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Helicobacter pylori and gastric cancer

14th World Congress on Gastrointestinal Cancer. Helicobacter pylori and gastric cancer. Thomas Seufferlein Department of Internal Medicine I Ulm University, Germany. Helicobacter pylori. Spiral shaped, flagellated microaerophilic Gram negative bacteria

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Helicobacter pylori and gastric cancer

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  1. 14th World Congress on Gastrointestinal Cancer Helicobacter pylori and gastric cancer Thomas Seufferlein Department of Internal Medicine I Ulm University, Germany

  2. Helicobacter pylori • Spiral shaped, flagellated microaerophilic Gram negative bacteria • Colonizes the gastric mucosa in more than 50% of the human population • Transmitted within the family in childhood, likely by fecal-oral transmission

  3. Helicobacter pylori - prevalence • world wide 7% - 87% • highest in developing countries • Europe up to 30% (depending on immigration background) MPI Infektionsbiologie Aachen

  4. H. pylori • Present in oral cavity -> reinfection of gastric mucosa? • Majority of infected population remains asymptomatic In some cases development of • chronic gastritis • peptic ulcer • gastric mucosa associated lymphoid tissue (MALT) lymphoma • associated with increased risk of cancer

  5. H. Pylori is a risk factor for gastric cancer • H. pylori is recognized as a class I carcinogen since 1994

  6. Helicobacter and gastric cancer • Maastricht IV: • H. pylori infection is the most consistent factor for gastric cancer • Increase in gastric cancer risk: ≥ 20 fold when • lesion is gastric in nature • originates below the cardia Ekstrom Gastroenterology 2001; Brenner, Am J Epidemiol 2004; GUT, JUNE 2012

  7. Pathological outcome of H pylori: H. pylori and the mucosal immune system • H pylori specific Treg in gastric mucosa • suppress mucosal immune responses • contribute to infection persistence • modulate H pylori-induced gastritis • immune response to H pylori infection and pathological oucome might be different according to the age of infection (children – adult) • role of CagA: CagA-positive, but not CagA-negative bacteria promote CagA dependent T-cell priming Szczepanik, JPP 2008 Lundgren Infect Immun 2005; Freire de Melo, Microbes Infect 2012; Kido, BBRC 2011

  8. H. pylori and mutagenesis • H. pylori has direct mutagenic effects in mice • F (duration of infection, gender) • Causes genetic instability of chromosmal and mitochondrial DNA • Causes preneoplastic lesions and cancer in experimental models Touati, Gastroenterology 2003; Helicobacter 2006; Sheh, PNAS 2010; Machade, BBA 2010; CCR 2009

  9. Pathological outcome of H pylori • Pathological outcome of H pylori infection depends on • bacterial action • host response • susceptibility • gastric cancer susceptibility <-> inflammation-related gene polymorphisms • Allele 2 of IL1R antagonist <-> gastric cancer • > causes high circulating IL-1Ra and IL-1b levels • > severe and prolonged inflammatory response Persson, Am J Epidemiol 2011

  10. H. pylori pathophysiology • Types of pathogen-host interaction • Type 1: • H pylori escapes immune system and gets nutrients from the host tissue • Asymptomatic gastritis • Type 2: • Proinflammatory genetic backgound plus H pylori strains with dangerous factors -> • Immune response initiates • chronic inflammation • hypochlorhydria • malignancy

  11. Bacterial action: H- pylori strains • Type I: • Cag PAI complex • in their genome • Express CagA protein • More toxic s1 allele of VacA • Most severe infections • Type II: • Cag negative • less toxic s2m2 allele of VacA • Mainly asymptomatic gastritis

  12. H pylori – bacterial action • cagPAI complex: encodes T4SS – type IV secretion system • Molecular syringe that translocates CagA into eukaryotic cells • Phosphorylation and nuclear translocation of CagA • IL-8 production • NF-kB production • remodeling of cytoskeleton by epithelial cells Onishi PNAS 2008

  13. CagA– pathogenetic mechanisms • CagA induces p53 degradation via binding to and inactivation of ASPP2 (activates p53) -> inhibition of apoptosis Buti, PNAS 2011; Ruggiero, Co infectious diseases 2012;

  14. CagA is a bacterial oncogene • CagA attaches H. pylori near the intracellular junctional complex and alters the differentiation and behaviour of polarized cells • Intracellular Cag contributes to EMT • CagA-expressing transgenic mice: • gastric epithelial hyperplasia • gastric adenocarcinomas in the absence of gastritis Ohnishi, PNAS 2008

  15. 1526 Japanese with • duodenal ulcers • gastric ulcers • gastric hyperplasia, • nonulcer dyspepsia • mean follow up 7.8 Jahre • gastric cancer • development • 2.9% in infected • (n =36) • 0% in not infected • patients Uemura, NEJM 2001

  16. H. pylori infection associated with • development of intestinal type and • diffuse-type gastric cancer. Uemura, NEJM 2001

  17. Helicobacter and gastric cancer • High risk profile for gastric cancer • active corpus gastritis (34 x risk) • gastric atrophy und IM (5-6 x risk) • gastric hypochlorhydria • lack of ascorbic acid (scavenges carcinogenic N-nitrosamines and ROS) • gastric ulcer Ekstrom, Gastroenterology 2001 Uemura, NEJM 2001; Sobala, Carcinogenesis 1991

  18. What can be achieved by H pylori eradication? • H pylori eradication • abolishes the inflammatory response • slows or may arrest the progression of atrophy • may even reverse atrophy to some degree • Abolishing the active inflammatory process with • infiltration of polymorphonuclear cells takes 4 weeks • Chronic inflammation with lymphocyte infiltration • persists up to 1 year. • Metaanalysis: • corpus atrophy potentially reversible • antral atrophy most likely irreversible • IM is irreversible Tulassy, Scand J Gastroenterol 2010; Rokkas, Helicobacter, 2007

