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Background and aims: Several methods are available to diagnose Helicobacter pylori infection. Our objective was to evaluate the tests used for both the initial diagnosis and the confirmation of eradication after treatment in Europe. Methods: The European Registry on the management of Helicobacter pylori infection is an international, multicentre, prospective, non-interventional registry aiming to evaluate the management of Helicobacter pylori-infected patients in Europe. Countries with at least 100 cases registered from June 2013 to April 2021, and with a validated diagnostic method were analysed. Data were quality reviewed. Results: A total of 34,920 adult patients from 20 countries were included (mean age 51 years; 61% women). To establish the initial diagnosis, invasive tests were performed in 19,801 (71%) patients, non-invasive in 11,369 (41%), and both in 3437 (12%). The most frequent were histology (n = 11,885; 43%), a rapid urease test (n = 10,636; 38%) and an urea breath test (n = 7577; 27%). According to the age, invasive tests were indicated in 11,179 (77%) ≥50 years, and in 8603 (65%)

ObjectiveTo evaluate the use, effectiveness and safety ofHelicobacter pyloriempirical rescue therapy in third and subsequent treatment lines in Europe.DesignInternational, prospective, non-interventional registry of the clinical practice of European gastroenterologists. Data were collected and quality reviewed until October 2021 at Asociación Española de Gastroenterología-Research Electronic Data Capture. All cases with three or more empirical eradication attempts were assessed for effectiveness by modified intention-to-treat and per-protocol analysis.ResultsOverall, 2144 treatments were included: 1519, 439, 145 and 41 cases from third, fourth, fifth and sixth treatment lines, respectively. Sixty different therapies were used; the 15 most frequently prescribed encompassed >90% of cases. Overall effectiveness remained ConclusionEmpirical rescue treatment in third and subsequent lines achieved suboptimal effectiveness in most European regions. Only quadruple bismuth-metronidazole-tetracycline (10-day single-capsule or 14-day traditional scheme) and triple amoxicillin-levofloxacin therapies reached acceptable outcomes in some settings. Compliance with empirical therapy optimisation principles is still poor 5 years after clinical practice guidelines update.Trial registration numberNCT02328131.

Helicobacter pylori infections are responsible for tremendous morbidity and mortality worldwide, leading to efforts to eradicate the organism. However, the effectiveness of antimicrobial therapy has been undermined by the progressive development of antimicrobial resistance. Treatments and treatment guidelines have been based on traditional pairwise meta-analyses of randomised controlled trials. More recently, network meta-analyses have also been used in an attempt to provide useful information to the clinician regarding which therapies appear best and which to avoid as the least efficacious. However, both forms of meta-analysis have been undermined by the same problems including the poor quality of the clinical trials using unoptimised regimens and incomparable comparisons related to marked geographic and ethnic genotypic and phenotypic heterogeneity. In addition, the comparator regimens often consist of invalid strawman comparisons. New approaches concerning H. pylori treatment and analysis of therapies are needed. H. pylori therapies should be based on antimicrobial stewardship, as in other infectious diseases. This approach requires the use of only optimised therapies proven to be reliably highly effective in the local population (eg, a cure rate of >90%) for both the study and the comparator regimens. Meta-analyses should be restricted to regimens that meet these criteria and must take into account the presence of marked geographical and host genetic and phenotypic heterogeneity. In addition, to provide clinically relevant results, treatment outcomes should focus on, and present, actual cure rates in addition to odd ratios.

Background Helicobacter pylori is the most infamous constituent of the gastric microbiota and its presence is the strongest risk factor for gastric cancer and other gastroduodenal diseases. Although historically the healthy stomach was considered a sterile organ, we now know it is colonised with a complex microbiota. However, its role in health and disease is not well understood. Aim To systematically explore the literature on the gastric microbiota in health and disease as well as the gut microbiota after bariatric surgery. Methods A systematic search of online bibliographic databases MEDLINE/EMBASE was performed between 1966 and February 2019 with screening in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomised controlled trials, cohort studies and observational studies were included if they reported next-generation sequencing derived microbiota analysis on gastric aspirate/tissue or stool samples (bariatric surgical outcomes). Results Sixty-five papers were eligible for inclusion. With the exception of H pylori-induced conditions, overarching gastric microbiota signatures of health or disease could not be determined. Gastric carcinogenesis induces a progressively altered microbiota with an enrichment of oral and intestinal taxa as well as significant changes in host gastric mucin expression. Proton pump inhibitors usage increases gastric microbiota richness. Bariatric surgery is associated with an increase in potentially pathogenic proteobacterial species in patient stool samples. Conclusion While H pylori remains the single most important risk factor for gastric disease, its capacity to shape the collective gastric microbiota remains to be fully elucidated. Further studies are needed to explore the intricate host/microbial and microbial/microbial interplay.

Background Helicobacter pylori (H. pylori) is the most common chronic bacterial infection. Its management has to rely on local effectiveness, given the geographical variability of bacterial antibiotic resistance. We evaluated treatment effectiveness in naïve patients in Greece, as part of the European Registry on the management of H. pylori (Hp-EuReg). Methods Patients were registered in the AEG-REDCap Electronic Case Report Form from 2013-2020. All cases with a first-line treatment were included. Modified intention-to-treat (mITT) analysis was used. Results A total of 547 patients from 5 medical institutions were treated with the following regimens: concomitant with proton pump inhibitors (PPIs), clarithromycin, amoxicillin and metronidazole (concomitant-C+A+M) (38%); hybrid with PPI, clarithromycin, amoxicillin and metronidazole (hybrid-C+A+M) (20%); sequential with PPI, clarithromycin, amoxicillin and tinidazole (sequential-C+A+T) (12%); sequential with PPI, clarithromycin, amoxicillin and metronidazole (sequential-C+A+M) (12%); concomitant with PPI, clarithromycin, amoxicillin and tinidazole (concomitant-C+A+T) (8%); triple with PPI, clarithromycin and amoxicillin (triple-C+A) (7%); and other (3%). Overall compliance was 99%. Triple-C+A, sequential-C+A+T, sequential-C+A+M and concomitant-C+A+T were used from 2013-2015. The respective mITT cure rates (95% confidence interval) were 92% (78-98), 87% (76-94), 67% (54-78) and 91% (79-98). Since 2015, patients were also treated with concomitant-C+A+M and hybrid-C+A+M regimens, with respective mITT cure rates of 90% (85-94) and 88% (80.5-94). Adverse events were reported by 31% of the patients, dysgeusia being the most frequent (15%). Conclusions “Optimized” H. pylori therapies should achieve cure rates over 90%. In Greece, at present, only non-bismuth quadruple concomitant regimens achieve this target and can be recommended as first-line treatment.

