Hematopoietic Stem Cell Transplantation in Crohn's Disease: State-of-the-Art Treatment.

Both autologous and allogeneic haemopoietic stem cell transplantation (HSCT) have been tried in Crohn's disease (CD). In allogeneic HSCT, the host bone marrow is ablated and replaced by bone marrow from a donor. This substitution of a genetically different bone marrow is effective in a number of conditions including those with an immunological basis such as CD. While the toxicity of allogeneic HSCT has precluded its uptake in idiopathic CD, there is interest in its utility in the management of early onset infantile (inflammatory bowel disease), which behaves as a monogenic disorder, with abnormalities of the interleukin 10 signalling system as the best recognized. In autologous HSCT, the patient's own stem cells are harvested before proceeding to lymphoablation and transplantation of the patient's own uncommitted stem cells, which generate an immune system with an altered T-cell repertoire. In a limited number of cases, this has led to substantial and prolonged remission tantamount to possible cure of CD. However, case series and controlled data from the Autologous Stem Cell International Crohn's Disease study suggest that although this method has its own advantages, most patients are still at risk of redeveloping CD, albeit with an arguably improved response to conventional treatment. The availability of new treatments for CD means that an HSCT is not a suitable treatment method for a majority of patients because of its greater toxicity, even though efficacy may be superior. Wider usage would depend upon the development of protocols that are safer and better targeted.

Stem cells as treatment in inflammatory bowel disease.

BACKGROUND: The Autologous Stem Cell Transplantation International Crohn's Disease (ASTIC) trial is a randomised controlled evaluation of the proposition that immunoablation and haemopoietic stem cell transplantation improves the course of Crohn's disease. Recruitment of all 48 patients in the trial will be completed in early 2012 and the results to date are descriptively presented here. METHODS: Patients with an impaired quality of life due to active Crohn's disease, despite the administration of at least 3 immunosuppressive agents, all received mobilisation treatment (cyclophosphamide 4 g/m(2) over 2 days followed by recombinant human granulocyte colony stimulating factor (filgrastim) 10 µg/kg daily before randomisation to immediate (after 1 month) or delayed (after 1 year) immunoablation and stem cell transplantation. The conditioning regime was cyclophosphamide 50 mg/kg/day for 4 days, anti-thymocyte globulin 2.5 mg/kg/day and methylprednisolone 1 mg/kg on days 3-5. The bone marrow was reconstituted by the infusion of an unselected graft of 3-8 × 10(6)/kg CD34-positive stem cells. Results were compared 1 year after mobilisation alone or after transplantation. RESULTS: Twelve months after stem cell transplantation (early or delayed) the Crohn's Disease Activity Index (CDAI) fell from 324 (median, interquartile range 229-411) to 161 (85-257, n = 17) compared to 351 (287-443) to 272 (214-331) following mobilisation alone (n = 11). Six patients had a normal CDAI after transplantation versus 1 after mobilisation. C-reactive protein fell from 16.6 (6.7-32.0) to 6.5 (3.5-12.5) mg/l versus 14 (8.0-27.0) to 9.0 (2.0-23.4) mg/l following mobilisation alone. The Crohn's Disease Endoscopic Index of Severity (CDEIS) (aggregate for upper and lower endoscopy) fell from 18 (10-25) to 5 (1-11) following transplantation versus 14 (12-16) to 9 (4-22) following mobilisation. Three patients achieved the goal of a normal CDAI, no drug therapy and normal upper and lower endoscopy 1 year after transplantation, but so did 1 patient following mobilisation alone. Serious adverse events were common (n = 100 to date) with 42 infective episodes requiring or prolonging hospitalisation, following both mobilisation and conditioning and transplantation. There were 7 episodes of viral (re)activation. Temporary flare of Crohn's disease activity or a need for surgery occurred in 8 patients. CONCLUSIONS: Immunoablation and haemopoietic stem cell transplantation appear to be an effective treatment for some patients with Crohn's disease, although full results will be required for a firm conclusion. The risks are significant, making it potentially suitable for only a limited number of patients. Data from the whole trial will be needed to judge whether mobilisation alone has any benefits.

