Cesare Hassan

Sequential Therapy versus Standard Triple-Drug Therapy for Helicobacter pylori Eradication: A Randomized Trial

Context Eradication rates for Helicobacter pylori infection are decreasing worldwide because of increasing antimicro-bial resistance. Contribution This double-blind trial randomly assigned 300 adults with dyspepsia or peptic ulcers to a 10-day sequential regimen (pantoprazole, amoxicillin, and placebo taken for 5 days followed by pantoprazole, clarithromycin, and tinidazole taken for 5 days) or standard 10-day therapy (pantoprazole, clarithromycin, and amoxicillin). The eradication rate of H. pylori infection was greater with the sequential regimen (89%) than with the standard treatment (77%). Approximately 5% of patients in each group had epigastric pain and 3% to 5% had mild diarrhea. Implication Sequential therapy eradicates H. pylori infection more often than does standard therapy. The Editors Helicobacter pylori infection causes peptic ulcers, gastric mucosaassociated lymphoid tissue lymphoma, and gastric cancer (1). Standard treatments for H. pylori infection that have been endorsed by U.S. and European authorities rely on clarithromycin or metronidazole in conjunction with other antibiotics and acid inhibitors (2, 3). The prevalence of clarithromycin and metronidazole resistance has increased substantially in recent years, and there has been a corresponding decrease in the eradication rate for H. pylori infection (4). Eradication rates in most western countries have declined to unacceptable levels. Eradication therapy fails in approximately 1 in 5 patients (5). A simple, short treatment regimen that would return eradication levels to those seen at the advent of H. pylori treatment is urgently needed (5). Such a regimen should have high efficacy against clarithromycin-resistant and metronidazole-resistant strains of H. pylori because these strains are increasingly encountered in routine clinical practice. Novel 10-day sequential therapy consisting of 5-day dual therapy (proton-pump inhibitor plus amoxicillin) followed by 5-day triple therapy (proton-pump inhibitor, clarithromycin, and tinidazole) has had good eradication success in unblinded trials in elderly and pediatric patients (68). However, no double-blind, controlled trials using conventional therapy have been reported, and the effect of clarithromycin and metronidazole resistance on the outcome of sequential therapy has not been studied prospectively. The aim of this study was to compare a 10-day sequential treatment regimen for H. pylori infection with standard 10-day triple therapy in a randomized, controlled trial. Secondary objectives were to determine the efficacy of the treatment regimen in patients with resistant strains of H. pylori, to assess treatment adherence, and to evaluate side effects. Methods Design Overview This was a prospective, double-blind, controlled study with a parallel-group design. At baseline, patients were evaluated for inclusion and exclusion criteria and provided written informed consent. Patients were then randomly assigned to a treatment group and had follow-up evaluations to assess the eradication rate of H. pylori infection, treatment adherence, and side effects. The study was performed according to good clinical practice and the Declaration of Helsinki. The ethics committees at the 2 participating centers approved the study. The consent form indicated that patients would be randomly assigned to treatment that was the current standard or a new therapy that might have higher eradication rates. Patients were told that eradication failure was possible with any therapy regimen. All patients with eradication failure were offered a rescue therapy on the basis of the results of sensitivity testing. Setting and Participants Between September 2003 and April 2006, consecutive patients with dyspepsia who were at least 18 years of age, who had never received treatment for H. pylori infection, and who had been referred to our hospitals (Bologna, Italy, and Rome, Italy) for a gastroenterology consultation were asked to participate in the study. No special recruitment techniques (such as advertisements or letters sent to primary care physicians) were used. Exclusion criteria were previous treatment for H. pylori infection; use of proton-pump inhibitors, H2-receptor antagonists, bismuth preparations, or antibiotics in the previous 2 weeks; concomitant use of anticoagulants or ketoconazole (because of potential interaction with the nonsteroidal anti-inflammatory drugs) and glucocorticoids (because of association with ulcer disease); the ZollingerEllison syndrome; previous surgery of the esophagus or upper gastrointestinal tract (except appendectomy, polypectomy, or cholecystectomy); severe or unstable cardiovascular, pulmonary, or endocrine disease; clinically significant renal or hepatic disease or dysfunction; hematologic disorders; any other clinically significant medical condition that could increase risk; malignant disease of any kind except for successfully