Major issues in the organization and implementation of the National Cooperative Gallstone Study (NCGS).

The National Cooperative Gallstone Study (NCGS) was a cooperative, randomized, controlled trial of a drug, chenodiol, for the medical dissolution of gallstones. The design and procedures of the NCGS were complex, having developed as a result of extensive involvement of many experts in the field of gallstone disease and biliary lipids. During the design and implementation of the protocol, many important issues required consideration and resolution. The aim of this article is to review these issues and the deliberations surrounding their resolution and provide personal conclusions and recommendations that may be helpful to other investigators involved in cooperative, controlled trials.

Low-dose chenodiol to prevent gallstone recurrence after dissolution therapy.

Chenodiol is a safe and effective agent for the medical dissolution of gallstones in selected patients; however, after dissolution and cessation of treatment, gallstones recur. This study was done to determine the recurrence rate after successful medical treatment and cessation of chenodiol therapy; compare the efficacy and safety of low-dose chenodiol, as compared to placebo, for prophylaxis against recurrence; and identify factors predictive of recurrence. In a randomized, double-blind fashion, 53 patients with gallstone dissolution received either chenodiol, 375 mg/d, or placebo, for at least 2 years. Standardized oral cholecystograms were done at 6 months, 1 year, and then yearly thereafter. Routine laboratory testing was done every 6 months. The cumulative rate of recurrence (life-table) was 27% in patients followed for up to 3.5 years. Chenodiol, 375 mg/d, was ineffective in preventing the recurrence of gallstones. No demographic, clinical, roentgenographic, or biochemical characteristics were predictive of recurrence.

Additional chenodiol therapy after partial dissolution of gallstones with two years of treatment.

During the National Cooperative Gallstone Study, therapy with chenodiol, 750 or 375 mg/d, for 2 years resulted in confirmed, complete gallstone dissolution in 14% and 5% of patients, respectively, and partial dissolution (greater than 50%) in 27% and 18%. The present study was done to determine the frequency with which complete dissolution occurs in patients having partial dissolution of gallstones who receive additional therapy. Eighty-six of one hundred thirty-eight eligible patients continued to receive 750 mg/d (61 patients) or 375 mg/d (25 patients) of chenodiol for 1 year. Patients whose oral cholecystogram at the end of the year showed further (greater than 50%) dissolution continued to receive chenodiol, (28 patients at 750 mg/d and 11 patients at 375 mg/d) for a second year (total duration of therapy, 4 years). A final oral cholecystogram was taken at the end of the fourth year. Complete dissolution occurred in 23% and 16% of patients receiving chenodiol, 750 or 375 mg/d, respectively, for an additional 1 or 2 years.

Drug and treatment efficacy of chenodeoxycholic acid in 97 patients with cholelithiasis and increased surgical risk.

Patients with symptomatic cholelithiasis who represent higher than normal surgical risks may be the most suitable candidates for medical dissolution of gallstones. Chenodeoxycholic acid was given to 97 patients in a dosage of 15 mg/kg of body weight per day for a period of two years. Complete gallstone dissolution occurred in 27 of 97 patients (28%). If dropouts are excluded then the success rate is 27 of 64 patients (42%). Diarrhea was a common but manageable side effect for most. Thirty-two percent of patients developed chemical liver test abnormality; however, in only 13% was the degree of abnormality sufficient to require temporary (3%) or permanent (10%) cessation of therapy. Although better chemotherapeutic agents are needed, chenodeoxycholic acid is a reasonable choice for patients with non-calcified cholelithiasis in a functioning gallbladder if the patient is a heightened surgical risk. Because of the prolonged treatment period and the possibility of hepatotoxicity this treatment program requires a substantial commitment on the part of both the patient and the physician.

Pretreatment biliary lipid composition in white patients with radiolucent gallstones in the National Cooperative Gallstone Study.

