Endoscopic submucosal dissection for superficial premalignant and malignant epithelial neoplasms of the digestive tract: a real-life experience in Italy.

OBJECTIVE: Endoscopic submucosal dissection (ESD) is a technique for en bloc resection of neoplastic lesions of the digestive tract. Endoscopic submucosal dissection was developed in Asia, and data from Western countries are scarce. Our study aimed to assess the efficacy and safety of ESD for resection of superficial premalignant and malignant epithelial neoplasms in a tertiary center in Italy. PATIENTS AND METHODS: All patients with gastrointestinal lesions who underwent ESD between January 2013 and December 2018 in our center were retrospectively evaluated. Technical success, en bloc, R0, curative resection, and complication rates were assessed. RESULTS: A total of 107 lesions (stomach, no.=41; rectum, no.=32; colon, no.=28; esophagus, no.=5; duodenum, no.=1) were resected by ESD in 93 patients. Endoscopic submucosal dissection was technically successful in 99.1% (106/107) of lesions. Among the 90 superficial premalignant and malignant epithelial neoplasms, en bloc, and R0 resection rates were 97.8% (no.=88) and 75.6% (no.=68), respectively. Major complications occurred in 9.3% (10/107) of cases: 4 (3.7%) were perforations and 6 (5.6%) were major bleedings. All complications, but two which needed surgery, were managed endoscopically. CONCLUSIONS: Our study shows that ESD is a feasible, effective, and safe technique in a Western country.

Systematic review with meta-analysis: diagnostic performance of the combination of pepsinogen, gastrin-17 and anti-Helicobacter pylori antibodies serum assays for the diagnosis of atrophic gastritis.

BACKGROUND: The combination of pepsinogen, gastrin-17 and anti-H. pylori antibodies serological assays (panel test) is a non-invasive tool for the diagnosis of atrophic gastritis. However, the diagnostic reliability of this test is still uncertain. AIM: To assess the diagnostic performance of the serum panel test for the diagnosis of atrophic gastritis. METHODS: Medline via PubMed, Embase, Scopus, Cochrane Library databases and abstracts of international conferences proceedings were searched from January 1995 to December 2016 using the primary keywords "pepsinogens," "gastrin," "atrophic gastritis," "gastric precancerous lesions." Studies were included if they assessed the accuracy of the serum panel test for the diagnosis of atrophic gastritis using histology according to the updated Sydney System as reference standard. RESULTS: Twenty studies with a total of 4241 subjects assessed the performance of serum panel test for the diagnosis of atrophic gastritis regardless of the site in the stomach. The summary sensitivity was 74.7% (95% confidence interval (CI), 62.0-84.3) and the specificity was 95.6% (95%CI, 92.6-97.4). With a prevalence of atrophic gastritis of 27% (median prevalence across the studies), the negative predictive value was 91%. Few studies with small sample size assessed the performance of the test in detecting the site of atrophic gastritis. CONCLUSIONS: The combination of pepsinogen, gastrin-17 and anti-H. pylori antibodies serological assays appears to be a reliable tool for the diagnosis of atrophic gastritis. This test may be used for screening subjects or populations at high risk of gastric cancer for atrophic gastritis; however, a cost-effectiveness analysis is needed.

Downregulation of neuronal vasoactive intestinal polypeptide in Parkinson's disease and chronic constipation.