treated skin cancer (basal- or squamous-cell carcinoma) during the previous 5 years; Barrett esophagus or high-grade dysplasia; drug, alcohol, or medication abuse within the past year; severe psychiatric or neurologic disorders; and pregnancy or lactation, as well as sexually active women of child-bearing years who were not willing to practice medically acceptable contraception (oral or injectable contraceptives, implantable or mechanical intrauterine or vaginal devices, or vasectomy for the partner) for the study duration. Randomization and Interventions Patient allocation was determined with a random-number chart that was concealed from investigators and patients by using numbered blister packs of the study medication that corresponded to the random-number chart. A computer-generated randomization chart was used to determine allocation, which was stratified according to center by using a block design and a block size of 4. Allocation was concealed with an opaque envelope, which contained a number that corresponded to the numbered blister packs. The envelope was opened when the patient met the inclusion criteria and provided informed consent. Patients and investigators were blinded to treatment group. Patients were randomly allocated to receive a 10-day sequential regimen (40 mg of pantoprazole, 1 g of amoxicillin, and placebo, each administered twice daily for the first 5 days, followed by 40 mg of pantoprazole, 500 mg of clarithromycin, and 500 mg of tinidazole, each administered twice daily for the remaining 5 days); or standard therapy (40 mg of pantoprazole, 500 mg of clarithromycin, and 1 g of amoxicillin, each administered twice daily for 10 days). Medications were contained in individual blisters in the package. A placebo that was identical in color and shape to the clarithromycin capsule was administered during the first 5 days of sequential therapy to maintain blinding. This ensured that all patients took 3 medications twice a day for 10 days. Measurements and Outcomes The primary outcome of the study was eradication of H. pylori infection. Secondary outcomes were to determine the efficacy of sequential treatment against clarithromycin-resistant strains of H. pylori, to assess adherence to therapy, and to determine the frequency of self-reported side effects. 13C-Urea Breath Test Urea breath tests were done after an overnight fast. A baseline breath sample was obtained, and 75 mg of 13C-urea with citric acid (1.5 g) was administered as an aqueous solution. Another breath sample was collected 30 minutes after the test solution was administered. The results of the test were considered positive if the difference between the baseline sample and the 30-minute sample exceeded 4.5 parts per 1000 of 13CO2. All breath samples were analyzed in Bologna by using a single gas isotope ratio mass spectrometer (Finnigan, Bremen, Germany). The accuracy of the urea breath test was previously validated in our laboratory. We reported sensitivity and specificity values of 94.7% and 95.7%, respectively (9). Endoscopy All patients with positive results on the urea breath test had upper endoscopy, and 5 biopsy specimens were obtained during the procedure. Two specimens were taken from the antrum and 2 were taken from the corpus for histologic evaluation. The specimens were stained with hematoxylin and eosin and Giemsa stains, and gastritis was scored by using the updated Sydney System (10). The pathologist who performed the histologic examination was blinded to the results of all other tests. One biopsy specimen was obtained from the antrum for the rapid urease test (Campylobacter pylori test, Yamanouchi Pharma S.p.A, Corrugate, Milan, Italy). Two additional biopsy samples from the antrum were collected for bacterial culture and susceptibility testing. We performed cultures without knowing the other test results. For this purpose, biopsy specimens were sent to a single microbiological laboratory in Bologna within 24 hours and were stored at 70C. Isolated strains were tested for primary clarithromycin and metronidazole resistance by using an agar dilution method, which was defined as a minimal inhibitory concentration greater than 1 mg/L and greater than 8 mg/L for clarithromycin and metronidazole, respectively (11). Strains were classified as having isolated resistance to clarithromycin or metronidazole if the organisms were only resistant to 1 antibiotic. Dual resistance was defined as resistance to clarithromycin and metronidazole. At baseline, patients were classified as having H. pylori infection if the results on the urea breath test were positive and if the results on at least 2 of the following 3 tests were positive: rapid urease test, histologic examination, and culture. An expert panel recommended these criteria for use in clinical trials of H. pylori infection (12). Follow-up Procedures Treatment Adherence and Side Effects Patients were asked to return at the completion of therapy for a physical evaluation and to assess adherence to therapy and side effects. We first aske

