Long-term outcomes of thalidomide in refractory Crohn's disease.

BACKGROUND: Several open-label and retrospective studies have indicated that thalidomide may be beneficial in patients with refractory Crohn's disease (CD). AIM: To report our long-term experience with the use of thalidomide for adults with refractory Crohn's disease. METHODS: We conducted a retrospective study of long-term clinical and safety outcomes among adults treated with thalidomide for refractory Crohn's disease. Response was defined as a clinician's assessment of improvement after at least 7 days treatment of one or more of the following: bowel movement frequency, fistula output, rectal bleeding, abdominal pain, extraintestinal manifestations, or well-being. Remission required all of the following: <3 stools/day, no bleeding, abdominal pain or extraintestinal manifestations and increased well-being. RESULTS: Thirty-seven adults with refractory Crohn's disease were treated with thalidomide for a median of 4.4 months and followed up for a median of 58 months. Clinical response and remission rates were 54% and 19%, respectively. About 40% of patients were able to stop steroids. Response rates were higher for those treated with more than 50 mg/day (85%) than for those treated with a maximum of 50 mg/day (40%; P = 0.01). An adverse event occurred in 68% of patients. Approximately one-third of patients (38%) experienced neuropathy. CONCLUSIONS: Thalidomide appears to be safe and effective in some patients with refractory Crohn's disease. Although side effects may limit long-term use, thalidomide has potential to induce significant clinical responses.

Esophageal biopsy.

Esophageal biopsy is a natural extension of the endoscopic evaluation of many patients. It has a high likelihood of diagnostic accuracy in malignant and infectious esophageal disease. With careful attention to landmarks and good communication between the gastroenterologist and the pathologist BE should be readily diagnosed. With proper attention to the recommended biopsy protocols dysplasia should be detected accurately. Future research will determine the value of biopsy in the patient with gastroesophageal reflux and a normal endoscopy.

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.

Esophageal motility abnormalities in cirrhotic patients before and after endoscopic variceal treatment.

Esophageal motility abnormalities in patients treated endoscopically for variceal hemorrhage are rarely studied and usually are not addressed in the clinical setting. However, a review of the literature revealed that esophageal varices reduce the mean amplitude and increase the mean duration of peristaltic waves but have little effect on lower esophageal sphincter function. Transit time is delayed and gastroesophageal reflux disease is common in up to 64% of the patients. Whereas band ligation appears to have little impact on esophageal motility, data are limited and are hampered by lack of standardization, rendering conclusions about safety rather premature. Injection sclerotherapy spares the lower esophageal sphincter, as well, but it significantly reduces mean amplitude contractions, mainly in the lower one-third to one-half of the esophagus. In addition, normal peristalsis may be occasionally or completely replaced by nonpropagating simultaneous contractions that may result in chest pain and/or dysphagia in the absence of stricture. Transient prolongation of acid clearance usually resolves within a week, except in patients who have developed stricture. Pathogenesis of the abnormal motility remains poorly understood, and treatment has been empirical. However, a short course of anti-reflux treatment after each therapeutic session is justified, as well as long-term treatment for patients with stricture. The choice of treatment for esophageal motility abnormalities is less clear and requires future studies.

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.

Two doses of omeprazole versus placebo in symptomatic erosive esophagitis: the U.S. Multicenter Study.

Two hundred thirty patients with reflux symptoms and endoscopically proven erosive esophagitis were enrolled from 15 U.S. centers into a randomized, double-blind, dose-ranging study comparing placebo with omeprazole, 20 or 40 mg given once daily in the morning. Esophagitis grade 2 was present in 44% of patients, grade 3 in 37% of patients, and grade 4 in 19% of patients. Endpoints, defined as complete relief of heartburn and complete esophageal mucosal healing, were assessed after 4 and 8 weeks of treatment. Both omeprazole doses were significantly superior to placebo in complete endoscopic healing. After 8 weeks of treatment, 73.5% of patients in the 20-mg omeprazole group and 74.7% in the 40-mg omeprazole group, compared with 14.0% in the placebo group, had complete healing of the esophageal mucosa. At the end of the study, complete relief of daytime heartburn was obtained in 79.5% of patients in the 20-mg omeprazole group, 81.6% in the 40-mg omeprazole group, and 37.2% in the placebo group (P less than or equal to 0.05). Complete relief of nighttime heartburn was noted by 79.5% of patients in the 20-mg omeprazole group, 85.1% in the 40-mg omeprazole group, and 34.9% in the placebo group (P less than or equal to 0.05). The median time to complete relief of daytime and nighttime heartburn occurred earlier in the 40-mg group than in the 20-mg group (9 vs. 17 days and 9 vs. 20 days, respectively); however, these differences were not statistically significant. Relief of acid regurgitation and dysphagia also occurred earlier in the 40-mg group. Omeprazole was well tolerated in this group of patients. No unexpected adverse experiences occurred. The results of this study confirm those of six multicenter, international trials in which omeprazole in doses of 20-60 mg provided a degree of esophageal mucosal healing and complete relief of reflux symptoms superior to any other medical treatment.

