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Objective: During the last decade, the management of gastric intestinal metaplasia (GIM) has been addressed by several distinct international evidence-based guidelines. In this review, we aimed to synthesise these guidelines and provide clinicians with a global perspective of the current recommendations for managing patients with GIM, as well as highlight evidence gaps that need to be addressed with future research., Design: We conducted a systematic review of the literature for guidelines and consensus statements published between January 2010 and February 2023 that address the diagnosis and management of GIM., Results: From 426 manuscripts identified, 16 guidelines were assessed. There was consistency across guidelines regarding the purpose of endoscopic surveillance of GIM, which is to identify prevalent neoplastic lesions and stage gastric preneoplastic conditions. The guidelines also agreed that only patients with high-risk GIM phenotypes (eg, corpus-extended GIM, OLGIM stages III/IV, incomplete GIM subtype), persistent refractory Helicobacter pylori infection or first-degree family history of gastric cancer should undergo regular-interval endoscopic surveillance. In contrast, low-risk phenotypes, which comprise most patients with GIM, do not require surveillance. Not all guidelines are aligned on histological staging systems. If surveillance is indicated, most guidelines recommend a 3-year interval, but there is some variability. All guidelines recommend H. pylori eradication as the only non-endoscopic intervention for gastric cancer prevention, while some offer additional recommendations regarding lifestyle modifications. While most guidelines allude to the importance of high-quality endoscopy for endoscopic surveillance, few detail important metrics apart from stating that a systematic gastric biopsy protocol should be followed. Notably, most guidelines comment on the role of endoscopy for gastric cancer screening and detection of gastric precancerous conditions, but with high heterogeneity, limited guidance regarding implementation, and lack of robust evidence., Conclusion: Despite heterogeneous populations and practices, international guidelines are generally aligned on the importance of GIM as a precancerous condition and the need for a risk-stratified approach to endoscopic surveillance, as well as H. pylori eradication when present. There is room for harmonisation of guidelines regarding (1) which populations merit index endoscopic screening for gastric cancer and GIM detection/staging; (2) objective metrics for high-quality endoscopy; (3) consensus on the need for histological staging and (4) non-endoscopic interventions for gastric cancer prevention apart from H. pylori eradication alone. Robust studies, ideally in the form of randomised trials, are needed to bridge the ample evidence gaps that exist., Competing Interests: Competing interests: No conflicts of interest are declared by MD-R, SS, HE-S, MB, NU, HT, LGC, DL, EL, AR, J-YF, LM, JB, EJK, EME-O. PM is a member of advisory board/lecturer of Aboca, Alfasigma, Allergosan, Bayer, Biocodex, Menarini advisory boards/lectures., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: PM declares honoraria for lectures sponsored by Alfasigma, Allergosan, Bayer, Biocodex, and Menarini. J-ML declares honoraria for lectures sponsored by Biocodex and a research grant for an investigator-initiated trial from Takeda. All other authors declare no competing interests. During the preparation of this Comment, the authors used ChatGPT version 3.5 in order to improve language and readability; after using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Background & Aims: We aimed to assess the secular trend of the global prevalence of Helicobacter pylori (H pylori) infection in adults and children/adolescents and to show its relation to that of gastric cancer incidence., Methods: We performed a systematic review and meta-analysis to calculate overall prevalence, adjusted by multivariate meta-regression analysis. The incidence rates of gastric cancer were derived from the Global Burden of Disease Study and Cancer Incidence in Five Continents., Results: Of the 16,976 articles screened, 1748 articles from 111 countries were eligible for analysis. The crude global prevalence of H pylori has reduced from 52.6% (95% confidence interval [CI], 49.6%-55.6%) before 1990 to 43.9% (95% CI, 42.3%-45.5%) in adults during 2015 through 2022, but was as still as high as 35.1% (95% CI, 30.5%-40.1%) in children and adolescents during 2015 through 2022. Secular trend and multivariate regression analyses showed that the global prevalence of H pylori has declined by 15.9% (95% CI, -20.5% to -11.3%) over the last 3 decades in adults, but not in children and adolescents. Significant reduction of H pylori prevalence was observed in adults in the Western Pacific, Southeast Asian, and African regions. However, H pylori prevalence was not significantly reduced in children and adolescents in any World Health Organization regions. The incidence of gastric cancer has decreased globally and in various countries where the prevalence of H pylori infection has declined., Conclusions: The global prevalence of H pylori infection has declined during the last 3 decades in adults, but not in children and adolescents. The results raised the hypothesis that the public health drive to reduce the prevalence of H pylori as a strategy to reduce the incidence of gastric cancer in the population should be confirmed in large-scale clinical trials., (Copyright © 2024 AGA Institute. All rights reserved.)

Four decades ago the discovery of Helicobacter pylori was first reported in the international medical literature. Since then, there have been significant developments in basic and clinical science that have been translated into daily clinical practice. Changes in the management of H. pylori infection have occurred in diagnostic algorithms, indications for therapy and therapy itself. A special focus is directed to strategies of gastric cancer prevention.This manuscript briefly reviews the milestone in 40 years of H. pylori management., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

At the end of the last century, a far-sighted 'working party' held in Sydney, Australia addressed the clinicopathological issues related to gastric inflammatory diseases. A few years later, an international conference held in Houston, Texas, USA critically updated the seminal Sydney classification. In line with these initiatives, Kyoto Global Consensus Report, flanked by the Maastricht-Florence conferences, added new clinical evidence to the gastritis clinicopathological puzzle.The most relevant topics related to the gastric inflammatory diseases have been addressed by the Real-world Gastritis Initiative (RE.GA.IN.), from disease definitions to the clinical diagnosis and prognosis. This paper reports the conclusions of the RE.GA.IN. consensus process, which culminated in Venice in November 2022 after more than 8 months of intense global scientific deliberations. A forum of gastritis scholars from five continents participated in the multidisciplinary RE.GA.IN. consensus. After lively debates on the most controversial aspects of the gastritis spectrum, the RE.GA.IN. Faculty amalgamated complementary knowledge to distil patient-centred, evidence-based statements to assist health professionals in their real-world clinical practice. The sections of this report focus on: the epidemiology of gastritis; Helicobacter pylori as dominant aetiology of environmental gastritis and as the most important determinant of the gastric oncogenetic field; the evolving knowledge on gastric autoimmunity; the clinicopathological relevance of gastric microbiota; the new diagnostic horizons of endoscopy; and the clinical priority of histologically reporting gastritis in terms of staging. The ultimate goal of RE.GA.IN. was and remains the promotion of further improvement in the clinical management of patients with gastritis., Competing Interests: Competing interests: DSB has served as speaker for Abbott, AstraZeneca, Alfasigma, Biocodex, Pfizer, Reckitt Benckiser, Takeda, KRKA, PRO.MED.CS Praha and Dr Reddy’s Laboratories. LGC has served as speaker for Takeda and EMS. FDM has served as consultant for Biohit Healthcare. MD-R has served as consultant for Roche and Medtronic. DD has served as consultant for Reckits, Dr Reddy’s, Zentiva, AbbVie, Terapia and Takeda. EME-O is Editor of Gut. EJK is member of the Editorial Board of Gut. MLe has served as research consultant for Eiken Chemical. MLi has served as speaker for Abbott, AstraZeneca, Alfasigma, Biocodex, KRKA and PRO.MED.CS Praha. TM-B received research grants from: AstraZeneca, BMS, Biohit and Fujirebio; and has been involved in congresses and educational supported by AAA, AstraZeneca, MSD, BMS, Viatris and Pierre Fabre. FM has served as consultant for Phathom and Biocodex. ES has served as speaker for AbbVie, Agave, AGPharma, Alfasigma, Aurora Pharma, CaDiGroup, Celltrion, Dr Falk, EG Stada Group, Fenix Pharma, Fresenius Kabi, Galapagos, Janssen, JB Pharmaceuticals, Innovamedica/Adacyte, Malesci, Mayoly Biohealth, Omega Pharma, Pfizer, Reckitt Benckiser, Sandoz, SILA, Sofar, Takeda, Tillots and Unifarco; has served as consultant for AbbVie, Agave, Alfasigma, Biogen, Bristol-Myers Squibb, Celltrion, Diadema Farmaceutici, Dr Falk, Fenix Pharma, Fresenius Kabi, Janssen, JB Pharmaceuticals, Merck & Co, Nestlè, Reckitt Benckiser, Regeneron, Sanofi, SILA, Sofar, Synformulas, Takeda and Unifarco; and has received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, Unifarco and Zeta Farmaceutici. NS has served as speaker for Astellas and consultant for Bristol-Myers Squibb. KS has served as consultant for Fuji Film Co. NU has served as speaker for lectures for: Olympus Co, Fuji Film Co, Boston Scientific Japan, Daiichi-Sankyo Co, Takeda Pharmaceutical Co, EA Pharma Co, Otsuka Pharmaceutical Co, AstraZeneca Co, Miyarisan Pharmaceutical Co and AI Medical Service Co., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture., Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO., Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level., Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO., Funding: German Research Foundation (DFG)., Competing Interests: Declaration of interests MDR reports consulting fees from Roche Diagnostics and Medtronic; leadership or fiduciary role in the European Society of Gastrointestinal Endoscopy (ESGE) and World Endoscopy Organization (WEO). All other authors report no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Helicobacter pylori infection causes chronic gastritis, which can progress to severe gastroduodenal pathologies, including peptic ulcer, gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. H. pylori is usually transmitted in childhood and persists for life if untreated. The infection affects around half of the population in the world but prevalence varies according to location and sanitation standards. H. pylori has unique properties to colonize gastric epithelium in an acidic environment. The pathophysiology of H. pylori infection is dependent on complex bacterial virulence mechanisms and their interaction with the host immune system and environmental factors, resulting in distinct gastritis phenotypes that determine possible progression to different gastroduodenal pathologies. The causative role of H. pylori infection in gastric cancer development presents the opportunity for preventive screen-and-treat strategies. Invasive, endoscopy-based and non-invasive methods, including breath, stool and serological tests, are used in the diagnosis of H. pylori infection. Their use depends on the specific individual patient history and local availability. H. pylori treatment consists of a strong acid suppressant in various combinations with antibiotics and/or bismuth. The dramatic increase in resistance to key antibiotics used in H. pylori eradication demands antibiotic susceptibility testing, surveillance of resistance and antibiotic stewardship., (© 2023. Springer Nature Limited.)

