Marino Venerito

Meta-analysis of bismuth quadruple therapy versus clarithromycin triple therapy for empiric primary treatment of Helicobacter pylori infection.

Background: In areas with high clarithromycin resistance, bismuth quadruple therapy (BQT) is recommended instead of clarithromycin triple therapy (CTT) as the first-line treatment for Helicobacter pylori eradication. Methods: Randomized clinical trials (RCTs) comparing BQT to CTT were identified through electronic and manual searches. A meta-analysis was performed to compare the efficacy and tolerability of these two regimens as first-line treatments for H. pylori infection. The effect of antibiotic resistance on treatment efficacy was also analyzed. Results: Twelve RCTs were included. BQT achieved eradication in 77.6% of patients, whereas CTT achieved an eradication rate of 68.9% [risk difference (RD) = 0.06, 95% CI: -0.01/0.13]. A high heterogeneity among the trials was found (χ2 = 50.16, p < 0.00001; I2 = 78%). In the subgroup analysis for treatment duration, the 10-day BQT was more effective than the 7-day CTT (RD = 0.25, 95% CI: 0.18/0.32), whereas no differences were observed between CTT and BQT given for 7 or 10 days. There were no statistical differences in side effects and compliance between both therapies (RD = 0.92, 95% CI: 0.76/1.12, and RD = -0.03, 95% CI: -0.05/0.00, respectively). The effect of antibiotic resistance on eradication rates was reported in 4 of the 12 RCTs. Clarithromycin resistance significantly affected the efficacy of CTT (RD = 0.75, 95% CI: 0.63/0.87), whereas BQT efficacy was not affected by metronidazole resistance (RD = 0.09, 95% CI: -0.06/0.25). Conclusions: The 10-day BQT was more effective than the 7-day CTT as a first-line therapy for H. pylori infection, whereas BQT and CTT for 7 or 10 days yielded similar eradication rates. Compliance and side effect rates were similar for both therapies. BQT overcomes clarithromycin resistance and its efficacy is not affected by metronidazole resistance.

Helicobacter pylori infection is associated with a reduced risk of developing eosinophilic oesophagitis

Eosinophilic oesophagitis (EoE) represents a chronic immune‐antigen‐mediated allergic disease of the oesophagus of still unknown aetiology. Environmental exposure has been postulated to play a pathogenetic role. Helicobacter pylori (H. pylori) infection has been inversely associated with allergic diseases including atopic dermatitis, asthma and allergic rhinitis and H. pylori may play a protective role in these conditions. Little is known about the relationship between EoE and H. pylori.

Serological Prevalence of Helicobacter pylori Infection in Saxony-Anhalt, Germany, in 2010

ABSTRACT Epidemiological studies from different countries have shown a steady decline of the prevalence of Helicobacter pylori infection. In order to investigate the current seroprevalence of H. pylori infection in the area of Magdeburg, a city of the former East Germany, H. pylori antibodies of patients presenting in our emergency wards were analyzed. In total, 2,318 patients (1,181 males and 1,137 females) enrolled between September 2009 and August 2010 were tested for immunoglobulin G (IgG) against H. pylori and anti-CagA antibodies by specific enzyme immunoassay (EIA). Patients with either anti-H. pylori IgG or anti-CagA antibodies were classified as H. pylori positive, whereas the lack of both antibodies led to the assignment of an H. pylori-negative status. The overall seroprevalence of H. pylori infection was 44.4% (n = 1,029 out of 2,318) and did not differ in relation to sex. The proportion of CagA-positive samples was 43.3% of all H. pylori-positive individuals (446 out of 1,029). The seroprevalence showed a birth cohort effect (0 to 20 years of age, 14.6%; 21 to 30 years, 22.4%; 31 to 40 years, 40.6%; 41 to 50 years, 45.5%; 51 to 60 years, 50.8%) up to the age of 60, while it remained between 40.7% and 50.5% for the following decades. Patients younger than 30 years were significantly less H. pylori positive (21.1%) than those older than 30 years of age (47.7%; P < 0.01), whereas CagA status was similar (44.3 versus 43.3%). Notably, young women (<30 years old) had significantly higher CagA positivity (59.3%) than corresponding men (32.5%; P = 0.016). Taken together, seroprevalence of H. pylori infection shows a significant drop in subjects born after 1980 in Saxony-Anhalt but still remains in the range of 40 to 50% in subjects born earlier.

Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

Summary Background Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barretts oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barretts oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barretts oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barretts oesophagus and oesophageal adenocarcinoma. Methods We did a meta-analysis of all genome-wide association studies of Barretts oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10−8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches—including functional annotation databases and gene-based and pathway-based methods—to identify pathophysiologically relevant cellular mechanisms. Findings Our sample comprised 6167 patients with Barretts oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barretts oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10−10), MSRA (rs17749155; p=5·2 × 10−10), LINC00208 and BLK (rs10108511; p=2·1 × 10−9), KHDRBS2 (rs62423175; p=3·0 × 10−9), TPPP and CEP72 (rs9918259; p=3·2 × 10−9), TMOD1 (rs7852462; p=1·5 × 10−8), SATB2 (rs139606545; p=2·0 × 10−8), and HTR3C and ABCC5 (rs9823696; p=1·6 × 10−8). The locus identified near HTR3C and ABCC5 (rs9823696) was associated specifically with oesophageal adenocarcinoma (p=1·6 × 10−8) and was independent of Barretts oesophagus development (p=0·45). A ninth novel risk locus was identified within the gene LPA (rs12207195; posterior probability 0·925) after reweighting with significantly enriched annotations. The strongest disease pathways identified (p<10−6) belonged to muscle cell differentiation and to mesenchyme development and differentiation. Interpretation Our meta-analysis of genome-wide association studies doubled the number of known risk loci for Barretts oesophagus and oesophageal adenocarcinoma and revealed new insights into causes of these diseases. Furthermore, the specific association between oesophageal adenocarcinoma and the locus near HTR3C and ABCC5 might constitute a novel genetic marker for prediction of the transition from Barretts oesophagus to oesophageal adenocarcinoma. Fine-mapping and functional studies of new risk loci could lead to identification of key molecules in the development of Barretts oesophagus and oesophageal adenocarcinoma, which might encourage development of advanced prevention and intervention strategies. Funding US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council UK, Cambridge NIHR Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, Else Kröner Fresenius Stiftung, Wellcome Trust, Cancer Research UK, AstraZeneca UK, University Hospitals of Leicester, University of Oxford, Australian Research Council.

Effects of low-dose aspirin on gastric erosions, cyclooxygenase expression and mucosal prostaglandin-E2 do not depend on Helicobacter pylori infection.

Background  The mechanisms by which Helicobacter pylori and low‐dose aspirin induce gastric damage are not completely elucidated.

Interaction of Helicobacter pylori Infection and Nonsteroidal Anti‐Inflammatory Drugs in Gastric and Duodenal Ulcers

Background:  Gastric (GU) and duodenal ulcers (DU) are in most instances either induced by Helicobacter pylori infection or by nonsteroidal anti‐inflammatory drugs (NSAIDs). Whether eradication of H. pylori is beneficial in NSAID users for preventing NSAID induced GU and DU has been the focus of different studies.

Helicobacter pylori: Gastric Cancer and Extragastric Malignancies – Clinical aspects

The best opportunity to reduce gastric cancer (GC)‐related mortality remains prevention. Mass eradication of Helicobacter pylori infection in a Taiwanese population >30 years of age reduced GC incidence with an effectiveness of 25% (rate ratio 0.753, 95% CI 0.372–1.524). In the Shandong intervention trial conducted on a Chinese population aged 35–64 years, cancer incidence was reduced by 39% in subjects who received H. pylori treatment compared with the placebo group after 14.7 years of follow‐up (absolute risk 3.0 vs 4.6%; odds ratio 0.61, 95% CI 0.38–0.96; p = .03). A high incidence of severe gastric atrophic changes and noninvasive gastric neoplasia has been reported in a Portuguese case‐control study on first‐degree relatives of patients with early‐onset gastric carcinoma (i.e., diagnosed before 45 years), which emphasizes again the importance of GC screening in this population. For patients with advanced GC, new targeted therapies to improve survival are under scrutiny. Trastuzumab resistance may be present from early on, or develop during trastuzumab therapy in patients with GC, and an overexpression of the HER2/neu protein. New molecules to overcome trastuzumab resistance are also being evaluated. The association between H. pylori‐induced gastritis and an increased risk of developing colonic neoplasms has been confirmed in a recent study, but the causality for this intriguing association has still to be clarified.

