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Waldum H, Modlin I. The central role of gastrin in Helicobacter pylori gastric carcinogenesis. Scand J Gastroenterol 2025:1-12. [PMID: 40411354 DOI: 10.1080/00365521.2025.2509094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2025] [Revised: 05/14/2025] [Accepted: 05/15/2025] [Indexed: 05/26/2025]
Abstract
Gastric cancer is still a prevalent and lethal cancer. Gastric hypoacidity and gastritis have long been recognized in the pathogenesis. The identification of Helicobacter(H.) pylori as the main cause of gastritis leading to peptic ulcer disease and gastric cancer was a breakthrough. H. pylori was the first bacterium accepted as a carcinogen. The mechanism was not found before H. pylori was shown to predispose to cancer only after having induced oxyntic atrophy incriminating reduced killing of microorganisms and/or secondary hypergastrinemia. H. pylori has an uncertain carcinogenic role in cardia cancer, making microbes more unlikely. Gastrin has a trophic effect on the oxyntic mucosa, particularly on the enterochromaffin like cell carrying the gastrin receptor. Every condition with long-term hypergastrinemia in whatever species predisposes to gastric neoplasia. All observations on gastric neoplasia connected to H. pylori gastritis (the protective effect of duodenal ulcer, increased risk with oxyntic atrophy and preserved risk after loss of H. pylori in complete oxyntic atrophy) may be explained by gastrin. The role of gastrin in gastric carcinogenesis is also reflected by autoimmune gastritis and profound long-term gastric acid inhibition.
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Affiliation(s)
- Helge Waldum
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Irvin Modlin
- School of Medicine, FCS (RSA) Emeritus Prof Yale University, New Haven, CT, USA
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2
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Kang SJ, Lee KJ. Association of Proton Pump Inhibitor Use With Gastric Cancer in Regions With High Prevalence of Gastric Cancer: Systematic Review and Meta-analysis. J Neurogastroenterol Motil 2025; 31:178-185. [PMID: 40205895 PMCID: PMC11986659 DOI: 10.5056/jnm24145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Accepted: 02/05/2025] [Indexed: 04/11/2025] Open
Abstract
Background/Aims Although the association between the use of proton pump inhibitors (PPIs) and the risk of gastric cancer has been postulated in casecontrol and cohort studies, it remains still controversial. We aim to evaluate association of PPI use with gastric cancer in regions with high prevalence of gastric cancer, particularly in patients who underwent eradication of Helicobacter pylori, by systemic review and meta-analysis. Methods Comprehensive literature search through the PubMed, Embase, and Cochrane database was performed in October 2023. We used random effects model to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs) between PPI use and gastric cancer. The Cochran Q-statistic and the I2 test were employed for evaluating potential heterogeneity between studies. Results Two case-control and 6 cohort studies were identified. PPI use was significantly associated with the development of gastric cancer (OR, 2.02; 95% CI, 1.35-3.01). In subgroup analysis carried out according to the study design, sample size, and adjustment of confounding factors (age, sex, and H. pylori), such association was significant. A meta-analysis of 4 studies performed in patients with H. pylori eradication history showed that the use of PPIs was significantly associated with an elevated incidence of gastric cancer (OR, 2.10; 95% CI, 1.48-2.97). Conclusions Long-term use of PPIs is associated with an increased risk of gastric cancer in Asian regions with high prevalence of gastric cancer, particularly in subjects who have eradication history of H. pylori. Optimization of long-term PPI use seems to be necessary in regions where gastric cancer is prevalent.
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Affiliation(s)
- Seung Joo Kang
- Department of Internal Medicine, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea
| | - Kwang Jae Lee
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Gyeonggi-do, Korea
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3
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Brusselaers N, Khodir Kamal H, Graham D, Engstrand L. Proton pump inhibitors and the risk of gastric cancer: a systematic review, evidence synthesis and life course epidemiology perspective. BMJ Open Gastroenterol 2025; 12:e001719. [PMID: 40253055 PMCID: PMC12010335 DOI: 10.1136/bmjgast-2024-001719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 04/09/2025] [Indexed: 04/21/2025] Open
Abstract
OBJECTIVES Since proton pump inhibitors (PPI) have been introduced, many concerns were raised regarding potential gastric carcinogenicity. We aim to summarise and weigh the epidemiological evidence and address possible causality. DESIGN Systematic literature review, evidence synthesis and life-course assessment. DATA SOURCES PubMed, Web of Science and Cochrane database (from inception up to October 2024), and back- and forward citation tracking (Web of Science). ELIGIBILITY CRITERIA Original studies and quantitative evidence syntheses assessing the association between PPIs and gastric cancer in humans, without language restrictions. DATA EXTRACTION AND SYNTHESIS Study design, definitions (and participant numbers) of PPI use and gastric cancer, study characteristics (setting, period, follow-up, lag-time), age and sex distribution presented in tables and evidence mapping. RESULTS We identified 33 original studies, 21 meta-analyses, three umbrella meta-analyses, one individual patient data meta-analysis and a Markov model (2006-2023). PPIs were consistently associated with an increased gastric cancer risk with 20/21 meta-analyses reporting pooled relative risks between 1.3 and 2.9. Available trials were underpowered. Reverse causation/protopathic bias, residual confounding (by indication) and lag time seem the largest methodological challenges, as well as disentangling the effects of Helicobacter pylori and its' eradication. Insufficient data are available on age and sex-specific risks, with no studies specifically addressing PPIs in young populations. We hypothesise a sensitive-period exposure model, in which PPI use during pregnancy and early life may be particularly damaging regarding long-term cancer risk. An exploration of Swedish cancer incidence data suggests potential cohort effects as overall gastric cancer risk decreased over time (1970-2022). The risk has increased in young (<40 years) men since the early 2000s, ~10 years after the introduction of Helicobacter pylori eradication and PPIs. CONCLUSION Although for older individuals with valid indications, the gastric cancer risk related to PPI use may be limited, we do argue for a more rational and evidence-supported use of PPIs in young populations.
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Affiliation(s)
- Nele Brusselaers
- Dept. of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
- Department of Family Medicine and Population Health, University of Antwerp, Antwerpen, Belgium
| | | | | | - Lars Engstrand
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, stockholm, Sweden
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4
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Kim SY, Lee KJ. Potential Risks Associated With Long-term Use of Proton Pump Inhibitors and the Maintenance Treatment Modality for Patients With Mild Gastroesophageal Reflux Disease. J Neurogastroenterol Motil 2024; 30:407-420. [PMID: 39397619 PMCID: PMC11474548 DOI: 10.5056/jnm24059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/16/2024] [Accepted: 06/01/2024] [Indexed: 10/15/2024] Open
Abstract
Gastroesophageal reflux disease (GERD) significantly affects the health-related quality of life and healthcare costs. The prevalence of this disease is increasing in Asia, leading to a rapid increase in the demand of proton pump inhibitors (PPIs). Despite effective symptom management during initial treatment, relapse rates after PPI cessation remain high in patients with GERD, warranting longterm maintenance therapy. Concerns regarding potential side effects related to the long-term use of PPIs are escalating with increased usage. Studies have reported diverse side effects of PPIs, such as increased fracture risk, cardiovascular concerns, enteric infections, neurological diseases, and potential associations with gastric cancer. However, definitive causal relationships remain unclear. This review comprehensively summarizes the latest knowledge on the potential risks associated with long-term use of PPIs. Continuous or noncontinuous therapy can be used as a maintenance treatment modality for GERD. For patients with mild GERD, including those with nonerosive and mildly erosive reflux disease, on-demand therapy following a sufficient period of continuous maintenance therapy is recommended as a long-term maintenance treatment option.
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Affiliation(s)
- Seung Young Kim
- Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Seoul, Korea
| | - Kwang Jae Lee
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Gyeonggi-do, Korea
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5
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Xie R, Yan X, Yu J, Shen K, Zhang M, Li M, Lv Z, Zhang Y, Zhang Z, Lyu Y, Cheng Y, Chu D. pH-responsive bioadhesive with robust and stable wet adhesion for gastric ulcer healing. Biomaterials 2024; 309:122599. [PMID: 38703409 DOI: 10.1016/j.biomaterials.2024.122599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/22/2024] [Accepted: 04/26/2024] [Indexed: 05/06/2024]
Abstract
Development of bioadhesives that can be facilely delivered by endoscope and exhibit instant and robust adhesion with gastric tissues to promote gastric ulcer healing remains challenging. In this study, an advanced bioadhesive is prepared through free radical polymerization of ionized N-acryloyl phenylalanine (iAPA) and N-[tris (hydroxymethyl) methyl] acrylamide (THMA). The precursory polymer solution exhibits low viscosity with the capability for endoscope delivery, and the hydrophilic-hydrophobic transition of iAPA upon exposure to gastric acid can trigger gelation through phenyl groups assisted multiple hydrogen bonds formation and repel water molecules on tissue surface to establish favorable environment for interfacial interactions between THMA and functional groups on tissues. The in-situ formed hydrogel features excellent stability in acid environment (14 days) and exhibits firm wet adhesion to gastric tissue (33.4 kPa), which can efficiently protect the wound from the stimulation of gastric acid and pepsin. In vivo studies reveal that the bioadhesive can accelerate the healing of ulcers by inhibiting inflammation and promoting capillary formation in the acetic acid-induced gastric ulcer model in rats. Our work may provide an effective solution for the treatment of gastric ulcers clinically.
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Affiliation(s)
- Ruilin Xie
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China; Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, School of Chemistry, Xi'an Jiaotong University, Xi'an, 710049, PR China
| | - Xueli Yan
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Jing Yu
- Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, School of Chemistry, Xi'an Jiaotong University, Xi'an, 710049, PR China
| | - Kaixiang Shen
- Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, School of Chemistry, Xi'an Jiaotong University, Xi'an, 710049, PR China
| | - Mengyuan Zhang
- Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, School of Chemistry, Xi'an Jiaotong University, Xi'an, 710049, PR China
| | - Meng Li
- Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, School of Chemistry, Xi'an Jiaotong University, Xi'an, 710049, PR China
| | - Zhuting Lv
- Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, School of Chemistry, Xi'an Jiaotong University, Xi'an, 710049, PR China
| | - Yuchen Zhang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710049, PR China
| | - Zixi Zhang
- Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Yi Lyu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Yilong Cheng
- Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, School of Chemistry, Xi'an Jiaotong University, Xi'an, 710049, PR China.
| | - Dake Chu
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China.
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Peng C, Xu X, Ouyang Y, Li Y, Lu N, Zhu Y, He C. Spatial Variation of the Gastrointestinal Microbiota in Response to Long-Term Administration of Vonoprazan in Mice With High Risk of Gastric Cancer. Helicobacter 2024; 29:e13117. [PMID: 39086007 DOI: 10.1111/hel.13117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 05/26/2024] [Accepted: 07/17/2024] [Indexed: 08/02/2024]
Abstract
BACKGROUND Vonoprazan, a potassium-competitive acid blocker, is superior to traditional proton pump inhibitor (PPI) in acid suppression and has been approved in the treatment of acid-related disorders. Accumulating evidence suggest associations between PPI use and gut microbiota, yet the effect of vonoprazan on GI microbiota is obscure. METHODS Transgenic FVB/N insulin-gastrin (INS-GAS) mice as a model of gastric cancer (GC) were administered vonoprazan by gavage every other day for 12 weeks. Stomachs were evaluated by histopathology, Ki-67 proliferation index, and inflammatory cytokines. The mucosal and lumen microbiota from stomach, jejunum, ileum, cecum, and feces were detected using 16S rRNA gene sequencing. RESULTS Higher incidence of intestinal metaplasia and epithelial proliferation were observed in the vonoprazan group than that in the control mice. Vonoprazan also elevated the gastric expression of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6. Each mice comprised a unique microbiota composition that was consistent across different niches. The structure of GI microbiota changed dramatically after vonoprazan treatment with the stomach being the most disturbed segment. Vonoprazan administration shifted the gut microbiota toward the enrichment of pathogenic Streptococcus, Staphylococcus, Bilophila, and the loss of commensal Prevotella, Bifidobacterium, and Faecalibacterium. Interestingly, compared to the controls, microbial interactions were weaker in the stomach while stronger in the jejunum of the vonoprazan group. CONCLUSIONS Long-term vonoprazan treatment promoted gastric lesions in male INS-GAS mice, with the disequilibrium of GI microbiome. The clinical application of vonoprazan needs to be judicious particularly among those with high risk of GC.