Intrahepatic cholesterol stones: a rationale for dissolution therapy.

A case of primary cholesterol hepatolithiasis is reported. Stone composition was documented by infrared spectroscopy, and the presence of cholesterol saturated bile was demonstrated using standard biochemical techniques. The patient was treated with operative stone extraction, choledochoscopy, biliary enteric anastomosis, and oral dissolution therapy. The administration of oral dissolution agents has altered the composition of the patient's bile and may prevent further stone formation. We advocate the use of both stone and biliary biochemical analysis for patients with primary hepatolithiasis to facilitate optimal therapy.

Complications of gastroesophageal reflux.

An edited summary of an Interdepartmental Conference arranged by the Department of Medicine of the UCLA School of Medicine, Los Angeles. The Director of Conferences is William M. Pardridge, MD, Professor of Medicine. Several specialists have recently recognized that gastrointestinal reflux causes complications resulting in significant disease. It causes discomfort, indigestion, esophagitis, Barrett's esophagus, and carcinoma of the esophagus. Pediatricians attribute many early pulmonary problems, and even some sudden deaths in infants, to the reflux of gastric contents. Otolaryngologists now recognize that many cases of nonbacterial, nonspecific pharyngitis and laryngitis are due to the reflux of gastrc acid secretions. Contact granuloma and cancer of the larynx may, in some instances, be secondary to nocturnal reflux. Thoracic surgeons and pulmonologists believe chronic tracheobronchitis and some cases of pulmonary disease are attributable to recurrent bathing of the respiratory epithelium by aspirated gastric contents. An awareness of the many complications of gastrointestinal reflux should lead to a multidisciplined attack on the factors responsible for these diseases.

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.

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.

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.

Healing of benign gastric ulcer with low-dose antacid or cimetidine. A double-blind, randomized, placebo-controlled trial.

We conducted a 12-week, double-blind, randomized, placebo-controlled trial to determine whether cimetidine (300 mg with meals and at bedtime) or a convenient, liquid aluminum-magnesium antacid regimen (15 ml one hour after meals and at bedtime) would expedite healing or relief of symptoms in patients with benign gastric ulcer. Of the 101 patients who completed the trial according to protocol, 32 received the antacid, 36 cimetidine, and 33 placebo. At 4, 8, and 12 weeks after entry, ulcers had healed in a larger percentage of patients treated with cimetidine than of those treated with placebo: 53, 86, and 89 per cent of the cimetidine group versus 26, 58, and 70 per cent of the placebo group (P = 0.02, 0.01, 0.05), respectively. Healing at the three intervals had occurred in 38, 70, and 84 per cent, respectively, of the antacid-treated patients. Neither cimetidine nor antacid was more effective than placebo in relieving symptoms. The presence or absence of symptoms during the fourth and eighth treatment weeks was a poor predictor of the presence of absence of an ulcer crater. We conclude that cimetidine significantly hastens the healing of benign gastric ulcer.

Failure of histamine H2-receptor antagonist therapy in Zollinger-Ellison syndrome.

Review of a 5 year clinical experience with the histamine H2-receptor antagonists metiamide, cimetidine, and ranitidine in 20 patients with Zollinger-Ellison syndrome disclosed a treatment failure rate of 50 percent. The criterion for failure was hemorrhage in four patients, obstruction followed by hemorrhage in one patient, perforation in one, and intractable pain in four. Nine of the 10 patients in whom treatment failed required total gastrectomy for control of complications; the 10th patient refused operation. Retrospective analysis identified hepatic metastases, the multiple endocrine adenomatosis-type I syndrome, refractory diarrhea, and breaks in the medication schedule as being more common in the treatment failure group, but these trends were not statistically significant in our small series of patients. Nonhealing or recurrent ulcers were found in 90 percent of the patients in whom drug therapy failed and in only 10 percent of those patients in whom therapy was successful (p less than 0.01). There were no differences related to age, sex, duration of symptoms, previous gastric operation, ulcer location, presence of diarrhea, or amount of drug prescribed. Basal and peak acid outputs, basal serum gastrin levels, and response to secretin challenge were also nondiscriminatory. The degree of acid inhibition in response to cimetidine was highly variable from one patient to another and on repeat testing in individual patients, and there was no correlation between acid secretory inhibition and clinical course. When severe complications occurred, reinstituting H2-receptor antagonist therapy or increasing the dose did not avert the need for total gastrectomy. Patients refractory to drug treatment who have persistent or recurrent ulcers should be managed with prompt total gastrectomy to prevent life-threatening complications.

