Prospective study of the frequency and size distribution of polyps missed by colonoscopy.

An important determinant in interpreting the results of colorectal polyp chemoprevention trials is the rate of polyps missed during colonscopic examination. We prospectively examined 90 patients by tandem colonoscopy performed by two alternating examiners. In 69 (76.7%) patients, 221 neoplastic lesions were documented histologically. Of a total of 58 lesions detected in 31 patients, no neoplastic lesion greater than or equal to 10 mm in size was missed; 16% of diminutive (less than or equal to 5 mm) neoplastic polyps and 12.3% of medium-sized (6-9 mm) neoplastic polyps were missed by the first examiner. We conclude that an experienced colonoscopist will miss about 15% of colorectal neoplastic polyps less than 10 mm in size in the setting of adequate bowel preparation. Large (greater than or equal to 10 mm) polyps were rarely missed, however, with the "miss" rate in our study equal to 0, with a 95% confidence limit of 4.64%.

Ornithine decarboxylase and polyamine levels in columnar upper gastrointestinal mucosae in patients with Barrett's esophagus.

Ornithine decarboxylase (ODC) activity was elevated in the premalignant metaplastic columnar epithelium (mean activity, 0.13 unit/mg protein, N = 18 individual samples from 18 patients), compared to either adjacent gastric (mean activity, 0.02 unit/mg protein, N = 9) or small intestinal (mean activity, 0.02 unit/mg protein, N = 9) epithelium in patients with Barrett's esophagus. Enzyme activity ranged from 0 (less than detectable) to more than 0.5 unit/mg protein in the metaplastic tissue. However, neither putrescine, spermidine, spermine (as individual parameters), nor total polyamine contents were related to ODC activity in the individual patient biopsies. Spermidine/spermine ratios ranged from 0.38 to 2.18 and were also not related to enzyme activity in any apparent manner. Nevertheless, cell strains derived from the metaplastic tissue were growth inhibited by alpha-difluoromethylornithine, an enzyme-activated, suicide inhibitor of ODC. In two different cell strains derived from Barrett's epithelium, growth was affected with drug concentrations as low as 0.05 mM. While the mechanism responsible for the elevation in enzyme activity is unknown, the regulation of polyamine metabolism appears to be altered in this premalignant tissue. The growth inhibition of Barrett's epithelium-derived cell lines by ODC inhibitors suggests a potential role for these compounds in the treatment of this disease.

A bile acid-induced apoptosis assay for colon cancer risk and associated quality control studies.

Bile acids are important in the etiology of colorectal cancer. Bile acids induce apoptosis in colonic goblet cells at concentrations comparable to those found in fecal water after high-fat meals. Preliminary evidence indicated that cells of the normal-appearing (nontumorous) portion of the colon epithelium of colon cancer patients are more resistant to bile salt-induced apoptosis than are cells from normal individuals. In the present study, 68 patients were examined, and biopsies were taken at 20 cm from the anal verge, cecum, and descending colon. The patients included 17 individuals with a history of colorectal cancer, 37 individuals with adenomas, and 14 individuals who were neoplasia free. The mean bile salt-induced apoptotic index among normal individuals was 57.6 +/- 3.47 (SE), which differed significantly (P < 0.05) from the mean value of 36.41 +/- 3.12 in individuals with a history of colon cancer. The correlation between independent observers was 0.89 (P < 0.001), indicating good interobserver reliability. Components of variance comparing interindividual versus intraindividual sources of variation suggested that site-to-site variability, both between regions of the colon and for adjacent biopsies, was larger than the interpatient variability for individuals with a history of neoplasia. Therefore, there was "patchiness" of the susceptibility of regions of the colon to bile acid-induced apoptosis in individuals with a history of neoplasia (a patchy field effect). There was no obvious correlation of low-apoptotic index regions with regions in which previous neoplasias had been found and removed. On the other hand, for normal, i.e., neoplasia-free, individuals, there was relatively less intraindividual variation compared to interindividual variation. Our assay shows an association between resistance to bile acid-induced apoptosis, measured at 20 cm from the anal verge, and colon cancer risk. Thus, this assay may prove useful as a biomarker of colon cancer risk.

