The Adenoma Prevention with Celecoxib Trial examined the efficacy and safety of the cyclooxygenase (Cox)-2 inhibitor, celecoxib, for sporadic colorectal adenoma prevention in patients at high risk for colorectal cancer. The trial randomized 2,035 subjects to receive either placebo, celecoxib 200 mg twice daily, or celecoxib 400 mg twice daily. The primary study safety and efficacy analyses involved 3 years of treatment. The results showed significant antitumor effect but also indicated increased cardiovascular adverse events in patients treated with celecoxib compared with placebo. A total of 933 patients participated in an extension of the Adenoma Prevention with Celecoxib Trial, with a planned total treatment and surveillance duration of 5 years. Study medication was stopped early, resulting in a median treatment duration of 3.1 years for those with a year 5 colonoscopy. Patients treated on the placebo arm had a cumulative adenoma incidence of 68.4% over 5 years of observation. This figure was 59.0% (P < 0.0001) for those receiving low-dose celecoxib, and 60.1% (P < 0.0001) for those receiving high-dose celecoxib. The cumulative incidence of advanced adenomas over 5 years was 21.3% of those taking placebo, 12.5% (P < 0.0001) of those taking low dose celecoxib and 15.8% (P < 0.0001) of those taking high-dose celecoxib. Investigator reported treatment emergent adverse events were similar across all treatment groups for categories including renal and hypertensive events and gastrointestinal ulceration and hemorrhage events. For a category composed of cardiovascular and thrombotic events, the risk relative to placebo was 1.6 (95% confidence interval, 1.0, 2.5) for those using 200 mg twice daily celecoxib and 1.9 (95% confidence interval, 1.2, 3.1) for those using 400 mg twice daily celecoxib. Secondary analysis showed an interaction between a baseline history of atherosclerotic heart disease and study drug use with respect to cardiovascular and thrombotic adverse events (P = 0.004). These results confirm the inhibitory effect of celecoxib on colorectal adenoma formation, and provide additional safety data indicating an elevated risk for cardiovascular and thrombotic adverse events, particularly for patients with preexisting atherosclerotic heart disease.

BACKGROUND:Low bone density and fractures are common in patients with inflammatory bowel disease (IBD). OBJECTIVE:To determine whether the bisphosphonate risedronate and calcium are safe and effective in preserving bone mass compared to calcium alone in IBD patients with low bone mass. PATIENTS:Sixty-one ambulatory patients with Crohn's disease (n = 31) or ulcerative colitis (n = 30) and low bone density. METHODS:Using a double-blind placebo-controlled trial format, patients were randomized to 12 months of therapy with risedronate 5 mg or placebo. All received a 600 mg calcium supplement. Bone density using dual energy X-ray absorptiometry was performed at baseline and at 12 months. Disease activity, use of corticosteroid, and adverse events were noted. RESULTS:Forty-eight patients completed the trial. Compared to the placebo group risedronate resulted in a 2.0% (95%CI, 0.02-3.97) and 1.9% (95%CI, 0.21-3.62) improvement in bone density at the spine and hip, respectively. IBD diagnosis, gender, therapy, and disease status had no effect on the results. There were no significant differences in the adverse events. CONCLUSIONS:Risedronate improved bone density at the spine and hip in patients with either Crohn's disease or ulcerative colitis and low bone mass. These data suggest that risedronate is a safe and effective therapy to improve bone mass in these patients.

BACKGROUNDStudies showing that drugs that inhibit cyclooxygenase-2 (COX-2) reduce the number of colorectal adenomas in animals and patients with familial adenomatous polyposis suggest that COX-2 inhibitors may also prevent sporadic colorectal neoplasia.METHODSWe randomly assigned patients who had adenomas removed before study entry to receive placebo (679 patients) or 200 mg (685 patients) or 400 mg (671 patients) of celecoxib twice daily. Randomization was stratified for the use of low-dose aspirin. Follow-up colonoscopies were performed at one and three years after randomization. The occurrence of newly detected colorectal adenomas was compared among the groups with the life-table extension of the Mantel-Haenszel test.RESULTSFollow-up colonoscopies were completed at year 1 in 89.5 percent of randomized patients, and at year 3 in 75.7 percent. The estimated cumulative incidence of the detection of one or more adenomas by year 3 was 60.7 percent for patients receiving placebo, as compared with 43.2 percent for those receiving 200 mg of celecoxib twice a day (risk ratio, 0.67; 95 percent confidence interval, 0.59 to 0.77; P<0.001) and 37.5 percent for those receiving 400 mg of celecoxib twice a day (risk ratio, 0.55; 95 percent confidence interval, 0.48 to 0.64; P<0.001). Serious adverse events occurred in 18.8 percent of patients in the placebo group, as compared with 20.4 percent of those in the low-dose celecoxib group (risk ratio, 1.1; 95 percent confidence interval, 0.9 to 1.3; P=0.5) and 23.0 percent of those in the high-dose group (risk ratio, 1.2; 95 percent confidence interval, 1.0 to 1.5; P=0.06). As compared with placebo, celecoxib was associated with an increased risk of cardiovascular events (risk ratio for the low dose, 2.6; 95 percent confidence interval, 1.1 to 6.1; and risk ratio for the high dose, 3.4; 95 percent confidence interval, 1.5 to 7.9).CONCLUSIONSThese findings indicate that celecoxib is an effective agent for the prevention of colorectal adenomas but, because of potential cardiovascular events, cannot be routinely recommended for this indication. (ClinicalTrials.gov number, NCT00005094 [ClinicalTrials.gov].).

