Ricardo Marcos-Pinto

Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED)

Atrophic gastritis, intestinal metaplasia, and epithelial dysplasia of the stomach are common and are associated with an increased risk for gastric cancer. In the absence of guidelines, there is wide disparity in the management of patients with these premalignant conditions. The European Society of Gastrointestinal Endoscopy (ESGE), the European Helicobacter Study Group (EHSG), the European Society of Pathology (ESP) and the Sociedade Portuguesa de Endoscopia Digestiva (SPED) have therefore combined efforts to develop evidence-based guidelines on the management of patients with precancerous conditions and lesions of the stomach (termed MAPS). A multidisciplinary group of 63 experts from 24 countries developed these recommendations by means of repeat online voting and a meeting in June 2011 in Porto, Portugal. The recommendations emphasize the increased cancer risk in patients with gastric atrophy and metaplasia, and the need for adequate staging in the case of high grade dysplasia, and they focus on treatment and surveillance indications and methods.

Gastric cancer: adding glycosylation to the equation

Gastric cancer has a high incidence and mortality, so there is a pressing need to understand the underlying molecular mechanisms in order to discover novel biomarkers. Glycosylation alterations are frequent during gastric carcinogenesis and cancer progression. This review describes the role of glycans from the initial steps of the carcinogenesis process, in which Helicobacter pylori adheres to host mucosa glycans and modulates the glycophenotype, as well as how glycans interfere with epithelial cell adhesion by modulating epithelial cadherin functionality in gastric cancer progression. Other mechanisms regulating gastric cancer malignant behavior are discussed, such as increased sialylation interfering with key signaling pathways and integrin glycosylation leading to an invasive phenotype. Applications of these glycosylation alterations in the clinical management of gastric cancer patients are discussed.

Helicobacter pylori CagA and VacA genotypes and gastric phenotype: a meta-analysis.

Background CagA+ and vacuolizing cytotoxin (VacA)-specific strains of Helicobacter pylori have been associated with different risks for developing gastric lesions. We aim to summarize a possible association between these genotypes and the risk for developing different gastric phenotypes. Materials and methods A MEDLINE database (PubMed) search was performed and a meta-analysis conducted. Results Forty-four studies were retrieved, all with either a case–control (n=13) or cross-sectional (n=31) design, including 17 374 patients. CagA positivity was associated with an increased risk for gastric cancer [odds ratio (OR) 2.09 (95% confidence interval (CI), 1.48–2.94)] compared with that in individuals without gastric lesions [OR 2.44 (95% CI 1.27–4.70)] and in those with previously identified gastritis. In addition, there was an increased risk for peptic ulcer disease [OR 1.69 (95% CI 1.12–2.55)]. Individuals harboring the H. pylori strains VacA s1 (vs. s2), m1 (vs. m2), s1m1 (vs. s1m2), and s1m1 (vs. s2m2) had an increased risk for development of cancer [OR of 5.32 (95% CI 2.76–10.26), 2.50 (95% CI 1.67–3.750), 2.58 (95% CI 1.24–5.38), and 4.36 (95% CI 2.08–9.10), respectively]. s1m1 strains (vs. s2m2) were also associated with peptic ulcer disease [OR 2.04 (1.01–4.13)]. Conclusion Our results indicate that individuals infected with CagA+ H. pylori strains and those infected with VacA s1 and m1 strains have an increased risk for gastric cancer. Cohort studies are welcome to integrate this information in the management of at-risk individuals such as those with precancerous cancer conditions and/or a family history of gastric cancer.

First-degree relatives of patients with early-onset gastric carcinoma show even at young ages a high prevalence of advanced OLGA/OLGIM stages and dysplasia

First‐degree relatives (FDRs) of early‐onset gastric carcinoma (EOGC) patients are at increased risk of cancer development. OLGA/OLGIM (Operative Link on Gastritis/Intestinal Metaplasia Assessment) classifications have been proposed for the identification of individuals at high risk of gastric cancer development.