  19. Eradication of H pylori and prevention of gastric cancer • Cohort studies show positive effect of H pylori eradication on prevention of gastric cancer • RCTs show benefit of H pylori eradication • on preneoplastic conditions • in primary and secondary gastric cancer prevention • Multicenter prospective cohort Yamagata/Japan (high incidence region) • 2000-2007, mean f-u 5.6 y; n = 4133 • Mean age: 53 years • Patients choice to receive eradication therapy (3090) or only antacid therapy (rest) • Annual endoscopy • Eradication rate: 80% • Incidence of gastric cancer decreased by 40% in the eradication group Correa, JNCI 2000; Leung, GUT 2004; Mera, GUT 2005, Fukase Lancet 2008; Wong, JAMA 204 Take, AJG 2005; Yanaoka, Int J Cancer 2009; Uemra, NEJM 2001; Kosunen, Int J Cancer 2011, Ogura, J Cli Gastroenterol 2008; Fuccio, Annals Internal Medicine 2009; Mabe, WJG 2009

  20. When should H pylori eradication best be performed? Intervention studies in • Columbia • China • Japan -> H.p. eradication is the most effective strategy to prevent gastric cancer -> particularly effctive before IM or gastric atrophy are present Mera, GUT, 2005; You JNCI 2006; Take Am J Gastroenterol 2005

  21. When should H pylori eradication be performed? • Pooled analysis 6 trials (mostly Asia), •  7000 participants • f-u 4-10 years: • RR for gastric cancer after H pylori eradication: 0.65 (0.43-0.98) • Significant reduction in gastric cancer incidence only when serum pepsinogen levels normal • Cancers originating after eradication related to extensive atrophic gastritis • The shorter the time between infection and eradication, the larger the preventive effect with respect to gastric cancer Fuccio, Ann Int Med 2009

  22. Incidence of gastric cancer following H.pylori eradication Effective prophylaxis only in patients without severe histological changes! Wong, JAMA 2004

  23. Since 2004 mass eradication of H pylori for Taiwanese population with prevalent H pylori infection and age > 30 years • Endpoint – prevalence of: • HP • Premalignant gastric lesions • Comparison between premalignant lesions and gastric cancer before (1995-2003) and after (2004-2008) mass eradication Lee, GUT 2012

  24. Results: Reduction • H pylori infection: 78.7% • Peptic ulcer: 67.4% • gastric atrophy 77.2% • intestinal metaplasia: n. s.

  25. Reduction of gastric cancer incidence: 25% rate ratio: 0.753, 0.372-1.524

  26. When does screening for H. pylori make sense? Screening • could prevent 17-25% of all gastric cancers in China • is sensible in high risk patients (resected early gastric cancer) and high risk regions Miki, AJG 2003 Malfertheiner, GUT 2012

  27. Who must / should get eradication treatment? • First-degree relatives of family members with a diagnosis of gastric cancer (2-3 fold) • Patients with previous gastric neoplasia already treated by endoscopic or subtotal gastric resection • Patients with risk of gastric cancer: • Severe pan-gastritis • corpus-dominant gastritis • severe atrophy • Patients with chronic gastritis and acid inhibition for more than 1 year • Patients with strong environmental risk factors for gastric cancer (heavy smoking, high exposure to dust, coal, quartz, cement, and/or work in quarries • H pylori postive patients with a fear of gastric cancer Rokkas, Eur J Gastroenterol Hepatol 2010; Malfertheiner GUT 2012

  28. What is the best eradication therapy for H pylori? • Proton pump inhibitor plus 2 antibiotics for 1-2 weeks (standard triple amoxicillin, clarithromycin, omeprazole) • efficacy has dropped below 80% • increasing antibiotic resistance • poor patient compliance First line quadruple therapy in Europe recommended in areas of high clarithromycin resistance bismuth subcitrate potassium metronidazole tetracycline hydrochloride omeprazole Eradication: 80% vs. 55% with standard triple (ITT) Malfertheiner, Lancet 2011

  29. H pylori eradication treatment – open issues • Eradication more efficacious in long term aspirin users? • Can probiotics increase the efficacy of H pylori tretament? • saccharomyces boulardii • lactoferrin • Kefir - fermented milk containing probiotics: • 50% -> 78% Goturk, Am J Med Sci 2011; Bekar J Med Food 2011; Niv, WJG 2008

  30. What to do in case of high risk (after eradication)? Endoscopic follow up in case of • pernicious anemia with histologically confirmed diagnosis of type A autoimmune atrophic gastritis • histological or serological signs of subtotal or total atrophic gastritis with hypo- or achlorhydria • intervals: • Dysplasia: 3-6 months • Moderate to severe atrophy: 2-3 years • Reinfection or reoccurence after eradication • About 1% in developed countries • Around 13% in developing countries • -> retesting/rescreening Malfertheiner GUT 2012 Niv, Helicobacter 2008

  31. Helicobacter pylori and gastric cancer - conclusion • H. pylori is an essential factor in 71%-95% of all gastric cancers • Eradication makes sense in high risk patients • corpus-dominant gastritis • first degree relatives of patients with gastric cancer • serum pepsinogen I as marker of atrophy • serological testing for H. pylori • Prospective trials: Eradication can only prevent gastric cancer if there are no major histological abnormalities such as atrophy, metaplasia or dysplasia • Eradication should therefore take place in early stages of infection to prevent carcinogenesis

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