Antacid therapy for duodenal and gastric ulcer: the experience in the United States.

An intensive antacid regimen, 15 to 30 ml 1 and 3 hours after each meal and at bedtime, has a significant effect on duodenal ulcer healing as compared to placebo and is as effective as cimetidine in endoscopically assessed trials. The healing rates at 4 weeks for placebo, antacid, and cimetidine are about 24%, 59%, and 62%, respectively. Smoking reduces the frequency of ulcer healing irrespective of therapy. Ulcer recurrences are as frequent after antacid as after cimetidine. Extensive placebo-controlled trials have not been reported for antacid treatment of gastric ulcer, but regular antacid dosing was as effective as cimetidine in one trial. Both the acute relief of ulcer pain and the pain relief during several weeks of therapy are similar between antacid and placebo, but pain relief per se is not a reliable indicator of ulcer healing.

Endocrine effects of acute and chronic cimetidine administration.

In normal men, acute oral administration of 300 mg cimetidine or intravenous injection of 50 mg of the drug had no effect on prolactin release. In contrast, intravenous injection of 150 or 300 mg led to substantial increments in serum prolactin. Peptic ulcer patients were randomly assigned to treatment with either cimetidine or antacid. Serial blood sampling until ulcer healing showed no significant changes in serum prolactin, testosterone, free testosterone, estradiol, LH, or FSH in either group. It is likely that the impotence and breast changes occasionally seen during cimetidine therapy are due to peripheral antagonism of androgen action rather than to alterations in circulating hormone levels.

Effect of oral and intravenous 16,16-dimethyl prostaglandin E2 in duodenal ulcer and Zollinger-Ellison syndrome patients.

Oral 16,16-dimethyl prostaglandin E2 is a potent inhibitor of meal-stimulated gastric acid secretion and gastrin release in humans. Experiments were performed in 5 patients with inactive duodenal ulcer to determine the effect of graded doses of intravenous 16,16-dimethyl PGE2 on meal-stimulated gastric acid secretion and gastrin release to demonstrate whether it is necessary for 16-16-dimethyl PGE2 to come into direct luminal contact with the oxyntic and antral gland portions of the stomach to produce its inhibitory effects. All doses of 16,16-dimethyl PGE2, between 0.01 and 0.1 microgram/kg i.v. and between 0.01 and 1.0 microgram/kg orally produced significant postprandial inhibitory effects on both gastric acid secretion and gastrin release as compared with saline control. 0.1 microgram/kg of intravenous of 1 microgram/kg of oral 16,16-dimethyl PGE2 inhibited meal-stimulated acid secretion and gastrin by 80-90%. In 6 unoperated Zollinger-Ellison syndrome patients, 1 microgram/kg of oral 16,16-dimethyl PGE2 significantly inhibited fasting gastric acid hypersecretion by approximately 85% without significantly altering serum gastrin. Each of the oral doses of 16,16-dimethyl PGE2 (0.01-1 microgram/kg) were without untoward effect, as were intravenous doses of 0.01-01 microgram/kg. Maximal inhibition of acid secretion was found with 0.1 microgram/kg 16,16-dimethyl PGE2 i.v. as compared with 1.0 microgram/kg orally. Since 16,16-dimethyl PGE2, whether given orally or intravenously, is a potent inhibitor of both gastric acid secretion and meal-stimulated gastrin release, without apparent untoward side effects, clinical trials with 16,16-dimethyl PGE2 are indicated in patients with acid peptic disease.

Effect of gastrin heptadecapeptide (G17) on oesophageal contractions in patients with diffuse oesophageal spasm.

An intravenous bolus of pentagastrin significantly increased the amplitude and duration of oesophageal body contractions in seven patients with diffuse oesophageal spasm (DES) when compared with five normal subjects (P greater than 0.05). In order to determine whether this stimulation also occurred at physiological gastrin concentrations, the effect of an intravenous infusion of gastrin heptadecapeptide (G17), 25 pmol/kg-h, on oesophageal contractions was studied in DES patients. G17 had no significant effect on the amplitude and duration of oesophageal contractions compared with a saline control. This dose of G17 was near the D50 for gastric acid secretion and produced a rise in serum gastrin concentration comparable with a meal. G17 infusions at doses of 100 and 200 pmol/kg-h increased the amplitude and duration of oesophageal contractions, but the corresponding serum gastrin concentrations were higher than postprandial levels. Thus, endogenous fluctuations in serum gastrin heptadecapeptide, alone, are unlikely to alter oesophageal contractions in DES patients.