The benefit of combination therapy depends on disease phenotype and duration in Crohn's disease.

BACKGROUND: The impact of combination therapy on disease-related morbidity in patients with established Crohn's disease (CD) or ulcerative colitis (UC) remains to be well-defined. AIM: To examine the effect of combination therapy on disease outcomes in CD and UC. METHODS: Using a multicenter prospective cohort, we classified CD and UC patients as being on monotherapy with anti-TNF or on combination with an immunomodulator. The primary outcome was a composite of new IBD-related surgery, hospitalisations, penetrating complications, need for corticosteroids or new biological at 1 year. Multivariable regression models adjusted for potential confounders. RESULTS: We included 707 patients with CD (45% combination therapy) and 164 with UC (38% combination therapy). Combination therapy was not associated with reduction in the composite outcome in either CD (OR: 0.87, 95% CI: 0.63-1.22) or UC (OR: 1.45, 95% CI: 0.63-3.38). However, while no difference was noted in those with nonstricturing, nonpenetrating CD, a significant reduction in the likelihood of the outcome was seen in those with stricturing or penetrating CD (30% vs 39%, OR: 0.58, 95% CI: 0.37-0.90). A stronger effect was also observed in those with disease duration <5 years (OR: 0.35, 95% CI: 0.14-0.87) compared to those with a longer duration (OR: 0.75, 95% CI: 0.45-1.27). A similar reduction in occurrence of composite outcome was noted with infliximab and with other anti-TNF biologics. CONCLUSION: The benefit of combination immunomodulator-biological therapy is stronger in those with complicated Crohn's disease, particularly early on in their disease course.

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].

Increased risk of herpes zoster among 108 604 patients with inflammatory bowel disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) on certain immunosuppressants have increased herpes zoster (HZ) risk. AIM: To determine the risk of HZ in IBD and how antitumour necrosis factor-alpha (anti-TNF) agents affect this risk. METHODS: We performed a retrospective cohort and nested case-control study using administrative data from IMS LifeLink(®) Information Assets-Health Plan Claims Database. In the cohort, we identified IBD patients

Statistical strategies to improve the efficiency of molecular studies of colorectal cancer prognosis.

The evaluation of tumour molecular markers may be beneficial in prognosis and predictive in therapy. We develop a stopping rule approach to assist in the efficient utilisation of resources and samples involved in such evaluations. This approach has application in determining whether a specific molecular marker has sufficient variability to yield meaningful results after the evaluation of molecular markers in the first n patients in a study of sample size N (n

Histamine receptor antagonists and incident colorectal adenomas.

BACKGROUND: Prior studies suggest that histamines may modulate the development of colorectal neoplasia. AIM: To assess whether histamine receptor antagonist use was associated with adenoma formation. METHODS: Patients (n = 2366) were drawn from three adenoma chemoprevention trials. All underwent baseline colonoscopy with removal of adenoma(s) and were deemed free of remaining lesions; they were followed with surveillance colonoscopy. Medication use was assessed by questionnaire. Adjusted risk ratios for adenoma formation related to histamine receptor antagonist use (histamine H1 and H2 receptor, H1RA and H2RA) were determined using log linear models. RESULTS: In pooled analyses, H1RA exposure was not associated with subsequent adenoma risk (RR = 1.10; 95% CI 0.97-1.25) or multiple adenoma formation (RR = 0.85; 95% CI 0.67-1.07). H2RA use also was not associated with adenoma (RR = 0.90; 95% CI 0.77-1.06), or multiple adenoma (RR = 0.77; 95% CI 0.57-1.04) in the pooled analyses, but H2RA users in the first trial had a decreased risk of adenoma (RR = 0.70; 95% CI 0.48-1.03) and multiple adenoma (RR = 0.31; 95% CI 0.12-0.79). CONCLUSION: H2RA use was associated with reduced risk for adenoma in one trial, but not in the pooled analyses. Further study would be warranted before undertaking randomized trials of H2RAs for adenoma chemoprevention.

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.