Helicobacter pylori chronic infection and mucosal inflammation switches the human gastric glycosylation pathways.

Helicobacter pylori exploits host glycoconjugates to colonize the gastric niche. Infection can persist for decades promoting chronic inflammation, and in a subset of individuals lesions can silently progress to cancer. This study shows that H. pylori chronic infection and gastric tissue inflammation result in a remodeling of the gastric glycophenotype with increased expression of sialyl-Lewis a/x antigens due to transcriptional up-regulation of the B3GNT5, B3GALT5, and FUT3 genes. We observed that H. pylori infected individuals present a marked gastric local pro-inflammatory signature with significantly higher TNF-α levels and demonstrated that TNF-induced activation of the NF-kappaB pathway results in B3GNT5 transcriptional up-regulation. Furthermore, we show that this gastric glycosylation shift, characterized by increased sialylation patterns, favors SabA-mediated H. pylori attachment to human inflamed gastric mucosa. This study provides novel clinically relevant insights into the regulatory mechanisms underlying H. pylori modulation of host glycosylation machinery, and phenotypic alterations crucial for life-long infection. Moreover, the biosynthetic pathways here identified as responsible for gastric mucosa increased sialylation, in response to H. pylori infection, can be exploited as drug targets for hindering bacteria adhesion and counteract the infection chronicity.

Helicobacter pylori cagA Promoter Region Sequences Influence CagA Expression and Interleukin 8 Secretion

Heterogeneity at the Helicobacter pylori cagA gene promoter region has been linked to variation in CagA expression and gastric histopathology. Here, we characterized the cagA promoter and expression in 46 H. pylori strains from Portugal. Our results confirm the relationship between cagA promoter region variation and protein expression originally observed in strains from Colombia. We observed that individuals with intestinal metaplasia were all infected with H. pylori strains containing a specific cagA motif. Additionally, we provided novel functional evidence that strain-specific sequences in the cagA promoter region and CagA expression levels influence interleukin 8 secretion by the host gastric epithelial cells.

Dysregulation of T cell receptor N-glycosylation: a molecular mechanism involved in ulcerative colitis

The incidence of inflammatory bowel disease is increasing worldwide and the underlying molecular mechanisms are far from being fully elucidated. Herein, we evaluated the role of N-glycosylation dysregulation in T cells as a key mechanism in the ulcerative colitis (UC) pathogenesis. The evaluation of the branched N-glycosylation levels and profile of intestinal T cell receptor (TCR) were assessed in colonic biopsies from UC patients and healthy controls. Expression alterations of the glycosyltransferase gene MGAT5 were also evaluated. We demonstrated that UC patients exhibit a dysregulation of TCR branched N-glycosylation on lamina propria T lymphocytes. Patients with severe UC showed the most pronounced defect on N-glycan branching in T cells. Moreover, UC patients showed a significant reduction of MGAT5 gene transcription in T lymphocytes. In this study, we disclose for the first time that a deficiency in branched N-glycosylation on TCR due to a reduced MGAT5 gene expression is a new molecular mechanism underlying UC pathogenesis, being a potential novel biomarker with promising clinical and therapeutic applications.