Background & Aims A number of double, triple, and quadruple therapies have been proposed as first-line empiric treatments for Helicobacter pylori infection. However, knowledge of their worldwide and regional comparative efficacy is lacking. We examined the comparative effectiveness of all empirically used first-line regimens tested against standard triple treatment using a network meta-analysis of published randomized controlled trials. Methods Data extracted from eligible randomized controlled trials were entered into a Bayesian network meta-analysis to investigate the comparative efficacy of H pylori infection empiric first-line regimens and to explore their effectiveness rank order. The ranking probability for each regimen was evaluated by means of surfaces under cumulative ranking values. Results Sixty-eight eligible randomized controlled trials were included, giving a total of 92 paired comparisons with 22,975 patients randomized to 8 first-line regimens. The overall results showed that only vonoprazan triple therapy and reverse hybrid therapy achieved cure rates of >90%. Levofloxacin triple therapy performed best in Western countries (eradication rate 88.5%). The comparative effectiveness ranking showed that vonoprazan triple therapy had the best results, whereas standard triple therapy was the least efficacious regimen (surfaces under cumulative ranking 92.4% vs 4.7% respectively; odds ratio, 3.80; 95% credible interval, 1.62–8.94). Conclusions For first-line empiric treatment of H pylori infection, vonoprazan triple therapy and reverse hybrid therapy achieved high eradication rates of >90%. Levofloxacin triple therapy achieved the highest eradication rates in Western countries. Standard triple therapy was the least efficacious regimen in this network meta-analysis.

INTRODUCTION: The safety of Helicobacter pylori eradication treatments and to what extent adverse events (AEs) influence therapeutic compliance in clinical practice are hardly known. Our aim was to assess the frequency, type, intensity, and duration of AEs, and their impact on compliance, for the most frequently used treatments in the European Registry on Helicobacter pylori management. METHODS: Systematic prospective non interventional registry of the clinical practice of European gastroenterologists (27 countries, 300 investigators) on the management of H. pylori infection in routine clinical practice. All prescribed eradication treatments and their corresponding safety profile were recorded. AEs were classified depending on the intensity of symptoms as mild/moderate/severe and as serious AEs. All data were subject to quality control. RESULTS: The different treatments prescribed to 22, 492 patients caused at least 1 AE in 23% of the cases ; the classic bismuth-based quadruple therapy was the worst tolerated (37% of AEs). Taste disturbance (7 %) , diarrhea (7 %) , nausea (6%), and abdominal pain (3%) were the most frequent AEs. The majority of AEs were mild (57%), 6% were severe, and only 0.08% were serious, with an average duration of 7 days. The treatment compliance rate was 97%. Only 1.3% of the patients discontinued treatment due to AEs. Longer treatment durations were significantly associated with a higher incidence of AEs in standard triple, concomitant, bismuth quadruple, and levofloxacin triple or quadruple therapies. DISCUSSION: Helicobacter pylori eradication treatment frequently induces AEs, although they are usually mild and of limited duration. Their appearance does not interfere significantly with treatment compliance.

The best approach forInternational multicentre prospective non-interventional registry starting in 2013 aimed to evaluate the decisions and outcomes in30 394 patients from 27 European countries were evaluated and 21 533 (78%) first-line empiricalManagement of

Background & Aims: H. pylori eradication is strongly affected by various factors, including the ongoing antibiotic resistance. We describe a “real life” scenario in patients managed for H. pylori-related conditions, living in a southern Italian region (Apulia), an area with clarithromycin resistance >15%.Methods: 2,224 subjects were studied in two tertiary referral centers in Apulia. Analyses included: reason for referral, H. pylori infection rates (13C-urea breath test – UBT or upper endoscopy), and eradication rates following distinct regimens previously prescribed or prospectively prescribed (such as the bismuth-based quadruple therapy Pylera®, recently marketed in Italy).Results. Over 80% of the patients were referred by family physicians (60% naïve subjects). The overall infection rate was 32.5% and it was similar in asymptomatic patients (31.1%) or with H. pylori-related symptoms/clinical conditions (34.3%). In the 987 H. pylori+ve patients receiving therapy, the overall eradication rate was 80.2% (ITT). Observed eradication rate varied greatly across different regimens: 57.1% (2nd line levofloxacin), 59.6% (unconventional), 70.7% (7-day triple), 73.2% (7-day undefined), 89% (10-day sequential) and 96.9% (ITT, 10 day Pylera®, 1st to 5th line regimens given to 227 patients).Conclusions. A heterogeneous “real life” scenario in Southern Europe shows that H. pylori+ve patients are put at risk of poor outcomes and points to the need of a susceptibility-based therapy according to guidelines and local microbial resistance. In the present setting (i.e. high clarithromycin resistance), despite the high observed eradication rate, sequential therapy should not be recommended (absent in guidelines, unneeded antibiotic). Bismuth-based quadruple treatment (1st, 2nd or subsequent lines) yields the highest eradication rates.Abbreviations: ALT: Altamura; BA: Bari; EGDS: esophagogastroduodenoscopy; GERD: gastro-esophageal reflux disease; H. pylori: Helicobacter pylori; ITT: intention-to-treat; PP: per-protocol; PPI: proton pump inhibitor; UBT: urea breath test.

