Randomised clinical trial: individualised vs. weight-based dosing of azathioprine in Crohn's disease.

BACKGROUND: Azathioprine (AZA), a pro-drug metabolised to the active metabolites 6-tioguanine nucleotides (6TGN), is a steroid-sparing therapy for Crohn's disease (CD). AIM: To investigate whether AZA therapy is optimised by individualised dosing based on thiopurine methyltransferase (TPMT) activity and 6TGN concentrations. METHODS: This multicentre, double-blind, randomised controlled trial compared the efficacy and safety of weight-based vs. individualised AZA dosing in inducing and maintaining remission in adults and children with steroid-treated CD. The primary outcome was clinical remission (CR) at 16 weeks. In the weight-based arm, subjects received 2.5 mg/kg/day. In the individualised dosing arm, the initial AZA dose was 1.0 mg/kg/day (if intermediate TPMT) or 2.5 mg/kg/day (if normal TPMT). Starting at week 5, the dose was adjusted to target 6TGN concentrations of 250-400 pmol/8 × 10(8) red blood cells (RBC), or to a maximal dose of 4 mg/kg/day. RESULTS: After randomising 50 subjects, the trial was stopped prematurely due to insufficient enrolment. In intention-to-treat analysis, CR rates at week 16 were 40% in the individualised arm vs. 16% in the weight-based arm (P = 0.11). In per-protocol (PP) analysis, week 16 CR rates were 60% in the individualised arm and 25% in the weight-based arm (P = 0.12). At week 16, median 6TGN concentrations in PP remitters and nonremitters were 216 and 149 pmol/8 × 10(8) RBC respectively (P = 0.07). CONCLUSIONS: Despite trends favouring individualised over weight-based AZA dosing, there were no statistically significant differences in efficacy, likely due to low statistical power and inability to achieve the target 6TGN concentrations in the individualised arm. [Clinicaltrials.Gov Identifier Nct00113503].

Randomised clinical trial: high-dose acid suppression for chronic cough - a double-blind, placebo-controlled study.

BACKGROUND: Cough may be a manifestation of gastro-oesophageal reflux disease (GERD). The utility of acid suppression in GERD-related cough is uncertain. AIM: To assess the impact of high-dose acid suppression with proton pump inhibitors (PPI) on chronic cough in subjects with rare or no heartburn. METHODS: Subjects were nonsmokers without history of asthma, with chronic cough for >8 weeks. All subjects underwent a baseline 24-h pH/impedance study, methacholine challenge test and laryngoscopy. Subjects were randomised to either 40 mg of esomeprazole twice daily or placebo for 12 weeks. The primary outcome measure was the Cough-Specific Quality of Life Questionnaire (CQLQ). Secondary outcomes were response on Fisman Cough Severity/Frequency scores and change in laryngeal findings. RESULTS: Forty subjects were randomised (22 PPI, 18 placebo) and completed the study. There was no difference between PPI and placebo in CQLQ (mean improvement 9.8 vs. 5.9 respectively, P = 0.3), or Fisman Cough Severity/Frequency scores. Proportion of patients who improved by >1 s.d. on the CQLQ was 27.8% (five of 18) and 31.8% (seven of 22) in the placebo and PPI groups respectively. CONCLUSION: In subjects with chronic cough and rare or no heartburn, high-dose proton pump inhibitor does not improve cough-related quality of life or symptoms.

Quality of life following radiofrequency ablation of dysplastic Barrett's esophagus.

