Robert J. Bailey

A randomized, placebo-controlled, double-blind trial of mesalamine in the maintenance of remission of Crohn's disease. The Canadian Mesalamine for Remission of Crohn's Disease Study Group

BACKGROUND & AIMS The efficacy of mesalamine for the maintenance of remission in patients with Crohns disease is controversial. The aim of this study was to conduct a double-blind, placebo-controlled study of mesalamine (750 mg four times a day for 48 weeks) in maintaining remission in 293 patients with Crohns disease. Patients were stratified according to the method of induction of remission (medical or surgical). METHODS Patients were assessed at weeks 4, 12, 24, 36, and 48. Relapse was defined as a Crohns Disease Activity Index of >150 (+60 points over baseline). RESULTS Of the 293 patients, 246 (84%) returned for at least 4 weeks of follow-up and were included in the final analysis. Thirty of the 118 (25%) who received mesalamine had a relapse compared with 47 of 128 (36%) receiving placebo (P = 0.056). Among those with relapse, the time to relapse was 119 days for the mesalamine-treated patients compared with 109 days for placebo-treated patients (P = NS). However, 25% of mesalamine-treated patients had relapsed by 249 days of follow-up compared with 154 days for placebo-treated patients. Subgroup analysis showed that patients with ileocecal-colonic disease or patients who were women had fewer relapses on mesalamine therapy than placebo-treated patients (21% vs. 41%, P = 0.018; and 19% vs. 41%, P = 0.003, respectively). CONCLUSIONS Mesalamine treatment reduced relapse compared with placebo treatment, although conventional statistical significance was not achieved.

Thiopurine Methyltransferase Enzyme Activity Determination before Treatment of Inflammatory Bowel Disease with Azathioprine: Effect on Cost and Adverse Events

BACKGROUND Azathioprine (AZA), used to treat inflammatory bowel disease (IBD), is metabolized by thiopurine methyltransferase (TPMT). The accumulation of individual metabolites varies because humans display genetic polymorphism for TPMT expression. Deficiencies in TPMT result in accumulation of toxic metabolites, followed by neutropenia and hepatic inflammation. Concern over acute toxicity frequently leads to under dosing and frequent monitoring tests and visits. OBJECTIVE To determine whether assessment of TPMT activity before the administration of AZA would predict acute toxicity and, thus, allow for reductions in health care costs related to biochemical screening for, and management of, AZA-induced adverse events. METHODS Before AZA treatment, 29 patients with IBD were prospectively randomized to one of two groups: group 1, in which no TPMT assay was performed, was started on AZA at 1 mg/kg/day and then titrated every two weeks to a target dose of 2.5 mg/kg/day; and group 2, in which TPMT assays were performed, was started on AZA at the target dose of 2.5 mg/kg/day. For both groups, complete blood count and liver enzymes were monitored weekly for six weeks and at monthly intervals thereafter. Additional tests and health care interventions were undertaken at the discretion of the attending physicians. RESULTS Of the 29 patients in the study, 15 were randomly assigned to group 1 and 14 to group 2. Demographics and disease activity were similar for both groups. Mean follow-up time was 7.1 months (range 3.5 to 10.7 months). Eight patients from group 1 and six patients from group 2 withdrew as a result of AZA-induced adverse events. There was no correlation between the TPMT activity and the development of AZA-induced adverse events. The direct health care costs for group 1 (300.11 dollars per patient) were lower than in group 2 (348.87 dollars per patient). CONCLUSION The prospective assessment of TPMT enzyme activity before initiating AZA therapy in IBD patients incurred additional cost and did not predict AZA-induced toxicity.

Safety and Antiviral Activity of Albinterferon Alfa-2b Dosed Every Four Weeks in Genotype 2/3 Chronic Hepatitis C Patients

BACKGROUND & AIMS A phase 2, randomized, multicenter, open-label study evaluated the safety and efficacy of albinterferon alfa-2b in interferon-alpha treatment-naïve patients with genotype 2/3, chronic hepatitis C virus infection. METHODS Forty-three patients were randomly assigned in a 1:1 ratio to receive subcutaneous albinterferon alfa-2b 1500 microg every 4 weeks (q4wk) or every 2 weeks (q2wk) with oral ribavirin 800 mg/day for 24 weeks. Primary efficacy end point was sustained virologic response (undetectable hepatitis C virus RNA 24 weeks after completion of treatment). Insulin resistance was also assessed. RESULTS The safety of albinterferon alfa-2b was acceptable, with a similar adverse event profile in both treatment arms. Discontinuation as a result of adverse events occurred in 4.5% and 14.3% of patients in the q4wk and q2wk arms, respectively. No dose reductions caused by adverse events were reported in the q4wk arm versus 9.5% in the q2wk arm. Rapid viral response rates at week 4 were 68.2% and 76.2% for the q4wk and q2wk arms, respectively; the corresponding sustained virologic response rates were 77.3% and 61.9%. Insulin resistance at baseline was significantly associated with lower sustained virologic response rates independent of body mass index. CONCLUSIONS Albinterferon alfa-2b administered at 4-week intervals was safe and well-tolerated and demonstrated significant antiviral activity in patients with genotype 2/3, chronic hepatitis C virus. Insulin resistance appeared to have an independent effect on treatment response.

