Clinical trial: comparison of the gastrointestinal safety of lumiracoxib with traditional nonselective nonsteroidal anti-inflammatory drugs early after the initiation of treatment--findings from the Therapeutic Arthritis Research and Gastrointestinal Event Trial.

BACKGROUND: The large (n = 18 325) Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) study demonstrated a significant gastrointestinal benefit with lumiracoxib 400 mg o.d. (4x the recommended dose in osteoarthritis) vs. naproxen 500 mg b.d. or ibuprofen 800 mg t.d.s. AIM: To investigate how early a reduction in ulcer complications could be detected with lumiracoxib vs. nonselective nonsteroidal anti-inflammatory drugs in TARGET. METHODS: Pointwise 95% confidence intervals were generated for the between-treatment differences in Kaplan-Meier estimates for definite or probable upper gastrointestinal ulcer complications (ulcer complications) and for all ulcers. RESULTS: In patients not on aspirin, there was a significant reduction in all ulcers by day 8 and in ulcer complications by day 16 with lumiracoxib compared with both nonselective nonsteroidal anti-inflammatory drugs combined, by day 6 (all ulcers) and day 14 (ulcer complications) vs. naproxen and by day 32 (all ulcers) and day 33 (ulcer complications) vs. ibuprofen. CONCLUSION: Even with short-term use, there are gastrointestinal safety benefits for lumiracoxib vs. nonselective nonsteroidal anti-inflammatory drugs.

Emerging gastritides.

The purpose of this review is to highlight two types of gastritis that have recently received much greater attention: lymphocytic gastritis and the gastritis associated with Crohn's disease. Lymphocytic gastritis is a distinctive pattern of inflammation that resembles that seen in celiac disease and lymphocytic colitis. It is associated with a diverse and unusual group of disorders in their own right, as well as having a possible relationship (real or phantom) with H. pylori infection. With respect to Crohn's disease, there is a growing recognition that, much more common than gastric granulomas, is the existence in one third or more of patients of a highly focal non-H. pylori gastritis. This recognition may help secure the diagnosis of Crohn's disease where it is equivocal, especially in children, in whom follow-up radiography and endoscopy cannot be done as readily as in adults.

Effective and safe endoscopic reversal of nondysplastic Barrett's esophagus with thermal electrocoagulation combined with high-dose acid inhibition: a multicenter study.

BACKGROUND: Barrett's esophagus is a metaplastic change in the esophageal lining with an increased risk for adenocarcinoma. Multiple endoscopic techniques have been applied in an effort to reverse Barrett's. This is a multicenter trial defining the efficacy and safety of multipolar electrocoagulation combined with high-dose acid inhibition. METHODS: Patients with a 2- to 6-cm segment of Barrett's esophagus without dysplasia were enrolled at 3 centers. They were treated with omeprazole 40 mg twice daily and then with up to 6 sessions with electrocoagulation aimed at eliminating all the endoscopically apparent Barrett's. Four quadrant large-capacity biopsies every 2 cm were centrally assessed for residual intestinal metaplasia. RESULTS: Fifty-eight patients reached the endpoint of failure of visual reversal of Barrett's after 6 treatment sessions or a 6-month follow-up after the last session. Eighty-five percent had visual reversal and 78% both visual and histologic reversal. Four patients had histologic evidence of residual intestinal metaplasia. Transient esophageal symptoms were common. One patient developed a stricture requiring dilation and one required overnight hospitalization for chest pain. CONCLUSIONS: The majority of patients with 2 to 6 cm of nondysplastic Barrett's esophagus can be safely reversed with this combination therapy. Long-term follow-up will be necessary to document the durability of the new squamous epithelium.

The quality of care in Barrett's esophagus: endoscopist and pathologist practices.