BACKGROUND AND STUDY AIMS: The impact of the diagnosis and treatment of dysplastic Barrett's esophagus on quality of life (QoL) is poorly understood. This study assessed the influence of dysplastic Barrett's esophagus on QoL and evaluated whether endoscopic treatment of dysplastic Barrett's esophagus with radiofrequency ablation (RFA) improves QoL. PATIENTS AND METHODS: We analyzed changes in QoL in the AIM Dysplasia Trial, a multicenter study of patients with dysplastic Barrett's esophagus who were randomly allocated to RFA therapy or a sham intervention. We developed a 10-item questionnaire to assess the influence of dysplastic Barrett's esophagus on QoL. The questionnaire was completed by patients at baseline and 12 months. RESULTS: 127 patients were randomized to RFA (n = 84) or sham (n = 43). At baseline, most patients reported worry about esophageal cancer (71 % RFA, 85 % sham) and esophagectomy (61 % RFA, 68 % sham). Patients also reported depression, impaired QoL, worry, stress, and dissatisfaction with the condition of their esophagus. Of those randomized, 117 patients completed the study to the 12-month end point. Compared with the sham group, patients treated with RFA had significantly less worry about esophageal cancer ( P=0.003) and esophagectomy ( P =0.009). They also had significantly reduced depression ( P=0.02), general worry about the condition of their esophagus ( P≤0.001), impact on daily QoL ( P=0.009), stress ( P=0.03), dissatisfaction with the condition of their esophagus ( P≤0.001), and impact on work and family life ( P=0.02). CONCLUSIONS: Inclusion in the treatment group of this randomized, sham-controlled trial of RFA was associated with improvement in disease-specific health-related quality of life. This improvement appears secondary to a perceived decrease in the risk of cancer.

Psychiatric symptoms during interferon treatment for hepatitis C: experiences from a tertiary care hepatology centre.

BACKGROUND: Most research on the psychiatric symptoms of peginterferon/ribavirin for the treatment of hepatitis C comes from VA centres and clinical trials with rigid entry criteria that often excluded patients with markers of mental health and substance use disturbance (MH/SUD). The findings from these lines of research may not be generalizable to patients treated under standard of care in a tertiary care setting. AIM: To investigate the incidence and outcomes of psychiatric symptoms in patients treated under standard of care protocol, not enrolled in clinical trials. METHODS: This is a retrospective analysis of 215 patients who underwent therapy from 2002 to 2006 at a university-based tertiary care centre. Survival curves explored the relationship between history of MH/SUD and the development of psychiatric symptoms on treatment. RESULTS: The cumulative history of MH/SUD was 67%. Of these, 39% had taken psychotropic medications previously, and 80% continued on them during therapy. On therapy, 46% developed depressive symptoms, 19% and 46% endorsed anxiety and irritability respectively. Cumulatively, 64% of patients indicated mood disturbance on therapy. Most symptoms developed between weeks 2 and 18, and rarely after week 20. Of those who developed mood symptoms, 66% required an intervention. Treatment discontinuation was infrequent. CONCLUSIONS: This large observational study provides important insights into the incidence and course of psychiatric symptoms in an unselected sample of patients treated in a tertiary care setting. Patients had higher rates of MH/SUD comorbidity, psychotropic medication use and exhibit higher rates of mood disturbance on therapy compared with previous reports, although a majority completed the prescribed treatment regimen.

Impact of dialysis and older age on survival after liver transplantation.

Because creatinine is heavily weighed in the MELD (model for end-stage liver disease) score, we sought to determine the impact of MELD-based organ allocation on outcomes after transplantation in the pre- and post-MELD eras, focusing on recipients over age 65 on dialysis prior to transplant. A total of 20 196 patients from the UNOS database were analyzed. Comparing the pre-MELD to MELD era, there was a 41% increase in patients on dialysis (p<0.0001), and a 117% increase in combined liver/kidney transplants (p<0.0001). In the pre-MELD era, 1-year patient survival in recipients greater and less than age 65 on dialysis who received liver transplant alone was 56.8% and 76.4%, respectively (p=0.13). In the MELD era these rates were 50.7% and 77.8% (p=0.04). In the pre-MELD era, 1-year patient survival in recipients greater and less than age 65 on dialysis who underwent combined liver/kidney transplantation was 25.0% and 83.2%, respectively (p=0.0002). In the MELD era, these rates were 67.0% and 82.5% (p=0.18). In conclusion, a greater proportion of patients in the MELD era are on dialysis prior to transplant, and more receive combined liver/kidney transplants compared with the pre-MELD era. Candidates over age 65 who are on dialysis at the time of transplant have decreased survival after isolated liver transplantation.