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Affiliation(s)
- Chao Peng
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xinbo Xu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yaobin Ouyang
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yu Li
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Nonghua Lu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yin Zhu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Cong He
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
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7
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Arai J, Miyawaki A, Aoki T, Niikura R, Hayakawa Y, Fujiwara H, Ihara S, Fujishiro M, Kasuga M. Association Between Vonoprazan and the Risk of Gastric Cancer After Helicobacter pylori Eradication. Clin Gastroenterol Hepatol 2024; 22:1217-1225.e6. [PMID: 38354970 DOI: 10.1016/j.cgh.2024.01.037] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 01/16/2024] [Accepted: 01/22/2024] [Indexed: 02/16/2024]
Abstract
BACKGROUND & AIMS Potassium-competitive acid blockers (PCABs) have been increasingly used to treat upper gastrointestinal disorders, replacing proton pump inhibitors (PPIs). Whereas PPIs are associated with an increased risk of gastric cancer (GC) after Helicobacter pylori (Hp) eradication, it is uncertain whether PCABs carry the same risk. METHODS Using a population-based claims database in Japan, we identified patients who were prescribed a clarithromycin-based first regimen of Hp eradication between 2015 and 2018. Patients who failed this regimen and those diagnosed with GC before or within 1 year after Hp eradication were excluded. We compared GC incidence between PCAB users and histamine type-2 receptor antagonist (H2RA) users, matching them on the basis of propensity scores calculated with considerations for age, sex, smoking, alcohol consumption, comorbidities, and co-administered medications. PCABs included only vonoprazan in this study. RESULTS Among 54,055 patients, 568 (1.05%) developed GC during the follow-up period (mean, 3.65 years). The cumulative incidence of GC was 1.64% at 3 years, 2.02% at 4 years, and 2.36% at 5 years in PCAB users and 0.71% at 3 years, 1.04% at 4 years, and 1.22% at 5 years in H2RA users. The use of PCABs was associated with a higher GC risk (matched hazard ratio, 1.92; 95% confidence interval, 1.13-3.25; P = .016). Longer PCAB use and high-dose PCAB use were significantly associated with higher incidence of GC. Sensitivity analyses showed the risk of GC incidence among PCAB users was comparable with that of PPI users. CONCLUSIONS The use of PCABs was associated with an increased risk of GC among Hp-eradicated patients, with duration/dose response effects.
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Affiliation(s)
- Junya Arai
- Division of Gastroenterology, The Institute of Medical Science, Asahi Life Foundation, Tokyo, Japan; Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Atsushi Miyawaki
- Department of Health Services Research, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tomonori Aoki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryota Niikura
- Department of Endoscopy, Graduate School of Medicine, Tokyo Medical University, Tokyo, Japan.
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Hiroaki Fujiwara
- Division of Gastroenterology, The Institute of Medical Science, Asahi Life Foundation, Tokyo, Japan
| | - Sozaburo Ihara
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masato Kasuga
- The Institute of Medical Science, Asahi Life Foundation, Tokyo, Japan
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8
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Namikawa K, Björnsson ES. Rebound Acid Hypersecretion after Withdrawal of Long-Term Proton Pump Inhibitor (PPI) Treatment-Are PPIs Addictive? Int J Mol Sci 2024; 25:5459. [PMID: 38791497 PMCID: PMC11122117 DOI: 10.3390/ijms25105459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/10/2024] [Accepted: 05/14/2024] [Indexed: 05/26/2024] Open
Abstract
Proton pump inhibitors (PPIs) are widely used in the long-term treatment of gastroesophageal reflux disease (GERD) and other upper gastrointestinal disorders, such as the healing of peptic ulcers and/or prophylactic treatment of peptic ulcers. PPIs are also widely used as symptomatic treatment in patients with functional dyspepsia. One of the adverse effects of the long-term use of PPI is rebound acid hypersecretion (RAHS), which can occur after the withdrawal of PPI therapy due to a compensatory increase in gastric acid production. Mechanisms of the RAHS have been well established. Studies have shown that pentagastrin-stimulated acid secretion after the discontinuation of PPIs increased significantly compared to that before treatment. In healthy volunteers treated with PPIs, the latter induced gastrointestinal symptoms in 40-50% of subjects after the discontinuation of PPI therapy but after stopping the placebo. It is important for practicing physicians to be aware and understand the underlying mechanisms and inform patients about potential RAHS before discontinuing PPIs in order to avoid continuing unnecessary PPI therapy. This is important because RAHS may lead patients to reuptake PPIs as symptoms are incorrectly thought to originate from the recurrence of underlying conditions, such as GERD. Mechanisms of RAHS have been well established; however, clinical implications and the risk factors for RAHS are not fully understood. Further research is needed to facilitate appropriate management of RAHS in the future.
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Affiliation(s)
- Ken Namikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Landspitali University Hospital, 101 Reykjavik, Iceland;
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
| | - Einar Stefan Björnsson
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Landspitali University Hospital, 101 Reykjavik, Iceland;
- Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
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9
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Lei C, Xu Y, Zhang S, Huang C, Qin J. The role of microbiota in gastric cancer: A comprehensive review. Helicobacter 2024; 29:e13071. [PMID: 38643366 DOI: 10.1111/hel.13071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 02/19/2024] [Accepted: 03/25/2024] [Indexed: 04/22/2024]
Abstract
BACKGROUND Gastric cancer (GC) continues to pose a significant global threat in terms of cancer-related fatalities. Despite notable advancements in medical research and therapies, further investigation is warranted to elucidate its underlying etiology and risk factors. Recent times have witnessed an escalated emphasis on comprehending the role of the microbiota in cancer development. METHODS This review briefly delves into recent developments in microbiome-related research pertaining to gastric cancer. RESULTS According to studies, the microbiota can influence GC growth by inciting inflammation, disrupting immunological processes, and generating harmful microbial metabolites. Furthermore, there is ongoing research into how the microbiome can impact a patient's response to chemotherapy and immunotherapy. CONCLUSION The utilization of the microbiome for detecting, preventing, and managing stomach cancer remains an active area of exploration.
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Affiliation(s)
- Changzhen Lei
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yitian Xu
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shaopeng Zhang
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chen Huang
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Qin
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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10
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Matsumoto S, Sugimoto M, Fukuzawa M, Uesugi N, Iwata E, Kagawa Y, Madarame A, Koyama Y, Morise T, Uchida K, Yamaguchi H, Kono S, Naito S, Kawai T, Itoi T. Risk of map-like redness development after eradication therapy for Helicobacter pylori infection. Helicobacter 2024; 29:e13046. [PMID: 38984721 DOI: 10.1111/hel.13046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 12/01/2023] [Accepted: 12/11/2023] [Indexed: 07/11/2024]
Abstract
BACKGROUND Map-like redness is a newly identified endoscopic risk factor for gastric cancer in patients who received Helicobacter pylori eradication therapy. However, the incidence rate of map-like redness in patients who received eradication, and the risk factors for the development of map-like redness remain unclear. We hence aimed to investigate the incidence rate of map-like redness at 1-year post H. pylori eradication, and evaluated its associations with map-like redness and gastric cancer in relation with gastric condition. MATERIALS AND METHODS Endoscopic severity of gastritis and map-like redness were retrospectively evaluated according to the Kyoto Classification of Gastritis in patients who had undergone endoscopy before and after H. pylori eradication therapy. RESULTS The incidence rate of map-like redness for all 328 patients at a mean of 1.2 ± 0.6 years after eradication was 25.3% (95% confidence interval [CI]: 20.7%-30.4%). Patients who developed map-like redness were older, had more severe atrophy and intestinal metaplasia, a higher total score of the Kyoto Classification of Gastritis both before and after eradication, and a higher rate of gastric cancer history than patients who did not have map-like redness. On multivariate analysis, risk of map-like redness was increased in patients with intestinal metaplasia (odds ratio [OR]: 2.794, 95% CI: 1.155-6.757) and taking acid inhibitors (OR: 1.948, 95% CI: 1.070-3.547). Characteristics of H. pylori-positive patients with gastric cancer history were patients who were older (OR: 1.033, 95% CI: 1.001-1.066), taking acid inhibitors (OR: 4.456, 95% CI: 2.340-8.484), and with occurrence of map-like redness after eradication therapy (OR: 2.432, 95% CI: 1.264-4.679). CONCLUSIONS Map-like redness is observed in one fourth of patients at 1-year post eradication. Patients who developed map-like redness were found to have severe intestinal metaplasia and taking acid inhibitors, and hence such patients require increased attention at surveillance endoscopy.
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Affiliation(s)
- Sho Matsumoto
- Department of Gastroenterology and Hepatology, Tokyo Medical University Hospital, Tokyo, Japan
| | - Mitsushige Sugimoto
- Department of Gastroenterological Endoscopy, Tokyo Medical University Hospital, Tokyo, Japan
| | - Masakatsu Fukuzawa
- Department of Gastroenterology and Hepatology, Tokyo Medical University Hospital, Tokyo, Japan
| | - Nana Uesugi
- Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Eri Iwata
- Department of Gastroenterological Endoscopy, Tokyo Medical University Hospital, Tokyo, Japan
| | - Yasuyuki Kagawa
- Department of Gastroenterology and Hepatology, Tokyo Medical University Hospital, Tokyo, Japan
| | - Akira Madarame
- Department of Gastroenterology and Hepatology, Tokyo Medical University Hospital, Tokyo, Japan
| | - Yohei Koyama
- Department of Gastroenterology and Hepatology, Tokyo Medical University Hospital, Tokyo, Japan
| | - Takashi Morise
- Department of Gastroenterology and Hepatology, Tokyo Medical University Hospital, Tokyo, Japan
| | - Kumiko Uchida
- Department of Gastroenterology and Hepatology, Tokyo Medical University Hospital, Tokyo, Japan
| | - Hayato Yamaguchi
- Department of Gastroenterology and Hepatology, Tokyo Medical University Hospital, Tokyo, Japan
| | - Shin Kono
- Department of Gastroenterology and Hepatology, Tokyo Medical University Hospital, Tokyo, Japan
| | - Sakiko Naito
- Department of Gastroenterology and Hepatology, Tokyo Medical University Hospital, Tokyo, Japan
| | - Takashi Kawai
- Department of Gastroenterological Endoscopy, Tokyo Medical University Hospital, Tokyo, Japan
| | - Takao Itoi
- Department of Gastroenterology and Hepatology, Tokyo Medical University Hospital, Tokyo, Japan
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11
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Waldum H, Mjønes P. The central role of gastrin in gastric cancer. Front Oncol 2023; 13:1176673. [PMID: 37941554 PMCID: PMC10628637 DOI: 10.3389/fonc.2023.1176673] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 09/19/2023] [Indexed: 11/10/2023] Open
Abstract
The prevalence of gastric cancer has markedly declined, but due to the high mortality rates associated with gastric cancer, it is still a serious disease. The preferred classification of gastric cancer is according to Lauren into either the intestinal type, which has a glandular growth pattern, or the diffuse type, which does not have glandular structures. Both types have been classified as adenocarcinomas, with the latter type based on periodic acid-Schiff (PAS) positivity presumed to reflect mucin. However, the presence of mucin in the diffuse type, in contrast to neuroendocrine/enterochromaffin-like (ECL) cell markers, has not been confirmed by immunohistochemistry and in situ hybridization. The ECL cells are probably prone to becoming cancerous because they do not express E-cadherin. Gastric cancer is unique in that a bacterium, Helicobacter pylori, is thought to be its main cause. H. pylori predisposes infected individuals to cancer only after having caused oxyntic atrophy leading to gastric hypoacidity and hypergastrinemia. No single H. pylori factor has been convincingly proved to be carcinogenic. It is probable that gastrin is the pathogenetic factor for gastric cancer due to H. pylori, autoimmune gastritis, and long-term prolonged inhibition of gastric acid secretion. Hypergastrinemia induces ECL cell hyperplasia, which develops into neuroendocrine tumors (NETs) and then into neuroendocrine carcinomas in rodents, a sequence that has also been described in humans. During carcinogenesis, the tumor cells lose specific traits, requiring that sensitive methods be used to recognize their origin. Gastric cancer occurrence may hopefully be prevented by H. pylori eradication at a young age, and by the reduced use of inhibitors of acid secretion and use of a gastrin antagonist in those with previous long-term H. pylori infection and those with autoimmune gastritis.
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Affiliation(s)
- Helge Waldum
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Patricia Mjønes
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Pathology, St. Olav’s Hospital – Trondheim University Hospital, Trondheim, Norway
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Gong EJ, Jung HK, Lee B, Hong J, Kim JW, Shin CM, Youn YH, Lee KJ. Proton pump inhibitor use and the risk of metachronous gastric cancer after H. pylori eradication in patients who underwent endoscopic resection for gastric neoplasms: A population-based cohort study. Aliment Pharmacol Ther 2023; 58:668-677. [PMID: 37589510 DOI: 10.1111/apt.17676] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/16/2023] [Accepted: 08/02/2023] [Indexed: 08/18/2023]
Abstract
BACKGROUND The association between proton pump inhibitors (PPI) use and gastric cancer remains controversial. AIMS To investigate the impact of long-term PPI use on metachronous gastric cancer after Helicobacter pylori eradication in high-risk patients who underwent endoscopic resection of gastric neoplasms. METHODS Using the Korean National Health Insurance Services database, we identified 1836 PPI users and 12,218 non-users among patients who received H. pylori eradication therapy after endoscopic resection for gastric neoplasms between 2009 and 2014. We then compared the incidence of metachronous gastric cancer between the PPI user and non-user groups. We conducted sensitivity analysis using various time lags and propensity score-matched analysis to ensure the robustness of the results. RESULTS After a median follow-up of 7.3 years, the incidence of metachronous gastric cancer was significantly higher in the PPI user group than in the non-user group, with a crude hazard ratio of 6.20 (95% confidence interval, 5.78-6.65). After adjustment, PPI use was associated with the development of metachronous gastric cancer, with an adjusted hazard ratio of 5.51 (95% confidence interval, 5.12-5.92). The PPI user group was categorised into three subgroups according to the cumulative PPI dose; the increased risk of metachronous gastric cancer remained significant regardless of the PPI dose. Moreover, these results remained robust after applying various time lags and propensity score-matched analyses. CONCLUSIONS Long-term PPI use is associated with an increased risk of metachronous gastric cancer in patients who undergo H. pylori eradication therapy after endoscopic resection of gastric neoplasms.