Heterocyclic amines, meat intake, and association with colon cancer in a population-based study.

The authors examined the association between colon cancer and meat intake categorized by level of doneness, cooking method, and estimated levels of heterocyclic amines (HCAs), benzo[a]pyrene, and mutagenicity. Data were collected as part of a population-based, case-control study of colon cancer in North Carolina between 1996 and 2000 that included 701 African-American (274 cases, 427 controls) and 957 White (346 cases, 611 controls) participants. Odds ratios were calculated by using unconditional logistic regression, comparing the fifth to the first quintile levels of intake or exposure. Intake of red meat was positively associated with colon cancer (odds ratio (OR) = 2.0, 95% confidence interval (CI): 1.3, 3.2). Associations with meat intake by cooking method were strongest for pan-fried red meat (OR = 2.0, 95% CI: 1.4, 3.0). Associations with meat intake by doneness were strongest for well-/very well done red meat (OR = 1.7, 95% CI: 1.2, 2.5). The strongest association for individual HCAs was reported for 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) across all levels of exposure, with odds ratios of 1.8-2.0. Overall, sophisticated exposure measures were used to report modest, positive associations between red meat intake and colon cancer consistent with the hypothesis that HCAs may be among the etiologically relevant compounds in red meat.

The living donor experience: donor health assessment and outcomes after living donor liver transplantation.

Despite the increasing use of living donor liver transplantation, little is known about donor needs, concerns, and experiences. The goal of this study is to assess morbidity associated with living donation from a donor perspective, functional status after donation, and overall satisfaction with the donation process. We surveyed all living donors (LDs) from our center. Demographics, perioperative experience, and satisfaction with donation were assessed. The Medical Outcomes Study 12-Item Short-Form Survey (SF-12), a well-validated tool, measured overall health-related quality of life. Of 27 subjects eligible for the study, 27 subjects (100%) participated. Forty percent reported an event they deemed an immediate complication, of which 60% were recorded in the medical record. Complications requiring readmission were reported by 22%. Mean recovery time was 12 weeks (range, 1 to 52 weeks). No significant change was reported in physical activity, social activity, or emotional stability, and 92% of donors resumed their predonation occupation. Regardless of recipient outcome, 100% of donors would donate again and recommend donation to someone in contemplation. All surveyed LDs at our institution are satisfied with their donation decision. Morbidity in the first year after donation may be greater than previously appreciated. Despite complications, postoperative functional status of donors is equal to or better than population norms.

Use of vitamins, minerals, and nutritional supplements by participants in a chemoprevention trial.

BACKGROUND: The growing use of vitamins, minerals, and nutritional supplements has the potential to influence the design and interpretation of randomized controlled trials of chemopreventive agents. To the extent that these complementary agents are effective, they could limit the ability of trials to demonstrate an effect of the agents under study. METHODS: During the course of a colorectal neoplasia chemoprevention trial using aspirin in a group of colorectal carcinoma survivors, the authors obtained information on the use of vitamins, minerals, and supplements at baseline and every 6 months. The information from 622 study participants was categorized and enumerated. RESULTS: One or more supplements were used at some time by 341 (55%) subjects. Among those who took supplements, 66% took more than 1 and 13% took 5 or more. The mean number of supplements taken was 2.6 (1.7 standard deviation). Vitamins were the most commonly used (49%), followed by minerals (22%), botanicals (13%), and others (5%). Among the vitamins, the most frequently used were multivitamins (38% of subjects), vitamin C (18%), and vitamin E (22%). Calcium (16%) was the most frequent mineral. Among users, there were no differences in supplement use by age or gender. CONCLUSIONS: Supplement use was common among colorectal carcinoma survivors enrolled in a prevention trial. Investigators should record the information on supplement use so that the possible impact of the supplements on trial endpoints can be evaluated. It may be necessary to increase the size of studies if many of the subjects take potentially effective supplements.

Measles virus and Crohn's disease: a critical appraisal of the current literature.

