Adrian P. Ireland

Outcome of adenocarcinoma arising in Barrett's esophagus in endoscopically surveyed and nonsurveyed patients

The value of endoscopic surveillance of Barretts esophagus and the appropriate management of high-grade dysplasia remain unclear. Seventeen patients who were referred from endoscopic surveillance programs for management of high-grade dysplasia or adenocarcinoma developing in Barretts esophagus were compared with 35 patients who had a newly recognized Barretts adenocarcinoma, who had not been in a surveillance program. The referral diagnosis in the surveyed group was adenocarcinoma in six and high-grade dysplasia in 11. After repeat endoscopy with aggressive biopsy, two additional patients with adenocarcinoma were identified. Of the nine patients who underwent esophagectomy for high-grade dysplasia, five had invasive adenocarcinoma in the esophagectomy specimen, which had been missed before the operation, despite the fact that the median number of biopsy specimens obtained per 2 cm of Barretts mucosa was 7.8 (range 1.5 to 15.0). Overall, 13 patients in the surveyed group had adenocarcinoma, 12 staged early and one staged intermediate by the WNM classification. Surveyed patients were operated on at an earlier stage than the nonsurveyed patients (10 early, 14 intermediate, and 11 late stage tumors; chi 2 = 15.6, p < 0.01). Despite the presence of adenocarcinoma in 13 of the 17 surveyed patients, their survival was significantly better than that of the nonsurveyed group (chi 2 = 5.8, p < 0.05). Patients referred from surveillance programs for Barretts esophagus have a better outcome and earlier stage tumors than nonsurveyed patients. Inasmuch as multiple biopsy procedures do not exclude the presence of adenocarcinoma, continued surveillance of high-grade dysplasia is dangerous and potentially destructive to surveillance efforts.

Mixed reflux of gastric and duodenal juices is more harmful to the esophagus than gastric juice alone. The need for surgical therapy re-emphasized.

Objective The authors goal was to determine the role of duodenal components in the development of complications of gastroesophageal reflux disease. Summary and Background Data There is a disturbing increase in the prevalence of complications, specifically the development of Barretts esophagus among patients with gastroesophageal reflux disease. Earlier studies using pH monitoring and aspiration techniques have shown that increased esophageal exposure to fluid with a pH above 7, that is, of potential duodenal origin, may be an important factor in this phenomenon. Methods The presence of duodenal content in the esophagus was studied in 53 patients with gastroesophageal reflux disease confirmed by 24‐hour pH monitoring. A portable spectrophotometer (Bilitec 2000, Synectics, Inc.) with a fiberoptic probe was used to measure intraluminal bilirubin as a marker for duodenal juice in the esophagus. Normal values for bilirubin monitoring were established for 25 healthy subjects. In a subgroup of 22 patients, a custom‐made program was used to correlate simultaneous pH and bilirubin absorbance readings. Results Fifty‐eight percent of patients were found to have increased esophageal exposure to gastric and duodenal juices. The degree of mucosal damage increased when duodenal juice was refluxed into the esophagus, in that patients with Barretts metaplasia (n = 27) had a significantly higher prevalence of abnormal esophageal bilirubin exposure than did those with erosive esophagitis (n = 10) or with no injury (n = 16). They also had a greater esophageal bilirubin exposure compared with patients without Barretts changes, with or without esophagitis. The correlation of pH and bilirubin monitoring showed that the majority (87%) of esophageal bilirubin exposure occurred when the pH of the esophagus was between 4 and 7. Conclusions Reflux of duodenal juice in gastroesophageal reflux disease is more common than pH studies alone would suggest. The combined reflux of gastric and duodenal juices causes severe esophageal mucosal damage. The vast majority of duodenal reflux occurs at a pH range of 4 to 7, at which bile acids, the major component of duodenal juice, are capable of damaging the esophageal mucosa.

Inflammation and specialized intestinal metaplasia of cardiac mucosa is a manifestation of gastroesophageal reflux disease.