BACKGROUND: Chronic constipation (CC) is a common and severe gastrointestinal complaint in Parkinson's disease (PD), but its pathogenesis remains poorly understood. This study evaluated functionally distinct submucosal neurons in relation to colonic motility and anorectal function in PD patients with constipation (PD/CC) vs both CC and controls. METHODS: Twenty-nine PD/CC and 10 Rome III-defined CC patients were enrolled. Twenty asymptomatic age-sex matched subjects served as controls. Colonic transit time measurement and conventional anorectal manometry were evaluated in PD/CC and CC patients. Colonoscopy was performed in all three groups. Colonic submucosal whole mounts from PD/CC, CC, and controls were processed for immunohistochemistry with antibodies for vasoactive intestinal polypeptide (VIP) and peripheral choline acetyltransferase, markers for functionally distinct submucosal neurons. The mRNA expression of VIP and its receptors were also assessed. KEY RESULTS: Four subgroups of PD/CC patients were identified: delayed colonic transit plus altered anorectal manometry (65%); delayed colonic transit (13%); altered manometric pattern (13%); and no transit and manometric impairment (9%). There were no differences in the number of neurons/ganglion between PD/CC vs CC or vs controls. A reduced number of submucosal neurons containing VIP immunoreactivity was found in PD/CC vs controls (P<.05). VIP, VIPR1, and VIPR2 mRNA expression was significantly reduced in PD/CC vs CC and controls (P<.05). CONCLUSIONS AND INFERENCES: Colonic motor and rectal sensory functions are impaired in most PD/CC patients. These abnormalities are associated with a decreased VIP expression in submucosal neurons. Both sensory-motor abnormalities and neurally mediated motor and secretory mechanisms are likely to contribute to PD/CC pathophysiology.

Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report.

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.

Van-Gogh-like 2 antagonises the canonical WNT pathway and is methylated in colorectal cancers.

BACKGROUND: Aberrant activation of the canonical WNT signaling is a feature of colorectal cancer (CRC). Van-Gogh-like 2 (VANGL2) belongs to the non-canonical WNT pathway whose activation inhibits canonical WNT signaling. In this study, we investigated the role of VANGL2 and its epigenetic regulation in CRC. METHODS: Van-Gogh-like 2 expression and promoter methylation after 5-aza-2'-deoxycytidine (5-aza) treatment were evaluated in CRC cells. DNA samples from 418 sporadic CRCs were tested for VANGL2 promoter methylation and microsatellite instability (MSI). Proliferation, colony formation and activation of the WNT pathway were tested in cells after VANGL2 overexpression. RESULTS: Van-Gogh-like 2 mRNA was significantly higher in 5-aza-treated RKO, LOVO and SW48, whereas no differences were found in SW480. Van-Gogh-like 2 was fully methylated in RKO, SW48, HCT116, DLD1 and Caco2; partially methylated in LOVO, LS174T and SW837; and unmethylated in SW480, SW620 and HT29. Higher expression of VANGL2 mRNA was found in the unmethylated cell lines. In CRC specimens (8.93% MSI), methylated VANGL2 was associated with MSI, higher grade, proximal colon location and BRAF mutation. Van-Gogh-like 2 overexpression in SW480 significantly decreased proliferation, colony formation and ß-catenin levels. CONCLUSION: Van-Gogh-like 2 is frequently methylated in MSI-CRCs with BRAF mutation and may act as a tumour suppressor gene, counteracting WNT/ß-catenin signaling.

Cholangioscopy using a new type of cholangioscope for the diagnosis of biliary tract disease: a case series.

We present an initial report regarding the clinical usefulness of peroral cholangioscopy, using a new type of cholangioscope, the Polyscope. Peroral cholangioscopy was performed in four patients with strictures after orthotopic liver transplantation (OLT) which were suspected of being ischemic biliary lesions, in three with indeterminate biliary strictures, in three with suspected retained bile duct stones, and in two for evaluation of the intraductal spread of adenomatous tissue after an ampullectomy. In all cases peroral cholangioscopy was performed successfully without complications. On the basis of direct viewing and/or tissue sampling a correct diagnosis was reached in all cases: in all patients who underwent OLT the strictures were not ischemic; the indeterminate strictures were all benign; and, in patients with suspected stones, complete clearance was confirmed. Intraductal spread was confirmed in one patient and excluded in the other. In our experience, peroral cholangioscopy using a Polyscope is a safe and effective method for diagnosing bile duct lesions.

Randomised clinical trial: preventive treatment with topical rectal beclomethasone dipropionate reduces post-radiation risk of bleeding in patients irradiated for prostate cancer.