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Affiliation(s)
- Eun Jeong Gong
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
| | - Hye-Kyung Jung
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, South Korea
| | - Bora Lee
- Institute of Health & Environment, Seoul National University, Seoul, South Korea
| | - Jitaek Hong
- Department of Internal Medicine, Digestive Disease Center, Inha University College of Medicine, Incheon, South Korea
| | - Jong Wook Kim
- Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, South Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Young Hoon Youn
- Department of Internal Medicine, Yonsei University Gangnam Severance Hospital, Seoul, South Korea
| | - Kwang Jae Lee
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
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13
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Liu K, Wang YH, Wang J, Chen B, Luo N, Gong J. Meta-analysis of proton pump inhibitor use and the risk of developing gastric cancer or colorectal cancer. Anticancer Drugs 2023; 34:971-978. [PMID: 37578746 DOI: 10.1097/cad.0000000000001418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
Abstract
To evaluate the relationship between the use of proton pump inhibitors (PPI) and the risk of gastric cancer and colorectal cancer by using meta-analysis. Computer search PUBMED, EMBASE, Cochrane Library, CNKI and Wanfang database to obtain relevant literature on the use of PPI and the risk of gastric cancer and colorectal cancer, extract relevant data, and use Stata14.0 for Meta-analysis. A total of 24 articles were included, including 12 articles for gastric cancer and 12 articles for colorectal cancer. A total of 5 313 749 persons were included in the study and analysis. Meta-analysis results showed that the risk of gastric cancer in PPI users was significantly increased [risk ratio (RR) = 2.04, 95% confidence interval (CI) (1.33-2.75)], and the regional subgroup analysis results showed that in Europe [RR = 2.01, 95% CI (0.92, 3.09), P < 0.05] and Asia [RR = 2.15, 95% CI (1.16, 3.14), P < 0.05] This risk is higher, and Asia is higher than Europe. The risk of colorectal cancer is slightly increased [RR = 1. 22, 95% CI (1.03, 1.40, P < 0.05], and the regional subgroup analysis results show that in Europe [RR = 1.05 95% CI (0.98, 1.12), P < 0.05] and Asia [RR = 1.18, 95% CI (1.10, 1.27), P < 0.05]. This risk is low, but Asia is higher than Europe. The use of PPI significantly increases gastric cancer However, the risk of colorectal cancer is not significantly increased. The risk of gastric cancer and colorectal cancer in the population using PPI in Asia is higher than that in Europe.
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Affiliation(s)
- Ke Liu
- Department of Gastrointestinal Surgery, People's Hospital of Leshan
- Department of Nursing, People's Hospital of Leshan, Sichuan, China
| | - Yong-Hong Wang
- Department of Gastrointestinal Surgery, People's Hospital of Leshan
| | - Jun Wang
- Department of Nursing, People's Hospital of Leshan, Sichuan, China
| | - Bing Chen
- Department of Nursing, People's Hospital of Leshan, Sichuan, China
| | - Na Luo
- Department of Nursing, People's Hospital of Leshan, Sichuan, China
| | - Juan Gong
- Department of Nursing, People's Hospital of Leshan, Sichuan, China
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14
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Pan S, Thrift AP, Akhdar G, El-Serag HB. Gastric Cancer Risk in Patients with Long-Term Use of Proton Pump Inhibitors: A Systematic Review and Meta-Analysis of Observational and Interventional Studies. Dig Dis Sci 2023; 68:3732-3744. [PMID: 37432532 DOI: 10.1007/s10620-023-08018-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 06/19/2023] [Indexed: 07/12/2023]
Abstract
BACKGROUND A growing number of studies that differ in design, quality, and results report an association between the use of proton pump inhibitors (PPIs) and the risk of gastric cancer (GC). We conducted a systematic review and meta-analysis, when possible, of observational and interventional studies examining PPI use and risk of GC. METHODS We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We identified studies fully published in English through January 2023 using MeSH and non-MeSH keywords. We used random effects models to calculate pooled risk estimates with 95% confidence interval (CI) between PPI use and overall GC, cardia GC, and non-cardia GC. We estimated heterogeneity (I2) among studies. We examined the effect of study design and quality, GC site, H. pylori infection, and PPI duration. We assessed quality using the Newcastle-Ottawa Quality Assessment Scale and Risk Of Bias In Non-randomized Studies of Interventions. RESULTS We identified 15 observational studies, of which 13 were included in the meta-analysis (six cohort and seven case-control). There was a modest 1.67-fold increase in overall GC risk (95% CI 1.39, 2.00) and no increase in cardia GC risk [odds ratio (OR) 1.12; 95% CI 0.80, 1.56] with PPI use. However, there was high heterogeneity (I2 = 61.3%, p = 0.004) among studies. All but one study had at least moderate risk of bias. In the six studies accounting for H. pylori, GC risk associated with PPI use increased slightly (OR 1.78; 95% CI 1.25, 2.52). Duration response was not reported consistently to allow pooled estimates. We identified only one interventional randomized controlled study that included GC as an outcome of interest, and it did not show increased GC risk. CONCLUSIONS The overall available evidence is not supportive of a meaningful change in GC risk, either cardia or non-cardia, with PPI use.
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Affiliation(s)
- Sharon Pan
- Texas A&M School of Medicine, Bryan, TX, USA
| | - Aaron P Thrift
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Ghida Akhdar
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Hashem B El-Serag
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA.
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
- Section of Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA.
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15
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Arai J, Hayakawa Y, Niikura R, Ihara S, Aoki T, Honda T, Okamura T, Hasatani K, Yoshida N, Nishida T, Sumiyoshi T, Kiyotoki S, Ikeya T, Arai M, Fujishiro M. Letter: Potassium-competitive acid blockers may increase the risk of gastric cancer after Helicobacter pylori eradication a retrospective multicentre-cohort analysis. Aliment Pharmacol Ther 2023; 57:1196-1198. [PMID: 37094303 DOI: 10.1111/apt.17461] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 02/16/2023] [Accepted: 02/28/2023] [Indexed: 04/26/2023]
Abstract
LINKED CONTENTThis article is linked to Piovani et al papers. To view these articles, visit https://doi.org/10.1111/apt.17360 and https://doi.org/10.1111/apt.17480
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Affiliation(s)
- Junya Arai
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryota Niikura
- Department of Gastroenterology, Graduate School of Medicine, Tokyo Medical University, Tokyo, Japan
| | - Sozaburo Ihara
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tomonori Aoki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tetsuro Honda
- Department of Gastroenterology, Nagasaki Harbor Medical Center, Nagasaki-shi, Nagasaki, Japan
| | - Takuma Okamura
- Department of Gastroenterology, Nagasaki Harbor Medical Center, Nagasaki-shi, Nagasaki, Japan
| | - Kenkei Hasatani
- Department of Gastroenterology, Fukui Prefectural Hospital, Fukui-shi, Fukui, Japan
| | - Naohiro Yoshida
- Department of Gastroenterology, Ishikawa Prefectural Central Hospital, Kanazawa-shi, Ishikawa, Japan
| | - Tsutomu Nishida
- Department of Gastroenterology, Toyonaka Municipal Hospital, Toyonaka-shi, Osaka, Japan
| | - Tetsuya Sumiyoshi
- Department of Gastroenterology, Tonan Hospital, Sapporo-shi, Hokkaido, Japan
| | - Shu Kiyotoki
- Department of Gastroenterology, Shuto General Hospital, Yanai-shi, Yamaguchi, Japan
| | - Takashi Ikeya
- Department of Gastroenterology, St. Luke's International Hospital, Chuo-ku, Tokyo, Japan
| | - Masahiro Arai
- Department of Gastroenterology, Nerima Hikarigaoka Hospital, Nerima-ku, Tokyo, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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16
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Haruma K, Kinoshita Y, Yao T, Kushima R, Akiyama J, Aoyama N, Kanoo T, Miyata K, Kusumoto N, Uemura N. Randomised clinical trial: 3-year interim analysis results of the VISION trial to evaluate the long-term safety of vonoprazan as maintenance treatment in patients with erosive oesophagitis. BMC Gastroenterol 2023; 23:139. [PMID: 37127558 PMCID: PMC10152792 DOI: 10.1186/s12876-023-02772-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 04/18/2023] [Indexed: 05/03/2023] Open
Abstract
BACKGROUND VISION is a randomised, phase 4, open-label, parallel-group, multicentre study conducted in 33 centres in Japan. The aim of this study was to assess the long-term safety of vonoprazan for maintenance treatment of healed erosive oesophagitis versus lansoprazole. METHODS Patients with endoscopically diagnosed erosive oesophagitis were randomised 2:1 to once-daily vonoprazan 20 mg or lansoprazole 30 mg, for a 4- to 8-week healing phase. Patients with endoscopically confirmed healing entered a 260-week maintenance phase with a once-daily starting dose of vonoprazan 10 mg or lansoprazole 15 mg. Primary endpoint was change in gastric mucosal histopathology. RESULTS Of 208 patients (vonoprazan, n = 139; lansoprazole, n = 69) entering the healing phase, 202 entered the maintenance phase (vonoprazan, n = 135; lansoprazole, n = 67). At 3 years, 109 vonoprazan-treated and 58 lansoprazole-treated patients remained on treatment. Histopathological evaluation of gastric mucosa showed that hyperplasia of parietal, foveolar and G cells was more common with vonoprazan than lansoprazole at week 156 of the maintenance phase. There was no marked increase in the occurrence of parietal, foveolar and G cell hyperplasia among patients in the vonoprazan group from week 48 to week 156. Histopathological evaluation of the gastric mucosa also showed no neoplastic changes in either group. No new safety issues were identified. CONCLUSIONS In this interim analysis of VISION, no new safety concerns were identified in Japanese patients with healed erosive oesophagitis receiving vonoprazan or lansoprazole as maintenance treatment for 3 years. (CT.gov identifier: NCT02679508; JapicCTI-163153; Japan Registry of Clinical Trials: jRCTs031180040).
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Affiliation(s)
- Ken Haruma
- Department of General Internal Medicine 2, Kawasaki Medical School, General Medical Center, Okayama, Japan
| | - Yoshikazu Kinoshita
- General Internal Medicine, Hyogo Prefectural Harima-Himeji General Medical Center, Himeji, Hyogo, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ryoji Kushima
- Department of Clinical Laboratory Medicine, Shiga University of Medical Science Hospital, Otsu, Shiga, Japan
| | - Junichi Akiyama
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Nobuo Aoyama
- GI Endoscopy and IBD Center, Aoyama Medical Clinic, Kobe, Hyogo, Japan
| | | | | | | | - Naomi Uemura
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Kohnodai Hospital, Ichikawa, Chiba, Japan
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17
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Guo H, Zhang R, Zhang P, Chen Z, Hua Y, Huang X, Li X. Association of proton pump inhibitors with gastric and colorectal cancer risk: A systematic review and meta-analysis. Front Pharmacol 2023; 14:1129948. [PMID: 37007006 PMCID: PMC10060974 DOI: 10.3389/fphar.2023.1129948] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 03/07/2023] [Indexed: 03/18/2023] Open
Abstract
Background: Proton pump inhibitors (PPI) are generally considered to be one of the well-established prescription drug classes and are commonly used to treat most acid-related diseases. However, a growing body of literature showing an association between gastric and colorectal cancer risk and PPI use continues to raise concerns about the safety of PPI use. Therefore, we aimed to investigate the association between proton pump inhibitor use and risk of gastric and colorectal cancer.Methods: We collected relevant articles using PubMed, Embase, Web of Science and Cochrane library from 1 January 1990 to 21 March 2022. The pooled effect sizes were calculated based on the random-effects model. The study was registered with PROSPERO (CRD42022351332).Results: A total of 24 studies (n = 8,066,349) were included in the final analysis in the screening articles. Compared with non-PPI users, PPI users had a significantly higher risk of gastric cancer (RR = 1.82, 95% CI: 1.46–2.29), but not colorectal cancer (RR = 1.22, 95% CI: 0.95–1.55). Subgroup analysis showed that there was a significant positive correlation between the use of PPI and the risk of non-cardiac cancer (RR = 2.75, 95% CI: 2.09–3.62). There was a significant trend between the duration dependent effect of PPI use and the risk of gastric cancer (<1 year RR = 1.56, 95% CI: 1.30–1.86; 1–3 years RR = 1.75, 95% CI: 1.28–2.37; >3 years RR = 2.32, 95% CI: 1.15–4.66), but not colorectal cancer (≤1 year RR = 1.00, 95% CI: 0.78–1.28; >1 year RR = 1.18, 95% CI: 0.91–1.54; ≥5 years RR = 1.06, 95% CI: 0.95–1.17).Conclusion: We found that PPI use increased gastric cancer risk, but not colorectal cancer risk. This result may be biased due to confounding factors. More prospective studies are needed to further validate and support our findings.Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022351332], identifier [CRD42022351332].