Propose: Rasuhs of prevmus endo~opic nijection techniques tbr the treatment of gastroesophageal reflux disease (GERD) were short-lived because of sloughing ur resorption of the imphnts.Ethylene-vinyl-alcohol (EVOH), a pol}aner which is mixed with radiopaque tantalum powder in an organic sofvem, precipitates once injected in vivo.In a pilot study between 1999 and 2000, endoscopic implantatiun of EVOH polymer in the lower esuphageal sphincter (LES) was performed in our center m 10 patients with GERD requiring daily PPIs to alleviate their symptoms.Methuds: Extension of follow-up during the 3rd year after the treatment was obtained to gather long term safety and efficacy data Questimrnaires including SF-36 and GERD-HRQL, concomitant medications and adverse events were recorded.A spiral CTscan with volumetric calculation of the amount of implant remaining was performed.Results: After 3 years of follow-up, one patient had died from unrelated cause and one patient was lost to follow-up.The remaining eight patients accepted to undergo extended follow-up.One patient without sympto~r.aticimprovement after EVOH polymer injection had a Nissen fundoplicatton Five patients out of eight had stopped or reduced their antisecretory medicanon to less than once a week.(Table ).Six ont of the eight patients reported improvement in their symptoms when compared to before the endoseop*c treatment.Spiral CT-scan revealed a significant volume of implant remaining, except fur two patient on daffy or un demand H2 blockers Implants were well-delineated in a circular or semi-circular ~:ashion in most of the patients.Conclusion: Three years after endoscopic EVOH polymer injection in the LES, most of (he patients show a sustained improvement in their GERD symptoms, and the persistence of the implant at the gastroemphageal junction,

BACKGROUND: Routine mucosal biopsy in patients undergoing colonoscopy for diarrhoea, in whom macroscopic examination is normal, remains controversial and practice varies widely without clear guidelines. Reported rates of clinically significant microscopic abnormalities vary from 2-27%.It is unclear if ileal biopsy adds anything to colonic biopsy alone. OBJECTIVES: We sought to evaluate the diagnostic yield of colonic and ileal mucosal biopsy in patients undergoing colonoscopy for diarrhoea in whom the macroscopic examination was normal. METHODS: We retrospectively reviewed all colonoscopies performed over a nine year period in a tertiary referral centre with an open access endoscopy service. Cases were selected where the sole indication for colonoscopy was diarrhoea, the musosa was macroscopically normal (other than diverticulosis) and biopsies were performed. Cases were excluded if the examination was inadequate. The histopathology reports of the selected cases were then reviewed. RESULTS: 362 cases were identified. Colonoscopy and biopsy was normal in 260 patients.Ileal biopsies were performed (in addition to colonic biopsies) in 158 cases, none of which revealed clinically significant abnormalities. Clinically significant histological findings were present in 18 cases (5%). Findings included collagenous colitis (5 cases), lymphocytic colitis (1 case), possible lymphocytic colitis (1 case), possible collagenous colitis (1 case), inflammatory bowel disease (2 cases), melanosis coli (2 cases) and significant eosinophil mucosal infiltration (6 cases). 28 patients (8%) had minor histological abnormalities with no specific diagnostic features. The diagnostic yield was highest in patients above 60 years old, where 10% had clinically significant histological abnormalities. All patients with collagenous colitis were female and only 1 was less than 60 years old. CONCLUSIONS: When colonoscopy is normal in patients with diarrhoea, routine colonic biopsy identifies significant pathology in 5% of cases. The diagnostic yield is highest in patients over 60 years old. Routine ileal biopsy is unhelpful.

determine the J3-catenin and full length APC protein expression in JPs.Methods-Records of all colonic endoscopic procedures performed at The Children's Hospital, 1/97 and 9/99 were reviewed.A diagnosis of JPC was made if 10 or more JPs were identified or at least I JP was found in a first-degree relative of a patient with JPC.J3-catenin immunohistochemistry was performed using a mouse anti-J3-catenin monoclonal antibody and full-length APC protein was localized using a rabbit polyclonal anti-APC antibody that was raised against a peptide corresponding to C-tenninal 20 amino acids of the human APe protein (Santa Cruz Biotechnology).Results-Forty samples of normal colon and 38 JPs were analysed from 36 children with JPs.Of the children, 28 had isolated JPs, 6 had JPe and in 2 cases the distinction between JPC and isolated JPs could not be made.In all 40 samples of normal mucosa, both APC and J3-catenin immunoreactivity was present in the epithelial cells of the JP.APC expression was cytoplasmic with maximal immunoreactivity in the goblet cells.J3-catenin expression was predominantly localized to the plasma membrane with no nuclear immunoreactivity.Normal APC immunoreactivity was also present in the epithelial cells of all of the 38 JPs examined but, surprisingly, the epithelial cells of all 38 of the JPs had nuclear accumulation of J3-catenin.In 35 of the JPs, 80-100% of the epithelial cells contained nuclear J3-catenin,in the other 3 JPs 30-50% of the cells contained nuclear J3-catenin.Conclusion-Nuclear accumulation of J3-cateninappears to occur universally in JPs regardless of whether they are from patients with isolated JP or JPC and it thus may be essential to the biology of JP formation, The nuclear J3-cateninaccumulation in JPs is due to a mechanism other than the loss of APe protein function.