NIS vs SAGES: a comparison of national and voluntary databases.

BACKGROUND: Surgical outcomes are increasingly examined in an effort to improve quality and reduce medical error. The Nationwide Inpatient Sample (NIS) is a retrospective, claims-derived and population-based database and the Society of American Gastrointestinal Endoscopic Surgeons (SAGES) Outcomes Project is a prospective, voluntary and specialty surgeon database. We hypothesized that these two sources of outcome data would differ in regard to a single, commonly performed procedure. METHODS: Both the NIS, a national sample of all nonfederal hospital discharges, and the gastroesophageal reflux disease log of the SAGES Outcomes Project were queried for all fundoplications performed between 1999 and 2001 using either ICD-9 procedure code 44.66 or CPT codes 43280 or 43324. Patients with an emergency admission, age <17 years, and/or diagnoses for either esophageal cancer or achalasia were excluded. Both demographic and outcome variables were compared by either t-test or chi-square analysis, with a p value of <0.05 as significant. RESULTS: Both data sets were comparable for age and gender; however, the SAGES group had a higher rate of teaching hospital affiliation (71 vs 48%, p < 0.001). SAGES fundoplications had a consistently higher rate of comorbidities, including Barrett's esophagus (2.3 vs 1.1%, p = 0.005). The NIS fundoplications had a clear trend toward more associated procedures, including cholecystectomy (7.2 vs 2%, p < 0.001). Complication rates for the NIS data set were higher, including pulmonary complications (1.7 vs 0.5%, p = 0.03). No statistically significant differences existed between the two data sets for either length of stay or mortality. CONCLUSIONS: The two databases indicate that fundoplication is an operation with low morbidity and mortality. The SAGES Outcomes Project demonstrated that participating surgeons had a higher affiliation with teaching hospitals, higher reporting of comorbidity, and lower associated procedures than the NIS. Despite having more comorbidity and technical difficulty, patients from the SAGES Outcomes Project had equivalent or lower complication rates.

T cell-mediated oral tolerance is intact in germ-free mice.

Commensal enteric bacteria stimulate innate immune cells and increase numbers of lamina propria and mesenteric lymph node (MLN) T and B lymphocytes. However, the influence of luminal bacteria on acquired immune function is not understood fully. We investigated the effects of intestinal bacterial colonization on T cell tolerogenic responses to oral antigen compared to systemic immunization. Lymphocytes specific for ovalbumin-T cell receptor (OVA-TCR Tg(+)) were transplanted into germ-free (GF) or specific pathogen-free (SPF) BALB/c mice. Recipient mice were fed OVA or immunized subcutaneously with OVA peptide (323-339) in complete Freund's adjuvant (CFA). Although the efficiency of transfer was less in GF recipients, similar proportions of cells from draining peripheral lymph node (LN) or MLN were proliferating 3-4 days later in vivo in GF and SPF mice. In separate experiments, mice were fed tolerogenic doses of OVA and then challenged with an immunogenic dose of OVA 4 days later. Ten days after immunization, lymphocytes were restimulated with OVA in vitro to assess antigen-specific proliferative responses. At both high and low doses of OVA, cells from both SPF and GF mice fed OVA prior to immunization had decreased proliferation compared to cells from control SPF or GF mice. In addition, secretion of interferon (IFN)-gamma and interleukin (IL)-10 by OVA-TCR Tg(+) lymphocytes was reduced in both SPF and GF mice fed OVA compared to control SPF or GF mice. Unlike previous reports indicating defective humoral responses to oral antigen in GF mice, our results indicate that commensal enteric bacteria do not enhance the induction of acquired, antigen-specific T cell tolerance to oral OVA.