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18
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Niikura R, Hayakawa Y, Nagata N, Miyoshi-Akiayama T, Miyabayashi K, Tsuboi M, Suzuki N, Hata M, Arai J, Kurokawa K, Abe S, Uekura C, Miyoshi K, Ihara S, Hirata Y, Yamada A, Fujiwara H, Ushiku T, Woods SL, Worthley DL, Hatakeyama M, Han YW, Wang TC, Kawai T, Fujishiro M. Non- Helicobacter pylori Gastric Microbiome Modulates Prooncogenic Responses and Is Associated With Gastric Cancer Risk. GASTRO HEP ADVANCES 2023; 2:684-700. [PMID: 39129877 PMCID: PMC11307406 DOI: 10.1016/j.gastha.2023.03.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 03/08/2023] [Indexed: 08/13/2024]
Abstract
Background and Aims Although Helicobacter pylori is the most important bacterial carcinogen in gastric cancer (GC), GC can emerge even after H. pylori eradication. Studies suggest that various constituents of the gastric microbiome may influence GC development, but the role of individual pathogens is unclear. Methods Human gastric mucosal samples were analyzed by 16SrRNA sequencing to investigate microbiome composition and its association with clinical parameters, including GC risk. Identified bacteria in the stomach were cocultured with gastric epithelial cells or inoculated into mice, and transcriptomic changes, DNA damage, and inflammation were analyzed. Bacterial reads in GC tissues were examined together with transcriptomic and genetic sequencing data in the cancer genome atlas dataset. Results Patients after Helicobacter pylori eradication formed 3 subgroups based on the microbial composition revealed by 16SrRNA sequencing. One dysbiotic group enriched with Fusobacterium and Neisseria species was associated with a significantly higher GC incidence. These species activated prooncogenic pathways in gastric epithelial cells and promoted inflammation in mouse stomachs. Sugar chains that constitute gastric mucin attenuate host-bacteria interactions. Metabolites from Fusobacterium species were genotoxic, and the presence of the bacteria was associated with an inflammatory signature and a higher tumor mutation burden. Conclusion Gastric microbiota in the dysbiotic stomach is associated with GC development after H. pylori eradication and plays a pathogenic role through direct host-bacteria interaction.
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Affiliation(s)
- Ryota Niikura
- Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
- Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
| | - Naoyoshi Nagata
- Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan
| | - Tohru Miyoshi-Akiayama
- Pathogenic Microbe Laboratory, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Koji Miyabayashi
- Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
| | - Mayo Tsuboi
- Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
| | - Nobumi Suzuki
- Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
| | - Masahiro Hata
- Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
| | - Junya Arai
- Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
| | - Ken Kurokawa
- Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
| | - Sohei Abe
- Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
| | - Chie Uekura
- Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
| | - Kotaro Miyoshi
- Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
| | - Sozaburo Ihara
- Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshihiro Hirata
- Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
| | - Atsuo Yamada
- Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroaki Fujiwara
- Department of Gastroenterology, The Institute for Medical Science, Asahi-life Foundation, Tokyo, Japan
| | - Tetsuo Ushiku
- Department of Pathology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
| | - Susan L. Woods
- Cancer Theme, SAHMRI, Adelaide, South Australia, Australia
- Medical Specialties, Medical School, The University of Adelaide, Adelaide, South Australia, Australia
| | | | - Masanori Hatakeyama
- Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yiping W. Han
- Division of Digestive and Liver Disease, Department of Medicine, Columbia University, New York, New York
- Department of Microbiology and Immunology, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York
- Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, New York, New York
| | - Timothy C. Wang
- Division of Digestive and Liver Disease, Department of Medicine, Columbia University, New York, New York
| | - Takashi Kawai
- Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
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19
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Piovani D, Tsantes AG, Schünemann HJ, Bonovas S. Meta-analysis: Use of proton pump inhibitors and risk of gastric cancer in patients requiring gastric acid suppression. Aliment Pharmacol Ther 2023; 57:653-665. [PMID: 36585832 DOI: 10.1111/apt.17360] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 11/22/2022] [Accepted: 12/06/2022] [Indexed: 01/01/2023]
Abstract
BACKGROUND Proton-pump inhibitors (PPIs) are suspected to increase the risk of gastric cancer. AIM To assess the risk of gastric cancer associated with the use of PPIs. METHODS We systematically searched Medline/PubMed, Embase and Scopus databases (until June 1, 2022) for randomised and non-randomised studies (NRS) of the association between PPIs and gastric cancer having considered Histamine-2 receptor antagonists (H2RAs) users as controls. We chose this comparison to minimise confounding by indication, and focus on patients requiring gastric acid suppression. Two authors independently extracted study data and assessed each study's risk of bias. Maximally-adjusted relative risk (RR) estimates were extracted. Heterogeneity and small-study effect were examined, and summary estimates were calculated using random- and fixed-effect models. Stratified analyses and meta-regression were employed to explore heterogeneity. We used GRADE to evaluate the certainty of evidence. RESULTS Of 8375 records, 12 NRS (>6 million patients; 11,554 gastric cancers) and two randomised clinical trials (498 patients; 1 gastric cancer) fulfilled the eligibility criteria. Randomised evidence was very imprecise and provided very-low certainty evidence. Meta-analysis of six NRS providing a comprehensive adjustment for confounding (2.5 million patients; 7372 gastric cancers) did not show any association between PPIs and gastric cancer (RRrandom = 1.07, 0.97-1.19; RRfixed = 1.05, 0.98-1.12). The certainty of the evidence was low. No convincing evidence of dose-response, or increased risk with long-term use, was found. Lack of or minimal adjustment for confounding was associated with larger effect sizes. CONCLUSIONS We found no association between PPIs and gastric cancer in NRS having adequately controlled for confounding. Published studies may suffer residual confounding. SYSTEMATIC REVIEW REGISTRATION CRD42022335971.
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Affiliation(s)
- Daniele Piovani
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,IRCCS Humanitas Research Hospital, Milan, Italy
| | - Andreas G Tsantes
- Laboratory of Haematology and Blood Bank Unit, "Attiko" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.,Microbiology Department, "Saint Savvas" Oncology Hospital, Athens, Greece
| | - Holger J Schünemann
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Michael G DeGroote Cochrane Canada and McMaster GRADE Centres, McMaster University, Hamilton, Ontario, Canada.,Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Stefanos Bonovas
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,IRCCS Humanitas Research Hospital, Milan, Italy
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20
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Abstract
BACKGROUND This study aimed to systematically analyze the association between long-term use of proton pump inhibitors (PPIs) and the risk of gastric cancer (GC). METHODS We performed a systematic search of articles on the relationship between long-term use of PPIs and the risk of GC from PubMed and EMBASE. We calculated the pooled odds ratio of GC in PPI users compared to non-PPI users using random-effects models. RESULTS This meta-analysis included 18 studies from 20 different databases with 4348,905 patients enrolled. In the random effects model, we found that an increased risk of GC among PPI users (OR = 1.94; 95% CI [1.43, 2.64]). The long-term use of PPIs compared with histamine-2 receptor antagonist users did not increase the risk of GC (OR = 1.65; 95% CI [0.92, 2.97]). Stratified analysis showed that PPI users had a significantly increased risk of noncardia GC (OR = 2.53; 95% CI [2.03, 3.15]), but had a relatively small relationship with the risk of gastric cardia cancer. (OR = 1.79; 95% CI [1.06, 3.03]). With the extension of PPI use time, the estimated risk value decreases (<1 year: OR = 6.33, 95% CI [3.76, 10.65]; 1-3 years: OR = 1.82, 95% CI [1.30, 2.55]; >3 years: OR = 1.25, 95% CI [1.00, 1.56]). Despite Helicobacter pylori eradication, the long-term use of PPIs did not alter the increased risk of GC (OR = 2.29; 95% CI [1.57, 3.33]). CONCLUSION Our meta-analysis found that PPI use may be associated with an increased risk of GC. Further research on the causal relationship between these factors is necessary.
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Affiliation(s)
- Huiqin Gao
- Department of Gastroenterology, Guoyang County People’s Hospital, Guoyang Branch of Anhui Provincial Hospital, Guoyang, Anhui, China
| | - Lunan Li
- Department of Gastroenterology, NO.2 People’s Hospital of Fuyang City, Fuyang, Anhui, China
| | - Ke Geng
- Department of Gastroenterology, Guoyang County People’s Hospital, Guoyang Branch of Anhui Provincial Hospital, Guoyang, Anhui, China
| | - Changzheng Teng
- Department of Gastroenterology, Guoyang County People’s Hospital, Guoyang Branch of Anhui Provincial Hospital, Guoyang, Anhui, China
| | - Yuanyuan Chen
- Department of Gastroenterology, Guoyang County People’s Hospital, Guoyang Branch of Anhui Provincial Hospital, Guoyang, Anhui, China
| | - Fei Chu
- Department of Gastroenterology, Guoyang County People’s Hospital, Guoyang Branch of Anhui Provincial Hospital, Guoyang, Anhui, China
| | - Yi Zhao
- Department of Gastroenterology, Guoyang County People’s Hospital, Guoyang Branch of Anhui Provincial Hospital, Guoyang, Anhui, China
- *Correspondence: Yi Zhao, Department of Gastroenterology, Guoyang County People’s Hospital, Guoyang Branch of Anhui Provincial Hospital, No. 189 Xiangyang Road, Guoyang 233600, Anhui, China (e-mail: )
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21
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Zeng R, Sha W, Wang J, Zhuo Z, Wu H, Leung FW, Chen H. Evaluation of proton pump inhibitors and risks of gastric cancer. Gut 2022; 71:1924-1926. [PMID: 34836917 DOI: 10.1136/gutjnl-2021-326291] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 11/09/2021] [Indexed: 02/07/2023]
Affiliation(s)
- Ruijie Zeng
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
- Shantou University Medical College, Shantou, Guangdong, China
| | - Weihong Sha
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Jinghua Wang
- Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Zewei Zhuo
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Huihuan Wu
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Felix W Leung
- Sepulveda Ambulatory Care Center, VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Hao Chen
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
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22
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Dilaghi E, Bellisario M, Esposito G, Carabotti M, Annibale B, Lahner E. The Impact of Proton Pump Inhibitors on the Development of Gastric Neoplastic Lesions in Patients With Autoimmune Atrophic Gastritis. Front Immunol 2022; 13:910077. [PMID: 35935934 PMCID: PMC9353125 DOI: 10.3389/fimmu.2022.910077] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/31/2022] [Indexed: 12/03/2022] Open
Abstract
INTRODUCTION Proton pump inhibitors (PPIs) have been widely prescribed as a primary treatment for acid-related disorders. A large body of literature reported several adverse outcomes due to PPI therapy, including an increased risk of gastric cancer (GC). Autoimmune atrophic gastritis (AAG) is a chronic inflammatory disorder affecting the oxyntic mucosa, leading to mucosal atrophy, intestinal metaplasia, and reduced gastric acid secretion, up to the possible development of dysplasia and intestinal-type GC. Whether PPI use may increase the GC risk in AAG patients has not yet been investigated. We conducted a case-control study in AAG patients to assess the association between the PPI use before AAG diagnosis and the development of GC at follow-up (FU). MATERIALS AND METHODS Patients were included from a prospective cohort of AAG patients (diagnosed 1992-2021) in a referral center for gastric autoimmunity; all patients adhered to an endoscopic-histological FU program according to Management of precancerous conditions and lesions in the stomach (MAPS) I/II (management of epithelial precancerous conditions) guidelines. At diagnosis, clinical/biochemical data and PPI use before AAG diagnosis (withdrawn at the time of diagnosis), for at least 12 months, were evaluated. Patients who developed gastric neoplastic lesions (GNLs) at FU were considered as cases; patients without a diagnosis of GNLs at FU were considered as controls. At a total FU of 2.3 years (1-13), 35 cases were identified, and controls were matched 2:1 by age ( ± 3 years), gender, and years of FU (n=70); therefore, a total of n=105 patients were included in the study. RESULTS The proportion of PPI users before AAG diagnosis was significantly higher in cases than in controls (54.3% vs. 18.6%, p<0.001). At logistic regression, considering as a dependent variable the development of GNLs at FU, a positive association was shown for PPI use before AAG diagnosis (OR 9.6, 95%CI 2.3-40.3), while other independent variables as the use of antiplatelets/anticoagulants (OR 2.8, 95%CI 0.7-12.0), age ≥ 50 years (OR 2.0, 95%CI 0.2-18.1), 1st-degree family history for GC (OR 2.4, 95%CI 0.4-15.2), and smoking habit (OR 0.4, 95%CI 0.1-2.1) were not associated. CONCLUSIONS PPI use before the diagnosis of AAG appears to considerably increase the risk of subsequent GNL development. Considering the common misuse of PPIs, physicians should regularly reevaluate the appropriateness of ongoing PPI therapy, in particular in patients with a clinical suspicion of or already diagnosed AAG.