BACKGROUND: Radiotherapy is an established treatment modality for prostate cancer; however, up to a third of patients develops a radiation-induced proctopathy. AIM: To assess the effect of topical beclomethasone dipropionate (BDP) in the prevention of radiation-induced proctopathy in patients undergoing radiotherapy for prostate cancer through a double-blind, placebo-controlled, randomised trial. METHODS: Patients were randomised either to BDP or to placebo (PL). Patients received daily a 3mg BDP enema or identical-looking PL during radiotherapy and, subsequently, two 3mg BDP suppositories or PL for 4 more weeks. Clinical and endoscopic evaluations before, 3 and 12months after the end of radiotherapy were assessed with the RTOG/EORTC toxicity scales, the modified Simple Clinical Colitis Activity Index (SCCAI), the modified Inflammatory Bowel disease Quality of Life Index (IBDQ) and the Vienna Rectoscopy Score (VRS). RESULTS: From June 2007 to October 2008, 120 patients were randomised to the BDP (n=60) and PL (n=60) arms and were followed up for 12months. The overall assessment of rectal side effects did not show significant differences between the two groups of treatment. However, when only rectal bleeding was considered, a significantly reduced risk was observed in patients on BDP (OR 0.38; 95% CI 0.17-0.86; P=0.02; NNT=5). Patients on BDP had also significantly lower VRS scores (P=0.028) and significantly higher IBDQ scores (P=0.034). CONCLUSIONS: Preventive treatment with topical rectal BDP during radiotherapy for prostate cancer significantly reduces the risk of rectal bleeding and radiation-induced mucosal changes and improves patient's quality of life, but does not influence other radiation-induced symptoms.

Can early precut implementation reduce endoscopic retrograde cholangiopancreatography-related complication risk? Meta-analysis of randomized controlled trials.

BACKGROUND AND STUDY AIMS: Precut papillotomy is considered a risk factor for endoscopic retrograde cholangiopancreatography (ERCP)-related complications; however whether the complication risk is due to precut itself or to the prior prolonged attempts is still debated; therefore, early precut implementation has been suggested to reduce the complication rate. We conducted a meta-analysis of randomized controlled trials (RCTs) comparing cannulation and complication rates of early precut implementation with persistent attempts by the standard approach. METHODS: RCTs that compared cannulation and complication rates of the early precut implementation and of persistent attempts by the standard approach were included. Summary effect sizes were estimated by odds ratio (OR) with a random-effects model and by Peto OR. RESULTS: Six RCTs with a total of 966 subjects met the inclusion criteria. Overall cannulation rates were 90 % in both randomization groups (OR 1.20; 95 % confidence interval [CI] 0.54 - 2.69). Post-ERCP pancreatitis developed in 2.5 % of patients randomized to the early precut groups and in 5.3 % of patients from the persistent attempts groups (OR 0.47; 95 %CI 0.24 - 0.91). The overall complication rates, considering pancreatitis, bleeding, cholangitis, and perforation rates, were 5.0 % in the early precut groups and 6.3 % in the persistent attempts groups (OR 0.78; 95 %CI 0.44 - 1.37). CONCLUSIONS: RCTs that investigated the issue of timing of the precut procedure were limited. Current evidence suggests that in experienced hands the early implementation of precut and persistent cannulation attempts have similar overall cannulation rates; early precut implementation reduces post-ERCP pancreatitis risk but not the overall complication rate. Further studies are needed to confirm these findings.

Endoscopic argon plasma coagulation for the treatment of gastric antral vascular ectasia-related bleeding in patients with liver cirrhosis.

