Biomedical subjects
W M Weinstein
Publications and source records attributed to W M Weinstein.
Activation of c-Ki-ras in human gastrointestinal dysplasias determined by direct sequencing of polymerase chain reaction products.
Activation of c-Ki-ras by point mutation within exon 1 was studied in 33 specimens of dysplastic gastrointestinal lesions or of cancers presumed to arise from dysplasia. Samples were obtained from patients with underlying ulcerative colitis or Barrett's esophagus, two diseases associated with dysplasia and increased rates of colonic or esophageal adenocarcinoma, respectively. Genomic DNA was amplified using primers bounding this exon in the polymerase chain reaction. Polymerase chain reaction products were analyzed by direct dideoxy sequencing. Three point mutations in codon 13 of c-Ki-ras were found, all in colonic specimens (two high-grade dysplasias and one adenocarcinoma arising in ulcerative colitis). No point mutations were observed in the second exon of c-Ki-ras or in and around codons 12, 13, and 61 of c-N-ras and C-Ha-ras in a partial sampling of the specimens. These data indicate that ras family protooncogene activation is an uncommon event at this level of malignant progression in these disease states. Carcinogenesis in ulcerative colitis and Barrett's esophagus may proceed via different pathways than in sporadic colon cancer, perhaps involving loss or inactivation of suppressor genes.
Campylobacter pylori in alcoholic hemorrhagic "gastritis".
Previously we have shown that alcohol-associated subepithelial hemorrhages histologically represent localized superficial mucosal hemorrhage, with edema in the surrounding mucosa. We studied the relationship between Campylobacter pylori (CP) and histology in gastric subepithelial hemorrhages from 20 actively drinking alcoholic patients. Biopsies of the hemorrhagic lesions and adjacent mucosa 1 and 3 cm away were taken with a "jumbo" forceps. Biopsy slides were coded and randomized before histologic scoring and examination for CP. CP was present in 15/20 (75%) biopsies of subepithelial hemorrhages and in 32/40 (80%) biopsies from surrounding mucosa. The mean hemorrhage score was not significantly different in biopsies of subepithelial hemorrhages with and without CP (2.7 +/- 0.4 vs 3.2 +/- 0.4) and the edema scores in adjacent, nonhemorrhagic mucosa were similar in specimens with and without CP (2.0 +/- 0.3 vs 1.6 +/- 0.5). The inflammatory cell density was significantly greater in CP-positive biopsies than in CP-negative specimens (2.0 +/- 0.2 vs 0.5 +/- 0.2, P less than 0.05) with the mononuclear cell and neutrophil scores contributing equally to the overall inflammatory cell score. Almost a quarter of CP-positive specimens (11/47) had no inflammation. The mean score for lining epithelial abnormalities was also significantly higher in biopsy specimens positive for CP (1.7 +/- 0.2 vs 0.5 +/- 0.3, P less than 0.05). In conclusion, CP is present in 75% of alcohol-associated subepithelial hemorrhages, but its prevalence is similar in adjacent, nonhemorrhagic mucosa. No relationship exists between the presence of CP and the characteristic histologic abnormalities of these subepithelial hemorrhages.(ABSTRACT TRUNCATED AT 250 WORDS)
Tissue-specific expression of c-Ha-ras in premalignant gastrointestinal mucosae.
The molecular mechanisms underlying premalignant gastrointestinal diseases, such as ulcerative colitis and Barrett's esophagus, remain unknown. For this reason, the expression of the protooncogene c-Ha-ras was studied in ulcerative colitis and Barrett's esophagus. Total cellular RNA was extracted from different regions of the gastrointestinal tract in these two diseases. Expression of c-Ha-ras was greater in proximal than in distal colon and undetectable in Barrett's esophagus. These regional differences in expression were not seen with the control gene beta-actin or with the protooncogenes c-myc and p53. In order to evaluate structural factors contributing to expression, amplification and methylation of c-Ha-ras DNA were studied in these tissues by Southern and slot blotting. No amplification of c-Ha-ras or six other protooncogenes was detected. These data suggest tissue-specific regulation of c-Ha-ras expression in the gastrointestinal tract in certain premalignant disease states.
