Original Article
Prophylactic Sclerotherapy for Esophageal Varices in Men with Alcoholic Liver Disease — A Randomized, Single-Blind, Multicenter Clinical Trial
N Engl J Med 1991; 324:1779-1784June 20, 1991
- Abstract
- Abstract
Background.
Sclerotherapy is an effective treatment for bleeding esophageal varices in patients with alcoholic liver disease. It has also been suggested that sclerotherapy might be effective in preventing initial episodes of bleeding and improving survival among such patients.
Methods.
We conducted a prospective, randomized trial comparing prophylactic sclerotherapy and sham therapy in 281 men with alcoholic liver disease who had at least three variceal channels and no history of variceal bleeding. All the patients underwent endoscopy; 143 received sclerotherapy, and 138 received sham therapy.
Results.
The two patient groups were well matched at entry with respect to the extent of liver disease and other clinical indexes, except that other medical illnesses were significantly more common in the sclerotherapy group. The study's data-monitoring board terminated the trial 22.5 months after it began because the rate of mortality from all causes was significantly higher in the sclerotherapy group (32.2 percent) than in the sham-therapy group (17.4 percent, P = 0.004), despite the fact that the men who received sclerotherapy had significantly fewer episodes of esophageal variceal bleeding. The causes of death varied, and there is no obvious explanation for the excess mortality in the sclerotherapy group. After the termination of treatment, the excess mortality rate in the sclerotherapy group promptly declined. There were 53 episodes of upper gastrointestinal bleeding (including 10 from esophageal varices and 9 from esophageal ulcers) in the sclerotherapy group and 40 episodes (including 19 from esophageal varices) in the sham-therapy group. Complications of sclerotherapy were frequent but seldom life-threatening.
Conclusions.
For unknown reasons, prophylactic sclerotherapy is associated with increased mortality among men with moderate-to-severe alcoholic liver disease and esophageal varices. Sclerotherapy should not be performed until after an initial episode of bleeding from esophageal varices has occurred. (N Engl J Med 1991; 324: 1779–84.)
Article Activity
- Article
SCLEROTHERAPY has become an accepted treatment for bleeding esophageal varices. Several randomized clinical trials have demonstrated that sclerotherapy stops variceal bleeding.1 , 2 Other studies have shown that sclerotherapy, continued to the point of variceal obliteration, reduces the frequency of recurrence of bleeding from esophageal varices.3 4 5 6 7 The reduction in recurrent bleeding episodes was associated with improved survival in some but not all of these studies.
The recognition that sclerotherapy could prevent the recurrence of bleeding suggested that it might also prevent first episodes of variceal bleeding in susceptible patients. Paquet concluded that sclerotherapy reduced the number of initial episodes of esophageal variceal bleeding and also improved survival.8 In five subsequent trials comparing prophylactic sclerotherapy with no treatment,9 10 11 12 13 the number of bleeding episodes was found to be reduced in three studies, not reduced in one, and increased in one. Survival among the treated patients was increased in three studies and unchanged in the other two. The discrepancy in the outcomes of these studies has been attributed to differences in the patient populations.
The Veterans Affairs cooperative study of prophylactic sclerotherapy was initiated in early 1985 to confirm and expand on the initial observations of Paquet.8 This study differs from those previously reported in that only men with alcoholic liver disease were studied, the sample was substantially larger, and the control group underwent both endoscopy and sham sclerotherapy.
Methods
Selection of Patients
Patients with alcoholic liver disease who were seen at 12 Veterans Affairs medical centers from February 1, 1985, through October 9, 1986, were screened for the study. Eligible patients had to meet the following entry criteria: male sex, consumption of more than 48 g of alcohol per day for more than a year, biopsy-proved or clinically diagnosed alcoholic liver disease, no history of upper gastrointestinal bleeding in the past four years or documentation by endoscopy that bleeding, if it had occurred, was from a nonvariceal source, and endoscopic evidence of at least three esophageal variceal channels. Patients were excluded if they had any of the following: contraindications to upper endoscopy, a positive test for hepatitis B surface antigen in serum, a history of sclerotherapy, previous shunt surgery, malignant disease of the esophagus or the stomach, a myocardial infarction within the past six months, a need for beta-adrenergic—antagonist drug therapy, past or current bleeding from gastric varices, active bleeding from any source, or a decision by the treating physician to exclude the patient.