The association of body mass index with Barrett's oesophagus.

BACKGROUND: Obesity has been linked to gastro-oesophageal reflux disease symptoms and oesophageal adenocarcinoma; however, there is no published evidence for an association with Barrett's oesophagus. AIM: To investigate the association between obesity and Barrett's oesophagus. METHODS: We conducted a retrospective cross-sectional study of patients who underwent upper endoscopy at the Southern Arizona Veteran's Affairs Healthcare System between 1998 and 2004. We examined male patients without malignancy, with available information on weight and height. Based on endoscopic and histological findings, patients were classified as cases with Barrett's oesophagus or non-cases without Barrett's oesophagus. Multivariable logistic regression analysis was conducted to examine the association of body mass index and obesity with Barrett's oesophagus and Barrett's oesophagus length while adjusting for age and race. RESULTS: There were 65 cases with Barrett's oesophagus and 385 non-cases without Barrett's oesophagus. The mean body mass index was significantly higher in cases than in non-cases (29.8 vs. 28.0, P = 0.03). Cases had significantly greater mean weight than controls (206 lb vs. 190,P = 0.005). The proportions of cases with body mass index 25-30 and body mass index > or =30 were greater than those in non-cases (44.6% vs. 37.7%) and (40.0% vs. 33.5%), respectively (P = 0.08). In the multivariable logistic regression model adjusting for race and age, when compared with body mass index < 25, the odds ratio was 2.43 (95% confidence interval: 1.12-5.31) for body mass index 25-30 and 2.46 (1.11-5.44) for body mass index > or =30. When examined as a continuous variable the adjusted odd ratio for each five-point increase in body mass index was 1.35 (95% confidence interval: 1.06-1.71, P = 0.01). The association between weight and Barrett's oesophagus was also statistically significant (adjusted odd ratio for each 10 pound increase = 1.10, 1.03-1.17, P =0.002). Among the 65 cases of Barrett's oesophagus, there was no correlation between the length of Barrett's oesophagus at the time of diagnosis and the body mass index (correlation coefficient = 0.03, P = 0.79). CONCLUSION: This retrospective cross-sectional study in male veterans shows that overweight is associated with a two-and-half-fold increased risk of Barrett's oesophagus. Larger studies of the underlying mechanism are warranted to better understand how and why obese patients are at greater risk for Barrett's oesophagus.

Lack of predictors of normalization of oesophageal acid exposure in Barrett's oesophagus.

BACKGROUND: Barrett's oesophagus patients may continue to have abnormal oesophageal acid exposure on proton pump inhibitor therapy. The effect of factors such as Barrett's oesophagus length, hiatal hernia size and Helicobacter pylori infection on intra-oesophageal pH in Barrett's oesophagus patients has not been adequately studied. AIM: To evaluate oesophageal acid exposure in a large Barrett's oesophagus population on b.d. proton pump inhibitor therapy and determine clinical factors predicting normalization of intra-oesophageal pH on therapy. METHODS: Barrett's oesophagus patients were studied using 24 h pH monitoring to evaluate intra-oesophageal acid suppression on b.d. dosing of rabeprazole. RESULTS: Forty-six Barrett's oesophagus patients completed the study. Median total percentage time pH < 4 was 1.05% (range: 0-29.9%) in the entire group and respective values for upright and supine percentage time pH < 4 were 1.15% and 0%. However, 34 of the Barrett's oesophagus patients (73.9%) had a normal pH study (median total percentage time pH < 4: 0.2%) and 12 patients (26.1%) had an abnormal result (median total percentage time pH < 4: 9.3%). There were no significant differences between patients with a normal and abnormal 24 h pH result with respect to age, Barrett's oesophagus length, hiatal hernia size and presence of H. pylori infection. CONCLUSIONS: Approximately 25% of Barrett's oesophagus patients continue to have abnormal total intra-oesophageal pH profiles despite b.d. proton pump inhibitor therapy. Factors such as age, Barrett's oesophagus length and hiatal hernia size cannot be used to predict persistent abnormal intra-oesophageal pH on proton pump inhibitor.

Barrett's esophagus: update on screening, surveillance, and treatment.