Background & Aims: 13 C-Urea Breath Test (UBT) is a non-invasive, highly accurate and recommended test to detect Helicobacter pylori (H. pylori) infection and to confirm post-therapy eradication. However, differences exist in terms of manufacturers, dose of labelled urea, addition of citric acid, solid vs. liquid formulation, and sampling times of breath samples. In this study, we compared the diagnostic accuracy of “short” (15 minutes) vs. “standard” (30 minutes) time for a single type of liquid UBT. Methods: We compared the performance of a single UBT type (BREATHQUALITY, AB Analitica, Padua, Italy, 10 mL of 75 mg 13 C-Urea and 1.4 g citric acid) during a “short” vs. “standard” breath sampling time. Enrolled were 151 subjects requiring UBT as naïve (N=92) or post-eradication (N=59) checks. Results: UBT at 15 and 30 minutes were highly comparable, showing optimal correlation in all subsets of patients (i.e. naïve vs. post eradication, negative vs. post eradication check). One discrepant result occurred at the borderline zone of the DOB 4‰, but proved to be true positive at a later confirmation by a second UBT and stool antigen test. Conclusions: By shortening the testing time of BREATHQUALITY to 15 minutes (-50%) comparable accuracy will be maintained and in addition, it will bring some benefits to patients’ waiting lists, compliance, and hospital staff.

Introduction Helicobacter pylori infection (H pylori-I) affects more than half of the global population and consists an important burden to public health and healthcare expenditures, by contributing to many diseases' pathogenesis. Aim This study aimed to evaluate the current nonbismuth quadruple eradication regimens in a high antibiotic resistance area, such as Greece, concerning their cost-effectiveness, especially during financial crisis period. Materials and methods Eight hundred and nine patients who received eradication treatment against H pylori-I were included to evaluate five different regimens, using amoxicillin, clarithromycin, and metronidazole as antibiotics and one proton-pump inhibitor, based on their current eradication rates. Regimes compared 10-day concomitant use of (a) pantoprazole or (b) esomeprazole; 10-day sequential use of (c) pantoprazole or (d) esomeprazole; and 14-day hybrid using esomeprazole. Cost-effectiveness analysis ratio (CEAR) and incremental cost-effectiveness ratios were calculated taking into account all direct costs and cases who needed second-line treatment. Additionally, sensitivity analysis was performed to predict all potential combinations. Results Ten-day concomitant regimen with esomeprazole was characterized by the lowest CEAR (179.17€) followed by the same regimen using pantoprazole (183.27€). Hybrid regimen, although equivalent in eradication rates, was found to have higher CEAR (187.42€), whereas sequential regimens were not cost-effective (CEAR: 204.12€ and 216.02€ respectively). Discussion This is the first study evaluating the cost-effectiveness of H pylori-I treatment regimens in a high clarithromycin-resistance (≈26.5%) European area, suggesting the 10-day concomitant regimen with generics using esomeprazole 40 mg as the most appropriate one. National and regional guidelines should include cost-effectiveness in their statements, and further studies are required to clarify the necessity of a wide "test and treat" policy for H pylori-I.

Background Increasing evidence has suggested that Helicobacter pylori (H. pylori) eradication might prevent the development of gastric cancer (GC). This systematic review and meta-analysis aimed to better explore the role of H. pylori eradication in preventing GC, with particular reference to patients with precancerous lesions at baseline histology. Methods Searches for human studies were performed through October 2016 and risk ratios (RRs), were obtained. Heterogeneity between studies was estimated using the Cochran Q test and I2 values, whereas the possibility of publication bias was estimated with funnel plots. Additionally, we performed subgroup and sensitivity analyses. Results In 26 studies suitable for meta-analysis (10 randomized controlled trials and 16 cohort studies) 52,363 subjects were included. The risk of GC among patients in whom H. pylori was successfully eradicated was significantly lower than that among controls: pooled RRs [95% CI] 0.56 [0.48-0.66], Z= -7.27, P=0.00001. This finding applied separately for randomized controlled trials (0.65 [0.51-0.84], Z= -3.33, P=0.0009) and for cohort studies (0.51 [0.42-0.62], Z= -6.63, P=0.00001). Concerning H. pylori eradication in patients with precancerous lesions, subgroup analyses showed that patients with non-atrophic or atrophic gastritis benefited from H. pylori eradication for the risk of GC development, whereas those with intestinal metaplasia or dysplasia did not. Conclusion H. pylori eradication is associated with a significantly lower risk of GC; this finding has significant implications for the prevention of this cancer. The benefit is maximized when H. pylori eradication is applied at early stages of the infection. Keywords H. pylori, eradication, gastric cancer, prevention, meta-analysis Ann Gastroenterol 2017; 30 (4): 414-423

The validity and usefulness of the 7th edition of the UICC tumor node metastasis classification in the context of clinical management of gastric cancer are discussed. The most relevant new agent in gastric cancer therapy is trastuzumab for HER2-positive gastric carcinomas. This marks the success of continuous effort of translational research. Trastuzumab, initially applied in palliative settings, is currently being evaluated also in neoadjuvant treatment regimens. Several new meta-analyses support the carcinogenic effect of high salt intake and smoking in the context of Helicobacter pylori infection. Further data have become available on the efficacy of protective agents, acetyl salicylic acid/nonsteroidal anti-inflammatory drugs, and antioxidants. In search for a successful prevention strategy, the focus is on the identification of individuals at high risk who demand screening (testing) and surveillance. Serological assessment of gastric mucosal abnormalities with increased risk for gastric cancer development is extensively studied, and new data are presented from Asia as well as from Europe. New high-throughput techniques combined with bioinformatic vector analysis open the gate to the identification of new potential diagnostic and therapeutic targets. Furthermore, these approaches allow us to elucidate the interplay of bacterial virulence factors and the host's immune response as well as H. pylori-associated alterations of mucosal gene expression.