Tea consumption, apoptosis, and colorectal adenomas.

Induction of apoptosis has been suggested as a mechanism for the anti-carcinogenic effect of tea constituents in animals and in vitro studies. We addressed this hypothesis in a human study. Study participants were consecutive patients who underwent colonoscopy at the UNC Hospitals (August 1998 to March 2000). Biopsies were taken from normal rectal mucosa. Apoptosis was scored by the terminal deoxyribonucleotide transferase-mediated digoxigenin dUTP nick end labeling (TUNEL) method and by standard morphological criteria. The analysis included 171 patients with adenomas (cases) and 323 adenoma-free controls. After adjusting for sex, age, race, and BMI, apoptotic score was inversely associated with adenoma: the odds ratios (ORs) for linear trend associated with tertiles were 0.3 (0.3-0.5) for morphologic score and 0.5 (0.4-0.6) for the TUNEL score, respectively. Tea consumption (2-3 and >3 versus <2 servings/day) showed a weak negative association with adenoma: the ORs were 0.7 (0.3-1.4) and 0.5 (0.2-1.1), respectively. Neither measurement of apoptotic score changed by the level of tea consumption (P value for Kruskal-Wallis test > or =0.5). We did not find statistical interaction between apoptotic score and tea consumption. Tea exposure is not associated with apoptosis in normal rectal tissue in vivo.

Reduced serum amino acid concentrations in infants with necrotizing enterocolitis.

OBJECTIVE: To determine whether premature infants who have necrotizing enterocolitis (NEC) have deficiencies in glutamine (GLN) and arginine (ARG), which are essential to intestinal integrity. STUDY DESIGN: A 4-month prospective cohort study of serum amino acid and urea levels in premature infants was done. Serum amino acid and urea levels were measured by high-pressure liquid chromatography and enzymatic methods, respectively, on samples obtained on days of life 3, 7, 14, and 21. RESULTS: Infants in the control (n = 32) and NEC groups (n = 13) were comparable for birth weight, gestational age, and Apgar scores. NEC began on mean day of life 14.5 (95% CI, day of life 11 to 18). Median values of GLN were 37% to 57% lower in the NEC group on days 7, 14, and 21 compared with those in the control group (P <.05). On days 7 and 14, median values of ARG, GLN, alanine, lysine, ornithine, and threonine were decreased 36% to 67% (P <.05) in the NEC group. Total nonessential amino and total essential amino acids were 35% to 50% lower in the NEC group on days 7 and 14 (P <.05). Infants in the NEC group had significant reductions in GLN and ARG 7 days before the onset of NEC. CONCLUSIONS: Infants who have NEC have selective amino acid deficiencies including reduced levels of GLN and ARG that may predispose to the illness.

The practices and attitudes of primary care nurse practitioners and physician assistants with respect to colorectal cancer screening.

OBJECTIVES: Although nurse practitioners and physician assistants form a large and growing portion of the primary care workforce, little is known about their colorectal cancer screening practices. The aim of this study was to assess the colorectal cancer screening practices, training, and attitudes of nurse practitioners and physician assistants practicing primary care medicine. METHODS: All nurse practitioners (827) and physician assistants (1178) licensed by the Medical Board of the State of North Carolina were surveyed by mail. Both groups were further divided into primary care versus non-primary care by self-described roles. Self-reported practices, training, and attitudes with respect to colorectal cancer screening were elicited. RESULTS: Response rates were 71.4% and 61.2%, for nurse practitioners and physician assistants respectively. A total of 51.3% of nurse practitioners and 50.3% of physician assistants described themselves as adult primary care providers. No primary care nurse practitioners and only 3.8% of primary care physician assistants performed screening flexible sigmoidoscopy. However, 76% of primary care physician assistants and 69% of primary care nurse practitioners reported recommending screening flexible sigmoidoscopy. A total of 95% primary care physician assistants and 92% of primary care nurse practitioners reported performing fecal occult blood testing. Only 9.4% of physician assistants and 2.8% of nurse practitioners received any formal instruction in flexible sigmoidoscopy while in their training. Additionally, 41.4% of primary care physician assistants and 27.7% of primary care nurse practitioners reported that they would be interested in obtaining formal training in flexible sigmoidoscopy. CONCLUSIONS: Physician assistants and nurse practitioners are motivated, willing and underutilized groups with respect to CRC screening. Efforts to increase education and training of these professionals may improve the availability of CRC screening modalities.