Treatment of Relapsing Mild-to-Moderate Ulcerative Colitis With the Probiotic VSL#3 as Adjunctive to a Standard Pharmaceutical Treatment: A Double-Blind, Randomized, Placebo-Controlled Study

OBJECTIVES:VSL#3 is a high-potency probiotic mixture that has been used successfully in the treatment of pouchitis. The primary end point of the study was to assess the effects of supplementation with VSL#3 in patients affected by relapsing ulcerative colitis (UC) who are already under treatment with 5-aminosalicylic acid (ASA) and/or immunosuppressants at stable doses.METHODS:A total of 144 consecutive patients were randomly treated for 8 weeks with VSL#3 at a dose of 3,600 billion CFU/day (71 patients) or with placebo (73 patients).RESULTS:In all, 65 patients in the VSL#3 group and 66 patients in the placebo group completed the study. The decrease in ulcerative colitis disease activity index (UCDAI) scores of 50% or more was higher in the VSL#3 group than in the placebo group (63.1 vs. 40.8; per protocol (PP) P=0.010, confidence interval (CI)95% 0.51–0.74; intention to treat (ITT) P=0.031, CI95% 0.47–0.69). Significant results with VSL#3 were recorded in an improvement of three points or more in the UCDAI score (60.5% vs. 41.4%; PP P=0.017, CI95% 0.51–0.74; ITT P=0.046, CI95% 0.47–0.69) and in rectal bleeding (PP P=0.014, CI95% 0.46–0.70; ITT P=0.036, CI95% 0.41–0.65), whereas stool frequency (PP P=0.202, CI95% 0.39–0.63; ITT P=0.229, CI95% 0.35–0.57), physicians rate of disease activity (PP P=0.088, CI95% 0.34–0.58; ITT P=0.168, CI95% 0.31–0.53), and endoscopic scores (PP P=0.086, CI95% 0.74–0.92; ITT P=0.366, CI95% 0.66–0.86) did not show statistical differences. Remission was higher in the VSL#3 group than in the placebo group (47.7% vs. 32.4%; PP P=0.069, CI95% 0.36–0.60; ITT P=0.132, CI95% 0.33–0.56). Eight patients on VSL#3 (11.2%) and nine patients on placebo (12.3%) reported mild side effects.CONCLUSIONS:VSL#3 supplementation is safe and able to reduce UCDAI scores in patients affected by relapsing mild-to-moderate UC who are under treatment with 5-ASA and/or immunosuppressants. Moreover, VSL#3 improves rectal bleeding and seems to reinduce remission in relapsing UC patients after 8 weeks of treatment, although these parameters do not reach statistical significance.

The sequential therapy regimen for Helicobacter pylori eradication: a pooled-data analysis

Background:: Standard triple therapies are the most used treatment in clinical practice. However, a critical fall in the H pylori eradication rate following these therapies has been observed in the last few years. The sequential regimen is a novel, promising therapeutic approach. Objectives:: To evaluate the available data on the sequential therapy regimen. Methods:: A pooled-data analysis of all studies on the sequential regimen was performed. The eradication rate was calculated according to gastroduodenal pathology, proton pump inhibitor used, antibiotic resistance, as well as setting (paediatric or geriatric patients). Compliance, side effects, and cost implications were also evaluated. Results:: Overall, more than 1800 patients have been treated with the sequential regimen. Such a therapy was superior to 7–10 days triple therapies in paediatric, adult and elderly patients, achieving an eradication rate constantly higher than 90% at ITT analysis. Although primary clarithromycin resistance reduced the efficacy of such a therapy, a success rate significantly higher than that observed with the standard 7–10 days triple therapies was found. Conclusion:: The 10-day sequential treatment regimen achieves higher eradication rates than standard triple therapies.

Colorectal Cancer: CT Colonography and Colonoscopy for Detection—Systematic Review and Meta-Analysis