Gastric cancer still represents a global health care burden, and in the absence of strategies implemented for early detection, the disease continues to have a dismal prognosis. Patients presenting with clinical manifestations of gastric cancer have limited options for cure. Thus, early detection and prevention play a key role in the fight against gastric cancer. Serologic-based test methods have the potential to detect a subset of patients at high risk of gastric cancer that require a close clinical and endoscopic follow-up. More data have been produced to support Helicobacter pylori eradication as an efficient strategy to prevent gastric cancer. Treatment options for patients with an advanced disease are still limited, but the introduction of new agents opens a more optimistic perspective for the future.

Helicobacter pylori (H. pylori) is believed to predispose to gastric cancer by inducing the precancerous changes, that is, atrophy and intestinal metaplasia (IM). First-degree relatives of patients with gastric cancer might be at an increased risk of developing gastric cancer. However, this evidence is based on the scattered individual studies. The aim of this study was to examine the risk of first-degree relatives developing gastric cancer, in comparison with controls that have no family history of gastric cancer, by meta-analyzing all relevant studies.Extensive English language medical literature searches for human studies were performed up to the end of November 2009, using suitable keywords. Inclusion and exclusion criteria were identified and in eligible studies data on three parameters, that is, H. pylori prevalence, atrophy and IM, were extracted. Pooled estimates (odds ratio with 95% confidence intervals) were obtained using either the fixed or random-effects model as appropriate. Heterogeneity between studies was evaluated with the Cochran Q test, whereas the likelihood of publication bias was assessed by constructing funnel plots. Their symmetry was estimated by the Egger's regression asymmetry test.Out of 155 initially identified studies, 11 studies, from various countries, fulfilling the inclusion criteria, examined the risk of first-degree relatives developing gastric cancer (n=1500) in comparison with controls (n=2638). For H. pylori prevalence, the pooled odds ratio with 95% confidence interval was 1.925 (1.419-2.611) and the test for overall effect Z was 4.211 (P=0.000). The respective values for atrophy and IM were 2.200 (1.266-3.824), Z=2.797, (P=0.005) and 1.982 (1.363-2.881), Z=3.582 (P=0.000) respectively.The results of this meta-analysis showed that first-degree relatives of patients with gastric cancer might be at an increased risk of developing gastric cancer, as judged by significantly higher prevalence of H. pylori, gastric atrophy and IM, in comparison with controls. Consequently, H. pylori detection and prophylactic eradication of the infection should be offered to such individuals. However, follow-up studies are required to prove the above.

In spite of important new insights into the basic mechanisms of gastric carcinogenesis, progress in the management of gastric cancer has been modest. Some modifications in the chemotherapies used for palliation and strategies for downstaging of the disease prior to surgical intervention are noteworthy. The positive experience with endoscopic mucosal resection (EMR) and submucosal dissection (ESD) for treatment of early gastric cancer has been confirmed and extended. The procedure-related morbidity and post-interventional quality of life is clearly favorable compared to open surgical resection in well-selected patients. New data on Helicobacter pylori revealed that eradication after endoscopic resection of early gastric cancer significantly reduces the incidence of recurrent and metachronous gastric neoplasias. It can further improve healing rates of treatment induced gastric ulcers. Eradication therapy therefore remains the best target for prevention of the disease. Critical is the "point of no return" when mucosal alterations (i.e. intestinal metaplasia, glandular atrophy) are no longer reversible. A population-based screen-and-eradicate strategy for H. pylori infection can at present only be recommended in high incidence regions.

In humans there are epidemiological data suggesting a protective effect of Helicobacter pylori (H. pylori) infection against the development of autoimmune diseases and in addition, there are laboratory data illustrating H. pylori's ability to induce immune tolerance and limit inflammatory responses. Thus, numerous observational studies have examined the association between H. pylori infection and inflammatory bowel disease (IBD) with various results.We performed a meta-analysis of available studies to better define the association of H. pylori infection and IBD.Medical literature searches for human studies were performed through September 2014, using suitable keywords. In each study the risk ratio (RR) of H. pylori infection in IBD patients vs controls was calculated and pooled estimates were obtained using fixed- or random-effects models as appropriate. Heterogeneity between studies was evaluated using Cochran Q test and I(2) statistics, whereas the likelihood of publication bias was assessed by constructing funnel plots.Thirty-three studies were eligible for meta-analysis, including 4400 IBD patients and 4763 controls. Overall 26.5% of IBD patients were positive for H. pylori infection, compared to 44.7% of individuals in the control group. There was significant heterogeneity in the included studies (Q = 137.2, df (Q) =32, I(2) ( )= 77%, p 0.001) and therefore the random-effects model of meta-analysis was used. The obtained pool RR estimation was 0.62 (95% confidence interval (CI) 0.55-0.71, test for overall effect Z = -7.04, p 0.001). There was no evidence of publication bias.The results of this meta-analysis showed a significant negative association between H. pylori infection and IBD that supports a possible protective benefit of H. pylori infection against the development of IBD.

For the therapeutic management of Helicobacter pylori infection, the Maastricht 2-2000 Consensus Report have introduced the concept of the 'treatment package' that considers first- and second-line eradication therapies together. According to this consensus statement, the first-line therapy for H. pylori eradication is a combination of the proton pump inhibitors (PPI) or ranitidine bismuth citrate (RBC) and claritromycin plus either amoxicillin or metronidazole. The second-line treatment is suggested to be PPI-quadruple therapy for a minimum of 7 days. If bismuth compounds are not available, PPI-based triple therapy will have to be used as a second-line treatment only after susceptibility testing. Since no considerable progress has been made during the past year in treatment regimens, there is still a need for new compounds that are specific for H. pylori, which could constitute future therapies.