BACKGROUND: The diagnosis of Barrett's esophagus (BE) has important psychological and economic implications. Although accepted standards for endoscopic biopsy methods and pathological interpretation for BE exist, adherence to these standards as a measure of the quality of care in BE has not been evaluated. Our aim was to assess the quality of care in BE by evaluating the process of care and adherence to accepted standards of practice. METHODS: Explicit process-of-care criteria were developed using a systematic literature review and expert opinion in four domains of care: the quality of biopsy methods, the adequacy in identifying endoscopic landmarks, endoscopist-pathologist communication, and pathological interpretation and reporting. We reviewed all endoscopy and pathology reports of BE patients at two institutions from 1994-1997. An academic medical center (N = 237) with staff endoscopists and an academically affiliated community hospital (N = 100) with private-practice endoscopists were analyzed. RESULTS: Physicians showed the highest adherence to accepted standards of care in the "adequacy of identifying landmarks" and "endoscopist-pathologist communication" domains, with a > or =70% adherence rate in most criteria. Conversely, physicians demonstrated the poorest adherence with the "quality of biopsy methods" and "pathologist interpretation and reporting" domains, with adherence rates frequently <60%. Significantly, biopsies were taken in the presence of visible esophagitis 35% of the time. Performance on several of the quality indicators varied significantly by the practice setting. CONCLUSIONS: We have identified several opportunities for quality improvement efforts. In every domain, there is room for improvement, particularly in the quality of biopsy methods. As initiatives to screen the large population of gastroesophageal reflux disease patients for BE may be imminent, the time is now to define the critical process-of-care measures to minimize the risk of overdiagnosis and inadequate endoscopic surveillance.

Heterogeneity of gastric histology and function in food cobalamin malabsorption: absence of atrophic gastritis and achlorhydria in some patients with severe malabsorption.

BACKGROUND: The common but incompletely understood entity of malabsorption of food bound cobalamin is generally presumed to arise from gastritis and/or achlorhydria. AIM: To conduct a systematic comparative examination of gastric histology and function. SUBJECTS: Nineteen volunteers, either healthy or with low cobalamin levels, were prospectively studied without prior knowledge of their absorption or gastric status. METHODS: All subjects underwent prospective assessment of food cobalamin absorption by the egg yolk cobalamin absorption test, endoscopy, histological grading of biopsies from six gastric sites, measurement of gastric secretory function, assay for serum gastrin and antiparietal cell antibodies, and direct tests for Helicobacter pylori infection. RESULTS: The six subjects with severe malabsorption (group I) had worse histological scores overall and lower acid and pepsin secretion than the eight subjects with normal absorption (group III) or the five subjects with mild malabsorption (group II). However, histological findings, and acid and pepsin secretion overlapped considerably between individual subjects in group I and group III. Two distinct subgroups of three subjects each emerged within group I. One subgroup (IA) had severe gastric atrophy and achlorhydria. The other subgroup (IB) had little atrophy and only mild hypochlorhydria; the gastric findings were indistinguishable from those in many subjects with normal absorption. Absorption improved in the two subjects in subgroup IB and in one subject in group II who received antibiotics, along with evidence of clearing of H pylori. None of the subjects in group IA responded to antibiotics. CONCLUSIONS: Food cobalamin malabsorption arises in at least two different gastric settings, one of which involves neither gastric atrophy nor achlorhydria. Malabsorption can respond to antibiotics, but only in some patients. Food cobalamin malabsorption is not always synonymous with atrophic gastritis and achlorhydria, and hypochlorhydria does not always guarantee food cobalamin malabsorption.

Mucosal biopsy techniques and interaction with the pathologist.

The endoscopy era made it possible to see many of the diseases that were being treated by clinicians. The use of endoscopic biopsy further enhanced that ability. This article illustrates how gastrointestinal biopsy and other practices can be improved so that patients benefit more than they might otherwise. This article focuses on pinch biopsy forceps technique and on dialogue with the pathologist.

Gastric biopsy.

This article focuses on the global settings where biopsy is done, the practical issues of how to do it, and what might be the benefit. The section on biopsy tips is condensed to provide very practical guidelines and some new information for even the most seasoned of endoscopists. This article covers topics such as the three histologic zones of the stomach, when to biopsy to rule out neoplasia, and biopsy in benign gastric mucosal disease.

The histologic spectrum and clinical outcome of refractory and unclassified sprue.

The vast majority of patients with celiac disease respond to a gluten-free diet; yet, a small number of refractory patients do not respond and have persistent malabsorption and residual mucosal abnormalities of the small intestine. The histologic features of refractory/unclassified sprue have been published as case reports, often without long-term follow up, and no clear histologic picture has emerged. We present the results of a long-term study of the clinical and histologic features of 10 patients with refractory/unclassified sprue. The histologic features of small bowel biopsies in this group of patients were compared with those of 10 patients with responsive celiac disease and with 10 patients without malabsorption who had normal duodenal biopsies. Five of the 10 refractory patients ultimately developed collagenous sprue as a distinct histologic marker of refractory disease. Additional distinctive findings found in small bowel biopsies in the refractory group were subcryptal chronic inflammation (10 of 10) and marked mucosal thinning in three patients. Other nonspecific findings included acute inflammation and gastric metaplasia. One patient with collagenous sprue developed a B-cell lymphoma of the ileum, and in general collagenous sprue was associated with a poor prognosis. Two of five patients died whereas two others require total parenteral nutrition for survival. Pathologists evaluating small bowel biopsies in the setting of malabsorption should be aware of the subtle histologic changes described here that may portend a refractory course.