Informed Consent
This study and the consent forms were approved by the Cooperative Study Program human rights committee at the West Haven (Conn.) Veterans Affairs Medical Center and by the human rights committees at each participating Veterans Affairs Medical Center. Informed consent was obtained from all patients before the initial upper gastrointestinal endoscopy was performed.
Study Design
Randomization was carried out according to a permuted-blocks design14 just before the endoscopic procedure during which sclerotherapy or sham therapy was performed. Patients who had had bleeding from any source more than four years before enrollment were randomly assigned separately. Usually, only the members of the endoscopy—sclerotherapy team were aware of the patients' treatment assignments; all other care givers remained unaware of the treatment assignment.
If the patient consented to participate in the trial, a medical history was obtained and a physical examination and laboratory tests were performed. The patient then underwent endoscopy and either sclerotherapy or sham therapy. He was seen again after 4 to 6 days, 9 to 11 days, 1 month, and 3 months and then every 3 months thereafter. At each visit, a history was obtained, a physical examination and endoscopy were performed, and the assigned treatment was administered. As the study was originally planned, all patients were to receive sclerotherapy or sham therapy for two years. If the patient completed the two years of treatment, he would be asked to sign a separate consent form granting permission for continued follow-up. If he agreed, he could be seen again after three months, and then at six-month intervals for up to three more years. At these visits, a history would be obtained and a physical examination and a diagnostic endoscopy performed. Patient enrollment was expected to occur during the first three years of the study; the study was intended to last for five years. Because of an unexpected difference in mortality rates between the treatment groups (described below), however, treatment was discontinued in all patients 22.5 months after the study began. These patients were then seen in follow-up for the remainder of the five-year study period.
Sclerotherapy or Sham Therapy
Endoscopy was performed with the Olympus lT-10 endoscope. The sclerosing solution, 1.5 percent sodium tetradecyl sulfate, and the matching placebo were prepared by Elkins-Sinn. Antacids, sucralfate, and histamine H2 antagonists were not routinely prescribed. In the patients receiving sclerotherapy, 1 to 2 ml of sclerosing solution was injected into each esophageal varix, with a 25-gauge Microvasive injector, at the gastroesophageal junction and at a level 3 to 5 cm above this junction. No more than 20 ml was injected in any one session. Sclerotherapy was not carried out at any session if large ulcers or other contraindications were evident or if the varices were too small to inject or were no longer visible. Varices were considered to have been obliterated if they were not visible or were too small to inject on two consecutive visits. For patients assigned to sham therapy, the placebo solution was released through the injector into the upper stomach six to eight times at the initial session and with decreasing frequency at subsequent sessions to mimic the frequency and timing of sclerotherapy.
The randomized treatment assignment was maintained through-out the treatment phase of the study; an episode of upper gastrointestinal bleeding, if it was from the varices, necessitated an extra session of the assigned treatment, but crossover to the other treatment was not allowed. All the patients received the assigned treatment at least once. Standardized endoscopic treatment of all patients was ensured by a full-day meeting of the investigators with a sclerotherapy consultant before the study began, by regular monitoring of all endoscopy reports by the study chairman, and by discussions at regular meetings of the study group.
All the endoscopists participating in this trial had to have performed at least 20 sclerotherapy procedures to be eligible to be a study investigator, and all had acquired considerably more experience by the time the first patient was enrolled. Trainees participating in the endoscopic treatment performed the procedure only under the direct supervision of an investigator.
End Points
Upper gastrointestinal bleeding and death were the two chief end points in the study. Upper gastrointestinal bleeding was considered to have occurred if the episode met the following criteria: it was manifested by hematemesis, a nasogastric aspirate containing blood, the observation of bleeding on upper endoscopy, or rarely, melena from sources other than the small bowel or colon; the patient was in the hospital or entered the hospital because of the bleeding; and the patient received transfusions. Endoscopy was performed whenever possible to ascertain the cause of the bleeding. The number of units of blood transfused into each patient was recorded as a measure of the severity of bleeding.
Other recorded end points included hospitalization for any cause; the development of ascites, jaundice, encephalopathy, or infections; and the use of balloon tamponade or shunt surgery during the study. Consumption of alcohol was assessed by asking the patient about his drinking, recording the nurse's independent opinion, and measuring blood alcohol levels.
Treatment Failure
Treatment was considered to have failed if a patient had one episode of upper gastrointestinal bleeding for which he received more than six units of blood or if he had three episodes of upper gastrointestinal bleeding as defined above. The patient was removed from the treatment phase of the study only if he had three episodes of bleeding, if he underwent shunt surgery, or if his personal physician recommended withdrawal. Further sclerotherapy for patients withdrawn from the study was discouraged but not prohibited.