Nonalcoholic Fatty Liver Disease in Patients Investigated for Elevated Liver Enzymes

Nonalcoholic fatty liver disease (NAFLD) is a common diagnosis among patients referred to gastroenterology and hepatology clinics for the evaluation of elevated liver enzymes. The diagnosis of NAFLD is supported by blood work to exclude other liver diseases, and by ultrasound evidence of fat in the liver in patients without a significant history of alcohol intake. The gold standard, however, is a liver biopsy to show the typical histological features of NAFLD, which are almost identical to those of alcohol-induced liver damage and can range from mild steatosis to cirrhosis. A variety of retrospective series have linked NAFLD to obesity, diabetes, hyperlipidemia, total parenteral nutrition, jejunoileal bypass surgery and certain medications. A subset of patients with NAFLD that had an initial presentation of elevated liver enzymes was studied. Two hundred and two patients were reviewed, of whom 49 met the inclusion criteria including a liver biopsy. Patients were excluded if insufficient data were available, if the patients had a significant history of ethanol intake or if they had other coexisting liver disease. These patients were seen between 1996 and 2000 in gastroenterology and hepatology clinics in two community hospitals and one regional liver transplant centre in Edmonton, Alberta. NAFLD was associated with a spectrum of changes in the liver ranging from mild steatosis to more significant steatosis with inflammation and fibrosis. Cases of NAFLD with steatosis and mixed inflammatory infiltration but lacking ballooning degeneration or fibrosis were prevalent in young (20 to 40 years of age) patients with no other significant medical history except for obesity. NAFLD with biopsies showing significant fibrosis and ballooning cell degeneration was associated with obesity, diabetes and older age. It was concluded that, in this predominantly outpatient setting, age over 40 years and diabetes at any age are risk factors for both nonalcoholic steatohepatitis and nonalcoholic steatohepatitis with cirrhosis. It is therefore recommended that patients with raised liver enzymes and suspected NAFLD be targeted for liver biopsy in their evaluation.

Crohn's disease genotypes of patients in remission vs relapses after infliximab discontinuation.

AIM To investigate genetic differences between Crohns disease (CD) patients with a sustained remission vs relapsers after discontinuing infliximab while in corticosteroid-free remission. METHODS Forty-eight CD patients received infliximab and were in full corticosteroid-free clinical remission but then discontinued infliximab for reasons other than a loss of response, were identified by review of an electronic database and charts. Infliximab-associated remission was defined as corticosteroid-free plus normalization of clinical disease activity [CD activity index (CDAI) < 150] during follow-up visits based on physician global assessments. A CD relapse (loss of infliximab-induced remission) was clinically defined as a physician visit for symptoms of disease activity (CDAI > 220) and a therapeutic intervention with CD medication(s), or a hospitalization with complications related to active CD. Genetic analyses were performed on samples from 14 patients (n = 6 who had a sustained long term remission after stopping infliximab, n = 8 who rapidly relapsed after stopping infliximab). Nucleotide-binding oligomerization domain 2 (NOD2)/caspase activation recruitment domain 15 (CARD15) polymorphisms (R702W, G908R and L1007fs) and the inflammatory bowel disease 5 (IBD5) polymorphisms (IGR2060a1 and IGR3081a1) were analyzed in each group. RESULTS Five single nucleotide polymorphisms of IBD5 and NOD2/CARD15 genes were successfully analyzed for all 14 subjects. There was no significant increase in frequency of the NOD2/CARD15 polymorphisms (R702W, G908R and L1007fs) and the IBD5 polymorphisms (IGR2060a1 and IGR3081a1) in either group of patients; those whose disease relapsed rapidly or those who remained in sustained long term remission following the discontinuation of infliximab. Nearly a third of patients in full clinical remission who stopped infliximab for reasons other than loss of response remained in sustained clinical remission, while two-thirds relapsed rapidly. There was a marked difference in the duration of clinical remission following discontinuance of infliximab between the two groups. The patients who lost remission did so after 1.0 years ± 0.6 years, while those still in remission were at the time of this study, 8.1 years ± 2.6 years post-discontinuation of infliximab, P < 0.001. The 8 patients who had lost remission after discontinuing infliximab had a mean number of 5 infusions (range 3-7), with a mean treatment time of 7.2 mo (range 1.5 mo-15 mo). The mean duration of time from the last infusion of infliximab to the time of loss of remission was 382 d (range 20 d-701 d). The 6 patients who remained in remission after discontinuing infliximab had a mean number of 6 infusions (range 3-12), with a mean treatment duration of 12 mo (range 3.6 mo-32 mo) (P = 0.45 relative to those who lost remission). CONCLUSION There are no IBD5 or NOD2/CARD15 mutations that predict which patients might have sustained remission and which will relapse rapidly after stopping infliximab.