High definition colonoscopy vs. standard video endoscopy for the detection of colonic polyps: a meta-analysis.

BACKGROUND AND STUDY AIMS: High definition colonoscopy may improve adenoma detection rates but studies report conflicting results. The aim of this meta-analysis was to compare the diagnostic yield of colonic polyps between high definition colonoscopy and standard video endoscopy (SVE). METHODS: Various electronic databases were searched for articles reporting on high definition colonoscopy. The pooled incremental yield and pooled weighted mean difference of high definition colonoscopy over SVE for polyp detection was determined. RESULTS: Five studies involving 4422 patients provided data on the total number of polyps detected. The incremental yield of high definition colonoscopy for the detection of any polyp was 3.8 % (95 % confidence interval [CI] 1 % - 6.7 %) with a number needed to treat (NNT) of 26. For the detection of adenomatous polyps the incremental yield was 3.5 % (95 %CI 0.9 % - 6.1 %) with an NNT of 28. There were no differences between high definition and SVE in the detection of high risk adenomas, with an incremental yield of -0.1 % (95 %CI -1.7 % to 1.6 %). When grouped according to the overall adenoma detection rate of the studies (> 50 % or < 50 %) the pooled weighted mean difference in small adenoma detection was better with high definition colonoscopy ( P = 0.035). CONCLUSIONS: There were marginal differences between high definition colonoscopy and SVE for the detection of colonic polyps/adenomas. High definition colonoscopy did not improve the detection of high risk adenomas. Due to differences in the adenoma detection rate between the studies and the nonrandomized study design of three of the five studies, these results need to be interpreted with caution. Prospective randomized trials looking at long term outcomes such as rates of interval or missed cancers are needed to clarify the clinical implications.

Narrow band imaging for characterization of high grade dysplasia and specialized intestinal metaplasia in Barrett's esophagus: a meta-analysis.

BACKGROUND AND STUDY AIM: Narrow band imaging (NBI), a novel endoscopic technique that highlights mucosal surface structures and microvasculature is increasingly advocated as a tool to detect and characterize neoplasia and intestinal metaplasia in patients with Barrett's esophagus. We aimed to assess the diagnostic accuracy of NBI with magnification for the diagnosis of high grade dysplasia (HGD) and specialized intestinal metaplasia (SIM) in patients with Barrett's esophagus. METHODS: We performed a meta-analysis of studies which compared NBI-based diagnosis of HGD and SIM with histopathology as the gold standard. RESULTS: Eight studies including 446 patients with 2194 lesions met the inclusion criteria. For diagnosing HGD, the pooled sensitivity, specificity, diagnostic odds ratio (DOR), and area under the curve (AUC) were 0.96 (95 % confidence interval [CI] 0.93-0.99), 0.94 (95 %CI 0.84-1.0), 342.49 (95 %CI 40.49 - 2896.89) and 0.99 (SE 0.01) on a per-lesion analysis with similar results on per-patient analysis.. For the characterization of SIM, the pooled sensitivity, specificity, DOR, and AUC were 0.95 (95 %CI 0.87-1.0), 0.65 (95 %CI 0.52-0.78), 37.53 (95 %CI 6.50-217.62) and 0.88 (SE 0.08) on a per-lesion analysis. CONCLUSION: NBI with magnification is accurate with high diagnostic precision for diagnosis of HGD in Barrett's esophagus on the basis of irregular mucosal pit patterns and/or irregular microvasculature. NBI has high sensitivity but poor specificity for characterizing SIM.

Narrow-band imaging with magnification in Barrett's esophagus: validation of a simplified grading system of mucosal morphology patterns against histology.