Extending the scope in celiac disease.
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Subepithelial hemorrhages and erosions of human stomach.
Subepithelial hemorrhages and erosions of the stomach are being studied extensively in experimental animal models but have not been well-characterized in humans. The definitions of these hemorrhagic and erosive lesions are not uniform and are often further confused by being labeled with the blanket term "gastritis." We define these lesions from an endoscopic perspective, describe the clinical settings in which they occur, and provide endoscopic-histologic correlations, where available.
Endoscopic biopsy can detect high-grade dysplasia or early adenocarcinoma in Barrett's esophagus without grossly recognizable neoplastic lesions.
There is uncertainty regarding the value of endoscopic biopsy surveillance in Barrett's esophagus because, in retrospective studies, some patients with high-grade dysplasia in endoscopic biopsy specimens have had unexpected advanced adenocarcinoma discovered at the time of esophageal resection. We compared the accuracy of preoperative endoscopic biopsy diagnoses with the final pathologic diagnoses in esophagectomy specimens in 4 patients who had both high-grade dysplasia and intramucosal carcinoma and 4 other patients who had only high-grade dysplasia preoperatively. The histologic lesions in all 8 patients were documented in intact mucosa with no gross evidence of neoplasia by endoscopy. The preoperative diagnoses were defined with an endoscopic biopsy protocol in which specimens were taken with large-channel biopsy forceps at least every 2 cm throughout the length of Barrett's epithelium. Final pathologic diagnoses derived from detailed analysis of the resected specimens confirmed high-grade dysplasia without carcinoma in 4 patients and intramucosal carcinoma in 2 patients. The remaining 2 patients with a preoperative diagnosis of intramucosal carcinoma had focal submucosal invasion by carcinoma in the resected specimens, but no involvement of the muscularis propria or adventitial lymph nodes. Because the natural history of high-grade dysplasia is not known, the decision to operate on patients with this lesion must be carefully weighed and individualized for each patient. Two of our patients who underwent esophageal resection for high-grade dysplasia without cancer died, one immediately postoperatively and the other 9 mo later after a postoperative stroke. Once intramucosal carcinoma is documented, surgery should be considered if the patient is an acceptable operative risk. We conclude that systematic preoperative endoscopic biopsy of intact mucosa in Barrett's esophagus can correctly detect high-grade dysplasia, either alone or in combination with early, treatable adenocarcinoma.
Histology of alcoholic hemorrhagic "gastritis": a prospective evaluation.
The term "hemorrhagic gastritis" is frequently applied to the subepithelial hemorrhages seen at endoscopy in alcoholic patients without a clear understanding of the histologic nature of these lesions. We prospectively screened 125 actively drinking alcoholic patients undergoing upper endoscopy for gastrointestinal bleeding. Gastric subepithelial hemorrhages were found in 20 of these patients. Biopsy specimens of hemorrhagic lesions and nonhemorrhagic mucosa 1 and 3 cm away were taken with a "jumbo" forceps. Gastric biopsy specimens from 12 patients with Barrett's esophagus served as controls for biopsy-induced trauma. Biopsy slides from the patients and controls were coded before histologic scoring. Mean hemorrhage scores (range, 0-4) for the target lesions (2.9 +/- 0.3) were significantly greater than scores for the adjacent mucosa (1 cm, 1.0 +/- 0.2; 3 cm, 1.1 +/- 0.2) or control biopsy specimens (0.8 +/- 0.1). Hemorrhage was superficial, occurring primarily in the foveolar region. Mucosal edema (score range, 0-4) was a prominent feature in the adjacent, nonhemorrhagic mucosa (target lesion, 0.7 +/- 0.2; 1 cm, 1.9 +/- 0.4; 3 cm, 2.0 +/- 0.3; controls, 0.8 +/- 0.1). Edema extended into the deeper gland zones in 11 of 20 patients but in none of the 12 controls (p less than 0.05). Inflammatory cell infiltrates were mild and scores did not vary significantly among the three biopsy sites in alcoholic patients. We conclude that subepithelial hemorrhages seen at endoscopy in alcoholic patients represent localized hemorrhage of the foveolar region with edema in the surrounding mucosa but without prominent inflammatory cell infiltration. Rather than use the term "hemorrhagic gastritis," endoscopists should simply describe these lesions as subepithelial hemorrhages.