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23
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Proton Pump Inhibitor Use and Risk of Gastric Cancer: Current Evidence from Epidemiological Studies and Critical Appraisal. Cancers (Basel) 2022; 14:cancers14133052. [PMID: 35804824 PMCID: PMC9264794 DOI: 10.3390/cancers14133052] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/16/2022] [Accepted: 06/19/2022] [Indexed: 12/12/2022] Open
Abstract
Proton pump inhibitors (PPIs) are used for maintaining or improving gastric problems. Evidence from observational studies indicates that PPI therapy is associated with an increased risk of gastric cancer. However, the evidence for PPIs increasing the risk of gastric cancer is still being debated. Therefore, we aimed to investigate whether long-term PPI use is associated with an increased risk of gastric cancer. We systematically searched the relevant literature in electronic databases, including PubMed, EMBASE, Scopus, and Web of Science. The search and collection of eligible studies was between 1 January 2000 and 1 July 2021. Two independent authors were responsible for the study selection process, and they considered only observational studies that compared the risk of gastric cancer with PPI treatment. We extracted relevant information from selected studies, and assessed the quality using the Newcastle−Ottawa scale (NOS). Finally, we calculated overall risk ratios (RRs) with 95% confidence intervals (CIs) of gastric cancer in the group receiving PPI therapy and the control group. Thirteen observational studies, comprising 10,557 gastric cancer participants, were included. Compared with patients who did not take PPIs, the pooled RR for developing gastric cancer in patients receiving PPIs was 1.80 (95% CI, 1.46−2.22, p < 0.001). The overall risk of gastric cancer also increased in patients with gastroesophageal reflux disease (GERD), H. pylori treatment, and various adjusted factors. The findings were also consistent across several sensitivity analyses. PPI use is associated with an increased risk of gastric cancer in patients compared with those with no PPI treatment. The findings of this updated study could be used in making clinical decisions between physicians and patients about the initiation and continuation of PPI therapy, especially in patients at high risk of gastric cancer. Additionally, large randomized controlled trials are needed to determine whether PPIs are associated with a higher risk of gastric cancer.
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24
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Arai J, Aoki T, Sato M, Niikura R, Suzuki N, Ishibashi R, Tsuji Y, Yamada A, Hirata Y, Ushiku T, Hayakawa Y, Fujishiro M. Machine learning-based personalized prediction of gastric cancer incidence using the endoscopic and histologic findings at the initial endoscopy. Gastrointest Endosc 2022; 95:864-872. [PMID: 34998795 DOI: 10.1016/j.gie.2021.12.033] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 12/29/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Accurate risk stratification for gastric cancer is required for optimal endoscopic surveillance in patients with chronic gastritis. We aimed to develop a machine learning (ML) model that incorporates endoscopic and histologic findings for an individualized prediction of gastric cancer incidence. METHODS We retrospectively evaluated 1099 patients with chronic gastritis who underwent EGD and biopsy sampling of the gastric mucosa. Patients were randomly divided into training and test sets (4:1). We constructed a conventional Cox proportional hazard model and 3 ML models. Baseline characteristics, endoscopic atrophy, and Operative Link on Gastritis-Intestinal Metaplasia Assessment (OLGIM)/Operative Link on Gastritis Assessment (OLGA) stage at initial EGD were comprehensively assessed. Model performance was evaluated using Harrel's c-index. RESULTS During a mean follow-up of 5.63 years, 94 patients (8.55%) developed gastric cancer. The gradient-boosting decision tree (GBDT) model achieved the best performance (c-index from the test set, .84) and showed high discriminative ability in stratifying the test set into 3 risk categories (P < .001). Age, OLGIM/OLGA stage, endoscopic atrophy, and history of malignant tumors other than gastric cancer were important predictors of gastric cancer incidence in the GBDT model. Furthermore, the proposed GBDT model enabled the generation of a personalized cumulative incidence prediction curve for each patient. CONCLUSIONS We developed a novel ML model that incorporates endoscopic and histologic findings at initial EGD for personalized risk prediction of gastric cancer. This model may lead to the development of effective and personalized follow-up strategies after initial EGD.
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Affiliation(s)
- Junya Arai
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Tomonori Aoki
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Masaya Sato
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Ryota Niikura
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Nobumi Suzuki
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Rei Ishibashi
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Yosuke Tsuji
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Atsuo Yamada
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Yoshihiro Hirata
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Tetsuo Ushiku
- Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
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25
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Arai J, Niikura R, Hayakawa Y, Aoki T, Yamada A, Kawai T, Fujishiro M. OLGIM staging and proton pump inhibitor use predict the risk of gastric cancer. Gut 2022; 71:1043-1044. [PMID: 34344784 DOI: 10.1136/gutjnl-2021-325551] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 07/11/2021] [Indexed: 12/22/2022]
Affiliation(s)
- Junya Arai
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Ryota Niikura
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan .,Department of Gastroenterological Endoscopy, Tokyo Medical University, Shinjuku-ku, Japan
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Tomonori Aoki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Atsuo Yamada
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Takashi Kawai
- Department of Gastroenterological Endoscopy, Tokyo Medical University, Shinjuku-ku, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
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26
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Arai J, Niikura R, Hayakawa Y, Suzuki N, Hirata Y, Ushiku T, Fujishiro M. Clinicopathological Features of Gastric Cancer with Autoimmune Gastritis. Biomedicines 2022; 10:biomedicines10040884. [PMID: 35453635 PMCID: PMC9031450 DOI: 10.3390/biomedicines10040884] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/01/2022] [Accepted: 04/06/2022] [Indexed: 02/01/2023] Open
Abstract
Most gastric cancers develop in patients with chronic gastritis. Chronic gastritis can be classified into two major subtypes: Helicobacter pylori (H. pylori)-induced gastritis and autoimmune gastritis (AIG). Whereas H. pylori-related gastric cancers are more common and have been extensively investigated, the clinicopathological features of gastric cancer with autoimmune gastritis are unclear. Patients diagnosed with gastric cancer and hospitalized in the University Tokyo Hospital from 1998 to 2017 were enrolled. Diagnosis of autoimmune gastritis was based on positivity for serum anti-parietal cell antibody (APCA). We evaluated mucin expression and immune cell infiltration by immunohistochemical staining for MUC5AC, MUC6, PD-L1, CD3, CD11, Foxp3, and PD1. We also examined the presence of bacterial taxa that are reportedly enriched in AIG. Survival analyses of recurrence and 5-year mortality were also performed. In total, 261 patients (76 APCA-positive and 185 APCA-negative) were analyzed. Immunohistochemical staining in the matched cohort showed that AIG-related gastric cancer had higher MUC5AC expression (p = 0.0007) and MUC6 expression (p = 0.0007). Greater infiltration of CD3-positive (p = 0.001), Foxp3-positive (p < 0.001), and PD1-positive cells (p = 0.001); lesser infiltration of CD11b-positive (p = 0.005) cells; and a higher prevalence of Bacillus cereus (p = 0.006) were found in AIG-related gastric cancer patients. The cumulative incidences of gastric cancer recurrence were 2.99% at 2 years, 15.68% at 6 years, and 18.81% at 10 years in APCA-positive patients; they were 12.79% at 2 years, 21.35% at 6 years, and 31.85% at 10 years in APCA-negative patients. The cumulative incidences of mortality were 0% at 3 years and 0% at 5 years in APCA-positive patients; they were 1.52% at 3 years and 2.56% at 5 years in APCA-negative patients. We identified molecular differences between AIG and non-AIG gastric cancer. Differences in T-cell populations and the gastric microbiota may contribute to the pathogenesis of gastric cancers and potentially affect the response to immunotherapy.
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Affiliation(s)
- Junya Arai
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (J.A.); (N.S.); (Y.H.); (M.F.)
| | - Ryota Niikura
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (J.A.); (N.S.); (Y.H.); (M.F.)
- Department of Gastroenterological Endoscopy, Tokyo Medical University, Tokyo 160-0023, Japan
- Correspondence: (R.N.); (Y.H.); Tel.: +81-3-3342-6111 (R.N.); +81-3-3815-5411 (Y.H.)
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (J.A.); (N.S.); (Y.H.); (M.F.)
- Correspondence: (R.N.); (Y.H.); Tel.: +81-3-3342-6111 (R.N.); +81-3-3815-5411 (Y.H.)
| | - Nobumi Suzuki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (J.A.); (N.S.); (Y.H.); (M.F.)
| | - Yoshihiro Hirata
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (J.A.); (N.S.); (Y.H.); (M.F.)
| | - Tetsuo Ushiku
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan;
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (J.A.); (N.S.); (Y.H.); (M.F.)
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27
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Boo SJ. Are Proton Pump Inhibitors a Risk Factor for Gastric Cancer? THE KOREAN JOURNAL OF GASTROENTEROLOGY 2022. [DOI: 10.4166/kjg.2022.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Sun-Jin Boo
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Korea
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28
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Abrahami D, McDonald EG, Schnitzer ME, Barkun AN, Suissa S, Azoulay L. Proton pump inhibitors and risk of gastric cancer: population-based cohort study. Gut 2022; 71:16-24. [PMID: 34226290 DOI: 10.1136/gutjnl-2021-325097] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 06/18/2021] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To determine whether new users of proton pump inhibitors (PPIs) are at an increased risk of gastric cancer compared with new users of histamine-2 receptor antagonists (H2RAs). DESIGN Using the UK Clinical Practice Research Datalink, we conducted a population-based cohort study using a new-user active comparator design. From 1 January 1990 to 30 April 2018, we identified 973 281 new users of PPIs and 193 306 new users of H2RAs. Cox proportional hazards models were fit to estimate HRs and 95% CIs of gastric cancer, and the number needed to harm was estimated using the Kaplan-Meier method. The models were weighted using standardised mortality ratio weights using calendar time-specific propensity scores. Secondary analyses assessed duration and dose-response associations. RESULTS After a median follow-up of 5.0 years, the use of PPIs was associated with a 45% increased risk of gastric cancer compared with the use of H2RAs (HR 1.45, 95% CI 1.06 to 1.98). The number needed to harm was 2121 and 1191 for five and 10 years after treatment initiation, respectively. The HRs increased with cumulative duration, cumulative omeprazole equivalents and time since treatment initiation. The results were consistent across several sensitivity analyses. CONCLUSION The findings of this large population-based cohort study indicate that the use of PPIs is associated with an increased risk of gastric cancer compared with the use of H2RAs, although the absolute risk remains low.
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Affiliation(s)
- Devin Abrahami
- Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
- Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Montreal, Quebec, Canada
| | - Emily Gibson McDonald
- Division of General Internal Medicine, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
- Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
| | - Mireille E Schnitzer
- Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
- Faculty of Pharmacy and the Department of Social and Preventive Medicine, Universite de Montreal, Montreal, Quebec, Canada
| | - Alan N Barkun
- Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
- Gastroenterology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Samy Suissa
- Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
- Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Montreal, Quebec, Canada
- Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Laurent Azoulay
- Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
- Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Montreal, Quebec, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada
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29
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Arai J, Niikura R, Hayakawa Y, Kawahara T, Honda T, Hasatani K, Yoshida N, Nishida T, Sumiyoshi T, Kiyotoki S, Ikeya T, Arai M, Suzuki N, Tsuji Y, Yamada A, Kawai T, Koike K. Chemoprevention of Oesophageal Squamous-Cell Carcinoma and Adenocarcinoma: A Multicentre Retrospective Cohort Study. Digestion 2021; 103:192-204. [PMID: 34929693 PMCID: PMC9153329 DOI: 10.1159/000520924] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 11/09/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND Oesophageal cancer comprises 2 different histological variants: oesophageal squamous-cell carcinoma (ESCC) and adenocarcinoma (EAC). While there are multiple therapeutic options for both types, patients with advanced or metastatic oesophageal cancer still suffer from poor prognosis. AIMS The study aimed to examine the association between the risk of oesophageal cancer and medications and to estimate the chemopreventive effects of commonly used drugs. METHODS A multicentre retrospective cohort study was conducted using data from 9 hospital databases of hospitalized patients between 2014 and 2019. The primary outcomes were ESCC and EAC. The association of oesophageal cancer with drug use and clinical factors was evaluated. Odds ratios (ORs) were adjusted for age, sex, Charlson comorbidity index scores, and smoking with/without gastro-oesophageal reflux disease. RESULTS The use of proton pump inhibitors (PPIs) (adjusted OR [aOR] 0.48, p < 0.0001), aspirin (aOR 0.32, p < 0.0001), cyclooxygenase-2 inhibitor (COX2I) (aOR 0.70, p = 0.0005), steroid (aOR 0.19, p < 0.0001), statin (aOR 0.43, p < 0.0001), and metformin (aOR 0.42, p < 0.0001) was associated with a lower risk of ESCC than that in non-use. The use of aspirin (aOR 0.33, p = 0.0006) and steroids (aOR 0.54, p = 0.022) was associated with a lower risk of EAC than that in non-use. CONCLUSION COX2Is, statins, metformin, and PPIs could help in prevention of ESCC, and aspirin and steroids may be chemopreventive for both types of oesophageal cancer.