Inflammation of the gastro-oesophageal junction (carditis) in patients with symptomatic gastro-oesophageal reflux disease: a prospective study.

BACKGROUND: Recent data have suggested that cardia biopsy specimens may be more reflective of gastro-oesophageal reflux disease (GORD) than squamous biopsy specimens. AIMS: To assess the distribution, severity, and types of mucosal injury in GORD. PATIENTS: Thirty patients with symptomatic GORD with no or minimal erosions. METHODS: Biopsies were performed at the squamocolumnar junction (Z-line) and 1-2 cm below the Z-line. Injury to the columnar mucosa was scored for inflammatory cells, epithelial cell abnormalities, and for the presence of intestinal metaplasia and Helicobacter pylori. A carditis score above 2 was considered positive (maximum score = 9). RESULTS: Mean carditis scores and percentages of patients with a positive carditis score were higher in Z-line biopsy specimens containing both squamous and columnar mucosa than in those with just columnar mucosa or in specimens taken 1-2 cm below the Z-line. Carditis at the Z-line was focal in 49% of the specimens and was always present adjacent to the squamous epithelium. Goblet cells were present more frequently in the specimens immediately at the Z-line than in those 1-2 cm below the Z-line. H pylori was present in only four patients. The mean carditis scores of specimens 1-2 cm below the Z-line in these patients was significantly higher than in those patients without H pylori. CONCLUSIONS: Mucosal injury at the gastric cardia is highly localised to the region adjacent to the squamocolumnar junction in patients with GORD. Morphological studies of the cardia in GORD should focus on tissue samples that contain both squamous and columnar epithelium in order to obtain an accurate picture of the spectrum of injury.

Collagenous colitis: a study of the distribution of morphological abnormalities and their histological detection.

In collagenous colitis, the literature is conflicting concerning where in the colon the lesions are most likely to be present and most severe. Conflicting data furthermore shed doubt on the sensitivity of the histological detection of the morphological abnormalities and the threshold criteria for diagnosis. We addressed these questions in 56 patients with collagenous colitis. Two hundred ninety-one coded biopsy specimens were analyzed according to six standardized sites from cecum to rectum. Subepithelial collagen deposits were subjectively graded in hematoxylin and eosin (H&E) sections and quantitatively measured in trichrome-stained sections, respectively. Semiquantitative grading was also done for inflammatory changes of the lamina propria and abnormalities of the surface and crypt epithelium. The transverse colon yielded the largest percentage of biopsy specimens (83%) interpreted as diagnostic of collagenous colitis and also had the largest percentage of biopsy specimens with inflammatory changes (98%). Biopsy specimens from both the rectosigmoid and the right colon (ascending and cecum) were significantly less likely to be diagnostic (P<.01). Only 66% of specimens obtained from the rectosigmoid were diagnostic, and 18% of these were interpreted as normal. Subepithelial collagen deposits proved to be significantly thicker in the transverse (median, 46.8 microm; range, 12 to 212.4) and descending (median, 49.2 microm; range, 6 to 230.4) than in the rectosigmoid (median, 33.6 microm; range, 9.6 to 178.8) and right colon (median, 35.4 microm; range, 6 to 140.4), respectively (P<.01). Almost all biopsy specimens (97%) had collagen deposits thicker than 10 microm. However, the subjective interpretation "diagnostic of collagenous colitis" proved to be most consistent with a threshold of 30 microm. Our results indicate that biopsy specimens from at least as proximal as the transverse colon should be obtained to definitely rule out collagenous colitis. Furthermore, it is evident that in a given biopsy specimen, markedly abnormal subepithelial collagen deposition had to be present for an unequivocal histological diagnosis of collagenous colitis.

Proton pump inhibitors and H. pylori infection: why the concern?