BACKGROUND AND STUDY AIMS: Validation of a simplified classification of mucosal morphology in prediction of histology in Barrett's esophagus using narrow-band imaging with magnification (NBI-Z) and assessing its reproducibility by endoscopists experienced in the use of NBI (NBI-experts) and by endoscopists who were new to NBI (non-NBI-experts). PATIENTS AND METHODS: In a prospective cohort study of 109 patients with Barrett's esophagus at a single tertiary referral center, mucosal patterns visualized in Barrett's esophagus on NBI-Z were classified into four easily distinguishable types: A, round pits with regular microvasculature; B, villous/ridge pits with regular microvasculature; C, absent pits with regular microvasculature; D, distorted pits with irregular microvasculature. The NBI-Z grading was compared with the final histopathological diagnosis, and positive (PPV) and negative predictive values (NPV) were calculated. The reproducibility of the grading was then assessed by NBI-expert and non-NBI-expert endoscopists, and interobserver and intraobserver agreement were calculated using kappa statistics. RESULTS: Per-biopsy analysis: In 903 out of 1021 distinct areas (87.9%) the NBI-Z grading corresponded to the histological diagnosis. Per-patient analysis: The PPV and NPV for type A pattern (columnar mucosa without intestinal metaplasia) were 100% and 97% respectively; for types B and C (intestinal metaplasia) they were 88% and 91% respectively, and for type D (high-grade dysplasia) 81% and 99% respectively. Inter- and intraobserver agreement: The mean kappa values in assessing the various patterns were 0.71 and 0.87 in the non-expert group; 0.78 and 0.91 in the expert group. CONCLUSIONS: This study has validated a simplified classification of the various morphologic patterns visualized in Barrett's esophagus and confirmed its reproducibility when used by NBI-expert and non-NBI-expert endoscopists.

Novel endoscopic observation in Barrett's oesophagus using high resolution magnification endoscopy and narrow band imaging.

BACKGROUND: High resolution magnification endoscopy with narrow band imaging (NBI) may improve the detection of specialised intestinal metaplasia (SIM) and dysplasia in Barrett's oesophagus. AIMS: To describe the magnified endoscopic features with the use of NBI in Barrett's oesophagus. METHODS: Three hundred and forty-four areas from 50 patients with Barrett's oesophagus were studied using high resolution magnification endoscopy (HRME) with NBI and targeted biopsies were obtained. The sensitivity, specificity, predictive values of the various patterns for the prediction of SIM and dysplasia were calculated. RESULTS: The magnified endoscopic features of Barrett's oesophagus with the use of NBI consist of microstructural/microvascular patterns. The yield of SIM according to the patterns was: (i) Regular microstructural pattern with tubular/linear/villous pattern 90.6% and with circular pattern 0%; and (ii) Absent microstructural pattern 98.9%. The sensitivity, specificity, positive and negative predictive values of the combination of regular microstructural pattern (tubular/villous/linear) and absent microstructural pattern to detect SIM were 100%, 78.8%, 93.5% and 100%, respectively. The sensitivity, specificity, positive and negative predictive values of the irregular microvascular/microstructural pattern for the prediction of high grade dysplasia were 90%, 100%, 99.2% and 100%, respectively. CONCLUSION: High resolution magnification endoscopy with NBI allows clear visualisation of microstructural and microvascular patterns within Barrett's oesophagus, and allows targeted biopsy with a high yield of SIM and high grade dysplasia.

Clinical trial: healing of NSAID-associated gastric ulcers in patients continuing NSAID therapy - a randomized study comparing ranitidine with esomeprazole.