Documentation of the Source of Upper Gastrointestinal Bleeding
The source of bleeding was considered known if upper endoscopic examination, performed within 24 hours of the onset of bleeding, showed active bleeding from a particular lesion, stigmata of recent hemorrhage were evident in the lesion, or it was the only lesion present. Endoscopy was not carried out for study purposes in moribund patients or in patients whose clinical condition considerably increased the risks of the procedure.
Statistical Analysis
Base-line categorical variables were compared by the chi-square test, and continuous variables by Student's t-test. The length of time to the first episode of upper gastrointestinal bleeding and the length of time to death were estimated by the Kaplan–Meier method15 and tested by the log-rank test and the Wilcoxon test.16 A logistic regression model was constructed with death as the dependent variable and with selected base-line variables and their interactions with treatment as independent predictors of risk.17 Analyses to adjust for the possible contribution of an imbalance in base-line characteristics between the two groups were performed with use of the proportional-hazards regression model.18 All analyses were based on intention to treat, and all P values were two-sided.14
Termination of the Study
The rate of enrollment, the characteristics of the patients, and the major end points in the study were reviewed at six-month intervals by an independent data-monitoring board. This review was carried out without knowledge of the treatment assigned. Enrollment was discontinued 20.5 months after the study began because the projected sample size had been exceeded. A disturbing trend in mortality rates that was evident at that time led to a request for analysis in greater depth. A significant increase in the number of deaths in one treatment group led to the termination of the treatment phase of the study two months later. At the termination of treatment, the median length of follow-up was 302 days. Follow-up continued for 37 months after treatment ended.
Results
Study Population
Approximately 2200 patients were screened for entry into the study. Of the 433 patients who met the entry criteria, 65 were eliminated because of the exclusion criteria, 87 declined to participate, and 281 were enrolled in the study. Of these, 143 were randomly assigned to receive sclerotherapy and 138 sham therapy. Of the 281 patients, 13 had had bleeding from unknown sources more than four years earlier; the remainder had never had bleeding. The 11 medical centers that participated in the entire study enrolled from 17 to 34 patients each. One additional center withdrew 12 months after the study began, after enrolling 10 patients. All 10 were included in the data analysis.
Selected base-line characteristics of the patients are shown in Table 1.Table 1
Base-Line Data on the Two Groups of Men with Alcoholic Liver Disease and Esophageal Varices at Entry into the Study.* The patients were middle-aged, most were white, and they had a long history of drinking alcohol. About 25 percent had been abstinent for at least six months before enrollment. The average daily intake of alcohol in the month before randomization for all other patients was about 150 g. In about 90 percent of the patients the width of the varices was more than 5 mm. The proportion of patients with a history of at least one other medical illness was significantly higher in the sclerotherapy group than in the sham therapy group (P = 0.001). The severity of the liver disease, indicated by the proportions of patients in the three Child's score groups,19 was not significantly different in the two treatment groups, and the average Child's score was almost identical in the two groups. The initial physical findings and laboratory-test results (Table 2Table 2
Selected Findings on Physical Examination and Laboratory-Test Results in the Two Groups of Men with Alcoholic Liver Disease and Esophageal Varices at Entry into the Study.*) were comparable in the two groups.Mortality
When the treatment phase of the study was stopped, 46 patients in the sclerotherapy group and 24 patients in the sham-therapy group had died. More deaths had occurred in the sclerotherapy group at 10 of the 12 participating centers. The survival curves for the treatment phase of the study (Fig. 1Figure 1
Kaplan—Survival Curves during the 22.5-Month Treatment Phase in the Two Groups of Men with Alcoholic Liver Disease and Esophageal Varices.) showed a highly significant difference between the two groups (P = 0.004). During the 37 months of follow-up after treatment was ended, 76 of the surviving patients died: 42 of the surviving 114 (36 percent) in the sham-therapy group and 34 of the surviving 97 (35 percent) in the sclerotherapy group. Thus, the excess mortality in the sclerotherapy group did not persist after the treatment was terminated.Table 3Table 3