Retreatment with Pegylated Interferon Alpha-2a and Ribavirin in Patients with Chronic Hepatitis C Who Have Relapsed or Not Responded to a First Course of Pegylated Interferon-Based Therapy

BACKGROUND Pegylated interferon (pegIFN) and ribavirin combination therapy remains the first-line treatment for chronic hepatitis C virus (HCV) infection. In contrast to the wealth of studies in treatment-naive patients, the effectiveness of retreatment in patients who have previously failed pegIFN-based therapy is largely unreported. AIM To assess the effectiveness of the retreatment of patients who have previously failed an initial course of pegIFN-based therapy with pegIFNalpha-2a and ribavirin. METHODS A post-hoc analysis of a multicentre open-label study was performed. Patients received pegIFNalpha-2a and ribavirin at a dose of 800 mg/day and later 1000 mg/day to 1200 mg/day for 24 to 48 weeks at the discretion of the investigator. Outcomes at week 12 (early virological response [EVR]) and week 24 (sustained virological response [SVR]) were analyzed. RESULTS Eighty-seven patients who had relapsed after previous pegIFN-based therapy (n=28; 78% genotype 1) or were nonresponders (n=59; 71% genotype 1) were analyzed. Of the relapsers, 86% achieved an EVR and 68% achieved an SVR. In relapsers to pegIFN monotherapy (n=15) or pegIFN plus ribavirin (n=13), 60% and 77% achieved an SVR, respectively. Fibrosis and genotype did not affect the likelihood of SVR in relapsers although this may be the result of the relatively small number of patients. In previous nonresponders, an EVR was achieved in 53% but an SVR occurred in only 17%. In nonresponders to pegIFN monotherapy (n=9) and pegIFN plus ribavirin (n=50), 33% and 14% achieved an SVR, respectively. Genotype did not affect SVR in nonresponders. Only 10% with a METAVIR score of F3 or F4 on liver biopsy achieved an SVR. CONCLUSIONS Relapse after previous pegIFN-based therapy is associated with a strong probability of treatment success whereas retreatment of those with previous nonresponse does not.

A Randomized Trial of Topical Anesthesia Comparing Lidocaine Versus Lidocaine Plus Xylometazoline for Unsedated Transnasal Upper Gastrointestinal Endoscopy

BACKGROUND The optimal topical anesthesia regimen for unsedated transnasal endoscopy is unknown. The addition of a nasal decongestant, such as xylometazoline (X), to a topical anesthestic may improve patient comfort. OBJECTIVE To determine the effectiveness of lidocaine (L) versus L plus X (LX) for anesthesia in unsedated transnasal endoscopy. METHODS Consecutive participants of the Aklavik Helicobacter pylori project were prospectively randomly assigned to receive LX or L for unsedated transnasal 4.9 mm ultrathin endoscopy. The primary outcome was overall procedure discomfort on a validated 10-point visual analogue scale (1 = no discomfort, 10 = severe discomfort). Secondary outcomes included pain, endoscope insertion difficulty, gagging, adverse events and encounter times. Results were presented as mean +/- SD, difference in mean, 95% CI. RESULTS A total of 181 patients were randomly assigned to receive LX (n=94) and L (n=87). Baseline characteristics between the two groups were similar (mean age 40 years, 59% women). Overall, patient procedural discomfort with LX and L were 4.2+/-2.4 versus 3.9+/-2.1, respectively (0.29; 95% CI -0.39 to 0.96). Transnasal insertion difficulty was significantly lower with LX than with L (2.4+/-2.1 versus 3.2+/-2.8, respectively [-0.80; 95% CI -1.54 to -0.06]). Compared with L, the use of LX was associated with significantly less time needed to apply anesthesia (2.4+/-1.8 min versus 3.5+/-2.2 min, respectively [-1.10; 95% CI -1.71 min to -0.50 min]) and less time for insertion (3.2+/-1.8 min versus 3.9+/-2.2 min, respectively [-0.70 min; 95% CI -1.30 min to -0.10 min]). Epistaxis was rare but occurred less frequently with LX (1.1%) than with L (4.6%) (P=0.19). CONCLUSIONS LX did not improve patient comfort for transnasal endoscopy compared with L alone. However, LX was associated with less difficulty with endoscope transnasal insertion and reduced insertion time. Further studies on the optimal regimen and dosing of anesthesia are required.