BACKGROUND: The use of non-steroidal anti-inflammatory drugs (NSAID) is associated with an increased risk of gastric ulcer (GU) development. METHODS: This multicentre, randomized, double-blind, parallel-group trial compared endoscopic healing rates at 4 and 8 weeks after treatment with oral esomeprazole 40 or 20 mg once daily, or ranitidine 150 mg twice daily, in patients with 1 baseline GU > or = 5 mm but no GUs or duodenal ulcers >25 mm in diameter who received continued cyclooxygenase-2-selective or non-selective NSAID therapies. The primary outcome was the percentage of patients in each treatment group who had no GUs at week 8. RESULTS: Four hundred and forty patients were randomized to treatment. At week 8, GU healing rates (95% CI) with esomeprazole 40 mg, esomeprazole 20 mg and ranitidine were 85.7 (79.8-91.7)%, 84.8 (78.8-90.8)% and 76.3 (69.2-83.3)%, respectively; between-group differences were not statistically significant. Week-4 GU healing rates were 70.7 (62.9-78.4)% and 72.5 (65.0-79.9)% with esomeprazole 40 and 20 mg, respectively, and were significantly higher (P < 0.01 for both doses) than those with ranitidine [55.4 (47.1-63.7)%]. CONCLUSION: In patients who require continued NSAID therapy, GU healing rates at 8 weeks numerically favoured esomeprazole but were not significantly different from ranitidine.

Efficacy of esomeprazole for resolution of symptoms of heartburn and acid regurgitation in continuous users of non-steroidal anti-inflammatory drugs.

BACKGROUND: The use of non-steroidal anti-inflammatory drugs (NSAIDs) is often associated with upper gastrointestinal symptoms such as heartburn and acid regurgitation. AIM: To assess the efficacy of esomeprazole 20 and 40 mg for resolution of heartburn and acid regurgitation in continuous NSAIDs. METHODS: A post hoc analysis of five clinical trials was performed. Two identically designed, placebo-controlled, 4-week studies (NASA1, SPACE1) enrolled non-ulcer, NSAIDs-treated patients with upper abdominal pain, discomfort or burning. PLUTO and VENUS were identically designed, placebo-controlled, 6-month studies that enrolled patients at risk of NSAIDs-induced ulcers. Study 285 was an 8-week comparative study with ranitidine (300 mg/day) in patients with NSAIDs-induced gastric ulcers. Resolution of investigator-assessed heartburn and acid regurgitation was defined as symptom severity of 'none' in the last 7 days. RESULTS: In NASA1/SPACE1, heartburn resolved in 61% and 62% of patients taking esomeprazole 20 and 40 mg, respectively (vs. 36% on placebo, P < 0.001), and acid regurgitation resolved in 65% and 67% (vs. 48%, P < 0.001). Resolution of both symptoms was greater with esomeprazole than with placebo in PLUTO/VENUS (P

A randomized, double-blind, placebo-controlled trial of lenalidomide in the treatment of moderately severe active Crohn's disease.

BACKGROUND: Therapy targeted at tumour necrosis factor-alpha has an established role in Crohn's disease. Lenalidomide, an analogue of thalidomide, is an oral immunomodulatory agent with powerful antitumour necrosis factor-alpha properties. It is licensed for myeloma and myelodysplastic syndrome. Based upon reports of thalidomide efficacy, lenalidomide was evaluated in Crohn's disease. AIM: To evaluate the efficacy and safety of lenalidomide in subjects with moderately severe active Crohn's disease. METHODS: In a multicentre, double-blind, placebo-controlled parallel group study 89 subjects were randomized to lenalidomide 25 mg daily, 5 mg daily or placebo. Subjects were treated for 12 weeks. The primary end point was a 70-point reduction in Crohn's Disease Activity Index. RESULTS: The overall clinical response rate was not significantly different between the three groups: lenalidomide 25 mg 26%, lenalidomide 5 mg 48% and placebo 39%. Lenalidomide was generally well tolerated with only one serious adverse event, a deep vein thrombosis, being attributed to treatment. CONCLUSION: Lenalidomide, an oral agent with antitumour necrosis factor-alpha properties, was not effective in active Crohn's disease in contrast to reports of benefit from thalidomide. The reasons for this lack of efficacy are speculative, other physiological activities may offset its action on inflammatory cytokines, or its antitumour necrosis factor-alpha action without apoptosis may be insufficient for activity in Crohn's disease.