Helicobacter pylori (H. pylori) infection has been considered as the main causal factor in gastric carcinogenesis, but other bacterial species may also play an important role in pathophysiology of gastric cancer. The aim of the study was to explore the link between gastric cancer prognosis and the mucosal microbial community in tumorous and adjacent gastric tissue. The bacterial profile was analysed using 16S sequencing (V1-V2 region). Microbial differences were mostly characterized by lower relative abundances of H. pylori in tumorous gastric tissues. Bacterial community and outcome data analysis revealed the genus Fusobacterium and Prevotella significantly associated with worse overall survival in gastric cancer patients. In particular, Fusobacterium was associated with significant increase in hazard ratio in both univariable and multivariable analysis and independently validated using TCMA data. Phylogenetic biodiversity of Fusobacterium species in the stomach revealed F. periodonticum as the most prevalent in healthy subjects, while F. nucleatum was most abundant in patients with gastric cancer. Bacterial community network analysis in gastric cancer suggests substantial complexity and a strong interplay between F. nucleatum and Prevotella. In summary, mucosal microbial community in the stomach was associated with worse overall survival in gastric cancer patients. Strongest negative impact on prognosis was linked to the abundance of F. nucleatum in tumorous specimens, suggesting its translational relevance in management of gastric cancer patients., (© 2023. The Author(s).)

Purpose: In a post hoc analysis of the MAGIC trial, patients with curatively resected gastric cancer (GC) and mismatch repair (MMR) deficiency (MMRd) had better median overall survival (OS) when treated with surgery alone but worse median OS when treated with additional chemotherapy. Further data are required to corroborate these findings., Methods: Between April 2013 and December 2018, 458 patients with curatively resected GC, including cancers of the esophagogastric junction Siewert type II and III, were identified in the German centers of the staR consortium. Tumor sections were assessed for expression of MLH1, MSH2, MSH6 and PMS2 by immunohistochemistry. The association between MMR status and survival was assessed. Similar studies published up to January 2021 were then identified in a MEDLINE search for a meta-analysis., Results: MMR-status and survival data were available for 223 patients (median age 66 years, 62.8% male), 23 patients were MMRd (10.3%). After matching for baseline clinical characteristics, median OS was not reached in any subgroup. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd and MMRp had a HR of 0.67 (95% CI 0.13-3.37, P = 0.63) and 1.44 (95% CI 0.66-3.13, P = 0.36), respectively. The meta-analysis included pooled data from 385 patients. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd had an improved OS with a HR of 0.36 (95% CI 0.14-0.91, P = 0.03), whereas those with MMRp had a HR of 1.18 (95% CI 0.89-1.58, P = 0.26)., Conclusion: Our data support a positive prognostic effect for MMRd in GC patients treated with surgery only and a differentially negative prognostic effect in patients treated with perioperative chemotherapy. MMR status determined by preoperative biopsies may be used as a predictive biomarker to select patients for perioperative chemotherapy in curatively resectable GC., (© 2022. The Author(s).)

Objective: Autoimmune gastritis (AIG) is an immunomediated disease targeting parietal cells, eventually resulting in oxyntic-restricted atrophy. This long-term follow-up study aimed at elucidating the natural history, histological phenotype(s), and associated cancer risk of patients with AIG consistently tested H. pylori -negative (naïve H. pylori -negative subjects)., Design: Two-hundred eleven naïve H. pylori -negative patients (tested by serology, histology, molecular biology) with AIG (F:M=3.15:1; p<0.001) were prospectively followed up with paired biopsies (T1 vs T2; mean follow-up years:7.5 (SD:4.4); median:7). Histology distinguished non-atrophic versus atrophic AIG. Atrophy was further subtyped/scored as non-metaplastic versus metaplastic (pseudopyloric (PPM) and intestinal (IM)). Enterochromaffin-like-cell (ECL) status was categorised as diffuse versus adenomatoid hyperplasia/dysplasia, and type 1 neuroendocrine tumours (Type1-NETs)., Results: Over the long-term histological follow-up, AIG consistently featured oxyntic-predominant-mononuclear inflammation. At T1, PPM-score was greater than IM (200/211 vs 160/211, respectively); IM scores increased from T1 to T2 (160/211 to 179/211), with no changes in the PPM prevalence (T1=200/211; T2=201/211). At both T1/T2, the prevalence of OLGA-III-stage was <5%; no Operative Link on Gastritis Assessment (OLGA)-IV-stage occurred. ECL-cell-status progressed from diffuse to adenomatoid hyperplasia/dysplasia (T1=167/14 vs T2=151/25). Type1-NETs (T1=10; T2=11) always coexisted with extensive oxyntic-atrophy, and ECL adenomatoid-hyperplasia/dysplasia. No excess risk of gastric or other malignancies was found over a cumulative follow-up time of 10 541 person years, except for (marginally significant) thyroid cancer (SIR=3.09; 95% CI 1.001 to 7.20)., Conclusions: Oxyntic-restricted inflammation, PPM (more than IM), and ECL-cell hyperplasia/neoplasia are the histological AIG hallmarks. Compared with the general population, corpus-restricted inflammation/atrophy does not increase the GC risk. The excess of GC risk reported in patients with AIG could plausibly result from unrecognised previous/current H. pylori comorbidity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Epigenetic modifications in mammalian DNA are commonly manifested by DNA methylation. In the stomach, altered DNA methylation patterns have been observed following chronic Helicobacter pylori infections and in gastric cancer. In the context of epigenetic regulation, the regional nature of the stomach has been rarely considered in detail., Results: Here, we establish gastric mucosa derived primary cell cultures as a reliable source of native human epithelium. We describe the DNA methylation landscape across the phenotypically different regions of the healthy human stomach, i.e., antrum, corpus, fundus together with the corresponding transcriptomes. We show that stable regional DNA methylation differences translate to a limited extent into regulation of the transcriptomic phenotype, indicating a largely permissive epigenetic regulation. We identify a small number of transcription factors with novel region-specific activity and likely epigenetic impact in the stomach, including GATA4, IRX5, IRX2, PDX1 and CDX2. Detailed analysis of the Wnt pathway reveals differential regulation along the craniocaudal axis, which involves non-canonical Wnt signaling in determining cell fate in the proximal stomach. By extending our analysis to pre-neoplastic lesions and gastric cancers, we conclude that epigenetic dysregulation characterizes intestinal metaplasia as a founding basis for functional changes in gastric cancer. We present insights into the dynamics of DNA methylation across anatomical regions of the healthy stomach and patterns of its change in disease. Finally, our study provides a well-defined resource of regional stomach transcription and epigenetics., (© 2022. The Author(s).)