The performance of serological methods used to detect Helicobacter pylori varies with the ethnicity and prevalence of the infection in the community. We have prospectively evaluated the performance of two commercially available serum enzyme immunoassays (EIA) detecting H. pylori immunoglobulin G (IgG) antibodies in the sera of untreated Greek patients.One-hundred-and-thirty consecutive untreated dyspeptic patients underwent endoscopy with biopsies from the gastric body (n = 2) and antrum (n = 2). Serum samples were also obtained from each patient. Serum H. pylori IgG antibody titres were determined with two EIA kits (Pyloriset EIA-G and Milenia H. pylori IgG). Sensitivities, specificities and optimal cut-off values of serum EIAs were determined for the population under investigation by using receiver operating characteristic (ROC) curve analysis and histology as gold standard.Ninety-seven patients were defined H. pylori-positive and 33 negative by histology. ROC curve analysis for the Pyloriset kit yielded 86% (95% CI, 78%-92%) sensitivity and 85% (68%-95%) specificity at an optimal cut-off value of358 units/ml. The respective values for the Milenia kit were 86% (78%-92%) and 82% (65%-93%) at an optimal cut-off value of51 units/ml. The suggested cut-off values of the manufacturers for Pyloriset and Milenia kits are300 and44 EIA units, respectively, which yield 2% and 4% higher sensitivity, but 9% lower specificity for both EIA kits.Both serum EIA kits performed well in our study. Our data show that EIA cut-off values should be optimized for the population under investigation.

In a retrospective study performed in California, U.S.A., ca. 3% of patients with gastric intestinal metaplasia (GIM) developed gastric cancer (GC) within a median time period of 4.6 years after diagnosis of GIM. This observation stresses the importance of targeted surveillance even in regions with a low GC prevalence. Patients with alcoholic liver disease as well as survivors of colorectal and lobular breast cancer were found to be at increased risk of secondary GC. A population-based Chinese study confirmed "serologic biopsy" as a useful screening tool for stratifying the individual risk of developing GC. Concerning GC therapy, a post hoc analysis of the MAGIC trial reported that regression of lymph node metastases, but not the tumor regression itself, predicts overall survival. Furthermore, in patients with high microsatellite instable tumors, perioperative chemotherapy leads to an increased risk of mortality. Two studies confirmed that eradication therapy is worthwhile as an initial treatment for gastric mucosa-associated lymphoid tissue (MALT) lymphoma irrespective of the H. pylori infection status and stage. An increased risk of a second primary malignancy including GC was observed in these patients treated with immuno/chemotherapy but not in patients treated solely with an H. pylori eradication treatment. With respect to gastrointestinal malignancies other than GC, discrepant data have been published regarding the association of H. pylori with pancreatic cancer whereas no association has been reported with esophageal squamous cell carcinoma. The majority of published studies still support an association of H. pylori with colon neoplasms.

There is evidence that Helicobacter pylori eradication might predispose to gastroesophageal reflux disease (GERD). The aim of this prospective study was to examine the effectiveness of antisecretory treatment, after successful H. pylori eradication, in preventing GERD, since no data exist so far. Eighty initially H. pylori(+) patients, without GERD at the time of H. pylori eradication [50 peptic ulcer (PU) and 30 nonulcer (NU), 55 men, 25 women, median age 38 years, range 19–57], after successful H. pylori eradication were randomized to recieve either omeprazole 20 mg daily (group A) or no treatment (group B) for one year. All patients underwent upper gastrointestinal endoscopy at 0, 6, and 12 months or when GERD symptoms occurred. There were 40 patients in each group, and there were no statistically significant differences between the two groups in terms of sex, age, body weight, ulcer/no ulcer ratio, and other demographic data. Seven patients from group A and five patients from group B were lost to follow-up, and therefore there were 33 and 35 patients in groups A and B, respectively, who completed the study. One of 33 patients in group A (3%) and 10/35 (28.5%) in group B developed GERD symptoms during follow-up (P = 0.0022). The respective values for esophagitis were 0/33(0%) and 6/35(17.1%) (P = 0.0083). In conclusion, antisecretory treatment in H. pylori(+) patients, after successful eradication, is effective in preventing GERD.

We have compared apoptosis and proliferation in antral epithelium from individuals not infected with H. pylori (Hp), those with Hp-induced gastritis and those with Hp-induced gastritis containing areas of gastric intestinal metaplasia, the precursor lesion to gastric adenocarcinoma. Antral biopsies from 42 patients were assessed for evidence of Hp infection, severity of gastritis and intestinal metaplasia. Apoptosis was evaluated by the TUNEL assay and proliferation by Ki-67 immunohistochemistry and were expressed as apoptotic (AI) and proliferation (PI) indices. In the 31 Hp-positive (Hp+) patients, apoptosis and proliferation were increased compared with the 11 Hp-negative (Hp−) patients (AI = 1.22 ± 0.13% vs. 0.15 ± 0.03%, p < 0.0001; PI = 24 ± 1% vs. 13 ± 2%, p < 0.0001). Increases were proportional to the severity of the inflammation. Within foci of intestinal metaplasia, in 9 of the Hp+ patients, apoptosis was significantly reduced compared with surrounding gastritis (AI = 0.20 ± 0.06% vs. 1.34 ± 0.23%, p = 0.0014), whereas proliferation was not altered (PI = 25.4 ± 4% vs. 24.7 ± 2%, p = 0.87), resulting in a lower AI/PI ratio in intestinal metaplasia than in surrounding gastritis (0.008 ± 0.005 vs. 0.054 ± 0.009, p < 0.02). Hp-induced gastritis is thus associated with increased epithelial apoptosis and proliferation compared with uninfected controls. In intestinal metaplasia, proliferation remains increased but apoptosis reverts to normal levels, and this perhaps contributes to Hp-associated gastric carcinogenesis. Int. J. Cancer 85:192–200, 2000. ©2000 Wiley-Liss, Inc.