The last 2 decades have seen dramatic advances in Barrett's esophagus. The definition has evolved; the rising incidence of adenocarcinoma has been recognized; and effective therapy to control gastroesophageal reflux disease has been developed. Both proton pump inhibitor therapy and laparoscopic fundoplication represent major developments. Studies of patients with dysplasia have helped to clarify appropriate surveillance intervals and treatment strategies for these patients, although controversy still exists. The possibility of reversing Barrett's esophagus in selected high-risk patients offers major hope for the future prevention of adenocarcinoma of the esophagus.

Evaluation of hepatic injury arising during fluconazole therapy.

Previous reports have described hepatotoxicity associated with ketoconazole therapy. There is also concern that therapy with fluconazole might cause the same side effect as ketoconazole. We describe two patients who developed unexplained liver test abnormalities after beginning fluconazole therapy. To determine whether fluconazole might have been responsible, liver biopsies were performed. Specimens from both patients demonstrated an absence of hepatocyte necrosis, which, if present, would have necessitated discontinuation of fluconazole therapy. A critical review of other case reports of fluconazole-associated hepatitis also failed to produce a consistent picture. Our experience indicates that a liver biopsy may be useful in selected patients to exclude clinically relevant hepatotoxicity due to fluconazole therapy and to allow its continued use.

Significance of isolated hepatitis B core antibody in blood donors.

BACKGROUND: About 25% of blood donors who test positive for antibody to hepatitis B core antigen (anti-HBc) have no other positive hepatitis B serologic results. Because of the potential importance and diagnostic uncertainty of this test result, we studied its significance by assessing the serologic response to hepatitis B vaccine in donors with an isolated anti-HBc pattern. METHODS: Specimens from 300 blood donors that were positive for anti-HBc by enzyme immunoassay were tested for anti-HBc by radioimmunoassay and for antibody to hepatitis B surface antigen (anti-HBs). A subgroup of 37 were further studied after administration of hepatitis B vaccine and compared with 34 similarly vaccinated age- and sex-matched seronegative controls. Measurements of anti-HBs were made at vaccination and 1, 2, 4, 8, 25, and 30 weeks after initial vaccination. RESULTS: Among 300 donors who tested positive for anti-HBc by enzyme immunoassay, the radioimmunoassay for anti-HBc was negative in 76 (25.3%) and the test for anti-HBs was negative in 104 (34.7%). Significant differences were observed for radioimmunoassay anti-HBc and anti-HBs titers, alanine aminotransferase, and male-female ratios between four distinct serogroups (A through D) defined by the combination (positive/negative) of radioimmunoassay anti-HBc and anti-HBs results. No significant differences between the study and control groups were observed in the magnitude of anti-HBs responses at any of the six postvaccine testing periods. CONCLUSIONS: Isolated anti-HBc in US blood donors is usually a false-positive result, regardless of the titer.

Clinical and economic assessment of the omeprazole test in patients with symptoms suggestive of gastroesophageal reflux disease.

OBJECTIVE: To evaluate the diagnostic accuracy of a trial of a high-dose proton pump inhibitor (the omeprazole test) in detecting gastroesophageal reflux disease (GERD) in patients with heartburn symptoms. DESIGN: A randomized, double-blind, placebo-controlled, crossover trial. PATIENTS AND SETTING: Forty-three consecutive patients with symptoms suggestive of GERD were enrolled at a Veterans Affairs medical center. MAIN OUTCOME MEASURES: Symptom response to the omeprazole test vs placebo in GERD-positive and GERD-negative patients; sensitivity, specificity, and positive and negative predictive values of the omeprazole test; and cost per correct diagnosis achieved with the omeprazole test compared with traditional diagnostic strategies. RESULTS: Of 42 patients (98%) who completed the study, 35 (83%) were classified as GERD positive and 7 (17%) as GERD negative. Twenty-eight GERD-positive and 3 GERD-negative patients responded to the omeprazole test, providing a sensitivity of 80.0% (95% confidence interval, 66.7%-93.3%) and a specificity of 57.1% (95% confidence interval, 20.5%-93.8%). Economic analysis revealed that the omeprazole test saves $348 per average patient evaluated, and results in a 64% reduction in the number of upper endoscopies performed and a 53% reduction in the use of pH testing. CONCLUSIONS: The omeprazole test is sensitive and fairly specific for diagnosing GERD in patients with typical GERD symptoms. This strategy could result in significant cost savings and decreased use of invasive diagnostic tests.