BACKGROUND AND AIM: Gastric antral vascular ectasia (GAVE) is a cause of bleeding in patients with liver cirrhosis. Argon plasma coagulation (APC) is the most used endoscopic treatment for GAVE-related bleeding. Treatment failures have been described in patients with haemorrhagic diathesis; post-procedure complications include haemorrhages and septicaemia. The aim of the study was to evaluate efficacy and safety of APC treatment of GAVE-related bleeding in patients with liver cirrhosis. METHODS: Patients included were suffering from GAVE-related bleeding and liver cirrhosis. APC treatment was performed until eradication. Resolution of transfusion-dependent anaemia and evaluation of complications were the primary outcomes. RESULTS: 20 patients (16 Child C and 4 Child B) were enrolled and prospectively followed for a mean period of 28 months. GAVE eradication was achieved in all patients after a median of 3 sessions (range 1-10). Resolution of anaemia was achieved in 18 patients. Six patients had relapse of GAVE after a mean of 7.7 months, successfully retreated by APC. Hyperplastic polyps developed in 3 patients causing active bleeding in 2 cases. Five patients had liver transplants and 1 had a relapse of GAVE after transplantation. CONCLUSION: APC is an effective and safe endoscopic treatment for GAVE in patients with liver cirrhosis.

Gastro-oesophageal reflux symptoms, oesophagitis and Barrett's oesophagus in the general population: the Loiano-Monghidoro study.

OBJECTIVE: Existing endoscopy-based data on gastro-oesophageal reflux disease (GORD) in the general population are scarce. This study aimed to evaluate typical symptoms and complications of GORD, and their associated risk factors, in a representative sample of the Italian population. METHODS: 1533 adults from two Italian villages were approached to undergo symptom assessment using a validated questionnaire and upper gastrointestinal endoscopy. Data were obtained from 1033 individuals (67.4% response rate). RESULTS: The prevalence of reflux symptoms was 44.3%; 23.7% of the population experienced such symptoms on at least 2 days per week (frequent symptoms). The prevalence rates of oesophagitis and Barrett's oesophagus in the population were 11.8% and 1.3%, respectively. Both frequent (relative risk (RR) 2.6; 95% confidence interval (CI) 1.7 to 3.9) and infrequent (RR 1.9; 95% CI 1.2 to 3.0) reflux symptoms were associated with the presence of oesophagitis. No reflux symptoms were reported by 32.8% of individuals with oesophagitis and 46.2% of those with Barrett's oesophagus. Hiatus hernia was associated with frequent reflux symptoms and oesophagitis, and was present in 76.9% of those with Barrett's oesophagus. We found no association between body mass index and reflux symptoms or oesophagitis. CONCLUSIONS: GORD is common in Italy, but the prevalence of Barrett's oesophagus in the community is lower than has been reported in selected populations. Both frequent and infrequent reflux symptoms are associated with an increased risk of oesophagitis. Individuals with oesophagitis and Barrett's oesophagus often have no reflux symptoms.

Systematic review: Helicobacter pylori eradication for the prevention of gastric cancer.

BACKGROUND: Helicobacter pylori is recognized as one of the most significant risk factors for gastric cancer, and H. pylori eradication has been proposed as a possible primary chemo-preventive strategy to reduce gastric cancer incidence. AIM: To evaluate the available evidence on the efficacy of H. pylori eradication in the prevention of gastric cancer. METHODS: Epidemiological, observational and interventional studies, as well as decisional models, were taken into account in this review. RESULTS: Large-scale epidemiological studies clearly link H. pylori infection with non-cardia gastric cancer. Current evidence suggests that, in a subpopulation of treated subjects, H. pylori eradication prevents the progression of preneoplastic lesions. Studies that have attempted to evaluate the effect of H. pylori eradication on the incidence of gastric cancer have not provided definitive answers. H. pylori eradication seems to reduce the incidence of gastric cancer in patients without baseline precancerous gastric lesions. Decisional models suggest that H. pylori screening could be cost-effective, but there is not yet sufficient evidence to support the setting up of a general screening programme. CONCLUSION: Helicobacter pylori eradication is a plausible intervention for gastric cancer prevention; however, it seems to be relevant in only a subset of subjects.

Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report.