Primary Cause of Death during the Phase of Treatment with Sclerotherapy or Sham Therapy among Men with Alcoholic Liver Disease and Esophageal Varices. shows the primary causes of death for the 70 patients who died during the treatment phase. The proportions of deaths due to each cause were not significantly different between the two groups. Also, the length of time between the episode of upper gastrointestinal bleeding and death was the same among the patients who had bleeding in the two groups; 44 percent (14 of 32) in the sclerotherapy group and 42 percent (10 of 24) in the sham-therapy group died within 30 days of an episode of bleeding. No association was found between the time of the sclerotherapy procedure and the date of death. The causes of death among patients who died after treatment was stopped were comparable in the two groups.Several base-line variables were associated with death. When either multivariate logistic-regression or Cox regression analyses were carried out, however, only the Child's score (P<0.001) and the assigned treatment (P = 0.01) were independent predictors of mortality. When a history of other medical illness (P = 0.11) was included in a Cox analysis with the Child's score (P<0.001), the difference in the mortality rate due to sclerotherapy was still significant (P = 0.03). The mortality rate for patients with at least one other medical illness was 18 percent (7 of 39) in the sham-therapy group and 38 percent (25 of 65) in the sclerotherapy group. For those with no other illness, the rate was 17 percent (17 of 99) in the sham-therapy group and 26 percent (20 of 78) in the sclerotherapy group. The mortality rate for the patients with Child's scores of less than 8 was 12 percent (7 of 60) in the sham-therapy group and 18 percent (11 of 62) in the sclerotherapy group; the mortality rates were 22 percent (17 of 78) and 42 percent (34 of 81), respectively, for patients with scores of 8 or above.
Upper Gastrointestinal Bleeding
During the period of treatment, 24 patients in the sham-therapy group had 40 documented episodes of upper gastrointestinal bleeding, whereas in the sclerotherapy group 32 patients had 53 episodes of such bleeding (P>0.05). However, the number of episodes of bleeding attributable to esophageal varices was significantly higher in the sham-therapy group than in the sclerotherapy group (19 vs. 10, P = 0.007). Esophageal ulcers caused nine episodes of bleeding among patients in the sclerotherapy group but none in the sham-therapy group (P = 0.006). The source of the bleeding was considered uncertain in 22 percent of the episodes. After the termination of treatment, the frequency of upper gastrointestinal bleeding was lower among the patients who had received sclerotherapy (15 episodes in 11 patients) than among those who had received sham therapy (41 episodes in 20 patients). Five episodes of bleeding in the sclerotherapy group and 11 in the sham-therapy group were from esophageal varices.
The total transfusion requirement for the patients who received sclerotherapy (320 units) was somewhat higher than that for those who received sham therapy (280 units). After treatment was stopped, the transfusion requirement in the sclerotherapy group was substantially lower (78 units) than that in the control group (202 units).
Other Outcomes
During the treatment phase of the study, the number of patients in whom treatment failed, who received vasopressin, or who underwent balloon tamponade or shunt surgery was similar in the two groups. The numbers of hospitalizations, for bleeding or other reasons, and the frequency of encephalopathy, jaundice, ascites, or infection were also similar. The proportion of patients who continued to abstain from alcohol was almost identical in both groups (approximately 45 percent after one year, approximately 33 percent after two years, and approximately 23 percent three years after enrollment in the study).
Variceal Obliteration
The esophageal varices were obliterated in 50 patients after an average of three sclerotherapy sessions (Table 4Table 4
Results and Complications of Sclerotherapy or Sham Therapy among Men with Alcoholic Liver Disease and Esophageal Varices.). In the majority of patients the varices were not obliterated either because they died or because treatment was stopped. The patients in the sclerotherapy group who died, were lost to follow-up, or had shunt surgery had undergone an average of three sclerotherapy sessions. The remaining patients whose varices were not obliterated had an average of 3.6 sclerotherapy sessions before treatment was stopped. The varices had disappeared spontaneously at 12 months in one patient in the sham-therapy group.Complications
Table 4 shows the numbers of patients who had complications during the study; all these complications, except induced variceal bleeding, were more frequent among the patients who received sclerotherapy. No patient had an esophageal perforation. Most esophageal ulcers developed within the first month of therapy. Strictures were easily treated by esophageal dilation. Complications required the omission of one or more treatment sessions in 33 patients in the sclerotherapy group but did not prevent continued sclerotherapy in any patient. One patient in the sclerotherapy group had bleeding from an esophageal ulcer after his third sclerotherapy session, then had a myocardial infarction and died shortly thereafter.