Multicenter survey on the use of device-assisted enteroscopy in Portugal

Background Device-assisted enteroscopies (DAEs) are recent endoscopic techniques that enable direct endoscopic small-bowel evaluation. Objective The objective of this article is to evaluate the implementation of DAEs in Portugal and assess the main indications, diagnoses, diagnostic yield, therapeutic yield and complication rate. Methods We conducted a multicenter retrospective series using a national Web-based survey on behalf of the Portuguese Small-Bowel Study Group. Participants were asked to fill out two online databases regarding procedural data, indications, diagnoses, endoscopic therapy and complications using prospectively collected institutional data records. Results A total of eight centers were enrolled in the survey, corresponding to 1411 DAEs. The most frequent indications were obscure gastrointestinal bleeding (OGIB), inflammatory bowel disease and small-bowel tumors. The pooled diagnostic yield was 63%. A relation between the diagnostic yield and the indications was clear, with a diagnostic yield for OGIB of 69% (p = 0.02) with a 52% therapeutic yield. Complications occurred in 1.2%, with a major complication rate of 0.57%. Perforations occurred in four patients (0.28%). Conclusion DAEs are safe and effective procedures, with complication rates of 1.2%, the most serious of which is perforation. Most procedures are performed in the setting of OGIB. Diagnostic and therapeutic yields are dependent on the indication, hence appropriate patient selection is crucial.

Double-balloon enteroscopy in the management of patients with Peutz-Jeghers syndrome: A retrospective cohort multicenter study

BACKGROUND AND OBJECTIVE Little is known about the clinical impact of double-balloon enteroscopy (DBE) in patients with Peutz- Jeghers syndrome (PJS).The aim of this study was to assess the efficacy and safety of DBE in the management of small-bowel polyps in PJS patients. PATIENTS AND METHODS We conducted a multicentre, retrospective cohort study, which included all consecutive patients diagnosed with PJS who underwent DBE for polypectomy between January 2006 and August 2012. In all cases, previous videocapsule enteroscopy had shown at least one polyp ≥ 10 mm in size. RESULTS Twenty-five patients (13 men; median age 36 years; 14 with prior laparotomy) underwent 46 DBE procedures (1 to 5 per patient, 44 via oral route). Polypectomy was performed in 39/46 DBEs. A total of 214 polyps were removed (median-size 30 mm), with a median number of polypectomies per procedure of 5.0 (range 1-18). The estimated maximum-sizes of resected polyps significantly decreased at each session: 30.0, 25.0, 20.0, 15.0, and 17.5 mm (p = 0.02). In 7 DBEs no polypectomy was performed (4-only minor polyps detected; 3-endoscopic irresecability). Complications occurred in 3/39 of therapeutic procedures (2-minor delayed bleeding; 1-mucosal tear), all of them dealt with conservative or endoscopic therapy. Six patients underwent elective surgery post DBE due to polyps not amenable for endoscopic resection. There were no small-bowel polyp related complications during a median follow-up of 56.5 months. CONCLUSION DBE showed to be a safe and effective technique in the management of small-bowel polyps in PJS patients, allowing a presymptomatic and non-surgical approach.

First degree relatives and familial aggregation of gastric cancer: who to choose for control in case–control studies?

Gastric carcinogenesis is a multifactorial process involving host gene and environmental interactions. Diverse case–control studies using different types of controls addressed the familial aggregation role for gastric cancer development. Our aim is to discuss the advantages and expected bias according to the different type of eligible controls. A PubMed search of papers on a query on first degree relatives of gastric cancer patients was conducted. The retrieved studies were evaluated regarding quality based on STROBE checklist. Data concerning risk of premalignant lesions and Helicobacter pylori infection was retrieved as the type of controls used on each study. Nine case–control studies were selected. A variety of controls were used ranging from general population to dyspeptic patients and spouses of the cases. We have observed that, independently of the type of control, the risk for the prevalence of premalignant lesions and H. pylori infection was higher for the cases. However, all of the evaluated case–control studies were average quality studies (mean 28 out of 45), with a small number of cases and controls (range from 39 to 300). Furthermore, concerning gene–environment interaction, each of the discussed type of control (general population, dyspeptic, spouse and neighbor) has potential advantages and disadvantages. The current data suggests that selection of any type of the aforementioned controls is feasible and seems to be mainly related to the feasibility of recruitment more than the genetic or environmental backgrounds. General population and dyspeptic patients would be equally appropriate for studies on familial aggregation of gastric cancer. Nevertheless, high-quality cohort studies are needed to validate this assumption.