The diagnosis and treatment of gastroesophageal reflux disease in a managed care environment, Suggested disease management guidelines.

A group of experts from gastroenterology, internal medicine, health economics, medical outcomes, and managed care met in San Francisco, Calif, on September 27, 1994, in an effort to develop clinically and economically effective disease management guidelines to assist physicians in their treatment of gastroesophageal reflux disease in a managed care environment. This article represents a consensus opinion based on the evidence and expert interpretation at the time of that meeting.

The impact of practice guidelines in the management of Barrett esophagus: a national prospective cohort study of physicians.

BACKGROUND: Surveillance of patients with Barrett esophagus (BE) is recommended to detect dysplasia and early cancer. In 1998, practice guidelines for the surveillance of patients with BE were developed under the auspices of the American College of Gastroenterology (ACG). Our objective is to assess physicians' awareness of agreement with and adherence to these guidelines. METHODS: A national prospective cohort study of practicing gastroenterologists who completed a self-administered questionnaire containing case studies prior to the release of the guidelines and another survey 18 months later. Analysis of adherence to the guidelines was done using the McNemar chi(2) test. RESULTS: Of the 154 gastroenterologists (66%) who responded to the follow-up survey, more than half (55%) were aware of the guidelines, and members of the ACG were more likely to know of their existence than nonmembers (61% vs 38%; P =.01). Overall, about 27% of physicians reported practicing in accordance with the guidelines at baseline; adherence increased modestly to 38% in the 18-month follow-up (P =.04) and was inversely related to fee-for-service reimbursement. Awareness was not associated with an increased likelihood of adherence, but agreement with the guidelines was strongly correlated with adherence (P<.001). The most frequent reasons for disagreement were concerns about liability, cancer risk, and inadequate evidence. CONCLUSIONS: Awareness of the guidelines published by the ACG was low. Guideline awareness did not predict adherence. Improvement in guideline adherence will require steps beyond mere dissemination and promotion. Addressing disagreements about liability, disease risk, and scientific evidence as well as restructuring payment incentives may help achieve optimal practice.

Chemopreventive studies in Barrett's esophagus: a model premalignant lesion for esophageal adenocarcinoma.

Barrett's esophagus is a premalignant lesion in which the lower esophagus is lined with metaplastic columnar epithelium rather than the normal stratified squamous epithelium. It is a precursor lesion for adenocarcinoma of the esophagus. We are studying Barrett's esophagus as a model premalignant lesion for adenocarcinoma from the standpoint of identifying biologic markers of increased cancer risk as well as therapeutic strategies for eradicating the lesion. Ornithine decarboxylase (ODC) activity in Barrett's mucosa was significantly higher than in normal adjacent mucosa from the same patient. However, polyamine content was not significantly altered, suggesting dysregulation of the polyamine pathway. Flow cytometry is being used to assess the presence of aneuploidy and its significance in a premalignant lesion. Initial results have demonstrated that aneuploidy and dysplasia can be discordant. Cytogenetic analysis using short-term epithelial cultures established from endoscopic biopsies of the lesion has demonstrated the presence of clonal karyotypic abnormalities. The clinical significance of aneuploidy and abnormal karyotype, however, remains to be proved. Chemopreventive intervention trials have included use of 13-cis-retinoic acid. Considerable toxicity was encountered, and the lesion showed no change in extent in 11 evaluable patients. A subsequent clinical trial with a biologic endpoint used alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, to test whether a low dose could produce changes in polyamine content in gastrointestinal mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastrointestinal tissue polyamine contents of patients with Barrett's esophagus treated with alpha-difluoromethylornithine.