The etiology of inflammatory bowel disease (IBD) is unknown. Recent reports in the literature have suggested that measles virus, both wild-type and vaccine-attenuated, might be a risk factor for Crohn's disease. We used the well-accepted Bradford-Hill criteria to evaluate the possible causal association between measles and IBD. Although the association may be biologically plausible, the literature lacks consistency, specificity, strength, and dose response. The current literature does not support an association between measles virus and IBD.

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.

Effectiveness and economic impact of screening for colorectal cancer by mass fecal occult blood testing.

OBJECTIVES: Fecal occult blood testing has been shown to reduce mortality from colorectal cancer in large randomized, controlled trials conducted in the United States, Denmark, and the United Kingdom, and mathematical simulation modeling found it to be cost-effective relative to other health care services. Before making a concerted effort to implement mass fecal occult blood testing based on this evidence alone, however, we considered it prudent to critically re-evaluate the effectiveness and economic impact of screening in the US population as a whole. METHODS: To assess the effectiveness of screening, we projected published outcomes from each of the three large randomized controlled trials of fecal occult blood testing to the US population, as if each clinical trial had been done in the population as a whole. We then determined the resource costs of detection and treatment that would be associated with the outcomes predicted from each trial. RESULTS: More than 1 million colorectal cancers could be expected to arise over 10 yr in the cohort of US residents eligible to enter a screening program in 1997, and trial outcomes indicate that > or = 60% of these cancers would be fatal. If the 60-67% compliance rate of the population-based randomized controlled trials were achieved, a fecal occult blood testing program would detect 30% of known colorectal cancers and save 100,000 lives over 10 yr. Screening would incur total costs of $3-4 billion over 10 yr, or $2,500 per life-year saved. CONCLUSIONS: Mass fecal occult blood testing is cost-effective, and, although not inexpensive, many would consider the total cost acceptable. Even with a concerted effort to achieve compliance, however, the effectiveness of fecal occult blood testing would be limited to saving the lives of < or = 15% of those who otherwise would die from their cancer in the first 10 yr after beginning mass screening. The limitations of fecal occult blood testing suggest the need to further evaluate the role of endoscopy in screening, and to develop more effective, noninvasive screening tools.

Disposable versus reusable biopsy forceps for colorectal epithelial cell proliferation in humans.

The performance of various measures of rectal mucosal proliferation has been evaluated in the literature, but the performance of the forceps used to obtain the tissue has received little attention. We used data from two large studies of proliferation at a single institution to compare reusable and disposable endoscopic forceps. Endoscopic pinch biopsies were taken 10 cm from the anal verge using either reusable or disposable, oval-cupped, sheathed forceps. The specimens were fixed, embedded, and sectioned, taking care to orient the specimens longitudinally. Five sections were placed on each slide. We determined how many slides did not contain eight scorable crypts (inadequate) and how many sections were necessary to identify eight complete crypts. There were 395 subjects who had biopsies taken with reusable forceps and 185 subjects who had biopsies taken with disposable forceps. The specimens were inadequate in 27.6% of the reusable forceps specimens versus 2.7% of the disposable forceps (P < 0.0001). The mean number of tissue sections necessary to identify eight scorable crypts for the reusable forceps was 3.82 (SD, 0.87) compared with 3.17 (SD, 0.83) for disposable forceps (P = 0.0001). The specimens taken with the disposable forceps were better, probably because the forceps were sharper. We believe that the better quality of the specimens and the sterility justify the higher cost of disposable forceps. We would urge investigators in proliferation studies to evaluate the biopsy equipment as carefully as they evaluate other aspects of their methods.

Food intake patterns and gallbladder disease in Mexican Americans.