Prospective randomized trial of early initiation and hospital discharge on a liquid diet following elective intestinal surgery.

Length of hospital stay after elective intestinal surgery may be related to patient tolerance of a diet. We hypothesized that early initiation and discharge home on a clear liquid diet would decrease the length of hospital stay without increasing morbidity. The aim of this study was to determine if early initiation and discharge on a clear liquid diet decreases the length of hospital stay and is safe. Forty-four patients were randomly assigned to either a standard diet or a clear liquid diet. A standard diet (n = 17) was begun after the passage of flatus or stool, and consisted of clear liquids to a volume of approximately 750 ml, then three solid meals, and discharge thereafter. Patients randomized to a clear liquid diet (n = 27) received 30 ml/hr of clear liquids on postoperative day 2, unlimited clear liquids on postoperative day 3, and were dismissed on a clear liquid diet on postoperative day 4. All patients were followed by a daily telephone call and clinic visit. The primary outcome variable was length of hospital stay. The incidence of postoperative intestinal-related sequelae, complications, and readmission rates did not differ between groups. Postdischarge intestinal symptoms were common in both groups but tended to resolve faster in the patients on a standard diet. The length of hospital stay was decreased in the patients on a clear liquid diet compared to those on a standard diet (6.1 +/- 1.1 days vs. 4.4 +/- 0.2 days; P = 0.09), but total hospital costs did not differ. Early initiation and hospital discharge on a clear liquid diet after elective intestinal surgery decreases the length of hospital stay and is safe.

Percutaneous drainage of pancreatic pseudocysts is associated with a higher failure rate than surgical treatment in unselected patients.

OBJECTIVE: The primary aim was to compare directly the effectiveness of percutaneous drainage versus surgical treatment of pancreatic pseudocysts in unselected patients. The authors also wished to identify factors that may predict a successful outcome with percutaneous drainage. SUMMARY BACKGROUND DATA: Pancreatic pseudocysts are a common complication of pancreatitis, and recent data suggest that many pseudocysts may be observed or treated successfully by percutaneous drainage. Failures with percutaneous drainage have been recognized increasingly, and a direct comparison of percutaneous and surgical treatment was initiated to identify factors that may affect outcome with these approaches. METHODS: A computerized index search of the medical records of patients with a diagnosis of pancreatic pseudocyst was performed from 1984 to 1995. One hundred seventy-three patients were identified retrospectively and assigned to treatment groups: observation (n = 41), percutaneous drainage (n = 66), or surgical treatment (n = 66). Data on demographics, clinical presentation, pseudocyst etiology and characteristics, diagnostic evaluation, management, and outcome were obtained. Treatment failure was defined as persistence of a symptomatic pseudocyst or the need for additional intervention other than the original treatment. RESULTS: The etiology of pancreatitis, clinical presentation, and diagnostic evaluation did not differ between groups. Twenty-seven percent had documented chronic pancreatitis, and the etiology of pancreatitis was alcohol in 61% of patients. Mean pseudocyst size was 4.2 +/- 1 cm, 8.2 +/- 1.1 cm, and 7.4 +/- 1.3 cm in the observed, percutaneously treated, and surgically treated groups, respectively. Expectant treatment was successful in 93% of patients. Percutaneous drainage was successful in 42% of patients, whereas surgical treatment resulted in a success rate of 88%. Patients treated by percutaneous drainage had a higher mortality rate (16% vs. 0%), a higher incidence of complications (64% vs. 27%), and a longer hospital stay (45 +/- 5 days vs. 18 +/- 2 days) than patients treated by surgery. Eighty-seven percent of patients in whom percutaneous drainage failed required surgical salvage therapy. Multiple logistic regression analysis failed to reveal any factors significantly associated with a successful outcome after percutaneous drainage. CONCLUSIONS: Percutaneous drainage results in higher mortality and morbidity rates and a longer hospital stay than surgical treatment of pancreatic pseudocysts. The clinical benefit of percutaneous drainage of pancreatic pseudocysts in unselected patients has not been realized, and the role of this treatment should be established in a clinical trial.