Despite the fact that the association of Helicobacter pylori (H. pylori)with an increased risk of gastric cancer has been well documented, the exact mechanisms of this association have not been fully elucidated. The aim of the present prospective study was to contribute to the exploration of these mechanisms by studying the relationship between H. pylori infection and proliferating cell nuclear antigen (PCNA) immunostaining in endoscopic biopsies in gastric antrum. Furthermore, we examined the impact of H. pylorieradication on this relationship. We studied 28 H. pyloripositive patients and the results were compared with 22 endoscopically and histologically normal H. pylorinegative patients (control group) who were comparable to the H. pyloripositive group for age and sex. In addition all H. pyloripositive patients were examined before and after treatment aiming to eradicate H. pylori. In the H. pylori(+) patients the median PCNA index was 35 (range 8-58) and this was significantly higher than the respective number in the control group [5.5 (2 14), p0.001]. In patients studied before and after successful eradication of H. pylori(n=10) the corresponding numbers were 35 (8-56) and 7 (4 13) (p0.01) the latter not being significantly different from the control group of H. pylori(-)patients. On the contrary, in patients without successful H. pylori eradication (n=18) the PCNA indices before and after treatment were similar [35.5 (21-58) vs 31.5 (20-56)]. It is concluded that H. pyloriinfection alters the replication cycle of the gastric mucosa inducing hyperproliferation, which return towards normal after successful H. pylori eradication.

Follicular gastritis is an important histological entity, because it may progress to overt gastric MALT lymphoma. However, there is no universal agreement on whether there is any correlation of follicular gastritis with histological features of the antral mucosa or on the prevalence of follicular gastritis. To shed further light on these issues, we studied antral biopsies obtained from 735 adult patients, who had participated in six consecutive clinical trials. They included 348 patients with duodenal ulcer, 82 with gastric ulcer, and 305 with nonulcer dyspepsia. The Sydney classification system of gastritis was used, using a score of 0-3 to grade degree and activity of inflammation, gland atrophy, intestinal metaplasia, and H. pylori colonization density. Follicular gastritis was defined as prominent lymphoid follicles with no lymphoepithelial lesion. None of the H. pylori-negative patients (N = 159) had follicular gastritis. Among H. pylori-positive patients, 80/340 (23.5%) with duodenal ulcer, 5/77 (6.5%) with gastric ulcer, and 20/159 (12.6%) with nonulcer dyspepsia had follicular gastritis (P < 0.001). Multivariate discriminant analysis selected the following four significant predictor variables for follicular gastritis (Wilks lambda = 0.91, chi2 = 70.6, df = 4, P < 0.001): gastritis sum score, atrophic gastritis, age of the patient, and disease. The prevalence of follicular gastritis was linearly correlated (gamma = 24.55 - 0.98chi, r = -0.62, F1,11 = 6.12, P = 0.03) with the age groups of the 576 H. pylori-positive patients studied. In conclusion, follicular gastritis is highly correlated with H. pylori-caused severe, active gastritis. It is mostly prevalent in the young H. pylori-infected patients with duodenal ulcer.

Despite the fact that the association ofHelicobacterpylori with an increased risk of gastriccancer is well documented, the exact mechanisms of thisassociation have not been elucidated. Our aim was to shed some light on these mechanisms by studyingThe relationship of H. pylori CagA status to gastriccell proliferation and apoptosis, since both play animportant role in gastrointestinal epithelial cell turnover and carcinogenesis. We studied fiftypatients [32 men, 18 women, median age 39.5 years (range18-67)], referred for upper gastrointestinal endoscopy,from whom antral biopsies were taken. On biopsy specimens gastritis was estimated byscoring the severity of inflammatory infiltrate, and thepresence of atrophy and intestinal metaplasia were alsonoted. The gastric cell proliferation index (PI) was estimated by AgNOR staining, the epithelialapoptotic index (AI) was measured by special stainingfor apoptosis, and CagA status was determinedserologically by immunoblotting the sera of patientsagainst H. pylori antigens. Thirty-eight (76%) of the50 patients were H. pylori (positive) and 12 (24%) H.pylori (negative). Among the 38 H. pylori (+) patients,28 (73.6%) were CagA(+) and 10 (24.6%) CagA(-). In the H. pylori CagA(+) and CagA(-) groups,the PI values [median (ranges)] were 5 (4-7) and 3.7(3.5-5.5), respectively (P < 0.05). In addition thedifference in PI between the H. pylori CagA(+) and H. pylori (-) groups was highly significant (P< 0.001). Concerning apoptosis, in the H. pyloriCagA(+) and CagA(-) groups, the values for AI were 1(1-30) and 5.5 (1-35), respectively (P < 0.05). In addition, the difference in AI between theH. pylori CagA(-) and H. pylori (-) groups, wassignificant (P < 0.05). We conclude that H. pyloriCagA(+) strains induce increased gastric cellproliferation, which is not accompanied by a parallel increasein apoptosis. This might explain the increased risk forgastric carcinoma that is associated with infection byH. pylori CagA(+) strains.

