. This letter which appeared in The Atlantic in response to Judith Hooper's "A New Germ Theory" suggests that perhaps his life, and certainly the lives of a multitude of others, could have been saved, if Germ Theory had prevailed over the dogma the Laskers imposed over the National Institutes of Health by means of their wealth and political connections: "In 1946 I was a first-year medical resident at the New York Hospital when the senior attending physician, Constance Guion, called to tell me that she was admitting a patient who was suffering with an acute, painful peptic stomach ulcer. Dr. Guion instructed me to start the patient on 'that new antibiotic, aureomycin,' the forerunner of the modern tetracycline family of antibiotics. 'But Dr. Guion,' I expostulated, 'I thought you said she had an ulcer. Why would you want to treat her with an antibiotic?' Dr. Guion replied, 'The latest research over at Mt. Sinai shows that 'peptic' ulcers are actually caused by germs, now do as I say and give her the aureomycin.' The patient went home three days later free of symptoms." (Paul Fremont Smith, Physician in Chief, Emeritus, New England Baptist Hospital, Boston, Massachusetts.)

Let this put to rest the faith of those naive and trusting souls who cling to the belief that, since the Laskers and their cronies themselves suffered and died from the diseases which they refused to consider might be caused by infection, they must have acted in good faith, and that their professed desires to find cures were sincere. In fact, the grip of their irrational ideology of infection-denialism is stronger than reason, or even their own instinct of self-preservation. They are the pure essence of evil, and have caused enormous harm not only to themselves but to society as well.

Letters re "A New Germ Theory"

"Dr. [Harvey] Cushing established definitely that the cause of stomach ulcers is due to disturbances in that portion of the brain which governs the automatic processes of living. Disturbances are set up in the diencephalon, a part of the brain which is the seat of the primitive emotions and which controls the digestive processes. He announced this discovery at Toronto in 1931 in a lecture at the University of Toronto. In the course of his long surgical career at Boston, Dr. Cushing has operated upon a number of Berkshire patients." (Special Honor for Dr. Cushing. North Adams Transcript, May 8, 1935.)

"Many doctors continue to claim that these bacteria are irrelevant, even in duodenal and gastric ulcer, blithely ignoring the hundreds of papers (990 during 1992 alone) indicating its importance." Goodwin CS. Comment. Gastric cancer and Helicobacter pylori: the whispering killer? Lancet 1993 Aug 28;342(8870):507-508).

(Christensen AH, Gjirup T, Andersen IB, Matzen P. Opinions in Denmark on the causes of peptic ulcer disease. A survey among Danish physicians and patients. Scan J Gastroenterol 1994 Apr;29(4):305-308).

  • 97% of doctors versus 41% of patients believed "side effects of medicine" cause ulcers
  • 95% of doctors versus 44% of patients believed smoking causes ulcers.
  • 82% of doctors versus 75% of patients believed "psychologic factors" cause ulcers.
  • 39% of doctors verus 3% of patients believed infections cause ulcers.
  • 3% of doctors versus 8% of patients believed "supernatural factors" cause ulcers.
  • Perhaps this will help put the anti-smokers' claim that "the tobacco companies lied about the health risks of smoking" into a radically different perspective.

    Jonathan Samet committed perjury at the Minnesota tobacco trial!

    This is the sworn testimony of Dr. Jonathan Samet, star witness for the anti-smoking side in Minnesota's lawsuit against the tobacco industry, on February 12, 1998, concerning the supposed causal role of smoking in peptic ulcer disease, and its pretended costs to the state and to Blue Cross Blue Shield. Note that Samet is now (2012) the head of the FDA Committee on Tobacco.

    BY MR. HAMLIN [attorney for the State of Minnesota and Blue Cross Blue Shield]:

    Q. Doctor, I want to address now the last disease, which is peptic ulcer. What is peptic ulcer?

    A. Peptic ulcer is -- refers to the erosions or ulcers that occur usually at the end of the stomach where the stomach empties out into the duodenum, and then in the first part of the duodenum, that's the very first part of the small intestine.

    Q. What are the symptoms?

    A. The symptoms may include pain when the stomach is empty. People may present with bleeding if the ulcer becomes deep enough and erodes into a blood vessel. There may actually be severe bleeding. People may have discomfort on -- on eating, weight loss, among other symptoms.

    Q. And what treatments are used to treat peptic ulcer?

    A. Typically, first the diagnosis needs to be made by usually at this point looking into the stomach with a tube very much like the bronchoscope, except for looking into the esophagus and stomach and duodenum. The basic treatment is medication, and for those individuals who have bleeding, surgery may be necessary to actually identify the bleeding point and sew it over so that the bleeding can be stopped.

    Q. Based on your clinical experience, how much do these treatments cost?

    A. Well it really would vary depending on need for medication alone up to emergency surgery.

    Q. Now did you do an investigation of the published literature regarding smoking and peptic ulcer?

    A. Yes.

    Q. You did that in connection with your investigation in this case?

    A. Yes.

    Q. And did you review reports of the Surgeon General?

    A. Yes.

    Q. Has the Surgeon General concluded that smoking is a cause of peptic ulcer?

    A. Yes.

    Q. And were they met?

    A. Yes.

    Q. And are those studies in the database that you've completed in this case?

    A. Yes.

    Q. Doctor, based on your education, training, your expertise in the science of smoking and health, and your review of the literature on the science of smoking and health, do you have an opinion regarding whether smoking is a cause of peptic ulcer?