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Affiliation(s)
- Junya Arai
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryota Niikura
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takuya Kawahara
- Clinical Research Promotion Center, The University of Tokyo Hospital, Tokyo, Japan
| | - Tetsuro Honda
- Department of Gastroenterology, Nagasaki Harbor Medical Center, Nagasaki, Japan
| | - Kenkei Hasatani
- Department of Gastroenterology, Fukui Prefectural Hospital, Fukui, Japan
| | - Naohiro Yoshida
- Department of Gastroenterology, Ishikawa Prefectural Central Hospital, Kanazawa-shi, Japan
| | - Tsutomu Nishida
- Department of Gastroenterology, Toyonaka Municipal Hospital, Osaka, Japan
| | | | - Shu Kiyotoki
- Department of Gastroenterology, Shuto General Hospital, Yamaguchi, Japan
| | - Takashi Ikeya
- Department of Gastroenterology, St. Luke's International Hospital, Tokyo, Japan
| | - Masahiro Arai
- Department of Gastroenterology, Nerima Hikarigaoka Hospital, Tokyo, Japan
| | - Nobumi Suzuki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yosuke Tsuji
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Atsuo Yamada
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takashi Kawai
- Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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30
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Segna D, Brusselaers N, Glaus D, Krupka N, Misselwitz B. Association between proton-pump inhibitors and the risk of gastric cancer: a systematic review with meta-analysis. Therap Adv Gastroenterol 2021; 14:17562848211051463. [PMID: 34777575 PMCID: PMC8586163 DOI: 10.1177/17562848211051463] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 09/20/2021] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION The use of proton-pump inhibitors (PPI) may be associated with an increased risk of gastric cancer (GC). OBJECTIVE To review and meta-analyse available literature investigating the association between PPI use and GC risk. METHODS Two independent reviewers systematically searched Ovid MEDLINE, EMBASE, and Cochrane Library (inception to July 2020) for case-control and cohort studies assessing the association between PPI use and GC according to a predefined protocol in PROSPERO (CRD42018102536). Reviewers independently assessed study quality, extracted data, and meta-analysed available and newly calculated odds ratios (ORs) using a random-effects model, and stratified for GC site (cardia versus non-cardia) and PPI duration (<1 year, 1-3 years, >3 years). RESULTS We screened 2,396 records and included five retrospective cohort and eight case-control studies comprising 1,662,881 individuals in our meta-analysis. In random-effect models, we found an increased GC risk in PPI users [OR: 1.94, 95% confidence interval (95% CI): 1.47-2.56] with high statistical heterogeneity (I 2 = 82%) and overall moderate risk of bias. Stratified analyses indicated a significant risk increase in non-cardia (OR: 2.20, 95% CI: 1.44-3.36, I 2 = 77%) with a similar non-significant trend in cardia regions (OR: 1.77, 95% CI: 0.72-4.36, I 2 = 66%). There was no GC increase with longer durations of PPI exposure (<1 year: OR: 2.29, 95% CI: 2.13-2.47, I 2 = 0%; 1-3 years: OR: 1.46, 95% CI: 0.53-4.01, I 2 = 35%; >3 years: OR: 2.08, 95% CI: 0.56-7.77, I 2 = 61%). CONCLUSION We found a twofold increased GC risk among PPI users, but this association does not confirm causation and studies are highly heterogeneous. PPI should only be prescribed when strictly indicated.
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Affiliation(s)
| | - Nele Brusselaers
- Department of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden
| | - Damian Glaus
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Niklas Krupka
- Department of Visceral Surgery and Medicine, Inselspital Bern and Bern University, Bern, Switzerland
| | - Benjamin Misselwitz
- Department of Visceral Surgery and Medicine, Inselspital Bern and Bern University, Bern, Switzerland,Clinic of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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Seo SI, Park CH, You SC, Kim JY, Lee KJ, Kim J, Kim Y, Yoo JJ, Seo WW, Lee HS, Shin WG. Association between proton pump inhibitor use and gastric cancer: a population-based cohort study using two different types of nationwide databases in Korea. Gut 2021; 70:2066-2075. [PMID: 33975868 DOI: 10.1136/gutjnl-2020-323845] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 04/23/2021] [Accepted: 04/24/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVE The association between proton pump inhibitor (PPI) use and gastric cancer related to Helicobacter pylori eradication has not been fully investigated in geographical regions with high risk of gastric cancer. We aimed to evaluate the association between PPIs and gastric cancer in Korea. DESIGN This study analysed the original and common data model versions of the Korean National Health Insurance Service database from 2002 to 2013. We compared the incidence rates of gastric cancer after 1-year drug exposure, between new users of PPIs and other drugs excluding PPIs, by Cox proportional hazards model. We also analysed the incidence of gastric cancer among PPI users after H. pylori eradication. RESULTS The analysis included 11 741 patients in matched PPI and non-PPI cohorts after large-scale propensity score matching. During a median follow-up of 4.3 years, PPI use was associated with a 2.37-fold increased incidence of gastric cancer (PPI≥30 days vs non-PPI; 118/51 813 person-years vs 40/49 729 person-years; HR 2.37, 95% CI 1.56 to 3.68, p=0.001). The incidence rates of gastric cancer showed an increasing trend parallel to the duration of PPI use. In H. pylori-eradicated subjects, the incidence of gastric cancer was significantly associated with PPI use over 180 days compared with the non-PPI group (PPI≥180 days vs non-PPI; 30/12 470 person-years vs 9/7814 person-years; HR 2.22, 95% CI 1.05 to 4.67, p=0.036). CONCLUSION PPI use was associated with gastric cancer, regardless of H. pylori eradication status. Long-term PPIs should be used with caution in high-risk regions for gastric cancer.
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Affiliation(s)
- Seung In Seo
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, South Korea
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, South Korea
| | - Chan Hyuk Park
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, South Korea
| | - Seng Chan You
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Jae Young Kim
- University Industry Foundation, Hallym University, Chuncheon, South Korea
| | - Kyung Joo Lee
- University Industry Foundation, Hallym University, Chuncheon, South Korea
| | - Jinseob Kim
- Department of Epidemiology, School of Public Health, Seoul National University, Seoul, South Korea
| | - Yerim Kim
- Department of Neurology, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, South Korea
| | - Jong Jin Yoo
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, South Korea
| | - Won-Woo Seo
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, South Korea
| | - Hyung Seok Lee
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea
| | - Woon Geon Shin
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, South Korea
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, South Korea
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Zeng R, Cheng Y, Luo D, Wang J, Yang J, Jiang L, Zhuo Z, Guo K, Wu H, Leung FW, Sha W, Chen H. Comprehensive analysis of proton pump inhibitors and risk of digestive tract cancers. Eur J Cancer 2021; 156:190-201. [PMID: 34481369 DOI: 10.1016/j.ejca.2021.07.030] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/20/2021] [Accepted: 07/26/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND For the past two decades, dispute on whether proton pump inhibitor (PPI) leads to digestive tract cancer remains, and emerging studies in recent years still demonstrate inconsistent results, which continues to perpetuate concerns over the safety of PPI use. We performed a systematic review and meta-analysis, with comprehensive evaluation by Bradford Hill criteria of causation, to assess the effect of PPI use on digestive tract cancers. METHODS Medline, Embase and Web of Science databases were searched for observational studies published up to 15th January 2021. Pooled relative risks (RRs) were estimated via random effects models. Cumulative defined daily dose- and duration-risk relationships using restricted cubic spline and fractional polynomial models were investigated. Bradford Hill criteria were applied to evaluate causation. PROSPERO Registration: CRD42020211103. RESULTS Thirty-two publications containing 4,355,254 participants were included. PPI use is associated with an increased risk of overall digestive tract cancers (RR = 1.63, 95% confidence interval (CI) 1.33 to 2.00). PPI use is correlated with increased risks of gastric cancer (RR = 1.78, 95% CI 1.38 to 2.31), pancreatic cancer (RR = 1.72, 95% CI 1.05 to 2.82) and liver cancer (RR = 1.62, 95% CI 1.04 to 2.52), but not of esophageal cancer (RR = 2.06, 95% CI 0.65 to 6.57) and colorectal cancer (RR = 1.24, 95% CI 0.93 to 1.66). The association between PPI and digestive tract cancers is stronger in people with minimal exposure. When cumulative defined daily dose or duration increases, the risks decline and become non-significant. Evaluation by Bradford Hill criteria indicates weak evidence of causation. CONCLUSIONS A causal relationship between PPI use and digestive tract cancers is not supported by the evidence in the current review. Concerns over carcinogenic side-effects of PPI might be unfounded.
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Affiliation(s)
- Ruijie Zeng
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China; Shantou University Medical College, Shantou 515041, China
| | - Yunjiu Cheng
- Department of Cardiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Dongling Luo
- Department of Cardiology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China
| | - Jinghua Wang
- Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Jun Yang
- Institute for Environmental and Climate Research, Jinan University, Guangzhou 511443, China
| | - Lei Jiang
- Guangdong Geriatrics Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Zewei Zhuo
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Kehang Guo
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Huihuan Wu
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Felix W Leung
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Sepulveda Ambulatory Care Center, Veterans Affairs Greater Los Angeles Healthcare System, North Hills, CA, USA.
| | - Weihong Sha
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
| | - Hao Chen
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
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Kang S, Cho SJ. Proton Pump Inhibitors and Gastric Cancer. THE KOREAN JOURNAL OF HELICOBACTER AND UPPER GASTROINTESTINAL RESEARCH 2021. [DOI: 10.7704/kjhugr.2021.0010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Concerns have been raised regarding the long-term use of proton pump inhibitors (PPIs) as an important risk factor for gastric cancer in clinical practice. PPIs can cause hypergastrinemia at clinical doses, and hypergastrinemia has been reported to induce malignant neoplasms in the stomach in previous animal studies. In humans, the proliferation of enterochromaffin-like (ECL) cells induced by hypergastrinemia is suspected as a potential mechanism of gastric cancer. Meanwhile, persistent Helicobacter pylori (H. pylori) infection causes gastric atrophic change, which itself is a major cause of gastric cancer, and it can further increase the risk of gastric cancer by strengthening corpus atrophy through interaction with PPIs. Recent epidemiologic studies have reported an important link between long-term PPI intake and gastric cancer risk even after successful eradication of H. pylori. However, due to the methodological limitations of observational clinical studies, the causal relationship is still not clear, and a recent big data-based study reported that long-term PPI use was not related to gastric cancer incidence. Taken together, despite the potential detrimental effects of PPIs, it is currently difficult to draw a definite conclusion about its association with gastric cancer. To minimize the possibility of gastric cancer in H. pylori-infected patients or precancerous lesions in long-term PPI users, long-term PPI administration should be limited to the minimum effective dose, and antibacterial treatment for H. pylori should be considered.
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Arai J, Niikura R, Hayakawa Y, Sato H, Kawahara T, Honda T, Hasatani K, Yoshida N, Nishida T, Sumiyoshi T, Kiyotoki S, Ikeya T, Arai M, Suzuki N, Tsuji Y, Yamada A, Koike K. Nonsteroidal anti-inflammatory drugs prevent gastric cancer associated with the use of proton pump inhibitors after Helicobacter pylori eradication. JGH Open 2021; 5:770-777. [PMID: 34263071 PMCID: PMC8264245 DOI: 10.1002/jgh3.12583] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 03/19/2021] [Accepted: 05/23/2021] [Indexed: 11/06/2022]
Abstract
BACKGROUND AND AIM Proton pump inhibitors (PPIs) are a potential cause of gastric carcinogenesis after Helicobacter pylori eradication. Thus, appropriate management including chemoprevention is required. The aim of this study was to evaluate the association between nonsteroidal anti-inflammatory drugs (NSAIDs) and the incidence of post-eradication gastric cancer in PPI users. METHODS A multicenter retrospective cohort study was conducted. Patients who used a PPI (≥30 days) after H. pylori eradication between 2014 and 2019 were analyzed in nine hospital databases. Gastric cancer incidence was a primary outcome, and their association with NSAIDs use and clinical factors was evaluated. Hazard ratios were adjusted by age, sex, smoking, and Charlson Comorbidity Index. RESULTS During the mean follow-up period of 2.38 years, 1.13% (31/2431) of all patients developed gastric cancer. The cumulative incidence of gastric cancer in PPI users was 0.25% at 1 year, 0.51% at 3 years, and 1.09% at 5 years in the NSAID users and 0.89% at 1 year, 2.32% at 3 years, and 3.61% at 5 years in nonusers. NSAIDs were associated with a lower gastric cancer risk (adjusted hazard ratio = 0.28, P = 0.005). No gastric cancer was observed in the cyclooxygenase-2 inhibitor users (n = 256). NSAID use with high dose and long duration was significantly associated with a lower incidence of gastric cancer. CONCLUSION NSAIDs were associated with a 60% decrease in the gastric cancer incidence in H. pylori-eradicated PPI users, with dose and duration response effects. NSAIDs may be effective for chemoprevention against PPI-related gastric cancer.
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Affiliation(s)
- Junya Arai
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoBunkyo CityTokyoJapan
| | - Ryota Niikura
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoBunkyo CityTokyoJapan
- Department of Gastroenterological EndoscopyTokyo Medical UniversityShinjuku‐kuTokyoJapan
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoBunkyo CityTokyoJapan
| | - Hiroki Sato
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoBunkyo CityTokyoJapan
| | - Takuya Kawahara
- Clinical Research Promotion CenterThe University of Tokyo HospitalBunkyo CityTokyoJapan
| | - Tetsuro Honda
- Department of GastroenterologyNagasaki Harbor Medical CenterNagasaki‐shiNagasakiJapan
| | - Kenkei Hasatani
- Department of GastroenterologyFukui Prefectural HospitalFukui‐shiFukuiJapan
| | - Naohiro Yoshida
- Department of GastroenterologyIshikawa Prefectural Central HospitalKanazawa‐shiIshikawaJapan
| | - Tsutomu Nishida
- Department of GastroenterologyToyonaka Municipal HospitalToyonaka‐shiOsakaJapan
| | - Tetsuya Sumiyoshi
- Department of GastroenterologyTonan HospitalSapporo‐shiHokkaidoJapan
| | - Shu Kiyotoki
- Department of GastroenterologyShuto General HospitalYanai‐shiYamaguchiJapan
| | - Takashi Ikeya
- Department of GastroenterologySt. Luke's International HospitalChuo‐kuTokyoJapan
| | - Masahiro Arai
- Department of GastroenterologyNerima Hikarigaoka HospitalNerima‐kuTokyoJapan
| | - Nobumi Suzuki
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoBunkyo CityTokyoJapan
| | - Yosuke Tsuji
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoBunkyo CityTokyoJapan
| | - Atsuo Yamada
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoBunkyo CityTokyoJapan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of MedicineThe University of TokyoBunkyo CityTokyoJapan
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Gastrin and the Moderate Hypergastrinemias. Int J Mol Sci 2021; 22:ijms22136977. [PMID: 34209478 PMCID: PMC8269006 DOI: 10.3390/ijms22136977] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/14/2021] [Accepted: 06/17/2021] [Indexed: 12/12/2022] Open
Abstract
The antral hormone gastrin potently regulates gastric acid secretion and fundic mucosal growth. Consequently, appropriate gastrin secretion and plasma concentrations are important for the early phases of digestion. This review describes as the first premise the normal biogenesis of gastrin in the antral mucosa, but also mentions the extraantral expression. Subsequently, the molecular nature and concentration levels of gastrin in serum or plasma are overviewed. Third, assays for accurate measurements of plasma or serum concentrations are commented. Finally, the problem of moderate hypergastrinemia due to Helicobacter pylori infections and/or treatment with proton-pump inhibitors (PPI) is discussed. The review concludes that accurate measurement of the true concentrations of bioactive gastrins in plasma is important. Moreover, it suggests that moderate hypergastrinemias are also essential health issues that require serious attention.