Biliary lipid classes (bile acids, phospholipids, cholesterol) as well as individual biliary bile acids were measured in duodenal bile samples obtained before treatment from 284 white men and 264 white women participating in the National Cooperative Gallstone Study. The patients had radiolucent gallstones present in visualizing gallbladders. Calculated biliary cholesterol saturation was significantly higher in women (143 +/- 43, mean +/- SD, vs. 132 +/- 39 for men). Chenodeoxycholic acid was the major biliary bile acid in both sexes (40.0 +/- 9.9 in men; 38.8 +/- 9.3 in women, NS). Cholic acid was the second most common bile acid, constituting 32.9 +/- 8.8 in men and 31.8 +/- 8.9 in women (NS). When other demographic and clinical characteristics, including serum lipids, were related with biliary lipid composition, only percent ideal body weight correlated significantly. The partial correlation coefficient adjusted for percent ideal body weight indicated that the proportion of chenodeoxycholic acid correlated negatively with the mole fraction of cholesterol in bile in men, but not in women. Multiple regression analyses showed that bile saturation could not be predicted reliably from any clinical, chemical, or radiologic measurement in either sex. Published data for biliary lipid composition in individuals with biliary disease showed considerable overlap with the National Cooperative Gallstone Study data reported here, suggesting that cholesterol gallstone disease is not caused solely by increased biliary cholesterol saturation.

Surgical treatment of gastroesophageal reflux.

Most investigators agree that the most important goal in correcting gastroesophageal reflux is restoring or developing a competent lower esophageal sphincter. Although the sphincter can be incompetent in its normal intra-abdominal position and rarely a patient may have a competent sphincter in the thorax, generally the sphincter is much more effective in the positive pressure abdominal position. The choice of operative technique will depend upon the abnormal conditions present and the general condition of the patient. The thoracic approach is elected if there is associated intrathoracic disease warranting surgical correction, such as diffuse spasm of the esophagus, achalasia, epiphrenic diverticulum, or a pulmonary lesion requiring biopsy and possible resection. Very obese patients, patients with recurrent hernias, and patients with shortened esophagus are better managed by the thoracic approach. Patients with an essentially normal esophagus are treated with a Mark IV Belsey procedure. If shortening of the esophagus is present, a combination Collis-Nissen technique with fixation below the diaphragm is preferable. The abdominal approach is indicated when there is another intraabdominal disease known or suspected warranting surgical correction. This approach is also useful for the thin or poor risk patient. Usually, through an abdominal incision, we elect to use a modified Nissen fundoplication, with fixation of the fundoplication to the median arcuate ligament or the right crus of the diaphragm. The crural sling is returned to normal dimensions with interrupted sutures. Reflux in the absence of an hiatal hernia initially is treated medically. If symptoms are significant and intractable, a competent lower esophageal sphincter is restored, or developed by the modified Nissen procedure just described. Most reflux strictures at the esophagogastric junction are reversible by dilatation and restoration of a competent sphincter. Firm, fixed, fibrous strictures occasionally cannot be safely dilated. These may be managed by a Thal procedure to correct the stricture and a Nissen fundoplication to prevent recurrent reflux.

Comparison of detectability of elevated amylase of serum and urine in pancreatic diseases by two amylase assay methods using starch substrates of different digestive rates to pancreatic amylase.

Detectability of abnormally high serum and urine amylases was investigated on patients with pancreatic diseases using amylase assays with substrates of different digestive rates to pancreatic amylase. Ratios of amylase activities determined by a chromogenic assay using a Remazolbrilliant Blue R starch (RBB assay) to those by Caraway's assay using a Lintner soluble starch (R/C ratio) were calculated on duodenal and salivary amylases obtained from 16 subjects undergoing a pancreozymin-secretin test. The R/C ratio of the duodenal amylase (M +/- SD = 0.56 +/- 0.12) was significantly higher (p less than 0.01 by F test) than that of the salivary amylase (M +/- SD = 0.36 +/- 0.10). Detectability of above-normal values of serum and urine amylases were compared with two assays in 77 pancreatic patients. The value for serum and urine amylases determined by the RBB and Caraway's assays exceeded the upper limit of normal in 37 and 58% by the RBB assay and 24 and 26% by Caraway's assay, respectively. Degrees of abnormality (ratio of the observed to the upper normal value) in serum and urine amylases were also significantly higher (p less than 0.05 for serum and p less than 0.01 upper for urine) by the RBB assay than by Caraway's assay. The RBB assay was more sensitive than Caraway's assay in detecting elevation of pancreatic amylase in serum and urine.