OBJECTIVE The purpose of the study was to test the hypothesis that cardiac mucosa, carditis, and specialized intestinal metaplasia at an endoscopically normal-appearing cardia are manifestations of gastroesophageal reflux disease. SUMMARY BACKGROUND DATA In the absence of esophageal mucosal injury, the diagnosis of gastroesophageal reflux disease currently rests on 24-hour pH monitoring. Histologic examination of the esophagus is not useful. The recent identification of specialized intestinal metaplasia at the cardia, along with the observation that it occurs in inflamed cardiac mucosa, led the authors to focus on the type and condition of the mucosa at the gastroesophageal junction and its relation to gastroesophageal reflux disease. METHODS Three hundred thirty-four consecutive patients with symptoms of foregut disease, no evidence of columnar-lined esophagus, and no history of gastric or esophageal surgery were evaluated by 1) endoscopic biopsies above, at, and below the gastroesophageal junction; 2) esophageal motility; and 3) 24-hour esophageal pH monitoring. The patients were divided into groups depending on the histologic presence of cardiac epithelium with and without inflammation or associated intestinal metaplasia. Markers of gastroesophageal reflux disease were compared between groups (i.e., lower esophageal sphincter characteristics, esophageal acid exposure, the presence of endoscopic erosive esophagitis, and hiatal hernia). RESULTS When cardiac epithelium was found, it was inflamed in 96% of the patients. The presence of cardiac epithelium and carditis was associated with deterioration of lower esophageal sphincter characteristics and increased esophageal acid exposure. Esophagitis occurred more commonly in patients with carditis whose sphincter, on manometry, was structurally defective. Specialized intestinal metaplasia at the cardia was only seen in inflamed cardiac mucosa, and its prevalence increased both with increasing acid exposure and with the presence of esophagitis. CONCLUSION The findings of cardiac mucosa, carditis, and intestinal metaplasia in an endoscopically normal-appearing gastroesophageal junction are histologic indicators of gastroesophageal reflux disease. These findings may be among the earliest signs of gastroesophageal reflux and contribute to the authors understanding of the pathophysiology of the disease process.

A prospective study of common bile duct calculi in patients undergoing laparoscopic cholecystectomy: Natural history of choledocholithiasis revisited

Objective:To define the incidence of problematic common bile duct calculi in patients undergoing laparoscopic cholecystectomy. Summary Background Data:In patients selected for laparoscopic cholecystectomy, the true incidence of potentially problematic common bile duct calculi and their natural history has not been determined. We evaluated the incidence and early natural history of common bile duct calculi in all patients undergoing laparoscopic cholecystectomy with intraoperative and delayed postoperative cholangiography. Methods:Operative cholangiography was attempted in all patients. In those patients in whom a filling defect was noted in the bile duct, the fine bore cholangiogram catheter was left securely clipped in the cystic duct for repeated cholangiography at 48 hours and at approximately 6 weeks postoperatively. Results:Operative cholangiography was attempted in 997 consecutive patients and was accomplished in 962 patients (96%). Forty-six patients (4.6%) had at least one filling defect. Twelve of these had a normal cholangiogram at 48 hours (26% possible false-positive operative cholangiogram) and a further 12 at 6 weeks (26% spontaneous passage of calculi). Spontaneous passage was not determined by either the number or size of calculi or by the diameter of the bile duct. Only 22 patients (2.2% of total population) had persistent common bile duct calculi at 6 weeks after laparoscopic cholecystectomy and retrieved by endoscopic retrograde cholangiopancreatography. Conclusions:Choledocholithiasis occurs in 3.4% of patients undergoing laparoscopic cholecystectomy but more than one third of these pass the calculi spontaneously within 6 weeks of operation and may be spared endoscopic retrograde cholangiopancreatography. Treatment decisions based on assessment by operative cholangiography alone would result in unnecessary interventions in 50% of patients who had either false positive studies or subsequently passed the calculi. These data support a short-term expectant approach in the management of clinically silent choledocholithiasis in patients selected for LC.

Nodal metastasis and sites of recurrence after en bloc esophagectomy for adenocarcinoma

The operative specimens from 43 patients undergoing en bloc esophagectomy for adenocarcinoma of the lower esophagus or cardia were analyzed. Depth of invasion of the tumor and extent and location of lymph node metastases were determined. Postoperative recurrence was identified from positive findings on successive 3-month computed tomographic scans. Positive nodes occurred in 33% (2/6) of intramucosal tumors, 67% (6/9) of intramural tumors, and 89% (25/28) of transmural tumors (p < 0.01). Commonly involved nodes were those in the lesser curve of the stomach (42%), parahiatal nodes (35%), paraesophageal nodes (28%), and celiac nodes (21%). Excluding perioperative deaths, follow-up was complete for 38 patients. Twenty patients had recurrence. Fifteen patients (40%, 15/38) had nodal recurrence: cervical, 7.9% (3/38); superior mediastinal, 21% (8/38); and abdominal, 24% (9/38) (retropancreatic in 7 and retrocrural in 2). Of 5 patients with nodal recurrence alone, 3 (60%) had recurrence at sites outside the margins of resection. Patients with four metastatic nodes or less had a survival advantage over those with more than four (p < 0.05). There was no difference in survival according to location of nodal metastases. Two (22.2%) of 9 patients with celiac node metastases survived longer than 4 years. Adenocarcinoma of the lower esophagus and cardia spreads widely to mediastinal and abdominal nodes, and death can occur from nodal disease. Rates of lymph node metastases increase with the depth of the primary tumor. Patients with lymphatic metastases can be cured particularly if there are fewer than four nodes involved. Curative surgical therapy necessitates wide lymph node resection to ensure removal of all metastatic nodes.