BACKGROUND: Guidelines on the management of Helicobacter pylori, which cover indications for management and treatment strategies, were produced in 2000. AIMS: To update the guidelines at the European Helicobacter Study Group (EHSG) Third Maastricht Consensus Conference, with emphasis on the potential of H pylori eradication for the prevention of gastric cancer. RESULTS: Eradication of H pylori infection is recommended in (a) patients with gastroduodenal diseases such as peptic ulcer disease and low grade gastric, mucosa associated lymphoid tissue (MALT) lymphoma; (b) patients with atrophic gastritis; (c) first degree relatives of patients with gastric cancer; (d) patients with unexplained iron deficiency anaemia; and (e) patients with chronic idiopathic thrombocytopenic purpura. Recurrent abdominal pain in children is not an indication for a "test and treat" strategy if other causes are excluded. Eradication of H pylori infection (a) does not cause gastro-oesophageal reflux disease (GORD) or exacerbate GORD, and (b) may prevent peptic ulcer in patients who are naïve users of non-steroidal anti-inflammatory drugs (NSAIDs). H pylori eradication is less effective than proton pump inhibitor (PPI) treatment in preventing ulcer recurrence in long term NSAID users. In primary care a test and treat strategy using a non-invasive test is recommended in adult patients with persistent dyspepsia under the age of 45. The urea breath test, stool antigen tests, and serological kits with a high accuracy are non-invasive tests which should be used for the diagnosis of H pylori infection. Triple therapy using a PPI with clarithromycin and amoxicillin or metronidazole given twice daily remains the recommended first choice treatment. Bismuth-containing quadruple therapy, if available, is also a first choice treatment option. Rescue treatment should be based on antimicrobial susceptibility. CONCLUSION: The global burden of gastric cancer is considerable but varies geographically. Eradication of H pylori infection has the potential to reduce the risk of gastric cancer development.

Cytokine gene polymorphisms in gastric cancer patients from two Italian areas at high and low cancer prevalence.

Polymorphisms of interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL1-RN), and tumor necrosis factor-alpha (TNF-alpha) genes are supposed to be key determinants of gastric cancer risk. Our aim was to study the association between these polymorphisms and gastric cancer in two areas characterized by high (Pavia/Bologna, North Italy) and low (San Giovanni Rotondo, South Italy) gastric cancer prevalence. Genomic DNA was obtained from 216 healthy donors and 98 gastric cancer patients from Pavia and Bologna, and 146 healthy donors and 86 gastric cancer patients from San Giovanni Rotondo. Two SNP in IL-1beta (-511 C/T) and TNF-alpha (-308 G/A) as well as the VNTR polymorphism of IL-1RN locus were studied. A significant linkage disequilibrium was found between IL-1beta -511 and IL-1RN. Genotype and allele frequencies at the IL-1beta, IL-1RN, and TNF-alpha loci in gastric cancer cases were not significantly different from controls. An epistatic effect between IL-1beta -511 and IL-1RN was found with the IL-1beta -511C/IL-1RN*2 haplotype conferring a significant protection against the intestinal-type of gastric cancer in the Southern population. In conclusion, IL-1beta, IL1-RN, and TNF-alpha genotypes are not associated with gastric cancer in Italian patients. An epistatic interrelationship between IL-1beta -511 and IL-1RN confers protection against gastric cancer in low-risk Italian population.

Review article: should NSAID/low-dose aspirin takers be tested routinely for H. pylori infection and treated if positive? Implications for primary risk of ulcer and ulcer relapse after initial healing.