Introduction: High expression of HOTAIR promotes tumor growth and carries a dismal prognosis for the patient. We investigated the prognostic value of HOTAIR expression in gastric cancer (GC) and systematically delineate the expression in relation to Helicobacter pylori infection and preneoplastic changes., Methods: HOTAIR expression was analyzed in surgical paired tissue samples of patients with GC and biopsy samples from patients with atrophic gastritis and/or intestinal metaplasia (AG ± -IM), chronic nonatrophic gastritis, and controls. The cancer genome atlas (TCGA) data were used for validation. HOTAIR expression was evaluated in sera and ascites of patients with GC. Quantitative HOTAIR expression analysis was performed using quantitative polymerase chain reaction, and LINE-1 methylation was assessed by bisulfite pyrosequencing., Results: HOTAIR was more frequently detected in tumor tissues compared with adjacent gastric mucosa (65.4% vs 8.6%). HOTAIR expression was associated with depth of tumor invasion and tumor location and with shorter overall survival in patients with diffuse-type GC as confirmed in the TCGA cohort. HOTAIR was not detectable in controls but was found in 2.2% of patients with chronic nonatrophic gastritis and 18.3% of patients with AG ± IM, which was further associated with IM, grade of IM, and H. pylori positivity., Discussion: HOTAIR expression was associated with GC and preneoplastic changes of stomach mucosa. Although HOTAIR expression was strongly linked to IM, HOTAIR expression was only associated with worse prognosis in Lauren diffuse and not intestinal type of GC. Further studies are needed to evaluate the value of HOTAIR as diagnostic and predictive biomarker in IM and translational therapeutic relevance of HOTAIR in diffuse-type GC., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

VEGF inhibition in gastric cancer has a proven benefit in the second line setting. Pazopanib, an oral tyrosine kinase inhibitor, selectively inhibits VEGFR-1, -2 and -3, c-kit and PDGF-R resulting in inhibition of angiogenesis. This open-label randomized phase II trial (2:1) investigated the efficacy of combining pazopanib with FLO (5-fluorouracil, oxaliplatin) vs FLO alone (internal control arm) as first-line treatment in patients with advanced adenocarcinoma of the stomach and gastroesophageal junction (GEJ). Eighty-seven patients were randomized and 78 patients were eligible and evaluable (PaFLO arm 51 patients, FLO arm 27 patients). The PFS rate at 6 months (primary endpoint) was 34% in the PaFLO arm vs 30% in the FLO arm. Comparing PaFLO with FLO median PFS was 4.66 months (95% confidence interval [CI] 2.87-6.46) vs 4.47 months (95% CI 1.79-7.14) (95% CI, hazard ratio [HR] 0.96 (0.60-1.55), P = .882 [exploratory]); median OS was 10.19 months (95% CI 5.46-14.92) vs 7.33 months (95% CI 4.93-9.73), (95% CI HR 1.01 [0.62-1.65], P = .953, exploratory), disease control rate was 72% vs 59%. PaFLO was well tolerable, toxicities were slightly higher in the PaFLO arm. Major adverse events were loss of appetite, nausea, fatigue, diarrhea, neutropenia and thrombocytopenia. Adding pazopanib to chemotherapy shows signs of efficacy but no major improvement in this randomized phase 2 trial. The PFS at 6 months in both arms was lower than expected from the literature. Biomarkers identifying subgroups who benefit and novel combinations are needed. ClinicalTrials.gov: NCT01503372., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Dyspepsia is one of the most common complaints in gastroenterology. While its etiology is usually benign, rare cases of malignancy have to be identified. Individualized risk stratification is essential for cost-effective management of dyspepsia. Here, we discuss the challenges of investigating dyspepsia at the specialist level and provide a framework for rational workup and surveillance strategies., Summary: Causes of dyspepsia can be functional or organic, including gastritis, peptic ulcers, or malignancy. H. pylori gastritis represents a specific entity of dyspepsia and increases the risk of gastric cancer. H. pylori eradication can improve symptoms in a subset of patients and reduce gastric cancer risk. In young patients without alarm features, malignancy is rare, and noninvasive testing for H. pylori is appropriate. In elder patients and those with alarm features, high-quality endoscopy is the method of choice to rule out malignancy. Advanced corpus-predominant atrophic gastritis with or without intestinal metaplasia represent precancerous lesions., Key Messages: Symptom assessment requires to distinguish dyspepsia of functional or organic origin. Risk stratification in dyspeptic patients is based on age, alarm features, and H. pylori status. Noninvasive test-and-treat is recommended in patients with low gastric cancer risk, while endoscopy is recommended in individuals at increased risk. H. pylori infection should be eradicated in order to obtain a symptomatic benefit and reduce gastric cancer risk. Advanced preneoplastic lesions require endoscopic surveillance., (© 2021 S. Karger AG, Basel.)

Throughout the past decades, considerable progress has been made in the (early) diagnosis and treatment of gastrointestinal cancers. However, the prognosis for advanced stages of gastrointestinal tumors remains limited for many patients and approximately one third of all tumor patients die as a result of gastrointestinal tumors. The prevention and early detection of gastrointestinal tumors is therefore of great importance.For this reason, we summarize the current state of knowledge and recommendations for the primary, secondary and tertiary prevention of esophageal, stomach, pancreas, liver and colorectal cancer in the following., Competing Interests: Bzgl. Nukleosid/Nukleotid-Analoga zur Behandlung der chronischen Hepatitis B: AT erhielt Beratungs- und Vortragshonorare sowie Forschungsförderung der Firma Gilead., (Thieme. All rights reserved.)

Long non-coding RNAs (lncRNA) play an important role in the carcinogenesis of various tumours, including gastric cancer. This study aimed to assess the associations of lncRNA ANRIL, H19, MALAT1, MEG3, HOTAIR single-nucleotide polymorphisms (SNPs) with gastric cancer and atrophic gastritis. SNPs were analyzed in 613 gastric cancer patients, 118 patients with atrophic gastritis and 476 controls from three tertiary centers in Germany, Lithuania and Latvia. Genomic DNA was extracted from peripheral blood leukocytes. SNPs were genotyped by the real-time polymerase chain reaction. Results showed that carriers of MALAT1 rs3200401 CT genotype had the significantly higher odds of atrophic gastritis than those with CC genotype (OR-1.81; 95% CI 1.17-2.80, p = 0.0066). Higher odds of AG were found in a recessive model (CC vs. TT + CT) for ANRIL rs1333045 (OR-1.88; 95% CI 1.19-2.95, p = 0.0066). Carriers of ANRIL (rs17694493) GG genotype had higher odds of gastric cancer (OR-4.93; 95% CI 1.28-19.00) and atrophic gastritis (OR-5.11; 95% CI 1.10-23.80) compared with the CC genotype, and carriers of HOTAIR rs17840857 TG genotype had higher odds of atrophic gastritis (OR-1.61 95% CI 1.04-2.50) compared with the TT genotype; however, the ORs did not reach the adjusted significance threshold ( p < 0.007). In summary, our data provide novel evidence for a possible link between lncRNA SNPs and premalignant condition of gastric cancer, suggesting the involvement of lncRNAs in gastric cancer development.