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Use of Proton Pump Inhibitors vs Histamine 2 Receptor Antagonists for the Risk of Gastric Cancer: Population-Based Cohort Study. Am J Gastroenterol 2021; 116:1211-1219. [PMID: 34074826 DOI: 10.14309/ajg.0000000000001167] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Accepted: 12/29/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Proton pump inhibitors (PPIs) are commonly prescribed medications. Long-term use of PPIs has been suspected to have a provocative effect on gastric cancer. This study was to determine the association between PPI vs histamine 2 receptor antagonist (H2RA) use and the risk of gastric cancer in a region where the risk of this malignancy is high. METHODS A population-based cohort study using the Korean National Health Insurance Services Database. The participants with first prescription of PPIs and H2RA with normal esophagogastroduodenoscopy finding from 2004 through 2015 were collected. Among them, 50% of participants were systematic stratified randomly sampled. There were 122,118 users of PPIs or H2RAs who use medication more than cumulative defined daily dose of 180 days. The users were followed up from long-term use threshold until gastric cancer, death from non-gastric cancer cause, gastric surgery, or study end (December 2017). RESULTS After calculating propensity score weights, we included 39,799 PPI and 38,967 H2RA users. Among the new PPI and H2RA users, we identified 411 cases of incident gastric cancer from 182,643 person-years of follow-up observation and 397 cases from 178,846 person-years of follow-up observation, respectively. Compared with H2RA users, PPI users did not experience significantly different gastric cancer incidence (adjusted hazard ratio, 1.01; 95% confidence interval, 0.88-1.16; P = 0.89). Sensitivity analyses confirmed that gastric cancer incidence did not differ between PPI and H2RA users. DISCUSSION In this large study, long-term treatment with PPIs vs H2RAs did not show higher risk of gastric cancer even in a high-risk region.
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Weltermann T, Schulz C, Macke L. Effect of frequently prescribed drugs on gastric cancer risk. Best Pract Res Clin Gastroenterol 2021; 50-51:101741. [PMID: 33975680 DOI: 10.1016/j.bpg.2021.101741] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 02/07/2023]
Abstract
Gastric cancer is the fifth leading cancer worldwide. Infection with Helicobacter pylori represents the major risk factor, but only a small fraction of infected individuals will develop neoplasia. The progression of advanced gastric lesions to cancer is influenced by characteristics of the bacterial strain, host genetic and environmental factors. Recently, the effect of medications on gastric cancer risk has gained interest, because many commonly prescribed drugs affect gastric homeostasis. While non-steroidal anti-inflammatory drugs (NSAIDs) are a frequent cause of gastric ulcer disease, low-dose aspirin has been propagated for chemoprevention of various tumour entities. Beneficial effects of cyclooxygenase-inhibition for gastric cancer prevention is plausible, but its clinical relevance remains unclear. Furthermore, anti-tumorous effects have been postulated for statins and metformin. On the contrary, proton pump inhibitors (PPIs), which are commonly used for prevention of gastric ulcers and bleeding, have been associated with an increased gastric cancer risk in large observational studies. Most of these observations still require confirmation in prospective controlled trials. NSAIDs, statins and metformin have also been investigated as concomitant cancer treatment, but studies did not show convincing results to date. Here, we review the available evidence and possible mechanisms for the role of PPIs, NSAIDs, statins and metformin in gastric carcinogenesis, and discuss possible implications for clinical practice.
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Affiliation(s)
- Theresa Weltermann
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany, Marchioninistr. 15, 81377, Munich, Germany.
| | - Christian Schulz
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany, Marchioninistr. 15, 81377, Munich, Germany.
| | - Lukas Macke
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany, Marchioninistr. 15, 81377, Munich, Germany.
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Oya Y, Hayakawa Y, Koike K. Tumor microenvironment in gastric cancers. Cancer Sci 2020; 111:2696-2707. [PMID: 32519436 PMCID: PMC7419059 DOI: 10.1111/cas.14521] [Citation(s) in RCA: 196] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 05/25/2020] [Accepted: 06/01/2020] [Indexed: 02/06/2023] Open
Abstract
The tumor microenvironment favors the growth and expansion of cancer cells. Many cell types are involved in the tumor microenvironment such as inflammatory cells, fibroblasts, nerves, and vascular endothelial cells. These stromal cells contribute to tumor growth by releasing various molecules to either directly activate the growth signaling in cancer cells or remodel surrounding areas. This review introduces recent advances in findings on the interactions within the tumor microenvironment such as in cancer-associated fibroblasts (CAFs), immune cells, and endothelial cells, in particular those established in mouse gastric cancer models. In mice, myofibroblasts in the gastric stroma secrete R-spondin and support normal gastric stem cells. Most CAFs promote tumor growth in a paracrine manner, but CAF population appears to be heterogeneous in terms of their function and origin, and include both tumor-promoting and tumor-restraining populations. Among immune cell populations, tumor-associated macrophages, including M1 and M2 macrophages, and myeloid-derived suppressor cells (MDSCs), are reported to directly or indirectly promote gastric tumorigenesis by secreting soluble factors or modulating immune responses. Endothelial cells or blood vessels not only fuel tumors with nutrients, but also interact with cancer stem cells and immune cells by secreting chemokines or cytokines, and act as a cancer niche. Understanding these interactions within the tumor microenvironment would contribute to unraveling new therapeutic targets.
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Affiliation(s)
- Yukiko Oya
- Department of GastroenterologyGraduate school of Medicinethe University of TokyoTokyoJapan
| | - Yoku Hayakawa
- Department of GastroenterologyGraduate school of Medicinethe University of TokyoTokyoJapan
| | - Kazuhiko Koike
- Department of GastroenterologyGraduate school of Medicinethe University of TokyoTokyoJapan
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Liu P, McMenamin ÚC, Johnston BT, Murchie P, Iversen L, Lee AJ, Vissers PAJ, Cardwell CR. Use of proton pump inhibitors and histamine-2 receptor antagonists and risk of gastric cancer in two population-based studies. Br J Cancer 2020; 123:307-315. [PMID: 32367073 PMCID: PMC7374738 DOI: 10.1038/s41416-020-0860-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 03/27/2020] [Accepted: 04/08/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Studies have shown increased gastric cancer risk in users of proton pump inhibitors (PPI) and histamine-2 receptor antagonists, questioning the safety of gastric acid suppression. Therefore, we conducted a case-control study within the Scottish Primary Care Clinical Informatics Unit (PCCIU) database and a cohort study in the UK Biobank. METHODS In PCCIU, five controls were matched to cases diagnosed in 1999-2011, and medications were determined from GP records. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression. In the UK Biobank, medications were self-reported at cohort entry 2006-2010, and gastric cancer ascertained from cancer registries until 2014. Hazard ratios (HR) were calculated using Cox regression. RESULTS PCCIU contained 1119 cases and 5394 controls. UK Biobank contained 250 cases in 471,779 participants. PPI users had a higher gastric cancer risk in PCCIU and UK Biobank when applying a 1-year lag (adjusted OR = 1.49, 95% CI 1.24, 1.80; adjusted HR = 1.28, 95% CI 0.86, 1.90, respectively), but these associations were attenuated when using a 2-year lag (adjusted OR = 1.13, 95% CI 0.91, 1.40; adjusted HR = 1.15, 95% CI 0.73, 1.82, respectively). CONCLUSIONS Overall, we observed little consistent evidence of an increased risk of gastric cancer with PPI use.
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Affiliation(s)
- Peipei Liu
- Centre for Public Health, Queen's University Belfast, Belfast, UK.
| | - Úna C McMenamin
- Centre for Public Health, Queen's University Belfast, Belfast, UK
| | | | - Peter Murchie
- Academic Primary Care, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK
| | - Lisa Iversen
- Academic Primary Care, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK
| | - Amanda J Lee
- Medical Statistics Team, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK
| | - Pauline A J Vissers
- Department of Research, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, The Netherlands
| | - Chris R Cardwell
- Centre for Public Health, Queen's University Belfast, Belfast, UK
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The association between acid-suppressive agent use and the risk of cancer: a systematic review and meta-analysis. Eur J Clin Pharmacol 2020; 76:1437-1456. [PMID: 32548678 DOI: 10.1007/s00228-020-02927-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 06/01/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Acid-suppressive agents (ASAs) may be associated with cancer; previous studies reported that the risk of cancer with acid suppressants has differed depending on the site of cancer. Here, we conducted a systematic review and meta-analysis of the association between ASA use and the type of cancer risk. METHODS MEDLINE, EMBASE, and Cochrane library databases were searched for publications up to the end of September 2019 for MeSH terms and text words related to cancer and ASAs. Studies on the association between ASAs and cancer risk, which included a control group and reported the relative risk of cancer, were included. The inverse-variance random effect model was used to estimate the pooled relative risk (RR) and 95% confidence interval (CI), and subgroup analysis for type of acid suppressants, drug uptake duration, and cumulative doses was performed. Heterogeneity was assessed using the I2 test and Q statistic. RESULTS Thirty-nine cohort and case-control studies were included. ASA use was found to be significantly associated with a 46% higher risk of gastric cancer (RR, 1.46; 95% CI, 1.18-1.80) and a 53% higher risk of liver cancer (RR, 1.53; 95% CI, 1.31-1.78) compared with nonuse; however, there was no significant association for esophageal, colorectal, pancreatic, lung, breast, prostate, and kidney cancer; melanoma; and lymphoma. CONCLUSIONS ASAs were significantly associated with an increased risk of gastric and liver cancer; therefore, special attention of ASA use considering the potential risk of gastric and liver cancer is needed.
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Nawata Y, Ichihara S, Hirasawa D, Tanaka I, Unno S, Igarashi K, Matsuda T. A case of gastric adenocarcinoma considered to originate from a sporadic fundic gland polyp in a Helicobacter pylori-uninfected stomach. Clin J Gastroenterol 2020; 13:740-745. [PMID: 32468503 DOI: 10.1007/s12328-020-01139-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 05/19/2020] [Indexed: 12/19/2022]
Abstract
We encountered a rare case of gastric adenocarcinoma considered to arise from a sporadic fundic gland polyp (FGP). A woman in her 70 s, who had been prescribed a proton pump inhibitor for 5 years, was referred to our institution for further investigation and treatment of a gastric lesion. White light endoscopy showed numerous isochromatic FGPs in the greater curvature of the gastric body and a 15-mm reddish polypoid lesion with uneven surface characteristics. Magnifying endoscopy with narrow band imaging revealed an irregular granular microsurface structure with irregular microvessels, which is suggestive of cancer. The absence of atrophic changes in the entire gastric mucosa was confirmed endoscopically and histologically, and multiple Helicobacter pylori (HP) tests were negative. An en bloc resection was performed by polypectomy. The specimen showed adenocarcinoma that was thought to arise from an FGP. The lesion consisted of cystically dilated fundic glands in the basal part and neoplastic cells with nuclear atypia and high nuclear-cytoplasmic ratio in the foveolar part; on the basis of these findings, noninvasive adenocarcinoma was diagnosed. Although both adenocarcinoma in an HP-uninfected stomach and epithelial high-grade dysplasia in a sporadic FGP are extremely rare, this possibility should be considered when performing esophagogastroduodenoscopy.
