To assess the value of simple protective isolation, we prospectively compared it with standard hospital care in 43 episodes of severe granulocytopenia, most occurring in patients with acute nonlymphocytic leukemia. Sterilized food and prophylactic oral antibiotics were not used. Twenty episodes in 17 patients were randomized to simple protective isolation (437 days), and 23 episodes in 20 patients to standard care (611 days). No statistically significant differences were observed in the overall incidence of infection, time to onset of first infection, or days with fever. Twenty-seven infections occurred in recipients of standard care (4.42 per 100 days), and 28 infections in isolated patients (6.41 per 100 days). Except for a threefold higher rate of bacteremia in patients in isolation (2.06 vs. 0.65 per 100 days), the profile of infection was similar in the two groups. Neither response to antileukemic therapy nor survival was improved by isolation. We conclude that protective isolation alone, as practiced in most hospitals, appears not to benefit granulocytopenic patients.

In studies to determine the optimal treatment for polycythemia vera, 431 previously untreated patients whose disease met established diagnostic criteria were entered into a prospective, randomized controlled trial between 1967 and 1974. Three treatment regimens were used: phlebotomy alone, chlorambucil supplemented by phlebotomy, or radioactive phosphorus supplemented by phlebotomy. Despite minor differences in age and sex, the three groups were comparable in initial hematocrit, white-cell and platelet counts, and disease-related symptoms. The median duration of follow-up is now more than 6 1/2 years. As of February 15, 1980, there were no statistically significant differences in survival among the groups. However, the risk of acute leukemia in patients given chlorambucil was 2.3 times that in patients given radioactive phosphorus and 13 times that in patients treated with phlebotomy alone. The increased incidence of leukemia during chlorambucil treatment is statistically significant (P less than or equal to 0.002); accordingly, the Polycythemia Vera Study Group has discontinued the use of chlorambucil in the treatment of polycythemia vera.

To study the efficacy of corticosteroids in chronic active hepatitis (CAH) positive for hepatitis B surface antigen (HBsAg), we pair-randomized 51 patients to receive either 15 to 20 mg of prednisolone per day or a placebo. After initial remission, the maintenance dosage of prednisolone was 10 mg per day, and the patients were prospectively followed for up to 3 1/2 years. Prednisolone decreased serum bilirubin (P < 0.05) and globulin (P < 0.01) at three months; it delayed other biochemical remission occurring after the second month of medication (P < 0.001); it hastened biochemical relapse (P < 0.0001); and it increased the frequency of complications (P < 0.0001) and the death rate (P < 0.01). We conclude that prednisolone has an overall harmful effect in patients with HBsAg-positive CAH.

The substitution of ambulatory for inpatient care has become a common cost-containment proposal; it assumes that an equivalent or better clinical outcome at lower cost will result. However, when criteria for measuring cost and efficacy are appropriately defined, there is little published information available that support this assumption. Only four of 134 relevant papers that we analyzed provided enough data on both cost and efficacy to allow statistically valid conclusions. Two of these four demonstrated that potential savings would be accompanied by a slightly poorer clinical outcome; two showed ambulatory care to be as effective as inpatient care and less costly. Future study should include both appropriate calculations of costs and properly controlled measurements of clinical outcome. Indirect costs cannot be ignored in such calculations if the total costs of illness, not simply payments to the health industry, are to be reduced.

We studied the effect of th bite acid sequestrant colestipol, alone and in combination with clofibrate or niacin, in patients with heterozygous familial hypercholesterolemia who were given a diet low in cholesterol and saturated fat. With colestipol alone, mean cholesterol levels in serum decreased 16 to 25 per cent. The addition of clofibrate produced a total mean decrement of only 28 per cent. In contrast, serum cholesterol levels fell 45 per cent when colestipol as combined with niacin. Low-density-lipoprotein (LDL) cholesterol decreased 55 per cent with colestipol and niacin, whereas high-density-lipoprotein (HDL) cholesterol increased. Mean LDL cholesterol was lower in patients given this regimen than in matched normal controls eating an unrestricted diet. Tendinous xanthomas, measured by quantitative xeroradiography, were significantly reduced (P < 0.01), indicating that this regimen mobilized cholesterol from tissue pools with slow turnover. Colestipol plus niacin promises to be useful in the treatment of patients at high risk from elevated levels of LDL.