Objective: A global consensus meeting was held to review current evidence and knowledge gaps and propose collaborative studies on population-wide screening and eradication of Helicobacter pylori for prevention of gastric cancer (GC)., Methods: 28 experts from 11 countries reviewed the evidence and modified the statements using the Delphi method, with consensus level predefined as ≥80% of agreement on each statement. The Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach was followed., Results: Consensus was reached in 26 statements. At an individual level, eradication of H. pylori reduces the risk of GC in asymptomatic subjects and is recommended unless there are competing considerations. In cohorts of vulnerable subjects (eg, first-degree relatives of patients with GC), a screen-and-treat strategy is also beneficial. H. pylori eradication in patients with early GC after curative endoscopic resection reduces the risk of metachronous cancer and calls for a re-examination on the hypothesis of 'the point of no return'. At the general population level, the strategy of screen-and-treat for H. pylori infection is most cost-effective in young adults in regions with a high incidence of GC and is recommended preferably before the development of atrophic gastritis and intestinal metaplasia. However, such a strategy may still be effective in people aged over 50, and may be integrated or included into national healthcare priorities, such as colorectal cancer screening programmes, to optimise the resources. Reliable locally effective regimens based on the principles of antibiotic stewardship are recommended. Subjects at higher risk of GC, such as those with advanced gastric atrophy or intestinal metaplasia, should receive surveillance endoscopy after eradication of H. pylori ., Conclusion: Evidence supports the proposal that eradication therapy should be offered to all individuals infected with H. pylori . Vulnerable subjects should be tested, and treated if the test is positive. Mass screening and eradication of H. pylori should be considered in populations at higher risk of GC., Competing Interests: Competing interests: J-ML reports receiving lecture fees from Takeda Pharmaceuticals (Taiwan) and Abbott Laboratories. PM reports receiving advisory and lecture fees from Bayer, Mayoly Spindler and Nordmark. DYG is a consultant for RedHill Biopharma and Phathom Pharmaceuticals regarding novel H. pylori therapies and has received research support for culture of Helicobacter pylori., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Fusobacterium nucleatum (F. nucleatum) is frequently detected in primary colorectal cancer (CRC) and matching metastasis, and has been linked to a worse prognosis. We investigated the presence of F. nucleatum in gastric cancer (GC) and gastric preneoplastic conditions of the stomach, and its potential prognostic value in GC patients. Fusobacterium spp. and F. nucleatum were quantified in various specimens from gastrointestinal tract including paired CRC and GC tissues using probe-based qPCR. Fusobacterium spp. and F. nucleatum were more frequently found in tumorous tissue of CRC and GC compared to non-tumorous tissues. The frequency and bacterial load were higher in CRC compared to GC patients. F. nucleatum positivity showed no association to chronic gastritis or preneoplastic conditions such as intestinal metaplasia. F. nucleatum-positivity was associated with significantly worse overall survival in patients with Lauren's diffuse type, but not with intestinal type GC. There was no association with gender, Helicobacter pylori-status, tumor stage or tumor localization. However, F. nucleatum was positively associated with patient's age and a trend for a lower global long interspersed element-1 DNA methylation. In conclusion, our work provides novel evidence for clinical relevance of F. nucleatum in GC by showing an association between F. nucleatum positivity with worse prognosis of patients with Laurens's diffuse type gastric cancer. Further studies are necessary to explore related mechanistic insights and potential therapeutic benefit of targeted antibiotic treatment in GC patients.

Clinical guidelines recommend particular approaches, including 'screen-and-treat' strategy for Helicobacter pylori, to prevent gastric cancer. However, little of this is implemented in clinical practice. The aim of the study was to identify barriers to implementation of international guidelines. A web-based questionnaire distributed globally to specialists in the field. Altogether 886 responses from 75 countries were received. Of the responders, 570 (64%) were men of mean age 47 years. There were 606 gastroenterologists and 65 epidemiologists among the responders. Altogether, 79.8% of the responders disagreed that the burden of gastric cancer is a diminishing problem. 'Screen-and-treat' strategy for H. pylori in the responder's country was considered appropriate by 44.4%, inappropriate by 24.3%, with 31.3% being uncertain. Population-based screening for gastric cancer was considered appropriate in the respective home-country by 62.2%, in other areas - but not the home country - by 27.6%, and inappropriate by 10.2%. As a screening tool, upper endoscopy was acceptable by 35.6%, upper X-ray series by 55.3%, pepsinogens by 26.2% and breath-tests by 23.4%; accuracy, cost-effectiveness and feasibility among the tests varied widely. The attitude towards H. pylori vaccination was that 4.6% of the responders were eager to start vaccination immediately, 55.9% were supporting vaccination but considered that more data are required 12% were negative, and 27.6% did not have an opinion. In general, the attitude of the specialists was in line with guidelines, but was not always translated into clinical practice, particularly in the case of 'screen-and-treat' strategy.

Gastric cancer (GC) is still the fifth most frequently diagnosed cancer and the third leading cause of cancer deaths in both sexes worldwide. Although the incidence of GC is predicted to continue declining in a growing number of countries in the future, on a global scale the number of newly diagnosed GC cases will remain high, or increase even further, due to changes in population size and increasing risks observed in younger generations. In a retrospective cohort study, collecting data from the Veterans Health Administration, treatment of Helicobacter pylori infection decreased GC risk only if eradication was successful. In a German case-control study, among GC patients with autoimmune gastritis, pernicious anemia was associated with earlier detection of GC, which translated into a significantly better 5-year survival. In an updated meta-analysis, H. pylori eradication therapy in healthy individuals significantly reduced both GC incidence and mortality from GC with a number needed to treat of 72 and 135, respectively. In Korea, successful H. pylori eradication substantially reduced GC incidence in first-degree relatives of GC patients as well. A meta-analysis of four trials including 1,556 patients with resectable GC reported that the patient subgroup tumors with high microsatellite instability undergoing surgery did not benefit from perioperative or adjuvant chemotherapy., (© 2020 John Wiley & Sons Ltd.)

Background: Data from clinical trials comparing Helicobacter pylori (H. pylori) management strategies in patients with dyspepsia are limited. Cost-effectiveness simulation models might help to identify the optimal strategy., Objective: To assess the cost-effectiveness of the H. pylori "Test and Treat" (T&T) strategy including the use of urea breath test (UBT) vs symptomatic treatment (ST) and vs upper gastrointestinal endoscopy (UGE) as a first procedure in patients with dyspepsia., Methods: Three main strategies: "T&T" strategy including the use of UBT, "UGE" and "ST" have been compared using cost-effectiveness models developed in accordance with the Spanish medical practice. For the model simulations, a time horizon of 4 weeks was considered for the endpoint "Dyspepsia symptoms relief" and 10 years when using "Peptic ulcer avoided" and "Gastric cancer avoided" endpoints., Results: For the endpoint "Dyspepsia symptoms relief", T&T strategy appears to be the most cost-effective (883€/success) compared to UGE strategy and to ST strategy (respectively 1628€ and 990€/success). For the endpoint "Probability of peptic ulcer", the T&T strategy appears to be the most cost-effective (421€/peptic ulcer avoided/y) compared to UGE strategy and ST strategy (respectively 728€ and 632€/peptic ulcer avoided/y). For the endpoint "Gastric cancer avoided", the T&T strategy appears to be the most cost-effective (524€/gastric cancer avoided/y) compared to UGE strategy and "ST" strategy (respectively 716€ and 696€/gastric cancer avoided/y)., Conclusions: T&T strategy including the use of UBT is the most cost-effective medical approach for management of dyspepsia and for the prevention of ulcer and gastric cancer., (© 2020 John Wiley & Sons Ltd.)

Objectives: Patients with autoimmune gastritis (AIG) are reported to have an increased risk of developing gastric cancer (GC). In this study, we assess the characteristics and outcomes of GC patients with AIG in a multicenter case-control study., Methods: Between April 2013 and May 2017, patients with GC, including cancers of the esophagogastric junction (EGJ) Siewert type II and III, were recruited. Patients with histological characteristics of AIG were identified and matched in a 1:2 fashion for age and gender to GC patients with no AIG. Presenting symptoms were documented using a self-administered questionnaire., Results: Histological assessment of gastric mucosa was available for 572/759 GC patients. Overall, 28 (4.9%) of GC patients had AIG (67 ± 9 years, female-to-male ratio 1.3:1). In patients with AIG, GC was more likely to be localized in the proximal (i.e. EGJ, fundus, corpus) stomach (odds ratio (OR) 2.7, 95% confidence interval (CI) 1.0-7.1). In GC patients with AIG, pernicious anemia was the leading clinical sign (OR 22.0, 95% CI 2.6-187.2), and the most common indication for esophagogastroduodenoscopy (OR 29.0, 95% CI 7.2-116.4). GC patients with AIG were more likely to present without distant metastases (OR 6.2, 95% CI 1.3-28.8) and to be treated with curative intention (OR 3.0, 95% CI 1.0-9.0). The five-year survival rates with 95% CI in GC patients with and with no AIG were 84.7% (83.8-85.6) and 53.5% (50.9-56.1), respectively (OR 0.25, 95% CI 0.08-0.75, p  = 0.001)., Conclusions: Pernicious anemia leads to earlier diagnosis of GC in AIG patients and contributes significantly to a better clinical outcome.