Proton pump inhibitor therapy, even on a short-term basis, is associated with a decrease in antral gastritis and an increase in gastritis of the body. On a long-term basis, some series show the development of atrophic gastritis and some show none or hardly any. All studies fail to show or to report any significant increase in the prevalence of intestinal metaplasia with long-term PPI therapy. If one wants to determine whether PPIs cause atrophic gastritis with intestinal metaplasia, then the angularis primarily and the gastric antrum secondarily need to be studied because that is where most IM resides in the intestinal types of cancer. Instead of focusing on the angularis and antrum, the studies have evaluated biopsies from the gastric body, the least likely spot to be intestinalized in association with the intestinal type of gastric cancer [11]. H. pylori is associated with both intestinal and diffuse types of gastric cancer. Obtaining an answer to the question of whether PPI therapy or any other type of therapy increases gastric cancer risk in H. pylori-positive patients will require epidemiologic studies in which cancer is the end point. Intermediate theoretic markers are not available for diffuse cancers. If intermediate markers are used for the intestinal type of gastric cancer, then atrophic gastritis with intestinal metaplasia might provide some insight on theoretical grounds. However, the published long-term studies to date have not addressed that question because of where they have focused the biopsy sampling, and/or because of failure to report data on intestinal metaplasia.

The prevalence of colonic neoplasia in patients with Barrett's esophagus: prospective assessment in patients 50-80 years old.

OBJECTIVE: An association between Barrett's esophagus and colorectal neoplasia has been suggested; however, several studies addressing this issue have reported conflicting results. The purpose of this study, therefore, was to determine the prevalence of colorectal neoplasia in a large group of patients (50-80 yr old; mean, 65 yr) with Barrett's esophagus and compare it with that of a similar group of asymptomatic, average-risk controls. METHODS: Seventy-nine subjects (71 men, eight women) with well-documented Barrett's esophagus underwent complete colonoscopy (cecum reached), which was performed as part of an initial screening evaluation for enrollment in a prospective study of Barrett's esophagus. The control population (N = 930) is represented by the cumulative results of four recent studies in which screening colonoscopy was performed in asymptomatic subjects of average risk. The age of the two groups were similar. RESULTS: A total of 38 adenomatous polyps were found in 26 patients in the study group. Three patients (4%) had polyps > 1 cm in size or with villous change, which was similar to the prevalence among asymptomatic controls (5%). The overall prevalence of colon adenomas was 32%, and the prevalence of colorectal cancer was 1% in the Barrett's group. In the control group, 30% had adenomas and 0.5% had cancer. CONCLUSION: The prevalence of adenomatous polyps, both large and small, in a group of patients (ages 50-80 yr) with well-documented Barrett's esophagus is no different from that in asymptomatic controls. These results do not support the assumption of an association between Barrett's esophagus and an increased risk of colon neoplasia, or justify an aggressive surveillance strategy for colon neoplasia in patients with Barrett's esophagus.

Precursor lesions for cancer of the cardia.

This article gives the rationale for the likelihood that the precursor lesion for cancer of the cardia is either short segments of Barrett's esophagus or even intestinalized (globlet cell change) mucosa at a normally located squamo-columnar junction. Intestinal metaplasia of the cardia is likely a wear and tear phenomenon in many individuals without gastroesophageal reflux disease (GERD). Markers that stratify risk further are required before routine biopsy specimens of the Z-line can be obtained in the clinical evaluation of patients with GERD.

Metaplastic columnar cells in Barrett's esophagus: a common and neglected cell type.

Goblet cells are considered by most to be a prerequisite for the diagnosis of Barrett's esophagus. Columnar cells that are alcian blue (AB) positive (as are goblet cells) are commonly observed in the surface epithelium of Barrett's esophagus, but their distribution in relation to goblet cells has not previously been defined. The authors analyzed the prevalence and distribution of these cell types in the surface but not pit epithelium (where they may sometimes be present in normal gastric mucosa). The distribution of the AB-positive columnar cells was mapped out in the entire mucosa of nine esophagectomy specimens, resected for Barrett's-associated high-grade dysplasia or carcinoma, and compared with other cell types, especially goblet cells. AB-positive goblet and columnar cells were present in 87.1% +/- 5.6% and 85.7% +/- 5.9%, respectively, of the evaluated sections of Barrett's mucosa, whereas gastric-type, AB-negative cells were observed in 46.3% +/- 8.7% of the sections. In 53% of the sections, the surface epithelium contained more than 25% AB-positive cells, and in more than three quarters of these sections, AB-positive columnar cells were the dominant AB-positive cell type. No difference in the distribution of the AB-positive epithelial cells was noticed between the proximal and distal halves of the Barrett's mucosae. In the cardia region, seven of nine cases showed a few scattered AB-positive columnar cells, and five of nine cases showed a few scattered goblet cells. No AB-positive cells were found in fundic gland mucosa. These findings indicate that the metaplastic AB-positive columnar cells are more prevalent than goblet cells. They may be analogous to incomplete metaplastic cells of the stomach, and, therefore, their role in the development of neoplasia needs further study.