Acetic acid-enhanced magnification endoscopy in the diagnosis of specialized intestinal metaplasia, dysplasia and early cancer in Barrett's oesophagus.

BACKGROUND: Barrett's surveillance is prone to sampling error. Aim To determine whether enhanced magnification endoscopy using acetic acid instillation improves diagnostic accuracy of specialized intestinal metaplasia/dysplasia in Barrett's oesophagus. METHODS: We examined the detection rate of the specialized intestinal metaplasia/dysplasia in 64 consecutive patients with Barrett's oesophagus using acetic acid to enhance mucosal pit patterns. Histology was compared with the previous findings at recent conventional surveillance in 62 patients. We also examined the inter-/intra-observer agreement in the assessment of the enhanced magnification endoscopy pit pattern findings. RESULTS: Histology revealed columnar-lined oesophagus in six (9%) patients, specialized intestinal metaplasia in 49 (77%), low-grade dysplasia in five (8%), high-grade dysplasia in one (2%), and adenocarcinoma in three (5%). There was discordance between the histologic findings from conventional surveillance with random biopsy. Fifteen patients (24%) had a histological upgrade with enhanced magnification endoscopy. There was a high detection rate of specialized intestinal metaplasia even in short segment Barrett's oesophagus (74%), and additionally, there were two cancers, one with 2-cm Barrett's oesophagus and one ultra-short (1 cm). The mean kappa values for inter- and intra-observer agreement in assessing the pit patterns were 0.571 (0.041) and 0.709 (0.038), respectively. CONCLUSIONS: Enhanced magnification endoscopy allows clear visualization of the epithelial pit patterns within Barrett's oesophagus, and targeted biopsy results in a high yield of specialized intestinal metaplasia and dysplasia.

Probiotics for maintenance of remission in Crohn's disease.

BACKGROUND: Crohn's disease (CD) is characterised by episodes of disease activity and symptom-free remission. Probiotics are microorganisms that can potentially benefit health, and have been evaluated as an alternate means of preventing relapse in patients with CD. OBJECTIVES: To assess the effectiveness of probiotics for the maintenance of remission in CD. SEARCH STRATEGY: The following databases were searched: the Cochrane Database of Systematic Reviews (2005, Issue 3); the Cochrane Central Register of Controlled Trials (2005, Issue 3); the Cochrane IBD/FBD Group Trials Register (2005), MEDLINE (1966-2005); EMBASE (1980-2005); ISI Web of Knowledge (BIDS) 1981-2005; On-line clinical trials databases (2005); and review articles. Experts in the field were contacted for unpublished data. SELECTION CRITERIA: Randomised controlled trials of probiotic therapy. DATA COLLECTION AND ANALYSIS: Two independent reviewers performed data extraction and assessment of methodological quality. The primary outcome was the relative risk (RR) of relapse after maintenance treatment (and 95% confidence intervals [CI]). MAIN RESULTS: Seven small studies were identified and varied according to probiotics tested, methodological quality and medication regimen. No studies were pooled for statistical analysis. There was no statistically significant benefit of E. coli Nissle for reducing the risk of relapse compared to placebo (RR 0.43, 95% CI 0.15 to 1.20), or Lactobacillus GG after surgically-induced remission (RR 1.58, 95% CI 0.30 to 8.40) or medically-induced remission (RR 0.83, 95% CI 0.25 to 2.80). There was no statistically significant benefit of probiotics for reducing the risk of relapse compared to maintenance therapy employing aminosalicylates or azathioprine (RR 0.67, 95% CI 0.13 to 3.30), and in this study the probiotic Lactobacillus GG was associated with adverse events. In children, there was there was no statistically significant difference between Lactobacillus GG and placebo for reducing the risk of relapse (RR 1.85, 95% CI 0.77 to 4.40). A small study using the yeast Saccharomyces boulardii demonstrated a difference that was not statistically significant in favour of probiotic combined with a reduced level of maintenance therapy over standard maintenance treatment alone (RR 0.17, 95% CI 0.02 to 1.23). AUTHORS' CONCLUSIONS: There is no evidence to suggest that probiotics are beneficial for the maintenance of remission in CD. All of the included studies enrolled small numbers of patients and may have lacked statistical power to show differences should they exist. Larger trials are required to determine if probiotics are of benefit in Crohn's disease.