alpha-Difluoromethylornithine (DFMO), an investigational chemopreventive agent, suppresses polyamine contents and decreases epithelial carcinogenesis in experimental models. The ability of this drug to decrease polyamine contents in human esophageal tissues has not yet been determined. Eight patients with Barrett's esophagus were treated with DFMO at a dose of 1.5 g/m2/day for 12 weeks. Four sites (Barrett's lesion, adjacent normal squamous esophagus, gastric tissue, and small bowel) were biopsied in each patient before, during, and after DFMO treatment in order to assess the effects of this drug on tissue polyamine levels. Ornithine decarboxylase activities and polyamine contents varied in each site analyzed. The rank orders were Barrett's > small bowel congruent to normal esophagus > gastric tissue for ODC activities, and small bowel > or = Barrett's congruent to normal esophagus > gastric tissue for putrescine contents. Spermidine, but not spermine, contents in the Barrett's lesions and normal squamous esophageal tissue were suppressed by systemic DFMO treatment and recovered to untreated control values when DFMO therapy was discontinued. Systemic DFMO treatment did not affect the levels of either of these two amines in gastric tissue and small bowel. Since DFMO can suppress polyamine contents in several gastrointestinal tissues, including Barrett's mucosa, we conclude that it is an effective agent with which to test the hypothesis that depletion of spermidine contents may prevent the development of adenocarcinoma of the esophagus in this specific patient group.

Gastric intestinal metaplasia in ethnic groups in the southwestern United States.

The incidence of gastric cancer has declined dramatically in the United States during this century. However, the incidence of gastric cancer among Hispanics, Blacks, and Native Americans remains 2-3-fold higher than among Whites in this country. Populations with an increased risk of gastric cancer have predominantly the "intestinal" type of gastric cancer, and intestinal metaplasia is regarded as a histological precursor lesion of this type of gastric cancer. We sought to establish the prevalence of intestinal metaplasia, identify associated epidemiological factors, and improve detection of this lesion in a patient population undergoing clinically indicated endoscopy in the Southwestern United States. Among the 440 patients studied, we observed an overall crude prevalence of intestinal metaplasia of 19%. However, the crude prevalence among Hispanics and Blacks was found to be markedly higher than among non-Hispanic Whites (50% versus 13%). Two biopsy protocols (two biopsies versus four biopsies) were used during this study, with a significantly higher rate of intestinal metaplasia detection under the four-biopsy protocol. Adjusting for protocol, we found that age and ethnicity were significantly and independently associated with the prevalence of intestinal metaplasia. The odds of intestinal metaplasia diagnosis was significantly higher in Hispanics compared to non-Hispanic Whites (P < 0.001), and the prevalence of intestinal metaplasia increased with advancing age (P = 0.01). The presence of Helicobacter pylori was also significantly associated with the presence of intestinal metaplasia (P = 0.02), although the direction of the association differed between Hispanics and non-Hispanic Whites.

Plasma selenium concentration predicts the prevalence of colorectal adenomatous polyps.

The objective of this cross-sectional study was to determine whether plasma selenium concentration predicts the prevalence of adenomatous polyps of the colon and rectum. The source population for the study was 101 patients undergoing sequential colonoscopies at the Veterans Affairs Medical Center, Tucson, AZ. The study population was then limited to the 48 patients (all male) undergoing their initial colonoscopy who did not have a diagnosis of colorectal cancer. For each of these patients, a prediagnostic fasting plasma selenium concentration was determined. The data from this study suggest that fasting plasma selenium concentrations may be an important risk factor for colorectal adenomas. Patients with fasting plasma selenium concentrations below the median (< 128 mcg/liter) were significantly more likely to have one or more adenomatous polyps (prevalence odds ratio 4.2) and more adenomatous polyps (3.5 times) per patient. There was also a suggestion of a more proximal distribution of adenomatous polyps in the patients with a lower level of selenium. These associations were not confounded by age or smoking. The results of this study are consistent with the experimental animal studies, geographic mortality studies, and prospective cohort studies of selenium and colorectal cancer.

Ornithine decarboxylase and polyamines in colorectal neoplasia and mucosa.