Cancers occurring at the gastroesophageal junction (GEJ) are classified as predominantly esophageal or gastric, which is often difficult to decipher. We hypothesized that the transcriptomic profile might reveal molecular subgroups which could help to define the tumor origin and behavior beyond anatomical location. The gene expression profiles of 107 treatment-naïve, intestinal type, gastroesophageal adenocarcinomas were assessed by the Illumina-HTv4.0 beadchip. Differential gene expression (limma), unsupervised subgroup assignment (mclust) and pathway analysis (gage) were undertaken in R statistical computing and results were related to demographic and clinical parameters. Unsupervised assignment of the gene expression profiles revealed three distinct molecular subgroups, which were not associated with anatomical location, tumor stage or grade (p > 0.05). Group 1 was enriched for pathways involved in cell turnover, Group 2 was enriched for metabolic processes and Group 3 for immune-response pathways. Patients in group 1 showed the worst overall survival (p = 0.019). Key genes for the three subtypes were confirmed by immunohistochemistry. The newly defined intrinsic subtypes were analyzed in four independent datasets of gastric and esophageal adenocarcinomas with transcriptomic data available (RNAseq data: OCCAMS cohort, n = 158; gene expression arrays: Belfast, n = 63; Singapore, n = 191; Asian Cancer Research Group, n = 300). The subgroups were represented in the independent cohorts and pooled analysis confirmed the prognostic effect of the new subtypes. In conclusion, adenocarcinomas at the GEJ comprise three distinct molecular phenotypes which do not reflect anatomical location but rather inform our understanding of the key pathways expressed., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Aims: Aim was to assess the feasibility of serum markers to identify individuals at risk for gastro-oesophageal adenocarcinoma to reduce the number of individuals requiring invasive assessment by endoscopy., Methods: Blood samples from 56 patients with Barrett's oesophagus and 202 non-Barrett controls who previously took part in a trial assessing the accuracy of the Cytosponge for Barrett's oesophagus were assessed for serum pepsinogen (PG) 1 and 2, gastrin-17, trefoil factor 3 (TFF3) and Helicobacter pylori infection., Results: PG1 was pathological (<50 ng/mL) in 26 patients (10.1%), none of whom had Barrett's oesophagus (p<0.001). Smoking and drinking had no influence on these results. Pathological PG1 was associated with stomach pain (p=0.029), disruption of sleep (p=0.027) and disruption of diet by symptoms (p=0.019). Serum TFF3 was not associated with any clinical parameter., Conclusions: Assessment of serum PG1 could be combined with a test for Barrett's oesophagus to identify additional patients requiring endoscopy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Gastric cancer (GC) was responsible for over 1 000 000 new cases in 2018 and an estimated 783 000 deaths, making it still the fifth most frequently diagnosed cancer and the third leading cause of cancer deaths in both sexes worldwide. Divergent trends for GC incidence were observed in the USA. Incidence rates, particularly for non-cardia GC, were stable or increasing among persons aged <50 years. In an analysis of data from a public hospital database in Hong Kong, treatment of Helicobacter pylori infection was associated with a lower risk of GC, particularly in older subjects who received treatment ≥10 years before. Based on the results of a 16-year endoscopy-based follow-up eradication trial, patients with incomplete-type intestinal metaplasia (IM) should receive endoscopic surveillance upon H. pylori eradication therapy. Updated guidelines on the endoscopic surveillance of preneoplastic conditions of the stomach (MAPS II) have been published. In the RAINFALL trial, the addition of ramucirumab to a backbone chemotherapy as a first-line regimen failed to improve overall survival (OS) of patients with metastatic disease. Also, pembrolizumab did not prolong OS when compared to paclitaxel in the second-line treatment of patients with advanced GC or esophagogastric junction (EGJ) cancer. Trifluridine/tipiracil improved OS by 2.1 months in the third or further treatment line of patients with advanced GC. In a systematic investigation conducted on Chinese patients with GC, CLDN18-ARHGAP26/6 fusion was associated with signet-ring cell content and was prognostic for a worse outcome and predictive for no benefit from oxaliplatin/fluoropyrimidine-based chemotherapy. Organoid cultures represent an appealing model that may be applied for therapy response testing in the near future., (© 2019 John Wiley & Sons Ltd.)

Background: Our aim was to evaluate the feasibility of a serological assessment of gastric cancer risk in patients undergoing colonoscopy in countries with low-to-moderate incidence rates., Methods: Serum samples were prospectively collected from 453 patients (>50 years old) undergoing colonoscopies. Of these, 279 (61.6%) also underwent gastroscopy to correlate the results for serum pepsinogen I and II (sPG-I and sPG-II), sPG-I/II ratio, and anti- H. pylori antibodies with gastric histopathology findings (graded according to the updated Sydney classification and the Operative Link of Gastritis Assessment (OLGA) and the Operative Link for Gastric Intestinal Metaplasia assessment (OLGIM) systems)., Results: H. pylori was found in 85 patients (30.5%). Chronic atrophic gastritis was diagnosed in 89 (31.9%) patients. High-risk OLGA (III⁻IV) stages were present in 24 patients, and high-risk OLGIM stages were present in 14 patients. There was an inverse correlation of sPG-I with the degree of atrophy and intestinal metaplasia (IM), as well as with the respective OLGA (r = -0.425; p < 0.001) and OLGIM (r = -0.303; p < 0.001) stages. A pathological sPG-I result was associated with a relative risk (RR) of 12.2 (95% confidence interval: 6.29⁻23.54; p < 0.001) for gastric preneoplastic changes., Conclusions: The assessment of serum pepsinogen allows the identification of patients at increased risk of gastric cancer. A prevention strategy of combining a screening colonoscopy with a serological screening for preneoplastic gastric changes should be considered in the general population.

Background and Aims: Previous genome-wide association studies showed that genetic polymorphisms in toll-like receptor 1 (TLR1) and protein kinase AMP-activated alpha 1 catalytic subunit (PRKAA1) genes were associated with gastric cancer (GC) or increased Helicobacter pylori (H. pylori) infection susceptibility. The aim of this study was to evaluate the association between TLR1 and PRKAA1 genes polymorphisms and H. pylori infection, atrophic gastritis (AG) or GC in the European population., Methods: Single-nucleotide polymorphisms (SNPs) were analysed in 511 controls, 340 AG patients and 327 GC patients. TLR1 C>T (rs4833095) and PRKAA1 C>T (rs13361707) were genotyped by the real-time polymerase chain reaction. H. pylori status was determined by testing for anti-H. pylori IgG antibodies in the serum., Results: The study included 697 (59.2%) H. pylori positive and 481 (40.8%) H. pylori negative cases. We observed similar distribution of TLR1 and PRKAA1 alleles and genotypes in H. pylori positive and negative cases. TLR1 and PRKAA1 SNPs were not linked with the risk of AG. TC genotype of TLR1 gene was more prevalent in GC patients compared to the control group (29.7% and 22.3% respectively, p=0.002). Carriers of TC genotype had a higher risk of GC (aOR=1.89, 95% CI: 1.26-2.83, p=0.002). A similar association was observed in a dominant inheritance model for TLR1 gene SNP, where comparison of CC+TC vs. TT genotypes showed an increased risk of GC (aOR=1.86, 95% CI: 1.26-2.75, p=0.002). No association between genetic polymorphism in PRKAA1 gene and GC was observed., Conclusions: TLR1 rs4833095 SNP was associated with an increased risk of GC in a European population, while PRKAA1 rs13361707 genetic variant was not linked with GC. Both genetic polymorphisms were not associated with H. pylori infection susceptibility or the risk of AG.