Discussion
Prophylactic sclerotherapy in this group of alcoholic men was associated with a mortality rate almost double that in the control group. The difference between the mortality rates in the two groups was statistically significant and unanticipated. Sclerotherapy eventually reduced the number of episodes of upper gastrointestinal bleeding, but not before the increased mortality rate forced the discontinuation of treatment. Despite careful review of individual causes of death, we found no plausible pathophysiologic explanation for the observed increase in mortality: nevertheless, we believe the higher mortality rate was due to sclerotherapy, for several reasons. The study groups were large, twice the size of those in the next largest study. We studied only patients with alcoholic liver disease, thereby reducing the confounding influence of different underlying liver diseases with different prognoses. The association of sclerotherapy with mortality was not due to unequal follow-up, since all patients were seen and underwent endoscopy and either active or sham treatment on the same schedule. The adverse treatment effect persisted even after we adjusted for the effects on prognosis of the base-line Child's score and the unbalanced distribution of other medical illnesses in the two treatment groups.The higher mortality rate was seen at all but two of the participating medical centers — an likely event if some investigators lacked technical skill. Moreover, there was no correlation between the time of sclerotherapy and that of death, a relation that might have been expected if the deaths were due to technical complications. Most important, the higher mortality rate in the sclerotherapy group did not persist after treatment was discontinued.
That an adverse outcome of prophylactic sclerotherapy was observed in this but not in other studies is probably due to the difference in study populations.8 9 10 11 12 13 The patients we studied all had long-standing chronic alcoholism and many of its complications. In contrast, the proportion of patients who were alcoholic ranged from 33 percent to 90 percent in the other studies of prophylactic sclerotherapy that reported these data.9 10 11 12 13 The study with the highest proportion of alcoholic patients was also the only one in which excess bleeding and an increase in bleeding-related deaths were found among the patients who underwent sclerotherapy.11
Differences in sample size may also explain the discordant results. We enrolled 281 patients, whereas the next largest study enrolled 140 patients.13 In one of the two largest previous studies,12 , 13 sclerotherapy reduced bleeding and improved survival, but the majority of the study patients did not have alcoholic liver disease.13 It is possible that the chance assignment of more patients who had other medical illnesses to the sclerotherapy group contributed to the unfavorable outcome in our study. However, the excess mortality in the sclerotherapy group was not limited to patients with other medical illness, and it persisted despite statistical adjustment for this factor.
The rates of complications in our study were comparable to those reported for a single-center study of prophylactic sclerotherapy in this country.11 The proportion of patients with esophageal ulcers was high, but all ulcers were counted regardless of size, and endoscopy was performed frequently. Complications sufficient to disrupt the sclerotherapy schedule occurred in 33 patients.
It seems unlikely that the choice of 1.5 percent sodium tetradecyl sulfate as the sclerosant caused the high mortality in the sclerotherapy group. This agent at the 1.5 percent concentration compared favorably to morrhuate sodium in one study20 and was as effective as many other sclerosants in dogs.21 It is also unlikely that continued drinking contributed to the results. The numbers of patients who resumed drinking or continued to drink alcohol were substantial but similar in the two treatment groups. A few of our patients had varices less than 5 mm in size, but the excess mortality in the sclerotherapy group was independent of the size of the varices.
The results of this study are reminiscent of those of the trials of prophylactic portacaval shunts that were conducted in patients with alcoholic cirrhosis 20 to 30 years ago.22 Prophylactic shunts effectively prevented the first episode of variceal hemorrhage but also produced accelerated hepatic encephalopathy and hepatic failure. Survival was not improved, and in some instances it worsened. In our study, prophylactic sclerotherapy reduced new episodes of variceal hemorrhage, but the procedure caused bleeding from esophageal ulcers and doubled the mortality rate. We conclude that prophylactic sclerotherapy is dangerous in men with alcoholic liver disease and esophageal varices. Physicians should wait until bleeding from the varices occurs before initiating sclerotherapy in such patients.
Address reprint requests to Dr. Peter B. Gregory at the Office of the Vice President and Dean, School of Medicine, Rm. M-121, Stanford University Medical Center, Stanford, CA 94305–5302.
Supported by the Cooperative Studies Program of the Medical Research Service, Department of Veterans Affairs.
The participants in the Veterans Affairs Cooperative Variceal Sclerotherapy Group are listed in the Appendix.
We are indebted to the participating patients for their contribution to this study and to Elkins Sinn, Inc., which donated the sclerosant and the matching placebo.