Twelve of 17 patients with histiocytosis-X were immunologically abnormal, as shown by the presence of circulating lymphocytes spontaneously cytotoxic to cultured human fibroblasts or of antibody to autologous erythrocytes. The patients also had a notable lack of histamine H2 surface receptors on their T lymphocytes, suggesting a suppressor-cell deficiency. The lymphocyte abnormalities were reversed in vitro after incubation in a crude extract of calf thymus gland, and therefore all 17 patients were treated with daily intramuscular injections of this extract. With this therapy, 10 patients entered complete remission -- a response at least as good as that observed in historical controls treated with chemotherapy. A positive clinical response was associated with an increase in the number of T-cell histamine H2 receptors to normal levels and with correction of the other immunologic abnormalities. The results of this preliminary study justify a larger prospective clinical trial of thymic extract and further investigation of the immunoregulatory mechanisms in histiocytosis-X.

We examined the value of maintenance theophylline at serum concentrations of 10 to 20 micrograms per milliliter in a placebo-controlled, randomized, double-blind trial of 33 children with steroid-dependent chronic asthma. Patients were free of all symptoms 63 +/- 6 per cent of the days (mean +/- S.E.M.) when taking theophylline as compared with 42 +/- 6 per cent when taking placebo (P < 0.01). Inhaled metaproterenol was required twice as often with placebo (P < 0.01), and additional daily corticosteroids were needed more than three times as often with placebo (P = 0.02). Daily peak flow measurements improved with theophylline (P < 0.01) as did monthly spirometric measurements and residual volume measured by plethysmography. Theophylline was associated with a 50 per cent increase in the number of patients able to complete an exercise test (P = 0.01) and with a smaller decrease in forced expiratory volume in one second among patients completing the exercise (P < 0.02). We conclude that maintenance bronchodilator therapy with theophylline can provide clinically important benefit for patients with chronic steroid-dependent asthma.

Before the introduction of tamoxifen, diethylstilbestrol (DES) was widely considered to be the hormonal treatment of choice in postmenopausal women with advanced breast cancer. We performed a randomized clinical trial of these two agents to determine their relative efficacy and toxicity. The trial involved 143 evaluable patients, of whom 99 had received no prior systemic therapy and 44 had received previous chemotherapy. The regression rates (complete plus partial) were higher in patients receiving DES (41 per cent) than in those receiving tamoxifen (33 per cent), but not significantly so (P = 0.37). In patients who had had no prior systemic therapy, the rates were 44 per cent and 38 per cent, respectively (P = 0.55), and in those who had had previous chemotherapy, 32 per cent vs. 23 per cent (P = 0.50). Analysis of the time until treatment failure for the two treatment groups showed no significant difference (medians: DES, 142 days; tamoxifen, 171 days). Toxicity was greater in patients receiving DES; nine of 74 patients (12 per cent) discontinued therapy solely because of adverse reactions. Since there was no statistically significant difference in efficacy and since tamoxifen was less toxic, tamoxifen appears to be the preferred agent.