Background: Whilst the role of Helicobacter pylori eradication in managing duodenal ulcers has been established, consensus regarding the ideal regimen has not been achieved. Methods: Patients with H. pylori-positive active duodenal ulcer were randomly assigned to receive triple therapy with amoxycillin 1000 mg b.d. + clarithromycin 500 mg b.d. + omeprazole 20 mg daily for 10 days (ACT-10) or dual therapy with clarithromycin 500 mg t.d.s. + omeprazole 40 mg daily for 14 days (Dual). No additional acid suppression was provided following eradication therapy. Endoscopy, with biopsy for culture and histology, as well as 13C-urea breath testing (13C-UBT) were performed pre-treatment to assess H. pylori infection. H. pylori eradication was established at 4–6 weeks follow-up with culture (2 antral, 1 corpus biopsies), histology (2 antral biopsies), and 13C-UBT. Ulcer healing by endoscopy and change in clinical symptoms were also assessed at 4–6 weeks. Results: Two hundred and sixty-seven (267) patients were randomized to ACT-10 (n=137) or Dual therapy (n=130). By per-protocol and intention-to-treat analyses, H. pylori eradication at 4–6 weeks follow-up was 91% (115/127) and 88% (120/136), respectively, for ACT-10 patients and 59% (68/115) and 55% (72/130), respectively, for Dual therapy patients (P

A close relationship has been found between Helicobacter pylori and peptic ulcer disease. Furthermore, eradication of H. pylori is associated with low recurrence rates. The aim of the present study was to examine whether eradication of H. pylori has any impact on the complications of ulcers, such as bleeding. Thirty-one patients hospitalized for duodenal ulcer bleeding, undergoing conservative treatment and with a previous history of bleeding, comprised the group studied. All patients had emergency endoscopy, and tests for H. pylori proved to be positive in all. After discharge, patients were given omeprazole 20 mg daily for 4 weeks for ulcer healing, which was achieved in all patients (100%). After this, patients were randomized to receive either omeprazole 20 mg t.i.d. alone (group O, n = 15) or the combination of omeprazole 20 mg t.i.d. + amoxicillin 500 mg q.i.d. (group O + A, n = 16) for 2 weeks. Endoscopy was performed 4 weeks after treatment ended to check for eradication of H. pylori and again when rebleeding or symptomatic relapse occurred. Groups O and O + A were similar in age, sex, smoking habits, and NSAID use. The follow-up period was 12 months for both groups. Eradication was achieved in 2 of 15 (13.3%) patients in group O and in 13 of 16 (81.3%) patients in group O + A (p < .001). Five patients rebled during follow-up. All of them belonged to group O and were patients in whom eradication had failed. In contrast, none of group O + A had rebleeding (p = 0.18).(ABSTRACT TRUNCATED AT 250 WORDS)

The greatest challenge in Helicobacter pylori–related diseases continues to remain prevention of gastric cancer. New evidence supports the beneficial effect of H. pylori eradication not only on prevention of gastric cancer but also on the regression of preneoplastic conditions of the gastric mucosa. Concerning early detection of gastric cancer there are still no adequate means and there is urgent need to define appropriate markers, for example, by genome-wide research approaches. Currently, the best available method is the “serologic” biopsy based on pepsinogen I and the pepsinogen I/II ratio for identification of patients with severe gastric atrophy at increased risk for gastric cancer development. The treatment of early gastric cancer by endoscopic techniques can be performed safely and efficiently, but patients need meticulous follow-up for detection of metachronous lesions. In case of advanced disease, laparoscopically assisted surgical procedures are safe and favorable compared to open surgery. Two phase III trials support the role of adjuvant systemic treatment with different regimens. Unfortunately, there is still only slow progress in the development of palliative treatment regimens or modification of the existing therapy protocols. There is accumulating evidence for a role of H. pylori infection also in colorectal carcinogenesis. Seropositive individuals are at higher risk for the development of colorectal adenomas and consequently adenocarcinomas of this anatomical region. This phenomenon can partly be attributed to the increase of serum gastrin as response to atrophic changes of the gastric mucosa.

The validity and usefulness of the 7th edition of the UICC tumor node metastasis classification in the context of clinical management of gastric cancer are discussed. The most relevant new agent in gastric cancer therapy is trastuzumab for HER2-positive gastric carcinomas. This marks the success of continuous effort of translational research. Trastuzumab, initially applied in palliative settings, is currently being evaluated also in neoadjuvant treatment regimens. Several new meta-analyses support the carcinogenic effect of high salt intake and smoking in the context of Helicobacter pylori infection. Further data have become available on the efficacy of protective agents, acetyl salicylic acid/nonsteroidal anti-inflammatory drugs, and antioxidants. In search for a successful prevention strategy, the focus is on the identification of individuals at high risk who demand screening (testing) and surveillance. Serological assessment of gastric mucosal abnormalities with increased risk for gastric cancer development is extensively studied, and new data are presented from Asia as well as from Europe. New high-throughput techniques combined with bioinformatic vector analysis open the gate to the identification of new potential diagnostic and therapeutic targets. Furthermore, these approaches allow us to elucidate the interplay of bacterial virulence factors and the host's immune response as well as H. pylori-associated alterations of mucosal gene expression.

Gastric cancer still represents a global health care burden, and in the absence of strategies implemented for early detection, the disease continues to have a dismal prognosis. Patients presenting with clinical manifestations of gastric cancer have limited options for cure. Thus, early detection and prevention play a key role in the fight against gastric cancer. Serologic-based test methods have the potential to detect a subset of patients at high risk of gastric cancer that require a close clinical and endoscopic follow-up. More data have been produced to support Helicobacter pylori eradication as an efficient strategy to prevent gastric cancer. Treatment options for patients with an advanced disease are still limited, but the introduction of new agents opens a more optimistic perspective for the future.