    A. Yes.

    Q. What is that opinion?

    A. That smoking is a cause of peptic ulcer.

    In fact, Dr. Samet's obsolete notions of the diagnosis and treatment of peptic ulcer are in flagrant disregard of the directive to physicians issued several years earlier in the Consensus Statement of the National Institutes of Health. A patient under his care who suffered the dire consequences he related would be fully entitled to sue the son-of-a-bitch for malpractice, and to take his arm and his leg and every other appendage for damages. In fact, for a patient with the symptoms described, the first step would be an inexpensive blood test for Helicobacter pylori, costing about twenty five dollars, and not an endoscopy costing from several hundred to several thousand dollars, depending on how it's inflated. And if the patient is positive for Helicobacter, as nearly all are except those cases caused exclusively by the use of non-steroidal anti-inflammatory medications for other ailments such as arthritis, the treatment would entail a couple hunded bucks for two weeks of antibiotics, and not, as in Jonathan Samet's brand of (mis)treatment, hundreds of dollars a month for proton pump inhibitors for the rest of the patient's life.

    Furthermore, the Surgeon General's pretense that "smoking causes ulcers" is founded on defective studies which falsely pretend that, because ulcers were found to be more common in smokers, this constitutes proof that smoking causes them. In fact, the state-of-the-art opinion is that the vast majority of infections by Helicobacter pylori occur very early in life, long before people become smokers. Therefore, smoking cannot even play the role speculated by the anti-smoking pseudo-scientists of increasing peoples' susceptibility to infection. The reason that ulcers are more common in smokers is that Helicobacter pylori infection is associated with lower socioeconomic origins, and smokers are more likely to have such origins than nonsmokers.

    To further the outrage, at no time during this kangaroo trial was Samet's testimony challenged by the attorney for the tobacco industy, Mr. Garnick. Even the lowliest public defender could have done a better job than Garnick did. Nor did the tobacco lawyers ever challenge Samet's similar perjury regarding other so-called smoking-related diseases" which are actually caused by infection. Plus, the tobacco industry settled rather than let the case go to the jury, even though it was believed by many observers that the tobacco industry would win. This is sufficient proof to any intelligent person that the tobacco industry lawyers threw the fight to the anti-smokers on purpose -- at a cost of $368 billion to the smokers of America.

    Shame on the Harvard School of Public Health!

    On the website of the Harvard School of Public Health, which purports to give legitimate medical advise about how to avoid cancer, there is no mention of Helicobacter pylori as a cause of stomach cancer (never mind Epstein-Barr virus)! As of May 18, 2002, these quacks maintain that salt, blood type, family history, and salt are significant risks for stomach cancer. (Link died http://www.yourcancerrisk.harvard.edu/hccpquiz.pl?func=show&quiz=stomach&page=risk_list.) As of May 16, 2013, they admit that H. pylori is a cause of stomach cancer, but of too low a percentage ("about half"). And they still blame smoking and ignore EBV.

    Fact Sheet - Stomach Cancer / Harvard School of Public Health

    The Harvard School of Public Health commits scientific fraud by using phony "smoking risks" based on lifestyle questionnaire studies to manufacture a bogus estimate of gastric cancer incidence. They're also guilty of ignoring the fact that rates of gastric cancer declined while smoking increased. Effects of Helicobacter pylori infection and smoking on gastric cancer incidence in China: a population-level analysis of trends and projections. JM Yeh, SJ Goldie, KM Kuntz, M Ezzati. Cancer Causes Control 2009 Dec;20(10):2021-2029.

    Yeh - Cancer Causes Control 2009 abstract / PubMed

    Shame on the International Journal of Epidemiology

    Prospective study on the relation of cigarette smoking with cancer of the liver and stomach in an endemic region. T Mizoue, N Tokui, K Nishisaka, S Nishisaka, I Ogimoto, M Ikeda, T Yoshimura. Int J Epidemiol 2000 Apr;29(2):232-237. This study considered no biomarkers whatsoever for either hepatitis viruses or stomach infections, and its mere publication reflects the dishonesty of the editors of the journal, who in 2006 include George Davey-Smith, co-author of a paper demonstrating how confounding occurs in exactly such circumstances.

    Mizoue / Int J Epidemiol 2000 full article
    Editorial Board, Int J Epidemiol / Oxford Journals

    Alton Ochsner

    Alton Ochsner recites the standard lies that reigned for decades, falsely blaming ulcers on "excess acid" supposedly produced by a faulty lifestyle. (Lung Cancer and Its Relationship to Smoking, by Alton Ochsner. American Temperance Society, 1951, pp. 4-6.)

    Ochsner, 1951 / UCSF (pdf, 16 pp)

    ABC News, 1967

    Peter Jennings and the News. WMAL TV, Washington DC, ABC Network. May 1, 1967 6:30 P.M. TOBACCO INDUSTRY REJOINDER FRAN REYNOLDS (SUBSTITUTING) "Another report today that smoking is bad for your health. The Public Health Service has completed a new study, cigarette smokers, according to this report, are more prone to develope chronic illness such as heart disease, ulsers [sic] and emphysema, but the tobacco industry has come right back with a rejoinder that there is no proof its the smoking that actually causes the diseases."

    Peter Jennings and the News, May 1, 1967 / UCSF (pdf, 1 p)

    See also:

    Epstein-Barr Virus Causes Lymphomas
    Epstein-Barr Virus Causes Gastric Carcinoma
    H. pylori is Implicated in Pancreatic Cancer
    H. pylori is Implicated in Colorectal Adenomas
    Confounding By Infection

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    cast 09-17-20