Observer variation in the diagnosis of dysplasia in Barrett's esophagus.
The potential value of biopsy surveillance of patients with Barrett's esophagus for dysplasia is diminished by a lack of agreement on the diagnostic criteria for dysplasia. In a preliminary consensus conference, experienced gastrointestinal pathologists from four medical centers agreed on criteria for a five-tiered histologic classification of dysplasia in Barrett's esophagus--negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia, and intramucosal carcinoma. Eight morphologists in the four centers tested the criteria for interobserver agreement by examining a set of coded slides that had been chosen to include some especially difficult interpretative problems in all five histologic classifications. Interobserver agreement of 85 and 87% was achieved in successive reviews when the combined group of high-grade dysplasia and intramucosal carcinoma was compared with the combined group of low-grade dysplasia, indefinite for dysplasia, and negative for dysplasia. Comparison of other groups yielded less agreement. For example, negative for dysplasia could be distinguished from all other diagnoses with an interobserver agreement of 72%. We conclude that experienced gastrointestinal morphologists can diagnose high-grade dysplasia and intramucosal carcinoma with a high degree of agreement and thus can detect those patients who may need immediate rebiopsy or esophageal resection. Either further refinement of histologic criteria or alternate diagnostic methods will be needed to achieve the reproducible diagnosis of indefinite changes and low-grade dysplasia. This is important because patients with such changes theoretically merit closer endoscopic surveillance.
Esophagitis in scleroderma. Prevalence and risk factors.
Of 53 patients with scleroderma (43 women and 10 men) evaluated by esophagoscopy and biopsy, 32 (60%) had erosive esophagitis. Symptoms of heartburn and dysphagia were significantly more frequent in the patients who had erosive esophagitis but often were present in those without this condition. Abnormal motility characterized by loss of peristalsis in the distal esophagus was present in all patients with erosive esophagitis, including the 5 who were asymptomatic. No patient with normal esophageal motility had erosive esophagitis at endoscopy. The patients with erosive esophagitis also had significantly diminished lower esophageal sphincter pressures and increased frequency and duration of gastroesophageal reflux episodes. Stricture was present in 13 of 32 patients with erosive esophagitis and was absent in the other 21 patients. The duration of disease, rate of gastric emptying, and fungal smear and culture were not significantly different in those with or without esophagitis. Treatment of fungal infection for a month had little beneficial effect. The pattern of esophageal motility in scleroderma identifies high and low risk groups for esophagitis and stricture, and can be used to select those who require further investigation, irrespective of symptoms.
Barrett's esophagus and adenocarcinoma.
Barrett's esophagus represents an epithelial metaplasia in which a columnar lining replaces normal squamous epithelium of the esophagus. It occurs in at least 10% of patients with chronic gastroesophageal reflux and is associated with an increased risk of adenocarcinoma of the esophagus. This review focuses on the criteria for the diagnosis of Barrett's esophagus, discusses its association with adenocarcinoma, and provides guidelines for surveillance for carcinoma.
Glycoconjugate expression in normal, metaplastic, and neoplastic human upper gastrointestinal mucosa.