Prevalence and incidence of gastroduodenal ulcers during treatment with vascular protective doses of aspirin.

BACKGROUND: Aspirin is valuable for preventing vascular events, but information about ulcer frequency is necessary to inform risk-benefit decisions in individual patients. AIM: To determine ulcer prevalence and incidence in a population representative of those given aspirin therapy and evaluate risk predictors. METHODS: Patients taking aspirin 75-325 mg daily were recruited from four countries. Exclusions included use of gastroprotectant drugs or other non-steroidal anti-inflammatory drugs. We measured point prevalence of endoscopic ulcers, after quantitating dyspeptic symptoms. Incidence was assessed 3 months later in those eligible to continue (no baseline ulcer or reason for gastroprotectants). RESULTS: In 187 patients, ulcer prevalence was 11% [95% confidence interval (CI) 6.3-15.1%]. Only 20% had dyspeptic symptoms, not significantly different from patients without ulcer. Ulcer incidence in 113 patients followed for 3 months was 7% (95% CI 2.4-11.8%). Helicobacter pylori infection increased the risk of a duodenal ulcer [odds ratio (OR) 18.5, 95% CI 2.3-149.4], as did age >70 for ulcers in stomach and duodenum combined (OR 3.3, 95% CI 1.3-8.7). CONCLUSIONS: Gastroduodenal ulcers are found in one in 10 patients taking low-dose aspirin, and most are asymptomatic; this needs considering when discussing risks/benefits with patients. Risk factors include older age and H. pylori (for duodenal ulcer).

Does concurrent prescription of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs substantially increase the risk of upper gastrointestinal bleeding?

BACKGROUND: A 15-fold increased risk of gastrointestinal bleeding has been reported with concurrent use of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs. Recent guidance cautions against concurrent prescription, particularly in older people. AIM: To quantify the risk of gastrointestinal bleeding associated with current exposure to non-steroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, and both drugs concurrently. METHODS: We conducted a case-control analysis of 11,261 cases with upper gastrointestinal bleeding and 53,156 controls matched by gender, age and general practice from computerized primary care data. We coupled this with self-controlled case series analysis. RESULTS: Both drugs were associated with a twofold increased risk of gastrointestinal bleeding (odds ratio =2.38, 95% confidence interval 2.08-2.72 for selective serotonin reuptake inhibitors and odds ratio = 2.15, 95% confidence interval 2.02-2.28 for non-steroidal anti-inflammatory drugs). This increased risk was marginally higher for concurrent prescription (odds ratio = 2.93, 95% confidence interval 2.25-3.82). The self-controlled analysis showed a greater incidence rate ratio for gastrointestinal bleeding with non-steroidal anti-inflammatory drugs (2.71, 95% confidence interval 2.51-2.91) and lower incidence rate ratio with selective serotonin reuptake inhibitors (1.71, 95% confidence interval 1.48-1.98). The incidence rate ratio when both drugs were combined was 3.25, 95% confidence interval 1.95-5.42. Estimates were similar after restricting to people over 80 years of age. Increased risk of gastrointestinal bleeding was not specifically related to class of non-steroidal anti-inflammatory drugs and was similar when we looked at tricyclic anti-depressants. CONCLUSIONS: Our study suggests that the risk of gastrointestinal bleeding is not substantially increased when non-steroidal anti-inflammatory drugs and selective serotonin reuptake inhibitors are prescribed together, compared with their use alone.

Dual COX inhibition and upper gastrointestinal damage.