Objectives: Gastritis OLGA-staging ranks the risk for gastric cancer (GC) in progressive stages (0-IV). This long-term follow-up study quantifies the GC risk associated with each OLGA stage., Methods: Consecutive patients (7436) underwent esophagogastroscopy (T-0), with mapped gastric biopsies, OLGA staging, and H. pylori status assessment. Patients with neoplastic lesion (invasive or non-invasive) at the index endoscopy (and/or within 12 months) were excluded. All patients were followed-up (T-1) by combining different sources of clinical/pathological information (Regional Registries of: (i) esophagogastroduodenoscopies; (ii) pathology reports; (iii) cancer, (iv) mortality). The endpoint was histologically documented development of gastric epithelial neoplasia., Results: At T-0, the patients' distribution by OLGA stage was: Stage 0 = 80.8%; Stage I = 12.6%; Stage II = 4.3%; Stage III = 2.0%; Stage IV = 0.3%; H. pylori infection was detected in 25.9% of patients. At the end of the follow-up (mean/median = 6.3/6.6 years), 28 incident neoplasia were documented (overall prevalence = 0.60 per 10 3 /person-years; low-grade intraepithelial neoplasia = 17/28; high-grade intraepithelial neoplasia = 4/28; GC = 7/28). By OLGA stage at the enrollment, the rate of incident neoplasia was: Stage 0 = 1 case; rate/10 3 person-years = 0.03; 95%CI: 0.004-0.19; Stage I = 2 cases; rate/10 3 person-years = 0.34; 95%CI: 0.09-1.36; Stage II = 3 cases; rate/10 3 person-years = 1.48; 95%CI: 0.48-4.58; Stage III = 17 cases; rate/10 3 person-years = 19.1; 95%CI: 11.9-30.7; Stage IV = 5 cases; rate/10 3 person-years = 41.2; 95%CI: 17.2-99.3. Multivariate analysis including gender, age, H. pylori status, and OLGA stage at enrollment only disclosed OLGA stage as predictor of neoplastic progression (OLGA stage III: HR = 712.4, 95%CI = 92.543-5484.5; OLGA stage IV: HR = 1450.7, 95%CI = 166.7-12626.0)., Conclusions: Among 7436 patients, OLGA stages at the enrollment correlated significantly with different risk for gastric neoplasia. Based on the obtained results, gastritis staging is a critical adjunct in endoscopy follow-up protocols aimed at GC secondary prevention.

Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine-mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 × 10 -04 ) and on chromosome 8q24 at rs2585176 (P = 1.09 × 10 -09 ). On chromosome 5p13 we found cis-eQTL effects with an upregulation of PTGER4 expression in GC risk allele carrier (P = 9.27 × 10 -11 ). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 × 10 -47 ). In addition, we found trans-eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 × 10 -09 ). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk-conferring GC pathomechanisms., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Gastric cancer (GC) is still the third leading cause of cancer death in both sexes worldwide. Helicobacter pylori infection is the most important risk factor for GC and, in spite of the consistent trend of a decreasing incidence, in 2015 approximately 4.4 billion individuals-more than half the world's population-were infected with H. pylori. The birth cohort pattern of decreased H. pylori infection reported in a systematic review contributes to explain the declining GC mortality in Japan. Current trends in estimated annual percentage change of GC incidence foreshadow expected reversals in both falling incidence and male predominance among US non-Hispanic whites. Combining serum pepsinogen 1 and H. pylori serology was shown to be useful for GC risk stratification in a Finnish population. Gastritis staging by operative link on gastritis assessment was confirmed to be reliable in predicting GC risk in a large prospective study. In a randomized trial from South Korea, H. pylori eradication therapy significantly reduced the rates of metachronous GC in patients who received curative endoscopic resection for early GC. A study based on a territory-wide health care database of the Hong Kong Hospital Authority showed that aspirin use is associated with a reduced GC risk. Another study based on the same database showed that proton pump inhibitors increase GC risk, but methodological biases have most likely acted as confounders. Confirmatory data on the role of endoscopic submucosal dissection in patients with early GC have been published. The phase III FLOT4 trial has shown that the FLOT triplet regimen (docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil) improves the outcome of patients with GC and locoregional disease as compared to the ECF triplet (epirubicin, cisplatin, and 5-fluorouracil). In the phase III ATTRACTION-2 trial, nivolumab was shown to be an effective treatment option with a relative safe profile for heavily pretreated patients with advanced GC., (© 2018 John Wiley & Sons Ltd.)

Gastric cancer, 1 of the 5 most common causes of cancer death, is associated with a 5-year overall survival rate less than 30%. A minority of cancers occurs as part of syndromic diseases; more than 90% of adenocarcinomas are considered as the ultimate consequence of a longstanding mucosal inflammation. Helicobacter pylori infection is the leading etiology of non-self-limiting gastritis, which may result in atrophy of the gastric mucosa and impaired acid secretion. Gastric atrophy establishes a field of cancerization prone to further molecular and phenotypic changes, possibly resulting in cancer growth. This well-understood natural history provides the clinicopathologic rationale for primary and secondary cancer prevention strategies. A large body of evidence demonstrates that combined primary (H pylori eradication) and secondary (mainly endoscopy) prevention efforts may prevent or limit the progression of gastric oncogenesis. This approach, which is tailored to different country-specific gastric cancer incidence, socioeconomic, and cultural factors, requires that the complementary competences of gastroenterologists, oncologists, and pathologists be amalgamated into a common strategy of health policy., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

LINE-1 hypomethylation is widely accepted as marker for global genomic DNA hypomethylation, which is a frequent event in cancer. The aim of the study was to evaluate LINE-1 methylation status at different stages of gastric carcinogenesis and evaluate its prognostic potential in clinical settings. LINE-1 methylation was analyzed in 267 tissue samples by bisulfite pyrosequencing including primary colorectal cancer tissues (T-CRC) with corresponding adjacent colon mucosa (N-CRC), gastric cancer tissues (T-GC) with corresponding gastric mucosa (N-GC), normal gastric tissues (N), chronic non-atrophic and atrophic gastritis (CG). LINE-1 methylation level was lower in both T-GC and T-CRC when compared to paired adjacent tissues. No difference was observed for LINE-1 methylation status between patients with normal gastric mucosa, CG and N-GC. LINE-1 methylation in T-GC but not N-GC tended to correlate with age. Subgroup stratification analysis did not reveal significant differences in LINE-1 methylation status according to tumor stage, anatomical location, histological subtype, differentiation grade. We observed similar overall survival data between patients with high or low LINE-1 levels. In summary, LINE-1 hypomethylation is a characteristic feature in GC but not very common in early preneoplastic stages of gastric carcinogenesis. Prognostic role of LINE-1 hypomethylation in GC patients could not be confirmed in this cohort.