Ornithine decarboxylase (ODC) and polyamines are intimately involved in normal cellular proliferation and are likely to play a role in carcinogenesis. ODC activity and polyamine content were measured in tissue samples obtained during colonoscopy from 48 benign neoplastic polyps (20 tubular adenomas; 28 villous adenomas), 18 cancers (including 5 malignant polyps), and adjacent mucosa. ODC activity in polyp and cancer tissue specimens was higher than in adjacent mucosa in 75 and 83% of pairs, respectively. Similarly, putrescine, spermidine, and spermine contents were higher in the majority of polyps and cancers compared to adjacent mucosa. ODC activity and polyamine content in colonic mucosa from 10 patients without a history of colorectal neoplasia were not different from adjacent mucosal values in the patients with neoplasia. In conclusion, ODC and polyamines are elevated in the majority of colorectal neoplasms, but amounts in normal mucosa do not differentiate between patients with cancer, benign neoplastic polyps, and normal subjects.

Severe pulmonary hypertension in a patient with Whipple's disease.

Rapidly progressive heart failure, in part related to severe pulmonary hypertension, developed in a patient with biopsy-proved Whipple's disease. The patient's pulmonary hypertension progressed despite antibiotic therapy and histologic remission of his intestinal disease. The combination of oral nifedipine and low-flow continuous oxygen led to both short- and long-term increases of at least 2 liters per minute in cardiac output and reductions of more than 10 mm Hg in mean pulmonary artery pressure. Accompanying these hemodynamic changes was an improvement of more than 10 percent in right ventricular ejection fraction. The relationship between this patient's pulmonary hypertension and his Whipple's disease is not known.

Progress report: the Arizona phase III study of the effect of wheat bran fiber on recurrence of adenomatous colon polyps.

A double-blind, placebo-controlled Phase III cancer prevention trial in subjects with previous resection of adenomatous colon polyps is nearing completion. The study's primary objective is to evaluate the effects of daily dietary supplementation with large (13.5 g/day) versus small (2.0 g/day) doses of wheat bran fiber for 3 years. A summary of the study design and a progress report are presented.

Mucosal ablation therapy of barrett esophagus.

Barrett esophagus is defined by the metaplasia of existing squamous mucosa into a specialized intestinal-type mucosa. The importance of this metaplasia is the association of this condition with the development of adenocarcinoma of the esophagus. Elimination of the metaplastic mucosa may decrease the cancer risk. Currently, several forms of therapy have evolved with the goal of replacing the specialized mucosa with normal squamous mucosa. These proposed treatments include photodynamic therapy and thermal techniques. The effectiveness of photodynamic therapy varies depending on the pharmaceutical photosensitizer used and the wavelength of light applied to activate the drug. Thermal techniques include multipolar coagulation, argon plasma coagulation, KTP:YAG laser therapy, Nd:YAG laser therapy, and argon laser therapy. Finally, mucosal resection has been attempted through the endoscope to remove large areas of the Barrett mucosa. All of these ablative strategies attempt to destroy the metaplastic mucosa and promote the regrowth of squamous epithelium. These therapies have demonstrated the ability to "reverse" the metaplasia to varying degrees, but a decrease in cancer risk has not been demonstrated conclusively with any of these treatment methods.

Medical decision analysis of endoscopic surveillance of Barrett's oesophagus to prevent oesophageal adenocarcinoma.

BACKGROUND: Barrett's oesophagus is associated with an increased risk of the development of oesophageal adenocarcinoma. Endoscopic surveillance every 2-5 years has been recommended to prevent death from adenocarcinoma. AIM: To assess the cost-effectiveness of this strategy. METHODS: The incremental cost-effectiveness of surveillance (as compared to no surveillance) was analysed with a computer model of a Markov process. RESULTS: Compared to no surveillance, the incremental cost-effectiveness of bi-annual endoscopy is 16,695 dollars per life-year saved. Surveillance is less cost-effective if the incidence rate of oesophageal adenocarcinoma is low and the 5-year survival rate is high. For surveillance to be cost-effective, there should be little reduction in health-related quality of life following surgical oesophagectomy to prevent death. Moreover, endoscopic surveillance and oesophagectomy need to be efficacious in reliably diagnosing high-grade dysplasia and preventing deaths from cancer. If such ideal conditions of surveillance are not met, the cost per life-year saved could rise five-fold. CONCLUSIONS: Endoscopic surveillance of patients with Barrett's oesophagus may be a cost-effective means to prevent death from oesophageal adenocarcinoma.