Early experience with unsedated ultrathin 4.9 mm transnasal gastroscopy: A pilot study

BACKGROUND Unsedated transnasal gastroscopy is a technique with unverified clinical advantages. OBJECTIVE To evaluate the efficacy and procedure times with transnasal gastroscopy by physicians with no previous experience in transnasal endoscopy. METHODS Unsedated transnasal gastroscopy using 4.9 mm ultrathin transnasal gastroscopes with randomization to two different biopsy forceps was prospectively evaluated during a single day in January 2008. The outcomes included patient tolerance (scale: 1, no discomfort; 10, severe discomfort), physician technical assessment (1, excellent; 10, very poor), gastric biopsy quality, adverse events and procedure times. RESULTS Twenty patients underwent transnasal gastroscopy. Nineteen patients (95%) successfully completed transnasal gastroscopy. The patient-reported mean (+/- SD) overall discomfort level during the procedure was 4.0+/-1.9 compared with a physician-estimated level of 3.2+/-1.7 (P=0.04). Only 10% (n=2) reported they would have preferred sedated over unsedated gastroscopy. Mean total encounter time from anesthesia to discharge was 33.5+/-9.3 min. The time from anesthesia to insertion was 7.0+/-5.3 min and from room exit to discharge 6.2+/-2.9 min. No patients who had gastric biopsies taken (zero of 14) had any of unacceptable quality. The only adverse event was distressing sensations (dyspnea, dizziness) in one patient that started during pre-endoscopy anesthetic application, persisting postendoscopy, but without any abnormalities in vital signs. CONCLUSION Assuming the adverse event was a rare reaction, early experience with unsedated ultrathin transnasal gastroscopy was an efficient, effective and well-tolerated procedure for evaluation of the upper gastrointestinal tract.

Survival in Cystic Neoplasms of the Pancreas

BACKGROUND The natural history of pancreatic cystic neoplasms remains poorly understood despite growing evidence on the subject. Pancreatic cysts display a wide spectrum of pathological phenotypes, each associated with a different prognostic implication. Many pancreatic cysts are of undetermined malignant potential at presentation and remain so until surgically resected. While the survival rates of patients with malignant cysts are known to be poor, survival rates in patients with undetermined pancreatic cysts are unknown. OBJECTIVE To identify the factors associated with survival in a group of patients diagnosed with a pancreatic cyst(s). METHODS The present study was a retrospective multicentre review of pancreatic cystic neoplasms. All patients with a diagnosis of a neoplastic pancreatic cyst from 1994 to 2003 were identified at five different institutions in Edmonton, Alberta. The data collected included patient age, sex, imaging modality, cyst location, cyst size, number of cysts, comorbid illnesses, history of upper abdominal surgery, previous cancer, previous or concurrent metastases, symptoms (pain, upper gastrointestinal bleeding, signs of biliary obstruction, nausea/vomiting), remarkable radiological features, elevated amylase or lipase, type of pancreatic surgery, final pathology (benign or malignant) and overall survival. Survival models were used to assess whether any covariates were predictors of the survival time. Patient data were plotted using the Kaplan-Meier method. The resulting plot was used to calculate survival in the cohort. RESULTS In total, 64 patients were identified as having neoplastic pancreatic cysts from 1994 to 2003 at the five institutions. The median overall patient survival time was 86 months. The median age at diagnosis for the patient population was 73 years, with 40 patients being women. Univariate analysis revealed that the risk of death was associated with patient age, sex and history of major comorbid illness. Multivariate models identified increased patient age and male sex as the factors that correlated most strongly with decreased overall survival. CONCLUSION Overall survival in patients with neoplastic pancreatic cysts is determined by patient factors (ie, age and sex) rather than factors descriptive of the cyst such as size and morphology. No conclusions could be made regarding the relationship between cyst pathology and patient survival.

The Effect of Bariatric Surgery on the Spectrum of Fatty Liver Disease

Nonalcoholic fatty liver disease is becoming one of the most common causes of liver disease in the western world. The most significant risk factors are obesity and the metabolic syndrome for which bariatric surgery has been shown to be an effective treatment. However, the effects of bariatric surgery on nonalcoholic fatty liver disease, specifically liver fibrosis and cirrhosis, are not well established. We review published bariatric surgery outcomes with respect to nonalcoholic liver disease. On the basis of this review we suggest that bariatric surgery may provide a viable treatment option for the treatment of nonalcoholic fatty liver disease, including patients with fibrosis and compensated cirrhosis, and that this topic should be a target of future investigation.