Background  In the federal state of Saxony-Anhalt, gastric cancer (GC) incidence ranks among the highest in Germany. Helicobacter pylori prevalence is a surrogate marker for GC risk in a given population. In 2010 we reported an H. pylori seroprevalence of 44.4 % in patients at the emergency ward of the University Hospital of Magdeburg, the capital of Saxony-Anhalt. Our aim is to update these findings in a cohort of healthy blood donors from the same region. Materials and methods  The sera of 516 consecutive blood donors (40.1 ± 14.1 years; 286 males and 230 females) were tested for antibodies against H. pylori and CagA. Data on demographics and previous H. pylori eradication therapy were obtained by means of a structured questionnaire. Blood donors with positive serology for H. pylori or CagA and/or history of eradication therapy were classified as H. pylori-positive. Results  Overall, 28.9 % of the study cohort were H. pylori-positive. The prevalence was higher in older generations (9 % in 18 - 20 years up to 47 % in 61 - 70 years). In 44.4 % of H. pylori IgG-positive donors, CagA serology was also positive. This proportion was not age-dependent. Study participants with siblings were by trend more often H. pylori-positive (p = 0.066). Conclusion  Compared to our previous study in patients at the emergency ward, we found by trend lower age-related H. pylori prevalence rates. In our cohort of healthy blood donors, we confirmed a lower H. pylori prevalence in younger generations., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Gastric premalignant conditions, atrophic gastritis (AG) and intestinal metaplasia (IM) are characterized by an increase of proliferation and a reduction of apoptosis in epithelial cells. The epithelial cell kinetics in AG and IM in gastric mucosa adjacent to gastric cancer is still unclear. The aim of this study was to evaluate the epithelial cell turnover and expression of proliferation and apoptosis-related genes in gastric cancer (GC) and adjacent mucosa with atrophic gastritis or intestinal metaplasia (AG/IM GC+), as well as in atrophic gastritis or intestinal metaplasia mucosa of patients without GC (AG/IM GC-) and in control biopsy samples of non-transformed gastric mucosa (Control)., Methods: We selected 58 patients (M: F = 34:24; age range 20-84 years, median 61.06 years) with 4 well defined histological conditions: 20 controls with histological finding of non-transformed gastric mucosa, 20 patients with AG or IM (AG/IM GC-), and 18 patients with intestinal type gastric adenocarcinoma (GC) and AG or IM in the adjacent mucosa (3 cm from the macroscopic tumour margin, AG/IM GC+). We performed an immunohistochemical staining of Ki67 and TUNEL and quantitative RT-PCR to determine the expression of PCNA and Bax/Bcl-2., Results: The immunohistochemical expression of Ki67 and TUNEL in AG/IM GC- was significantly increased compared to not transformed gastric mucosa (p < 0.0001) but not compared to AG/IM in gastric mucosa adjacent to GC. Levels of Bcl-2 were reduced in GC and AG/IM GC- compared to controls as well as in AG/IM GC- compared to AG/IM in mucosa adjacent to GC+ (p < 0.05). Proliferation and apoptosis markers did not correlate with H.pylori status in our study population., Conclusions: In AG/IM associated with GC, no significant changes in the epithelial cell turnover were detected. Decreased Bcl-2 gene expression signified atrophic gastritis and IM in presence of cancer, as well as intestinal type gastric adenocarcinoma.

Aim: To evaluate associations between miRNA target genes IL12B , INSR , CCND1 and IL10 polymorphisms and gastric cancer (GC) in European population., Methods: Gene polymorphisms were analyzed in 508 controls and 474 GC patients from 3 tertiary centers in Germany, Lithuania and Latvia. Controls were patients from the out-patient departments, who were referred for upper endoscopy because of dyspeptic symptoms and had no history of previous malignancy. Gastric cancer (GC) patients had histopathological verification of gastric adenocarcinoma. Genomic DNA was extracted using salting out method from peripheral blood mononuclear cells. IL12B T>G (rs1368439), INSR T>C (rs1051690), CCND1 A>C (rs7177) and IL10 T>C (rs3024498) SNPs were genotyped by the real-time polymerase chain reaction. Associations between gene polymorphism and GC were evaluated using multiple logistic regression analysis with adjustment for sex, age and country of birth., Results: We observed similar distribution of genotypes and allelic frequencies of all polymorphisms between GC patients and controls except of INSR rs1051690. The frequency of the T allele of INSR gene was significantly higher in GC patients than in controls (23.26% and 19.19% respectively, P = 0.028). CT genotype was also more prevalent in patients compared to control group (38.48% and 30.12% respectively, P < 0.021). Logistic regression analysis revealed that only one polymorphism (rs1051690 in INSR gene) was associated with increased risk of GC. Carriers of CT genotype had higher odds of GC when compared to CC genotype (OR = 1.45, 95%PI: 1.08-1.95, P = 0.01). Similar association was observed in a dominant model for INSR gene, where comparison of TT+CT vs CC genotypes showed an increased risk of GC (OR = 1.44, 95%PI: 1.08-1.90, P = 0.01). Other analyzed SNPs were not associated with the presence of GC., Conclusion: INSR rs1051690 SNP is associated with increased risk of GC, while polymorphisms in IL12B , CCND1 and IL10 genes are not linked with the presence of GC., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts.

Important progress has been made in the management of Helicobacter pylori infection and in this fifth edition of the Maastricht Consensus Report, key aspects related to the clinical role of H. pylori were re-evaluated in 2015. In the Maastricht V/Florence Consensus Conference, 43 experts from 24 countries examined new data related to H. pylori in five subdivided workshops: (1) Indications/Associations, (2) Diagnosis, (3) Treatment, (4) Prevention/Public Health, (5) H. pylori and the Gastric Microbiota. The results of the individual workshops were presented to a final consensus voting that included all participants. Recommendations are provided on the basis of the best available evidence and relevance to the management of H. pylori infection in the various clinical scenarios., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Gastric cancer (GC) ranks fifth for cancer incidence and second for cancer deaths. Epidemiological data showed that survivors of Hodgkin's lymphoma and patients with pernicious anemia etiologically linked to autoimmune gastritis are at increased risk of GC. Screening of patients with autoimmune thyroid disease by means of pepsinogen (PG) I and PG I/II detected autoimmune gastritis with oxyntic gastric atrophy in one of four patients and may be recommended for GC prevention purposes. The International Agency for Research on Cancer reported a positive association between consumption of processed meet and increased GC risk. A new GC risk prediction model based on biological markers, age, gender, smoking status, family history of GC, and consumption of highly salted food showed good predictive performance, and might prompt individuals to modify their lifestyle habits, attend regular check-up visits or participate in screening programs. A novel GC classification based on gene expression of primary resected cancers correlated with clinicopathological features. Noncoding RNA for GC screening remains the focus of multiple studies. Patients with early GC undergoing endoscopic resection are more likely to develop metachronous lesions than patients undergoing surgery and endoscopic surveillance is warranted in this special cohort. The addition of gastrectomy to chemotherapy did not improve survival of patients with advanced GC and a single noncurable factor. Apatinib, a novel oral vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor, improved the median overall survival of patients with advanced GC and progressive disease after two or more lines of prior chemotherapy of nearly 3 months., (© 2016 John Wiley & Sons Ltd.)

MicroRNAs (miRNA) are involved in posttranscriptional regulation of gene expression and are dysregulated during carcinogenesis. CpG island methylation of miR-137 is a common event in different cancers; however, the role of miR-137 in gastric cancer (GC) remains largely unexplored. In this study we aimed to characterize the epigenetic alterations of miR-137 in gastric carcinogenesis. We analyzed total 295 tissues including paired primary gastric cancer (T-GC) with corresponding adjacent gastric mucosa (N-GC), paired primary colorectal cancer (CRC) tissues with corresponding non-tumorous mucosa, gastric tissues from controls (N), and patients with chronic/atrophic gastritis (CG) with and without Helicobacter pylori infection. Bisulfite pyrosequencing and TaqMan RT-PCR were used to analyze miR-137 methylation and expression, respectively. Survival differences were evaluated using Kaplan-Meier analyses. miR-137 CpG island methylation was more frequent in tumorous compared to non-tumorous conditions and higher in CRC than in GC. In comparison to N-GC, miR 137 methylation level was lower in N and CG tissues, which correlates with Correas cascade. MiR-137 methylation inversely correlates with global LINE-1 methylation and miR-137 expression. miR-137 methylation was higher in intestinal type GC compared to diffuse one, and higher in antrum compared to cardia and corpus, however, miR-137 methylation was associated with worse prognosis in diffuse, but not in intestinal type of GC. The expression in colon was significantly higher compared to any gastric tissues suggesting functional difference. In summary, miR-137 methylation is a frequent event in gastrointestinal cancers which occurs early in stepwise manner during gastric carcinogenesis and inversely correlates with global methylation. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Canonical Wnt signaling is involved in gastric carcinogenesis. The aim of this study was to identify the link between Wnt signaling and aurora kinase A (AURKA), a target for the treatment of gastrointestinal cancers. Publicly available microarray data were used to identify phenotype-specific protein-protein interaction (PPI) subnetworks. The in silico analysis revealed a gastric cancer-specific PPI subnetwork consisting of 2745 proteins and 50,935 interactions. We focused on the link of AURKA to a Wnt-specific interaction module consisting of 92 proteins. There was a direct association of AURKA with Rac GTPase-activating protein 1 (RACGAP1), as well as with CTNBB1 (β-catenin) and CDKN1A as second-order interactors. Differential expression analysis revealed a significant downregulation of both AURKA and RACGAP1 in gastric cancer compared to noncancer controls. Biopsies from a prospective cohort of 56 patients with gastric cancer (32 intestinal type, 24 diffuse type) and 20 noncancer controls were used for validation of the identified targets. The RT-PCR data confirmed a strong correlation of AURKA and RACGAP1 gene expression both in the tumor, the tumor-adjacent and the tumor-distant mucosa. RACGAP1 in the tumor was also associated with CTNBB1 expression, and inversely associated with CDKN1A gene expression. Immunohistochemistry confirmed expression of the RACGAP1 protein in gastric cancer and the tumor-adjacent mucosa. RACGAP1 expression was not associated with tumor stage, grading, Lauren type, Helicobacter pylori infection, or age. In conclusion, AURKA is directly associated with the expression of RACGAP1, a modulator of the canonical Wnt signaling pathway., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Helicobacter pylori (H. pylori) is a Gram negative spiraliform bacterium that is commonly found in the stomach. H. pylori infection is still one of the world's most frequent infections, present in the stomachs of approximately one-half of the world's people. H. pylori infection is etiologically linked to histologic chronic active gastritis, peptic ulcer disease, and primary B-cell gastric lymphoma (gastric MALT lymphoma) and represents the major risk factor for the development of sporadic non-cardia gastric cancer (GC) of both intestinal and diffuse type. Studies that have examined the impact of GC prevention through H. pylori eradication have shown mixed results, but recent data suggest that prevention is only efficacious in patients without intestinal metaplasia or dysplasia. This indicates that, like in Barrett's esophagus, we need better clinical risk markers to indicate which patients are at greatest risk of developing cancer to guide clinical strategies. Furthermore, recent epidemiological data have suggested a possible contribution of H. pylori in modifying the risk of developing other gastrointestinal malignancies (including esophageal, pancreatic, hepatocellular, and colorectal cancer), although mechanistically these associations remain unexplained. We review clinically relevant aspects of H. pylori infection in the context of GC development as well as studies that have examined the impact of eradication on GC development and, lastly, discuss these recent epidemiological studies connecting H. pylori infection to extragastric gastrointestinal malignancies.