Aspirin and non-aspirin NSAIDs injure the gastrointestinal tract principally as a result of their inhibition of prostaglandin synthesis. This is mediated via abrogation of the secretion of mucus and bicarbonate and by reduction in mucosal blood flow. Topical injury and inhibition of platelet thromboxane may also contribute respectively to damage and ulcer bleeding. Recognition of a second cyclooxygenase, COX-2, enabled drugs to be developed that selectively target this enzyme which is expressed in inflamed joints. These have proved to be effective treatments whilst causing little or no acute gastroduodenal injury and reduced ulcers and their complications. Future strategies may capitalise upon the phenomenon of substrate diversion of lipoxygenase products. Balanced cyclooxygenase/lipoxygenase inhibition maybe less harmful than cyclooxygenase inhibition. Also, nitric oxide can subserve many of the protective effects of prostaglandins and NO-donating NSAIDs are under evaluation.

Gastrointestinal safety of selective COX-2 inhibitors.

It appears that selective Cox-2 inhibitors do not affect the gastro duodenal mucosa whilst having anti-inflammatory and analgesic efficacy similar to non-selective NSAIDs. Two broad categories of drugs are Cox-2 selective: coxibs and a number of pre-existing NSAIDs retrospectively found to have selectivity. Cox-2 inhibitors cause less dyspepsia than NSAIDs. They spare gastrointestinal mucosal generation of prostaglandins (PGs) and PG-dependent bicarbonate secretion. Coxibs cause no acute mucosal injury in endoscopic ulcers compared to NSAID comparators. In the VIGOR study all upper GI events were reduced from 4.5 per 100 patient years to 2.1 per 100 patient years with supra-therapeutic doses of rofecoxib compared with naproxen. In the CLASS study, over a period of 3 days to 6 months, incidence of ulcer complications was 0.76% with celecoxib and 1.45% for ibuprofen or diclofenac. The less substantial reduction in events in the CLASS study compared with the VIGOR may be due, at least in part, to the fact that 21% of the patients were also on low dose aspirin. However it is premature to say that the benefit of Cox-2 inhibitors is lost in patients taking aspirin. There is continuing debate on the role of Cox-2 inhibitors in patients who have other risk factors for complicated ulcer disease e.g. patients who are elderly, on aspirin or corticosteroids, have a previous ulcer or have H. pylori infection.

A novel flow cytometric assay for quantitating adherence of Helicobacter pylori to gastric epithelial cells.

Adherence may be an important virulence factor for Helicobacter pylori. Current methods available for quantitation of adherence are time consuming and liable to observer error. A new direct technique for fluorescent labelling of bacteria has been developed to quantitate adherence of H. pylori to epithelial cells by fluorescence activated cell sorting (FACS). Type strains of H. pylori, H. mustelae, H. cinaedi and H. fennelliae were grown microaerobically in broth culture for 24 h and fluorescently labelled by incubation with carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) at 37 degrees C. After washing to remove excess CFDA-SE, bacteria were co-incubated (ratio 10:1) with gastric epithelial cells at 37 degrees C for up to 24 h. After washing to remove non-adherent bacteria, epithelial cells were detached with EDTA (2 mM) and fixed with formaldehyde for flow cytometry. Adherence was quantitated both in terms of the proportion of cells with adherent H. pylori and as the mean number of adherent bacteria per cell. All H. pylori strains adhered to gastric-type epithelial cells. The proportion of cells with bound bacteria varied from 40-99% and the number of bacteria per cell from 1-50, both of which correlated with microscopy (r = 0.6, and r = 0.8 respectively, n = 35). Time course studies demonstrated saturation of binding by H. pylori within 90 min. For H. mustelae, H. cinaedi and H. fennelliae the proportion of cells with bound bacteria varied from 5-15% and the mean number of bacteria per cell was < 4. Binding of H. pylori to epithelial cells could be partly blocked by pre-incubation with polyclonal anti-sera or using oligosaccharides against potential binding epitopes of gastric mucus. Fluorescent labelling of H. pylori with CFDA-SE in combination with flow cytometry provides a quick, specific, and sensitive method to quantitate in vitro the adherence of H. pylori.