Glycoconjugate structure in upper gastrointestinal epithelium was studied using five lectins to determine the relationship between aberrant differentiation and glycoconjugate expression. Specimens of normal esophagus, stomach, and duodenum were examined and compared with specimens of columnar metaplasia in the esophagus (Barrett's esophagus) and specimens of adenocarcinoma of the esophagus and stomach. Specific terminal glycoconjugate structures were found for the esophagus, stomach, and duodenum. Minor differences were found between the antral and fundic gland mucosae, reflecting their respective cell populations. In biopsies of Barrett's esophagus, gastric-type columnar metaplasia expressed glycoconjugates indistinguishable from those in the normal stomach. In specialized-type columnar metaplasia, a more restricted expression of glycoconjugates was seen resembling the normal duodenum. The presence of low grade dysplasia in Barrett's esophagus associated with adenocarcinoma had no impact on glycoconjugate expression. However, a distinctive difference in glycosylation was seen in high grade dysplasia of the columnar-lined esophagus and in adenocarcinoma of the esophagus and stomach. Barrett's esophagus is a morphological mosaic in which the glycoconjugate expression resembles that seen in the normal stomach and duodenum. However, in high grade dysplasia and carcinoma, variable deletion of glycoconjugate expression can be found.
Immunoassay of pig and human gastric proton pump.
Monoclonal antibodies against the K+-dependent adenosine triphosphatase (ATPase) responsible for acid secretion in the pig gastric mucosa were generated by hybridoma technology. Two of these antibodies, shown to bind selectively to subunits of the ATPase and to label intracellular membranes of pig and rabbit parietal cells, were used to develop a sensitive (less than 1 pmol) immunoassay for the ATPase. Enzyme samples were adsorbed to the wells of polystyrene microtitration plates and then incubated sequentially with monoclonal antibody, antimouse immunoglobulin G coupled to alkaline phosphatase, and p-nitrophenyl phosphate. Standard curves relating the absorbance of the wells at 410 nm to log10 micrograms ATPase were fitted by a three-parameter logistic, with a useful assay range of 0.05-10 micrograms ATPase. The immunoassay allows measurement of proton-pumping ATPase levels in human gastric biopsy specimens and may therefore be useful in studies of gastric mucosal function.
Sucralfate therapy in patients with symptoms of alkaline reflux gastritis. A randomized, double-blind study.
The effects of sucralfate (6 g per day) and placebo on symptoms, endoscopic findings, and gastric mucosal histology were compared in 23 patients with symptoms of alkaline reflux gastritis who had undergone Billroth I, Billroth II, or vagotomy and pyloroplasty. Patients were randomly assigned to receive sucralfate (n = 11) or placebo (n = 12) for six weeks. Then all received six weeks of open sucralfate therapy before treatment codes were revealed. Twelve gastric biopsy specimens were obtained before patients began treatment and at six and 12 weeks. The two groups did not differ significantly with respect to symptom scores or endoscopic findings at baseline, after the double-blind phase, or after open sucralfate treatment. There were also no significant differences between the treatment groups with respect to epithelial cell scores and conventional gastritis scores. However, after the six-week, double-blind phase, the inflammatory cell score of the sucralfate-treated group was significantly lower (p less than 0.05) than that of the placebo-treated group (1.3 +/- 0.3 versus 1.9 +/- 0.4). After six weeks of open sucralfate treatment, patients who had initially received placebo had a significant reduction (1.4 +/- 0.3 versus 1.9 +/- 0.4) in their inflammatory cell score. Sucralfate lowered the inflammatory cell scores of patients with symptoms of alkaline reflux gastritis. This reduction, however, was not associated with an improvement in symptoms.
Electron microscopy of the intestine and rectum in acquired immunodeficiency syndrome.