PURPOSE To perform a systematic review and meta-analysis of published studies assessing the sensitivity of both computed tomographic (CT) colonography and optical colonoscopy (OC) for colorectal cancer detection. MATERIALS AND METHODS Analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. The primary data source was the results of a detailed PubMed search from 1994 to 2009. Diagnostic studies evaluating CT colonography detection of colorectal cancer were assessed by using predefined inclusion and exclusion criteria, in particular requiring both OC and histologic confirmation of disease. Studies that also included a mechanism to assess true-positive versus false-negative diagnoses at OC (eg, segmental unblinding) were used to calculate OC sensitivity. Assessment and data extraction were performed independently by two authors. Potential bias was ascertained by using Quality Assessment of Diagnostic Accuracy Studies guidelines. Specific CT colonography techniques were cataloged. Forest plots of per-patient sensitivity were produced on the basis of random-effect models. Potential bias across primary studies was assessed by using the I(2) statistic. Original study authors were contacted for data clarification when necessary. RESULTS Forty-nine studies provided data on 11,151 patients with a cumulative colorectal cancer prevalence of 3.6% (414 cancers). The sensitivity of CT colonography for colorectal cancer was 96.1% (398 of 414; 95% confidence interval [CI]: 93.8%, 97.7%). No heterogeneity (I(2) = 0%) was detected. No cancers were missed at CT colonography when both cathartic and tagging agents were combined in the bowel preparation. The sensitivity of OC for colorectal cancer, derived from a subset of 25 studies including 9223 patients, was 94.7% (178 of 188; 95% CI: 90.4%, 97.2%). A moderate degree of heterogeneity (I(2) = 50%) was present. CONCLUSION CT colonography is highly sensitive for colorectal cancer, especially when both cathartic and tagging agents are combined in the bowel preparation. Given the relatively low prevalence of colorectal cancer, primary CT colonography may be more suitable than OC for initial investigation of suspected colorectal cancer, assuming reasonable specificity. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11101887/-/DC1.

Post-polypectomy colonoscopy surveillance: European Society of Gastrointestinal Endoscopy (ESGE) Guideline

MAIN RECOMMENDATIONS The following recommendations for post-polypectomy endoscopic surveillance should be applied only after a high quality baseline colonoscopy with complete removal of all detected neoplastic lesions.1 In the low risk group (patients with 1 - 2 tubular adenomas < 10 mm with low grade dysplasia), the ESGE recommends participation in existing national screening programmes 10 years after the index colonoscopy. If no screening programme is available, repetition of colonoscopy 10 years after the index colonoscopy is recommended (strong recommendation, moderate quality evidence). 2 In the high risk group (patients with adenomas with villous histology or high grade dysplasia or ≥10 mm in size, or ≥ 3 adenomas), the ESGE recommends surveillance colonoscopy 3 years after the index colonoscopy (strong recommendation, moderate quality evidence). Patients with 10 or more adenomas should be referred for genetic counselling (strong recommendation, moderate quality evidence). 3 In the high risk group, if no high risk adenomas are detected at the first surveillance examination, the ESGE suggests a 5-year interval before a second surveillance colonoscopy (weak recommendation, low quality evidence). If high risk adenomas are detected at first or subsequent surveillance examinations, a 3-year repetition of surveillance colonoscopy is recommended (strong recommendation, low quality evidence).4 The ESGE recommends that patients with serrated polyps < 10 mm in size with no dysplasia should be classified as low risk (weak recommendation, low quality evidence). The ESGE suggests that patients with large serrated polyps (≥ 10 mm) or those with dysplasia should be classified as high risk (weak recommendation, low quality evidence).5 The ESGE recommends that the endoscopist is responsible for providing a written recommendation for the post-polypectomy surveillance schedule (strong recommendation, low quality evidence).

High eradication rates of Helicobacter pylori with a new sequential treatment

Background : Eradication rates of Helicobacter pylori with standard triple therapy are disappointing, and studies from several countries confirm this poor performance.

Bowel preparation for colonoscopy: European Society of Gastrointestinal Endoscopy (ESGE) Guideline

BACKGROUND AND AIM This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). It addresses the choice amongst regimens available for cleansing the colon in preparation for colonoscopy. METHODS This Guideline is based on a targeted literature search to evaluate the evidence supporting the use of bowel preparation for colonoscopy. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was adopted to define the strength of recommendation and the quality of evidence. RESULTS The main recommendations are as follows. (1) The ESGE recommends a low-fiber diet on the day preceding colonoscopy (weak recommendation, moderate quality evidence). (2) The ESGE recommends a split regimen of 4 L of polyethylene glycol (PEG) solution (or a same-day regimen in the case of afternoon colonoscopy) for routine bowel preparation. A split regimen (or same-day regimen in the case of afternoon colonoscopy) of 2 L PEG plus ascorbate or of sodium picosulphate plus magnesium citrate may be valid alternatives, in particular for elective outpatient colonoscopy (strong recommendation, high quality evidence). In patients with renal failure, PEG is the only recommended bowel preparation. The delay between the last dose of bowel preparation and colonoscopy should be minimized and no longer than 4 hours (strong recommendation, moderate quality evidence). (3) The ESGE advises against the routine use of sodium phosphate for bowel preparation because of safety concerns (strong recommendation, low quality evidence).