Progress in prophylaxis against nonsteroidal anti-inflammatory drug-associated ulcers and erosions. Omeprazole NSAID Steering Committee.

Four large clinical studies have shown that omeprazole, 20 mg once daily, is effective in preventing the significant gastroduodenal consequences of nonsteroidal anti-inflammatory drugs (NSAIDs). In the Scandinavian Collaborative Ulcer Recurrence (SCUR) study, patients were randomized (without initial endoscopy) to receive omeprazole or placebo for up to 3 months. Of the patients treated with omeprazole, 24.7% experienced treatment failure, compared with 50.0% of those on placebo. Fewer patients in the omeprazole group than in the placebo group developed a peptic ulcer (4.7% versus 16.7%, respectively) or dyspeptic symptoms (8.2% versus 20.0%, respectively). In the Omeprazole versus Placebo as Prophylaxis of Ulcers and Erosions from NSAID Treatment (OPPULENT) study, patients were also randomized to receive omeprazole or placebo. The estimated probability of remaining in remission for 6 months while receiving omeprazole was 0.78, compared with 0.53 for placebo. Fourteen (16.5%) patients on placebo developed peptic ulcer(s), compared with three (3.6%) patients on omeprazole. The Omeprazole versus Misoprostol for NSAID-Induced Ulcer Management (OMNIUM) study consisted of a healing and a prophylactic phase. Patients who successfully completed the healing phase were re-randomized to receive omeprazole, misoprostol, or placebo for up to 6 months. In patients receiving omeprazole, 36.5% experienced treatment failure, compared with 48.6% of those on misoprostol, and 67.7% of those on placebo. Omeprazole and misoprostol appeared to be equally effective in preventing gastric ulcer; by contrast, omeprazole was highly effective in preventing duodenal ulcer, when compared with misoprostol and placebo. The Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-Associated Ulcer Treatment (ASTRONAUT) study also consisted of a healing and a prophylactic phase. Patients who successfully completed the healing phase were re-randomized to receive omeprazole or ranitidine for up to 6 months. In patients receiving omeprazole, 26.2% experienced treatment failure, compared with 37.7% of those on ranitidine. The percentages of patients with a peptic ulcer relapse were 5.7% for omeprazole and 19.5% for ranitidine. The data show that omeprazole is an effective and well-tolerated agent for both primary and secondary (maintenance) prophylaxis in patients receiving NSAIDs.

Practical management: a keypad-based interactive session.

If controlled therapeutic, epidemiologic, and pathologic data are to be put rationally into clinical practice, they need to be evaluated against real clinical scenarios. This was done by presenting the symposium delegates with a clinical case and then asking management questions, which were answered using a keypad system.

Irritable bowel syndrome clinical trial design: future needs.

This article addresses a series of points that should be considered in the design of future clinical trials in irritable bowel syndrome (IBS). A precise, uncontroversial definition of the disorder and the affected patient is required that accurately describes the condition that practitioners recognize intuitively exists. Regarding patient source and selection, the principle should be applied that patients be recruited to trials from all sources to which an indication is intended. Because abdominal pain is the most central symptom of IBS, it should be used as the primary trial endpoint. Because there are currently no effective treatments, placebo-controlled trials pose no ethical problems. High placebo responses may equally well be the temporary spontaneous improvements that are characteristic of the condition. Clinical trials should be designed to meet specific aims of treatments: when taken as single doses to terminate an attack of pain; when taken over a brief period of time to speed resolution of a period of exacerbation of IBS; when taken after termination of a period of activity to prevent relapse; when taken regularly on a long-term basis to reduce the days on which a number of symptoms are experienced; when taken in form of discrete courses of treatment designed to achieve a pivotal change in the natural history of the condition.