Helicobacter pylori-induced downregulation of the secretory leukocyte protease inhibitor (SLPI) in gastric epithelial cell lines and its functional relevance for H. pylori-mediated diseases

Abstract The secretory leukocyte protease inhibitor (SLPI) exerts antiproteolytic activity towards serine proteases, as well as anti-microbial and anti-inflammatory effects. To investigate its role in H. pylori-mediated diseases, SLPI expression was analyzed by RT-PCR, ELISA and immunohistochemistry in clinical samples and gastric tumor cell lines. Determination of the mucosal SLPI levels in 126 patients confirmed the previously reported downregulation of SLPI in H. pylori-infected patients. The lower SLPI levels in antral biopsies of H. pylori-positive subjects were associated with a 30-fold increase (p<0.01) in neutrophil elastase activity, and a significant negative correlation was demonstrated for both parameters (R=-0.63, p=0.0002). Eradication of the bacterium in a long-term study (5–7 years) led to a recovery of mucosal SLPI expression. In vitro experiments using four gastric tumor cell lines (AGS, MKN-28, MKN-45, NCI-N87) generally confirmed the clinical findings. While the co-incubation of these cell lines with H. pylori resulted in lower or unchanged SLPI protein levels, the corresponding SLPI mRNA amounts were upregulated by up to five-fold (p=0.006) in all cell lines. Taken together, these results indicate that the reduction in antral SLPI levels in H. pylori-infected subjects has a functional relevance for gastric mucosa and the H. pylori-induced decrease in SLPI is primarily regulated at the posttranslational level.

Gastric cancer - clinical and epidemiological aspects.

Gastric cancer (GC) ranks fifth for cancer incidence and second for cancer deaths. Epidemiological data showed that survivors of Hodgkins 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.

Helicobacter pylori and Gastrointestinal Malignancies.

Helicobacter pylori infection is the principal trigger of gastric carcinogenesis and gastric cancer (GC) and remains the third leading cause of cancer‐related death in both sexes worldwide. In a big Japanese study, the risk of developing GC in patients with peptic ulcer disease who received H. pylori eradication therapy and annual endoscopic surveillance for a mean of 9.9 years was significantly lower after successful eradication therapy compared to the group with persistent infection (0.21%/year and 0.45%/year, respectively, p = .049). According to a recent meta‐analysis, H. pylori eradication is insufficient in GC risk reduction in subjects with advanced precancerous conditions (i.e., intestinal metaplasia and dysplasia). A microsimulation model suggested screening smokers over the age of 50 in the U.S. for serum pepsinogens. This would allow to detect advanced gastric atrophy with endoscopic follow‐up of subjects testing positive as a cost‐effective strategy to reduce GC mortality. In a Taiwanese study, the anti‐H. pylori IgG‐based test‐and‐treat program had lower incremental cost‐effectiveness ratios than that with 13C‐urea breath test in both sexes to prevent GC whereas expected years of life lost for GC were higher and the incremental cost‐effectiveness ratios of test‐and‐treat programs were more cost‐effective in young adults (30–69 years old) than in elders (>70 years old). With respect to gastrointestinal malignancies other than GC, a meta‐analysis confirmed the inverse association between H. pylori infection and esophageal adenocarcinoma. In a Finnish study, H. pylori seropositivity was associated with an increased risk of biliary tract cancers (multivariate adjusted OR 2.63; 95% CI: 1.08–6.37), another meta‐analysis showed a slightly increased rate of pancreatic cancer in patients with CagA‐negative strains (OR: 1.30; 95% CI: 1.02–1.65), whereas current data suggest that the association between H. pylori and colorectal neoplasms may be population dependent.