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Affiliation(s)
- Yoshitaka Nawata
- Department of Gastroenterology, Sendai Kousei Hospital, 4-15 Hirosemachi, Aoba-ku, Sendai-shi, Miyagi-ken, 980-0873, Japan.
| | - Shin Ichihara
- Department of Surgical Pathology, Sapporo Kosei General Hospital, 8-5 Kita3-johigashi, Chuo-ku, Sapporo-shi, Hokkaido, 060-0033, Japan
| | - Dai Hirasawa
- Department of Gastroenterology, Sendai Kousei Hospital, 4-15 Hirosemachi, Aoba-ku, Sendai-shi, Miyagi-ken, 980-0873, Japan
| | - Ippei Tanaka
- Department of Gastroenterology, Sendai Kousei Hospital, 4-15 Hirosemachi, Aoba-ku, Sendai-shi, Miyagi-ken, 980-0873, Japan
| | - Shuuhei Unno
- Department of Gastroenterology, Sendai Kousei Hospital, 4-15 Hirosemachi, Aoba-ku, Sendai-shi, Miyagi-ken, 980-0873, Japan
| | - Kimihiro Igarashi
- Department of Gastroenterology, Sendai Kousei Hospital, 4-15 Hirosemachi, Aoba-ku, Sendai-shi, Miyagi-ken, 980-0873, Japan
| | - Tomoki Matsuda
- Department of Gastroenterology, Sendai Kousei Hospital, 4-15 Hirosemachi, Aoba-ku, Sendai-shi, Miyagi-ken, 980-0873, Japan
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Gastric Corpus Mucosal Hyperplasia and Neuroendocrine Cell Hyperplasia, but not Spasmolytic Polypeptide-Expressing Metaplasia, Is Prevented by a Gastrin Receptor Antagonist in H +/K +ATPase Beta Subunit Knockout Mice. Int J Mol Sci 2020; 21:ijms21030927. [PMID: 32023822 PMCID: PMC7037105 DOI: 10.3390/ijms21030927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 01/28/2020] [Accepted: 01/29/2020] [Indexed: 11/23/2022] Open
Abstract
Proton pump inhibitor use is associated with an increased risk of gastric cancer, which may be mediated by hypergastrinemia. Spasmolytic polypeptide-expression metaplasia (SPEM) has been proposed as a precursor of gastric cancer. We have examined the effects of the gastrin receptor antagonist netazepide (NTZ) or vehicle on the gastric corpus mucosa of H+/K+ATPase beta subunit knockout (KO) and wild-type (WT) mice. The gastric corpus was evaluated by histopathology, immunohistochemistry (IHC), in situ hybridization (ISH) and whole-genome gene expression analysis, focusing on markers of SPEM and neuroendocrine (NE) cells. KO mice had pronounced hypertrophy, intra- and submucosal cysts and extensive expression of SPEM and NE cell markers in the gastric corpus, but not in the antrum. Numerous SPEM-related genes were upregulated in KO mice compared to WT mice. NTZ reduced hypertrophia, cysts, inflammation and NE hyperplasia. However, NTZ neither affected expression of SPEM markers nor of SPEM-related genes. In conclusion, NTZ prevented mucosal hypertrophy, cyst formation and NE cell hyperplasia but did not affect SPEM. The presence of SPEM seems unrelated to the changes caused by hypergastrinemia in this animal model.
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Jiang K, Jiang X, Wen Y, Liao L, Liu FB. Relationship between long-term use of proton pump inhibitors and risk of gastric cancer: A systematic analysis. J Gastroenterol Hepatol 2019; 34:1898-1905. [PMID: 31206764 DOI: 10.1111/jgh.14759] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 05/25/2019] [Accepted: 05/29/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM This study aims to systematically analyze the effect of long-term therapy with proton pump inhibitors (PPIs) on the risk of gastric cancer. METHODS PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), and China biomedical literature database (CBM) were searched for studies before February 2019. We evaluated the quality of the included articles through the Newcastle-Ottawa Scale and gathered relevant data to calculate the pooled odds ratio (OR) through Stata14.0. RESULTS Seven relevant articles conformed to the inclusion criteria; 943 070 patients were included. The pooled OR was 2.50; 95% CI (1.74, 3.85); the subgroup analysis results showed that patients who had used PPIs for more than 36 months were most likely to develop gastric cancer, and an increased risk was observed among patients after Helicobacter pylori eradication. Noncardia gastric cancer was more likely to develop. CONCLUSIONS Long-term use of PPIs can possibly increase the risk of gastric cancer even among patients after H. pylori eradication; in particular, for noncardia gastric cancer, the risk increases with longer durations of PPI use. Due to the limited number of studies, more high-quality studies are required to be designed.
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Affiliation(s)
- Kailin Jiang
- First College of Clinic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaotao Jiang
- First College of Clinic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yi Wen
- First College of Clinic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Liu Liao
- First College of Clinic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Feng-Bin Liu
- Department of Gastroenterology, First Affiliation Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
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Adverse Effects of Proton Pump Inhibitors-Evidence and Plausibility. Int J Mol Sci 2019; 20:ijms20205203. [PMID: 31640115 PMCID: PMC6829383 DOI: 10.3390/ijms20205203] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 10/17/2019] [Accepted: 10/18/2019] [Indexed: 12/12/2022] Open
Abstract
Proton pump inhibitors (PPIs) have been increasingly used over the last decades and there are concerns about overuse and the numerous reported side-effects. It is uncertain whether associations between PPI use and potential side effects are causal. However, important evidence from experimental and mechanistic studies that could support a causal relationship may have been underestimated by epidemiologists and meta-analysists. In the current manuscript we review the combined epidemiological and mechanistic evidence of the adverse effects of PPI use.
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Waldum HL, Rehfeld JF. Gastric cancer and gastrin: on the interaction of Helicobacter pylori gastritis and acid inhibitory induced hypergastrinemia. Scand J Gastroenterol 2019; 54:1118-1123. [PMID: 31524029 DOI: 10.1080/00365521.2019.1663446] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Gastric cancer, a disease with a reduced frequency for decades, now appears to be on the rise again in young Americans. The epidemiology of gastric cancer differs between tumors in the cardia and those of the more distal parts of the stomach. The tumors are divided into the intestinal type showing glandular growth pattern and the diffuse type with a different pattern. The latter often expresses neuroendocrine and more specifically ECL-cell markers suggesting that they originate from the ECL cell, the target cell for the antral hormone, gastrin. Helicobacter pylori gastritis is accepted as the major cause of gastric cancer, but only after having induced oxyntic atrophy which reduces gastric acid secretion and thus induces hypoacidity leading to hypergastrinemia. Long-term hypergastrinemia is known to induce malignant neoplasia in the stomach of animals as well as man. Recently treatment with proton pump inhibitor after Helicobacter pylori eradication in patients with gastroesophageal reflux disease, has been reported to predispose to gastric cancer. Since profound acid inhibition is a well-known cause of gastric neoplasia, it is to be expected that Helicobacter pylori infection and profound acid inhibition has an additive or possibly potentiating effect on the development of gastric cancer.
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Affiliation(s)
- Helge L Waldum
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology , Trondheim , Norway
| | - Jens F Rehfeld
- Department of Clinical Biochemistry , Rigshospitalet, Copenhagen , Denmark
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The Reduction in Gastric Atrophy after Helicobacter pylori Eradication Is Reduced by Treatment with Inhibitors of Gastric Acid Secretion. Int J Mol Sci 2019; 20:ijms20081913. [PMID: 31003453 PMCID: PMC6515232 DOI: 10.3390/ijms20081913] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 04/15/2019] [Accepted: 04/16/2019] [Indexed: 02/06/2023] Open
Abstract
Background: Helicobacter pylori (H. pylori) eradication therapy may improve gastric atrophy and intestinal metaplasia, but the results of previous studies have not always been consistent. The aim of this study was to compare the histological changes of intestinal metaplasia and gastric atrophy among the use of acid-suppressing drugs after H. pylori eradication. Methods: A cohort of 242 patients who underwent successful eradication therapy for H. pylori gastritis and surveillance endoscopy examination from 1996 to 2015 was analyzed. Changes in the histological scores of intestinal metaplasia and atrophy according to drug use (proton-pump inhibitors (PPIs), H2 receptor antagonists (H2RAs), and non-acid suppressant use) were evaluated in biopsies of the antrum and corpus using a generalized linear mixed model in all patients. Results: The mean follow-up period and number of biopsies were 5.48 ± 4.69 years and 2.62 ± 1.67 times, respectively. Improvement in the atrophy scores of both the antrum (p = 0.042) and corpus (p = 0.020) were significantly superior in patients with non-acid suppressant drug use compared with those of PPI and H2RA use. Metaplasia scores in both the antrum and corpus did not improve in all groups, and no significant differences were observed among groups in the antrum (p = 0.271) and corpus (p = 0.077). Conclusions: Prolonged acid suppression by PPIs or H2RAs may limit the recovery of gastric atrophy following H. pylori eradication.
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Wan QY, Wu XT, Li N, Du L, Zhou Y. Long-term proton pump inhibitors use and risk of gastric cancer: a meta-analysis of 926 386 participants. Gut 2019; 68:762-764. [PMID: 29615489 DOI: 10.1136/gutjnl-2018-316416] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 03/18/2018] [Accepted: 03/24/2018] [Indexed: 01/24/2023]
Affiliation(s)
- Qian-Yi Wan
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Xiao-Ting Wu
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Ni Li
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
| | - Liang Du
- Chinese Evidence-Based Medicine/Cochrane Center, Chengdu, China
| | - Yong Zhou
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
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Cheung KS, Leung WK. Long-term use of proton-pump inhibitors and risk of gastric cancer: a review of the current evidence. Therap Adv Gastroenterol 2019; 12:1756284819834511. [PMID: 30886648 PMCID: PMC6415482 DOI: 10.1177/1756284819834511] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 02/06/2019] [Indexed: 02/04/2023] Open
Abstract
Gastric cancer remains one of the leading cancers in the world with a high mortality, particularly in East Asia. Helicobacter pylori infection accounts for the majority of the noncardia gastric cancers by triggering gastric inflammation and subsequent neoplastic progression. Eradication of H. pylori can reduce, but not totally eliminate, subsequent risk of developing gastric cancer. Proton-pump inhibitors (PPIs) are one of the most widely prescribed medications worldwide. With their profound gastric-acid suppression, there are concerns about a possible carcinogenic role in gastric cancer, due to induced hypergastrinemia, gastric atrophy and bacterial overgrowth in the stomach. While randomized clinical trials to establish causality between long-term PPI use and gastric cancer are lacking, current evidence based on observational studies suggests PPIs are associated with an increased gastric cancer risk. However, opinions on causality remain divergent due to unmeasured and possible residual confounding in various studies. Our recent study has showed that even after H. pylori eradication, long-term PPI use is still associated with an increased risk of gastric cancer by more than twofold. Hence, long-term PPIs should be used judiciously after considering individual's risk-benefit profile, particularly among those with history of H. pylori infection. Further well-designed prospective studies are warranted to confirm the potential role of PPIs in gastric cancer according to baseline gastric histology and its interaction with other chemopreventive agents like aspirin, statins and metformin.
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Affiliation(s)
- Ka Shing Cheung
- Department of Medicine, The University of Hong Kong, Hong Kong
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Lai SW. Association between proton pump inhibitors therapy and the risk of gastric cancer. Scand J Gastroenterol 2019; 54:390. [PMID: 30856029 DOI: 10.1080/00365521.2019.1583367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- Shih-Wei Lai
- a College of Medicine , China Medical University , Taichung , Taiwan.,b Department of Family Medicine , China Medical University Hospital , Taichung , Taiwan
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50
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Brusselaers N, Lagergren J. Maintenance use of non-steroidal anti-inflammatory drugs and risk of gastrointestinal cancer in a nationwide population-based cohort study in Sweden. BMJ Open 2018; 8:e021869. [PMID: 29982219 PMCID: PMC6042574 DOI: 10.1136/bmjopen-2018-021869] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 05/17/2018] [Accepted: 05/24/2018] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are potential candidates for chemoprevention of gastrointestinal cancer. We aimed to assess the association between contemporary NSAID use (≥180 days) and gastrointestinal cancer. DESIGN Nationwide Swedish population-based cohort study (2005-2012). SETTING Sweden PARTICIPANTS: All adults exposed to maintenance NSAIDs use (aspirin, n=783 870; unselective NSAIDs, n=566 209, selective cyclo-oxygenase (COX)-2 inhibitors, n=17 948) compared with the Swedish background population of the same age, sex and calendar period. OUTCOME MEASURES The risk of different gastrointestinal cancer types expressed as standardised incidence ratios (SIR) and 95% CIs, taking into account concurrent proton pump inhibitors (PPIs) and statins usage. RESULTS The SIR for gastrointestinal cancer for aspirin use was 1.02 (95% CI 1.00 to 1.04), with clearly reduced risk for long-term users (SIR=0.31, 95% CI 0.30 to 0.33 for 5.5-7.7 years), but an increased risk for short-term users (SIR=2.77, 95% CI 2.69 to 2.85), and stronger protective effect for low-dose aspirin (SIR=0.86, 95% CI 0.85 to 0.88). Users of non-selective NSAIDs showed an overall decreased risk of gastrointestinal cancer (SIR=0.79, 95% CI 0.77 to 0.82), in particular for cancer of the stomach, colorectum and oesophagus, and the SIRs were further decreased among long-term users. Users of selective COX-2 inhibitors showed a SIR=0.89 (95% CI 0.73 to 1.09) for gastrointestinal cancers. Both aspirin and unselective NSAIDs users who also were using PPIs, had higher risks for all gastrointestinal cancer types; and lower risk if using statins. CONCLUSION Long-term use of (low-dose) aspirin and non-selective NSAIDs was associated with a decreased risk of all gastrointestinal cancer types.
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Affiliation(s)
- Nele Brusselaers
- Centre for Translational Microbiome Research, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden
- Science for Life Laboratory (SciLifeLab), Stockholm, Sweden
| | - Jesper Lagergren
- Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- Division of Cancer Studies, King’s College London, London, UK
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