Appendix
The participants in the Veterans Affairs Cooperative Variceal Sclerotherapy Group were as follows: Study Chairman: Peter B. Gregory, M.D.; Study Statistician: Pamela Hartigan, M.P.H., Ph.D.; Participating Investigators: Donald J. Amodeo, M.D., Richard A. Baum, M.D., Daniel S. Camara, M.D., Donald R. Campbell, M.D., Henry Colcher, M.D., Pamela L. Garjian, M.D., Roger L. Gebhard, M.D., John S. Goff M.D., Daniel M. Kruss, M.D., Peter M. Lance, M.D., Ramesh Luther, MD., Mark S. McPhee, M.D., Peter B. Meier, MD., Robert A. Rankin, M.D., Mark Reichelderfer, M.D., Robert A. Sanowski, M.D., David Shields, M.D., Stephen E. Silvis, M.D., Robert E. Weesner, M.D., Daniel H. Winship, M.D., and Harvey S. Young, M.D.; Study Nurses: Joan Barron, R.N., Dee Becker, R.N., Carol Cotton, R.N., Dana Driskell, R.N., Susie Frederick, R.N., Claire Halter, R.N., Michele Hawkins, R.N., Karen Hollstrom-Tarwater, R.N., Charlene Kuhr, R.N., Diane Lawhorne, R.N., Gertrude Leshko, R.N., Anne Livak, R.N., Monica McCullough, R.N., Diane Mentzer, R.N., Judy Nelson, R.N., Gail O'Hanlon, R.N., Kay Pardy, R.N., Mary Rinki, R.N., Linda Schlasner, R.N., and Judy Sullivan, R.N.; Planning Committee: Daniel S. Camara, M.D., Raphael S. Chung, M.D., Peter B. Gregory, M.D., Pamela Hartigan, M.P.H., Ph.D., Dennis M. Jensen, M.D., Walter L. Peterson, M.D., and Jane Weber, Pharm.D.; Executive Committee: Daniel S. Camara, M.D., Carol Fye, R.Ph., M.S., John S. Goff, M.D., Peter B. Gregory, M.D., Pamela Hartigan, M.P.H., Ph.D., Robert A. Sanowski, M.D., Stephen E. Silvis, M.D., and Daniel H. Winship, M.D.; Data-Monitoring Board: William Best, M.D., Marshall M. Kaplan, M.D. (chairman), John W. Singleton, M.D., Yick-Kwong Chan, Ph.D. (ad hoc member); and Dorothea Collins, M.S. (ad hoc member); West Haven Veterans Affairs Cooperative Studies Program Statistical Coordinating Center: Dorothea Collins, M.S. (chief), Pamela Hartigan, M.P.H., Ph.D., Margaret Antonelli (administrative officer), Lynn Durant (statistical assistant), Lillie Franklin (computer assistant), Mary Anne Hope, M.S. (programmer), Stella Marcinauskis (computer assistant), John Tuttle (computer assistant), and Velma Williams (computer assistant); Albuquerque Veterans Affairs Cooperative Studies Program Pharmacy Coordinating Center: Mike R. Sather, R.Ph., M.S. (chief), Carol L. Fye, R.Ph., M.S. (study pharmacist),Jane Weber, Pharm.D., John Recio (pharmacy technician), Steven Simpson (pharmacy technician), Linda Vasquez (computer assistant), and Gloria Martinez (clerk-typist); Palo Alto Veterans Affairs Medical Center Support Personnel: Theresa Hopper (secretary), Glenn Roldan (secretary), and Pam Roller (secretary).
The participating Veterans Affairs medical centers were in the following cities: Baltimore (R.A.B., P.L.G., G.L.), Buffalo, N.Y. (D.S.C., D.J.A., R.L., P.M.L., J.B.), Cincinnati (R.E.W., J.N., M.M.), Denver (J.S.G., K.H., S.F.), Hines, Ill. (D.M.K., C.H., A.L.), Kansas City, Mo. (M.S.M., D.H.W., D.R.C., D.D.), Madison, Wis. (M. Reichelderfer, C.K., D.B.), Minneapolis (S.E.S., R.L.G., P.B.M., L.S.), Oklahoma City (R.A.R., C.C., D.M., M.H.), Palo Alto, Calif. (P.B.G., D.S., H.S.Y., CO., M. Rinki), Phoenix, Ariz. (R.A.S.,J.S., K.P.), and Washington, D.C. (H.C., D.L.).
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