The European Helicobacter Study Group has recently issued the current concepts in the management of Helicobacter pylori infection (Maastricht III Consensus Report, 2005). The aim of the study was to examine the cumulative H. pylori eradication rates that can be achieved in clinical practice by adopting first and second regimens as proposed by the Maastricht III consensus and a third-line empirical levofloxacin-based regimen.H. pylori-positive patients were treated initially with a first-line eradication triple regimen consisting of omeprazole, amoxicillin, and clarithromycin and subsequently with a second-line quadruple regimen consisting of omeprazole, bismuth, metronidazole, and tetracycline. Finally, after two previous H. pylori eradication failures, patients received omeprazole, amoxicillin, and levofloxacin, as a third-line empirical strategy. The success rate was calculated by both intention-to-treat (ITT) and per protocol (PP) analyses.In total, 540 consecutive H. pylori-positive patients received first-line treatment (omeprazole, amoxicillin, and clarithromycin). H. pylori were eradicated in 380 patients and 40 patients were withdrawn (ITT, 70.3%; PP, 76%). The remaining 120 H. pylori-positive patients received second-line treatment (omeprazole, bismuth, metronidazole, and tetracycline). H. pylori were eradicated in 83 patients and 7 patients were withdrawn (ITT, 69.1%; PP, 73.45%). Finally, the remaining 30 H. pylori-positive patients received third-line treatment (omeprazole, amoxicillin, and levofloxacin). H. pylori were eradicated in 21 patients and 0 patients were withdrawn (ITT, 70%; PP, 70%). Thus, out of 540 patients initially included in the study, H. pylori were eradicated in 484 patients, 47 were withdrawn, and only 9 remained positive. These results give 89.6% ITT and 98.1% PP cumulative H. pylori eradication rates.By adopting first- and second-line regimens, as proposed by the Maastricht III consensus and a third-line levofloxacin-based empirical regimen, high cumulative H. pylori eradication rates can be achieved. Thus, a substantial number of cultures to determine sensitivity to antibiotics can be avoided with beneficial consequences concerning cost.

In recent years, the focus of Helicobacter pylori clinical research has been mainly on gastric malignancy. However, the role of H. pylori in non-malignant diseases, such as peptic ulcer, gastroesophageal reflux disease (GERD) and non-ulcer dyspepsia, as well as non-steroidal anti-inflammatory drug consumption, is still of great interest. A 1- to 2-week course of H. pylori eradication therapy is an effective treatment for H. pylori-positive peptic ulcer disease and a positive CagA status is a predictor for successful eradication of H. pylori. Antral prostaglandin-E2-basal levels appear to be critical for the development of aspirin-induced gastric damage in subjects without H. pylori infection. In clinical practice, among patients treated with proton-pump inhibitors, H. pylori status has no effect on the speed or degree of GERD symptom relief. For the management of dyspepsia in primary care, antisecretory therapy confers a small insignificant benefit compared to strategies based on H. pylori testing while these latter strategies may be cost-effective. H. pylori eradication therapy has a small but statistically significant effect on H. pylori-positive non-ulcer dyspepsia. An economic model suggests that this modest benefit may still be cost-effective but more research is needed.

Background. A high incidence of Helicobacter pylori among family members of children with H. pylori gastritis has previously been documented on biopsy material. The main objective of this study was the genetic clarification of H. pylori strains involved in intrafamilial dispersion. Materials and Methods. Formalin-fixed, paraffin-embedded material of antral mucosa from 32 members of 11 families was studied for the presence of genetic homogeneity. To achieve this goal, the entire genome of H. pylori was studied by the polymerase chain reaction (PCR)-based random amplified polymorphic DNA (RAPD) fingerprinting method. Furthermore, the Urease A gene was analyzed using a multiplex PCR-assay and an alternative mutation detection method based on the Hydrolink™ analysis. Results. RAPD fingerprinting confirmed that closely related H. pylori strains were involved in the intrafamilial dispersion. Mutations and small deletions in Urease A gene were found in 22 out of 32 individuals. Conclusions. The homology of the H. pylori genome in members of the same family strongly supports the hypothesis of transmission of H. pylori from person-to-person or from a common source.

BACKGROUND: Strains of Helicobacter pylori with the cytotoxine-associated gene A ( cagA ) are linked to severe forms of gastroduodenal disease. Although eradication of H. pylori may predispose to the development of reflux esophagitis, the effects of CagA status on risk of esophagitis after successful H. pylori treatment are not known. METHODS: We studied 50 consecutive patients without esophagitis in whom H. pylori was eradicated successfully. CagA status was determined by immunoblotting sera from patients against H. pylori antigens. Patients underwent upper gastrointestinal endoscopy before eradication and 6, 12, 18, and 24 months after eradication or when reflux symptoms occurred. Biopsy specimens of the antrum and corpus were evaluated for gastritis before H. pylori eradication and at the end of the study. The sum of the scores for acute and chronic inflammation (both measured on a 0 [absent] to 3 [severe] scale) comprised the total gastritis severity score. RESULTS: In a multivariate proportional hazards regression analysis, positive CagA serology (hazard ratio [HR] = 10, 95% confidence interval [CI]: 1.3 to 81) and moderate-to-severe corpus gastritis (total severity score ≥4) before eradication (HR = 2.3, 95% CI: 1.2 to 6.1) were independent risk factors for the development of esophagitis after H. pylori eradication. CONCLUSION: Patients infected with strains of H. pylori that are cagA -positive are at increased risk of developing esophagitis after eradication of H. pylori .

Successful Helicobacter pylori (H.pylori) treatment has been reported to predispose to the development of reflux esophagitis (RE). However, despite this evidence, to date no attention had been paid to the time trend for the appearance of RE after H.pylori treatment. This information could be of importance in dealing with patient management after eradication. The aim of this prospective study therefore was two fold. Firstly, to examine the RE rate after H.pylori eradication and secondly, to study the time trend for the appearance of RE. Methods: 50 consecutive, successfully eradicated patients, without RE at the time of H.pylori treatment [25 duodenal ulcer (DU) and 25 non-ulcer (NU), 30M, 20F, median age 41.5 yrs, range 21-57] were followed up for 24 months after H.pylori eradication or when reflux symptoms occurred. The chi-square test for trend and the life table analysis were performed for calculating the incidence and time trend for RE appearance after H.pylori eradication. Patients were censored if the end point was reached or if RE was noted at endoscopy. Results: Among the 50 H.pylori(+) successfully treated patients, 12/50(24%) developed RE during the 24 month follow up period. In 9/12 patients(75%), RE developed during the first year of the follow up, at months 5,6,7,9,10,11 and 12 (respective percentages of patients without RE 98,96,92,90,88,86 and 82%) as opposed to only 3/12(25%)patients (p