OBJECTIVE: Results of previous studies on diet and gallbladder disease (GBD), defined as having gallstones or having had surgery for gallstones, have been inconsistent. This research examined patterns of food intake in Mexican Americans and their associations with GBD. DESIGN: Cross-sectional. SUBJECTS: The study population included 4641 Mexican Americans aged 20-74 years who participated in the 1988-94 third National Health and Nutrition Examination Survey (NHANES III). GBD was diagnosed by ultrasound. Food intake patterns were identified by principal components analysis based on food frequency questionnaire responses. Component scores representing the level of intake of each pattern were categorized into quartiles, and prevalence odds ratios (POR) were estimated relative to the lowest quartile along with 95% confidence intervals (CI). RESULTS: There were four distinct patterns in women (vegetable, high calorie, traditional, fruit) and three in men (vegetable, high calorie, traditional). After age adjustment, none were associated with GBD in women. However, men in the third (POR = 0.42, 95%CI 0.21-0.85) and fourth (POR = 0.53, 95%CI 0.28-1.01) quartiles of the traditional intake pattern were half as likely to have GBD as those in the lowest quartile. CONCLUSIONS: These findings add to a growing literature suggesting dietary intake patterns can provide potentially useful and relevant information on diet-disease associations. Nevertheless, methods to do so require further development and validation.

Is there publication bias in the reporting of cancer risk in Barrett's esophagus?

BACKGROUND & AIMS: The published risk of adenocarcinoma in the setting of Barrett's esophagus (BE) varies. Publication bias, the selective reporting of studies featuring positive or extreme results, may result in overestimation of this cancer risk in the literature. The aim of this study was to assess those publications reporting a cancer risk in BE for evidence of publication bias. METHODS: A MEDLINE search for all published estimates between 1966 and 1998 of cancer risk in BE was performed. All studies reporting a cancer risk expressible in cancers per patient-year of follow-up were retrieved. Bibliographies of these studies were surveyed for additional estimates. All publications that required an initial endoscopy with histologic confirmation of BE and any cancer were included. The relationship of reported cancer risk to size of the study was assessed. Multivariable regression controlling for differences in definition of BE, as well as other study characteristics, was performed. The data were also analyzed by means of a funnel diagram, an epidemiologic method to assess publication bias. RESULTS: Five hundred fifty-four abstracts were reviewed. Twenty-seven publications met the stated criteria for inclusion. There was a strong correlation between cancer risk and the size of the study, with small studies reporting much higher risks of cancer than larger studies. This association persisted when differences in the definition of BE, retrospective vs. prospective nature of the study, surveillance interval, and the effect of cancer detected in the first year were considered. The funnel diagram analysis suggested publication bias. CONCLUSIONS: The cancer risk in BE may be overestimated in the literature due to publication bias.

Rectal mucosal proliferation and risk of colorectal adenomas: results from a randomized controlled trial.

Although rectal mucosal labeling index is thought to be a useful surrogate biomarker for colorectal cancer, the ability of the index to predict future neoplasia is unclear. We obtained rectal mucosal biopsies from 333 participants of a randomized controlled chemoprevention trial of calcium supplementation to determine whether labeling index was correlated with concurrent or future colorectal neoplasms. Labeling index was measured using proliferating cell nuclear antigen immunohistochemistry. Adenomas were enumerated at the time of the biopsies (cross-sectional) and 3 years later (prospective). We used logistic regression to test for an association of adenoma occurrence with overall labeling index, the mean proliferative height, and labeling index in the upper 40% of colon crypts. In the cross-sectional analysis, we found indications that higher proliferation was associated with an increase in the prevalence of adenomas. The overall adjusted odds ratios (OR) (95% confidence interval) were 1.14 (0.90-1.45) per % crypt labeling index, OR 1.08 (0.99-1.19) for upper crypt proliferation, and OR 1.07 (1.03-1.12) for proliferative height. In contrast, individuals with higher labeling index at baseline were actually less likely to have adenomas in the prospective analyses: OR 0.80 (0.62-1.02) per % crypt labeling index, OR 0.86 (0.73-1.00) for upper crypt index, and OR 0.97 (0.93-1.01) for proliferative height. Proliferative index does not predict future colorectal neoplasia, although it may be weakly associated with the presence of current adenomas. These results have important implications for the design of future intervention studies. Although it may be attractive to include the measurement of intermediate markers in large controlled trials, until we have more confidence in their performance, we should rely on better proven and more reliable intermediates, such as adenomas.