Rectal mucosal proliferation, dietary factors, and the risk of colorectal adenomas.

Colorectal cancer arises from a series of precursor stages, the so called adenoma-carcinoma sequence. Increased rectal mucosal proliferation may be an early step in this sequence. Because dietary factors are implicated in the etiology of colorectal cancer, one might predict that diet would also be associated with proliferation. We conducted this study to examine the association of diet with rectal mucosal proliferation. Rectal mucosal proliferation was measured in endoscopic biopsy specimens by proliferating cell nuclear antigen (PCNA) immunohistochemistry and whole crypt mitotic counts (WCMCs). Diet was evaluated using a validated quantitative food frequency questionnaire. The correlation between PCNA labeling index (LI) and WCMCs was determined using Kendall's tau, a nonparametric measure of correlation. Logistic regression was used to examine the effect of proliferation on adenoma status, controlling for confounders. The relationship between proliferation and dietary and demographic factors was examined using linear regression. There were 308 patients who had one or both measures of proliferation. There was no significant correlation between PCNA LI and WCMCs (Kendall's tau = 0.04; P = 0.35). Neither measure of proliferation was predictive of adenoma status, even after adjusting for potential confounders. Body mass index and calories per day were significant predictors of WCMC (P = 0.01 and P = 0.03, respectively). PCNA labeling index was not associated with any dietary variables, although its association with dietary fat nearly reached statistical significance (P = 0.09). The association between proliferation and diet were generally inconsistent. There appears to be no simple relationship between colorectal cancer risk factors, colorectal adenomas, and these two measures of rectal mucosal proliferation. We need simpler, more reliable intermediate markers for use in etiological and intervention studies.

Aspirin and nonsteroidal anti-inflammatory agents and risk for colorectal adenomas.

BACKGROUND & AIMS: Aspirin and nonsteroidal anti-inflammatory drugs have been reported to protect against the development of colorectal cancer. Because adenomas are precursors to most colorectal cancers, the aim of this study was to examine the relationship of these medications to the risk for colorectal adenomas in a colonoscopy-based case-control study. METHODS: Study participants were drawn from patients who underwent colonoscopy at the University of North Carolina Hospitals. Medication use was assessed by telephone using a comprehensive list of prescription and nonprescription drugs as well as questions about dietary and lifestyle factors that might be relevant for adenoma development. RESULTS: There were 210 patients with adenomas and 169 adenoma-free controls. After adjusting for potential confounders, regular users were half as likely to currently have adenomas compared with nonusers (adjusted odds ratio, 0.56; 95% confidence interval, 0.34-0.92). Regular users who stopped medication at least 1 year before colonoscopy were still protected (adjusted odds ratio, 0.59; 95% confidence interval, 0.21-1.67), although small numbers make this conclusion tentative. The protective effects of aspirin and the nonaspirin nonsteroidal anti-inflammatory drugs were similar. CONCLUSIONS: The results suggest that aspirin and nonsteroidal anti-inflammatory drugs cause early disruption of the adenoma-carcinoma sequence. The challenge for the future will be to learn more about dose, duration, and mechanism of action.