Background: Gastric atrophy and intestinal metaplasia (IM) are preneoplastic conditions in the development of gastric cancer. Histopathological assessment is based on the updated Sydney system and superordinate staging systems, operative link on gastritis assessment (OLGA) and operative link on gastritis assessment using IM (OLGIM), all requiring a biopsy from the incisura angularis (angulus)., Aim: To determine the value of the angulus biopsy for the detection of preneoplastic conditions and cancer risk evaluation using OLGA and OLGIM prospectively., Methods: Biopsies from antrum (2), angulus (1) and corpus (2) were obtained from 213 patients (age 19-94 years, median 54 years, female to male ratio 138:75) undergoing upper endoscopy. Histological assessment according to the updated Sydney system, OLGA and OLGIM staging was performed by gastrointestinal pathologists. Statistical analysis used exact confidence limits for dichotomous variables and repeated measurement analysis of variance., Results: 8% of the cases with atrophic gastritis and 3% with IM (17 vs 6/213) would have been missed without the angulus biopsy. More patients were diagnosed with a preneoplastic condition when the angulus biopsy was considered (13.1%, CI 8.9% to 18.4%), but the grade of atrophy, if present at both sides, did not vary significantly in angulus and antrum. OLGA and OLGIM scores dropped significantly when recalculated without the angulus (difference in means±SD 0.131±0.402 and 0.075±0.313, respectively). The impact on the identification of high-risk stages is limited., Conclusions: The angulus biopsy adds to the detection of mild gastric atrophy in particular. It allows identifying a small additional number of patients with high-risk gastritis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Regulation of MMP expression by activation of mTOR signalling has been demonstrated for several tumor types, but has thus far not been confirmed in gastric cancer., Findings: The study compromised 128 patients who underwent gastric resection for cancer (66.4 % male; 86 intestinal, 42 diffuse type). Immunohistochemical staining of MMPs was performed to analyse the topographical pattern of MMP expression at the tumor center and the invasive front, respectively. MMP2 showed higher expression at the invasive front compared to the tumor center, whereas MMP7 staining scores were higher in the tumor center, and there was no difference for MMP9. The expression of p-mTOR was higher in the tumor center than at the invasive front, with a similar trend for mTOR. For intestinal type gastric cancer there was a weak correlation of MMP9 with expression of mTOR in the tumor center. Otherwise, there was no correlation of the MMPs with mTOR. By treatment of MKN45 gastric cancer cells with rapamycin, a reduction of p-mTOR in the Western blot was achieved; however, expression of MMPs remained unaffected., Conclusions: Expression of MMP2 and MMP7 in gastric cancer is not associated with mTOR, MMP9 expression might be related to mTOR signalling in a subset of tumors.

Background: MicroRNAs (miRNAs) are widely studied non-coding RNAs that modulate gene expression. MiRNAs are deregulated in different tumors including gastric cancer (GC) and have potential diagnostic and prognostic implications. The aim of our study was to determine miRNA profile in GC tissues, followed by evaluation of deregulated miRNAs in plasma of GC patients. Using available databases and bioinformatics methods we also aimed to evaluate potential target genes of confirmed differentially expressed miRNA and validate these findings in GC tissues., Methods: The study included 51 GC patients and 51 controls. Initially, we screened miRNA expression profile in 13 tissue samples of GC and 12 normal gastric tissues with TaqMan low density array (TLDA). In the second stage, differentially expressed miRNAs were validated in a replication cohort using qRT-PCR in tissue and plasma samples. Subsequently, we analyzed potential target genes of deregulated miRNAs using bioinformatics approach, determined their expression in GC tissues and performed correlation analysis with targeting miRNAs., Results: Profiling with TLDA revealed 15 deregulated miRNAs in GC tissues compared to normal gastric mucosa. Replication analysis confirmed that miR-148a-3p, miR-204-5p, miR-223-3p and miR-375 were consistently deregulated in GC tissues. Analysis of GC patients' plasma samples showed significant down-regulation of miR-148a-3p, miR-375 and up-regulation of miR-223-3p compared to healthy subjects. Further, using bioinformatic tools we identified targets of replicated miRNAs and performed disease-associated gene enrichment analysis. Ultimately, we evaluated potential target gene BCL2 and DNMT3B expression by qRT-PCR in GC tissue, which correlated with targeting miRNA expression., Conclusions: Our study revealed miRNA profile in GC tissues and showed that miR-148a-3p, miR-223-3p and miR-375 are deregulated in GC plasma samples, but these circulating miRNAs showed relatively weak diagnostic performance as sole biomarkers. Target gene analysis demonstrated that BCL2 and DNMT3B expression in GC tissue correlated with their targeting miRNA expression.

Background: Clinical guidelines are essential in implementing and maintaining nationwide stage-specific diagnostic and therapeutic standards. In 2011, the first German expert consensus guideline defined the evidence for diagnosis and treatment of early and locally advanced esophagogastric cancers. Here, we compare this guideline with other national guidelines as well as current literature., Methods: The German S3-guideline used an approved development process with de novo literature research, international guideline adaptation, or good clinical practice. Other recent evidence-based national guidelines and current references were compared with German recommendations., Results: In the German S3 and other Western guidelines, adenocarcinomas of the esophagogastric junction (AEG) are classified according to formerly defined AEG I-III subgroups due to the high surgical impact. To stage local disease, computed tomography of the chest and abdomen and endosonography are reinforced. In contrast, laparoscopy is optional for staging. Mucosal cancers (T1a) should be endoscopically resected "en-bloc" to allow complete histological evaluation of lateral and basal margins. For locally advanced cancers of the stomach or esophagogastric junction (≥T3N+), preferred treatment is preoperative and postoperative chemotherapy. Preoperative radiochemotherapy is an evidence-based alternative for large AEG type I-II tumors (≥T3N+). Additionally, some experts recommend treating T2 tumors with a similar approach, mainly because pretherapeutic staging is often considered to be unreliable., Conclusions: The German S3 guideline represents an up-to-date European position with regard to diagnosis, staging, and treatment recommendations for patients with locally advanced esophagogastric cancer. Effects of perioperative chemotherapy versus chemoradiotherapy are still to be investigated for adenocarcinoma of the cardia and the lower esophagus.