Helicobacter pylori infection and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) can each result in gastric or duodenal ulcer(s) and ulcer complications. Together, H. pylori infection and NSAIDs account for approximately 90% of peptic ulcer disease. In 2003, the results of studies suggest, and guidelines recommend, the careful selection of anti-inflammatory drugs - NSAIDs or selective COX-2 inhibitors (coxibs) based upon patients gastrointestinal history and use of aspirin therapy. Testing for, and cure of, H. pylori infection is recommended in patients prior to the initiation of NSAID therapy and in those who are currently receiving NSAIDs and have a history of dyspepsia, peptic ulcer or ulcer complications. For patients who present with peptic ulcer bleeding but require NSAIDs long-term, H. pylori eradication therapy should be considered, followed by continuous proton pump inhibitor prophylaxis to prevent re-bleeding, regardless of which kind of NSAID (nonselective NSAID /coxib) is being prescribed. Routine testing for, and eradication of, H. pylori infection has not been recommended for current takers of NSAIDs with no or low risk of complications. The management of patients taking low-dose aspirin is complex, but eradication of H. pylori infection alone in those with a past history of bleeding does not guarantee complete protection and therefore a proton pump inhibitor should also be given. The success of eradication therapy should always be confirmed, because of the risk of ulcer recurrence and bleeding in H. pylori-infected patients who require anti-inflammatory treatments.

Measuring dyspepsia: a new severity index validated in Bologna.

BACKGROUND: Measurement of the severity of dyspepsia symptoms before and after treatment and determining what is a significant change is a major problem in designing dyspepsia treatment studies. OBJECTIVES: To assess the reproducibility, validity and responsiveness to treatment of a dyspepsia questionnaire to be used in clinical and population-based studies. METHODS: Seventy-three dyspeptic patients (35 male, 38 female; mean age 52 years) and 75 healthy volunteers (32 male, 43 female; mean age 52 years) were included. Subjects were interviewed for the presence/absence and severity/frequency of 19 gastrointestinal symptoms. Severity was measured on a 5-point scale. Frequency was also recorded on a 5-point scale. A global symptom index (severity x frequency) was calculated for the eight most severe symptoms; a mean global symptom index (8-MGSI) was considered for the evaluation of the instrument. To evaluate intra-observer variation, one author interviewed subjects (T0) and then repeated the interview 1 week later (T1). For inter-observer variation, two authors interviewed patients. VALIDITY was measured by comparing 8-MGSI of the dyspepsia patients to those of healthy volunteers. Responsiveness was assessed by comparing mean global symptom index before and 1 month after appropriate therapy. RESULTS: Reproducibility: The mean 8-MGSI was 4.5 at T0 and 3.7 at T1 with a correlation coefficient of 0.62. As for inter-observer variation, the average 8-MGSI was 4.8 by the first author and 3.9 by the second with a correlation coefficient of 0.60. VALIDITY: The mean 8-MGSI was, respectively, 1.4 in healthy volunteers and 4.8 in dyspeptic patients (p = 0.001). Responsiveness: After treatment, a significant improvement in 8-MGSI was detected (p = 0.001). CONCLUSIONS: This questionnaire is a reliable, valid and responsive instrument for measuring the presence, severity and frequency of dyspepsia.

European multicentre validation trial of two new non-invasive tests for the detection of Helicobacter pylori antibodies: urine-based ELISA and rapid urine test.

AIM: Non-invasive tests for the assessment of Helicobacter pylori status are now an integral part of the management strategies for patients with dyspepsia. The aim of this study was to evaluate a urine based antibody ELISA and a near patient urine test for the diagnosis of H. pylori infection in a European population. METHODS: Urine samples were collected from 449 patients (240 females, 209 males, mean age 54 years), with dyspeptic symptoms but no previous H. pylori eradication therapy, at five centres in four European countries. All patients underwent GI endoscopy and biopsies were taken for H. pylori diagnosis. Urine samples were analysed using an IgG ELISA (URINELISA) and a near patient urine test (RAPIRUN). In addition, a serum IgG ELISA (Pyloriset-EIA-GIII), a whole blood test (Pyloriset-Screen) and a 13C-urea breath test were performed. RESULTS: The sensitivity of the urine based ELISA and the near patient urine test was 90% and 82%, and the specificity 68% and 83%, respectively. The accuracy of the serum ELISA and the whole blood test was comparable with the urine based test. CONCLUSION: The urine based ELISA and the near patient urine test are just as accurate as the serological tests. This comparable accuracy and complete non-invasiveness of the former gives it an advantage over blood based tests. This limits the application of these tests in general practice.