We studied the therapeutic efficacy of sulfasalazine and its metabolites sulfapyridine and 5-aminosalicylic acid in nine patients with Crohn's disease and in 23 patients with ulcerative colitis. In a randomized, controlled trial, we treated 11 patients for six weeks with 1 g of sulfasalazine three times a day, seven patients with 0.5 g of sulfapyridine three times a day, and 14 patients with 0.5 g of 5-aminosalicylic acid suppositories three times a day. The clinical state of the disease was characterized by an activity index, quality of stool, and remission rate. In addition, we monitored plasma levels of sulfapyridine, 5-aminosalicylic acid, and their acetylated metabolites. The initial activity index (mean +/- S.D.) was significantly reduced by sulfasalazine (from 245 +/- 129 to 100 +/- 71; P < 0.001) and by 5-aminosalicylic acid (from 251 +/- 65 to 90 +/- 93; P < 0.0001), but sulfapyridine was without benefit. Stool quality was also improved by sulfasalazine (82 per cent of the cases) and by 5-aminosalicylic acid (79 per cent). The highest remission rate was achieved with 5-aminosalicylic acid (86 per cent), followed by sulfasalazine (64 per cent) and sulfapyridine (14 per cent). Our investigations show that 5-aminosalicylic acid is the active moiety of sulfasalazine and that this effective metabolite may be an alternative to sulfasalazine in inflammatory bowel disease.

To clarify the controversy regarding the benefits of long-term oral digoxin in the treatment of heart failure, we evaluated hemodynamics at rest and during exercise in nine patients in sinus rhythm with symptomatic heart failure. Patients were studied during long-term digoxin therapy, after withdrawal of the drug, and six hours after readministration. Upon withdrawal of digoxin, pulmonary capillary-wedge pressure increased from 21 +/- 8 to 29 +/- 10 mm Hg, and cardiac index decreased from 2.4 +/- 0.7 to 2.1 +/- 0.6 liters per minute per square meter of body-surface area, suggesting a deterioration in left ventricular function. In addition, heart rate tended to increase and stroke-work index, stroke-volume index, and radioangiographic ejection fraction decreased. Acute readministration restored the hemodynamic values to those observed during long-term digoxin therapy. The improvement in hemodynamics during long-term digoxin administration was also observed during exercise. This improvement demonstrated the value of long-term oral digoxin therapy in congestive heart failure.

Within three weeks of definitive surgical intervention, 467 patients with histologically proved malignant glioma were randomized to receive one of four treatment regimens: semustine (MeCCNU), radiotherapy, carmustine (BCNU) plus radiotherapy, or semustine plus radiotherapy. We analyzed the data for the total randomized population and for the 358 patients in whom the initial protocol specifications were met (the valid study group). Observed toxicity included acceptable skin reactions secondary to radiotherapy and reversible leukopenia and thrombocytopenia due to chemotherapy. Radiotherapy used alone or in combination with a nitrosourea significantly improved survival in comparison with semustine alone. The group receiving carmustine plus radiotherapy had the best survival, but the difference in survival between the groups receiving carmustine plus radiotherapy and semustine plus radiotherapy was not statistically significant. The combination of carmustine plus radiotherapy produced a modest benefit in long-term (18-month) survival as compared with radiotherapy alone, although the difference between survival curves was not significiant at the 0.05 level. This study suggests that it is best to use radiotherapy in the post-surgical treatment of malignant glioma and to continue the search for an effective chemotherapeutic regimen to use in addition to radiotherapy.

To evaluate the treatment of advanced islet-cell carcinoma, we randomly assigned 84 patients to streptozocin alone or streptozocin plus fluorouracil. Each regimen was given in five-day courses. The most frequent toxic effects were nausea and vomiting, mild and reversible renal toxicity, and bone-marrow depression with the combination regimen. The combination had advantages over streptozocin alone in overall rate of response (63 vs. 36 per cent) and in rates of complete response (33 vs. 12 per cent). There was no evidence of a preferential response among types of functional tumors. Objective responses were generally of long duration (median, 17 months) and of substantive clinical benefit. Treatment with the combination also yielded a survival advantage over treatment with streptozocin alone (medians, 26 and 16 1/2 months), but this difference is not statistically significant. In spite of gastrointestinal side effects, streptozocin combined with fluorouracil appears to be a valuable treatment for advanced islet-cell carcinoma.