Composition and concentration of bile acid reflux into the esophagus of patients with gastroesophageal reflux disease

BACKGROUND Reflux of duodenal contents into the esophagus of patients with gastroesophageal reflux disease has been suggested by pH and bilirubin monitoring but is rarely directly measured. A portable device has been developed and was used to collect and quantitate material refluxed into the esophagus under ambulatory conditions during a prolonged time period. The objective of this study was to use this device to quantitate the composition and concentration of bile acids refluxed into the esophagus of patients with gastroesophageal reflux disease. METHODS Esophageal aspiration was performed on 43 normal subjects and 37 patients with reflux disease during a 17-hour period. Aspiration was performed through a modified 16F Salem sump tube, positioned 5 cm above the lower esophageal sphincter and connected to a portable, battery powered pump that aspirated continuously at 100 mm Hg pressure. Validation studies showed that minimal amounts of saliva and swallowed liquids were aspirated and that gastric pressure was not altered. Postprandial, upright, and supine collections were performed. Total bile acids were assayed by a standard enzymatic assay; specific conjugated bile acids were analyzed by high-performance liquid chromatography. RESULTS There was no difference in the total aspiration volume between normal volunteers and patients with gastroesophageal reflux disease, although patients tended to have a higher volume in the supine and postprandial periods. Bile acids could be detected in 58% of normal subjects and 86% of patients (p < 0.003). The mean concentration of bile salt exposure (micromole per liter) was higher in patients during the postprandial and supine periods. The mean bile acid reflux rate (micromole per hour) during all three aspiration periods was significantly higher in patients. On a molar basis the composition of the bile acids was 60% glycocholic acid, 16% glycodeoxycholic acid, and 15% glycochenodeoxycholic acid. Taurocholic, taurodeoxycholic, taurochenodeoxycholic, and glycolithocholic acid constituted the remaining 10%. CONCLUSIONS Patients with reflux disease have an increased concentration of bile acids in their esophageal aspirates. Most of the exposure occurs during the postprandial and supine periods. A variety of bile acids were detected, most of which were in their glycine conjugated form.

A tailored approach to antireflux surgery.

Tailored surgical antireflux procedures were done in 104 patients during a 7-year period. Presenting symptoms included heartburn in 95 patients (91%), regurgitation in 83 patients (80%), and dysphagia in 61 patients (60%). Evaluation before operation included video barium esophagography, endoscopy, 24-hour esophageal pH monitoring, and esophageal motility studies. On the basis of anatomic and functional findings, the following procedures were performed: 15 laparoscopic and 49 open transabdominal Nissen fundoplications, 23 transthoracic Nissen fundoplications, seven Belsey partial fundoplications, and 10 Collis gastroplasty and Belsey partial fundoplications. The severity of symptoms was assessed before and after operation according to a previously published grading score. Eighty-five of the 104 patients (82%) were able to be contacted for a follow-up evaluation by means of a standardized questionnaire. Median length of follow-up was 4 years, with 40 patients having follow-up beyond 5 years. The tailored operation cured the symptoms of heartburn in 97%, regurgitation in 91%, and dysphagia in 92%. Ninety-eight percent of the patients reported that operation had cured their preoperative symptoms and 93% were satisfied with the outcome of the operation. To obtain optimal results, surgical treatment of gastroesophageal reflux disease should be tailored to the patients anatomic and functional assessments. For early, uncomplicated disease a transabdominal Nissen fundoplication is done, laparoscopically when expertise exists. Patients with complicated disease should undergo an open antireflux procedure tailored to specific anatomic or functional abnormalities.

Duodenoesophageal reflux induces esophageal adenocarcinoma without exogenous carcinogen

In the rat model, esophageal adenocarcinoma reproducibly develops following surgically induced duodenal reflux into the esophagus and administration of nitrosamine. In addition, decreasing gastric acid via partial or total gastrectomy increases the prevalence of adenocarcinoma in this model. We questioned whether carcinogen was necessary for cancer development in the gastrectomized model and whether esophageal acidification could reverse the effect of gastrectomy. Three groups of 26 rats each were randomized to a surgical procedure to produce one of the following reflux models: gastroduodenal reflux by esophagojejunostomy, duodenal reflux by total gastrectomy and esophagojejunostomy, or no reflux by Roux-en-Y reconstruction. In a second experiment, 42 rats were operated on to induce duodenal reflux. One week following surgery, they were randomized to receive acidified water (pH 1.8) or tap water. The animals were killed at 24 weeks of age, and the esophagus was evaluated histologically. All animals with reflux had severe esophagitis and 87% developed columnar lining of the distal esophagus. Nearly half (48%) developed adenocarcinoma at the anastomotic site 16 weeks postoperatively and without carcinogen administration. Cancer prevalence did not differ between animals with gastroduodenal or duodenal reflux but tended to be lower in animals receiving acidified water. Duodenoesophageal reflux is carcinogenic in the rat model. Exogenous carcinogen is not necessary for cancer development in gastrectomized rats.