Diagnostic accuracy of computed tomographic colonography for the detection of advanced neoplasia in individuals at increased risk of colorectal cancer

CONTEXT Computed tomographic (CT) colonography has been recognized as an alternative for colorectal cancer (CRC) screening in average-risk individuals, but less information is available on its performance in individuals at increased risk of CRC. OBJECTIVE To assess the accuracy of CT colonography in detecting advanced colorectal neoplasia in asymptomatic individuals at increased risk of CRC using unblinded colonoscopy as the reference standard. DESIGN, SETTING, AND PARTICIPANTS This was a multicenter, cross-sectional study. Individuals at increased risk of CRC due to either family history of advanced neoplasia in first-degree relatives, personal history of colorectal adenomas, or positive results from fecal occult blood tests (FOBTs) were recruited in 11 Italian centers and 1 Belgian center between December 2004 and May 2007. Each participant underwent CT colonography followed by colonoscopy on the same day. MAIN OUTCOME MEASURES Sensitivity and specificity of CT colonography in detecting individuals with advanced neoplasia (ie, advanced adenoma or CRC) 6 mm or larger. RESULTS Of 1103 participants, 937 were included in the final analysis: 373 cases in the family-history group, 343 in the group with personal history of adenomas, and 221 in the FOBT-positive group. Overall, CT colonography identified 151 of 177 participants with advanced neoplasia 6 mm or larger (sensitivity, 85.3%; 95% confidence interval [CI], 79.0%-90.0%) and correctly classified results as negative for 667 of 760 participants without such lesions (specificity, 87.8%; 95% CI, 85.2%-90.0%). The positive and negative predictive values were 61.9% (95% CI, 55.4%-68.0%) and 96.3% (95% CI, 94.6%-97.5%), respectively; after group stratification, a significantly lower negative predictive value was found for the FOBT-positive group (84.9%; 95% CI, 76.2%-91.3%; P < .001). CONCLUSIONS In a group of persons at increased risk for CRC, CT colonography compared with colonoscopy resulted in a negative predictive value of 96.3% overall. When limited to FOBT-positive persons, the negative predictive value was 84.9%.

Systematic review: endoscopic dilatation in Crohn’s disease

Background  Endoscopic dilatation for Crohn’s disease has been evaluated only in some small and heterogeneous studies.

Endoscopic submucosal dissection: European Society of Gastrointestinal Endoscopy (ESGE) Guideline

UNLABELLED This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system 1 2 was adopted to define the strength of recommendations and the quality of evidence. MAIN RECOMMENDATIONS 1 ESGE recommends endoscopic en bloc resection for superficial esophageal squamous cell cancers (SCCs), excluding those with obvious submucosal involvement (strong recommendation, moderate quality evidence). Endoscopic mucosal resection (EMR) may be considered in such lesions when they are smaller than 10 mm if en bloc resection can be assured. However, ESGE recommends endoscopic submucosal dissection (ESD) as the first option, mainly to provide an en bloc resection with accurate pathology staging and to avoid missing important histological features (strong recommendation, moderate quality evidence). 2 ESGE recommends endoscopic resection with a curative intent for visible lesions in Barretts esophagus (strong recommendation, moderate quality evidence). ESD has not been shown to be superior to EMR for excision of mucosal cancer, and for that reason EMR should be preferred. ESD may be considered in selected cases, such as lesions larger than 15 mm, poorly lifting tumors, and lesions at risk for submucosal invasion (strong recommendation, moderate quality evidence). 3 ESGE recommends endoscopic resection for the treatment of gastric superficial neoplastic lesions that possess a very low risk of lymph node metastasis (strong recommendation, high quality evidence). EMR is an acceptable option for lesions smaller than 10 - 15 mm with a very low probability of advanced histology (Paris 0-IIa). However, ESGE recommends ESD as treatment of choice for most gastric superficial neoplastic lesions (strong recommendation, moderate quality evidence). 4 ESGE states that the majority of colonic and rectal superficial lesions can be effectively removed in a curative way by standard polypectomy and/or by EMR (strong recommendation, moderate quality evidence). ESD can be considered for removal of colonic and rectal lesions with high suspicion of limited submucosal invasion that is based on two main criteria of depressed morphology and irregular or nongranular surface pattern, particularly if the lesions are larger than 20 mm; or ESD can be considered for colorectal lesions that otherwise cannot be optimally and radically removed by snare-based techniques (strong recommendation, moderate quality evidence).