To provide a better understanding of the morphologic changes that take place in the intestine and colon in acquired immunodeficiency syndrome (AIDS), electron microscopy was performed on intestinal or colonic biopsy specimens obtained from 6 patients with AIDS and from 2 patients with AIDS-related lymphadenopathy syndrome. Cryptosporidia were attached to the plasma membrane of epithelial cells in 2 patients and were noninvasive. An invasive protozoan organism identified as Microsporidia was found in 1 patient. Evidence for epithelial cell injury was limited. Unusually prominent secretory granules in colonic epithelial cells (a morphologic counterpart of secretion) was found in 2 patients. Tubuloreticular structures were observed in 7 patients. The structures were found in endothelial cells, lymphocytes, monocytes, intraepithelial lymphocytes, and free in the capillary lumen. Tube- and ring-shaped forms were observed in 2 patients, prominent intraepithelial mast cells in 4 patients, rectal spirochetosis in 1 patient, and pseudomembranous colitis in 1 patient with intestinal and systemic shigellosis. Vesicular rosettes, retroviruses, other viruses, and Mycobacterium avium-intracellulare were not observed. These observations expand our knowledge of morphologic changes in the colonic and intestinal mucosa in patients with AIDS. Tubuloreticular structures are so prominent, in contrast to our previous electron-microscopic observations in other disease and normal states of the intestine and colon, that their finding (though clearly nonspecific) may be a clue to the diagnosis of AIDS in an otherwise equivocal situation.
Barrett's esophagus in childhood.
This study describes the clinical, radiologic, esophageal function test, endoscopic, and histologic findings of Barrett's esophagus in 11 children aged 6-14 yr. All had long-standing symptoms of gastroesophageal reflux, which had begun in the first year of life in 10 of the 11. Eight of the 11 patients had mid or upper esophageal strictures and 10 of the 11 required fundoplication. Most patients had low lower esophageal sphincter pressures and abnormal pH probe studies. Only 6 of the 11 children had the characteristic pink-red appearance of the mucosa at endoscopy. Fifty endoscopic biopsy specimens taken at multiple levels in the esophagus contained columnar-lined epithelium above the gastroesophageal junction. Five of the patients had specialized (intestinal-type) epithelium as part of the histologic spectrum. The clinical expression of Barrett's esophagus in children is similar to that in adults except that strictures appear to be more common in children, and the endoscopic appearance of the mucosa is not always typical in color. As in adults, gastroesophageal reflux appears to be the etiology. In children beyond infancy, Barrett's esophagus is the most common indication for antireflux surgery at our institution. Biopsy specimens should be taken from multiple levels in the esophagus to avoid overdiagnosis and to establish the diagnosis with certainty.
The histology of the stomach in symptomatic patients after gastric surgery: a model to assess selective patterns of gastric mucosal injury.
We assessed selective patterns of histological injury in the gastric mucosa of 25 patients (12 Billroth II, 8 Billroth I, 5 vagotomy and pyloroplasty) with symptoms of alkaline reflux gastritis. Each patient had 12 biopsies taken from standardised sites. Histology was scored separately for surface epithelial changes and for inflammatory cells. The traditional grading of gastritis was also done using the categories of superficial and atrophic gastritis. The main histological changes were epithelial, especially in the pits (foveolae) of Billroth II patients. Although mild to moderate atrophic gastritis was present, the inflammatory cell density was only mild. Differences between surgery types for any given histological parameter became apparent only upon the analysis of regional changes within the stomach. Conventional grading of gastritis is based mainly on degrees of gland loss and thus is mainly of value to study chronic changes. However, the type of histological evaluation used here, with standardised biopsy sites, and separate scoring of epithelial and inflammatory changes is potentially more suitable to study shorter term changes as might occur with cytoprotective or damaging agents.
Recombinant alpha-2 interferon therapy for Kaposi's sarcoma associated with the acquired immunodeficiency syndrome.
In a randomized prospective study we tested the toxicity and efficacy of recombinant alpha-2 interferon in the treatment of Kaposi's sarcoma associated with the acquired immunodeficiency syndrome. High doses (50 X 10(6) U/m2 body surface area, intravenously) or low doses (1 X 10(6) U/m2, subcutaneously) of recombinant alpha-2 interferon were administered to 20 patients for 5 days/wk, every other week, for four treatment cycles. Therapy was well tolerated subjectively and caused only mild hematologic and hepatic toxicity at both dose levels. No consistent or sustained changes were seen in immunologic variables during or after treatment. Six patients with Kaposi's sarcoma, four at high dose and two at low dose, had objective responses (complete or partial) to treatment. However, therapy did not appear to eradicate cytomegalovirus carriage or prevent opportunistic infections related to cytomegalovirus.