Does duodenal juice reflux into the esophagus of patients with complicated GERD? Evaluation of a fiberoptic sensor for bilirubin.

BACKGROUND It is controversial whether duodenal juice can damage esophageal mucosa in patients with gastroesophageal reflux disease (GERD). The issue remains unresolved partly because of difficulties in detecting the presence of duodenal juice in the lower esophagus. OBJECTIVES AND METHODS This study utilized an in vitro portable spectrophotometer with a fiberoptic probe capable of detecting bile as a marker of duodenal juice. Absorbance/concentration curves were established with known bilirubin concentrations at pH 1.4 and pH 7.7. Esophageal pH and bilirubin absorbance were monitored in vivo over a 24-hour period in 20 healthy volunteers to determine the absorbance threshold for clinical use. The study population consisted of 21 patients with GERD. Four had no mucosal injury, 5 erosive esophagitis, and 12 Barretts esophagus. RESULTS The correlation between absorbance and bilirubin concentration was 0.98 and 0.99 for acid and alkaline environments, but bilirubin absorbance was 35% less in an acid environment. Using an absorbance threshold of 0.14, patients with GERD taken in toto had elevated esophageal exposure to bilirubin. No difference was observed in bilirubin exposure between reflux patients without mucosal injury and controls. Highest exposure occurred in patients with Barretts esophagus. An important observation was that esophageal bilirubin exposure frequently occurred during periods when the esophageal pH was in the normal range. CONCLUSIONS The fiberoptic probe accurately detects esophageal bilirubin as a marker of duodenal juice. Esophageal exposure to bilirubin is uncommon in normal subjects. Patients with erosive esophagitis and Barretts metaplasia have increased esophageal exposure to duodenal juice compared to normal subjects. Reflux of duodenal juice into the esophagus can occur when the esophageal pH is within its normal range and is undetectable by pH monitoring alone.

Gastric juice protects against the development of esophageal adenocarcinoma in the rat.

OBJECTIVE The authors investigate the effects of gastric juice on tumorigenesis in a rat model of esophageal adenocarcinoma. SUMMARY BACKGROUND DATA In rats treated with the carcinogen methyl-n-amyl nitrosamine, squamous cancer of the esophagus develops in a time- and dose-dependent manner. When methyl-n-amyl nitrosamine treatment is preceded by an operation to induce reflux of duodenal and gastric juice into the esophagus, there is an increased yield of esophageal tumors, many of which are adenocarcinomas. When only gastric juice refluxes into the esophagus, the tumor yield is less and adenocarcinomas are not found. METHODS Two hundred seventy 8-week old Sprague-Dawley rats were studied. Twenty unoperated rats served as controls. The remaining rats underwent the following operations: esophagoduodenostomy with gastric and vagal preservation to induce duodenogastroesophageal reflux (n = 48); esophagoduodenostomy with antrectomy and Billroth 1 reconstruction to produce reflux of duodenogastric juice with the exclusion of the antrum (n = 53); esophagoduodenostomy with proximal gastrectomy to induce hypergastrinemia and reflux of duodenogastric juice with exclusion of the body and forestomach (n = 51); esophagoduodenostomy plus total gastrectomy to produce reflux of duodenal juice alone (n = 50); and esophagoduodenostomy with vagal and gastric preservation but with division of the duodenum just beyond the pylorus and reimplantation into the jejunum, 13 cm distal to the esophagoduodenostomy. This produced reflux of duodenal juice with gastric juice diverted downstream, (n = 48). At 10 weeks of age, all rats were given 4 weekly doses of carcinogen (methyl-n-amyl nitrosamine, 25 mg/kg intraperitoneally), and survivors were killed at 36 weeks of age. RESULTS The prevalence rate of esophageal adenocarcinoma was 30% in rats with duodenogastroesophageal reflux and 87% in rats with reflux of duodenal juice alone. Fifty-six percent of rats with reflux of duodenogastric juice with exclusion of the antrum and 72% of rats with reflux of duodenogastric juice with the exclusion of the body and forestomach developed adenocarcinoma, showing a progression increase in the prevalence of adenocarcinoma as less gastric juice was permitted to reflux with duodenal juice into the esophagus. CONCLUSION In this rat model, the presence of gastric juice in refluxed duodenal juice against the development of esophageal adenocarcinoma. The protective effect appears to be due to acid secretion from the stomach. Continuous profound acid suppression therapy may be detrimental by encouraging esophageal metaplasia and tumorigenesis in patients with duodenogastroesophageal reflux.