The efficacy of corticosteroid treatment in the prophylaxis of the fat embolism syndrome was evaluated in a prospective, randomized, double-blind study of high-risk patients with long-bone fractures. Using a set of objective diagnostic criteria, we saw a significant difference in the incidence of the syndrome between corticosteroid- (0 of 21) and placebo-treated patients (9 of 41) (p less than 0.05). There were no complications related to corticosteroid treatment. No routine laboratory or physical findings reliably predicted the development of the fat embolism syndrome except petechial rash, which occurred only in 5 placebo-treated patients who developed the syndrome. Complement activation was present in all patients studied who had the syndrome (5 of 27) but also in many patients who did not meet our diagnostic criteria, suggesting a multifactorial cause. These data support the prophylactic value of corticosteroid treatment in patients at high risk for the fat embolism syndrome, particularly if several unfavorable predictors are present.

The four main conceptual paradigms of basic biomedical research are that the explication of mechanisms is a primary goal of science; that scientific data must be "hard"; that formulation of hypotheses and counter-hypotheses is a principal creative challenge; and that experiments are the main mechanism for using scientific methods to conduct investigations. Although suitable for the spectacular accomplishments of biomedical research, these paradigms do not offer a satisfactory foundation for the additional basic science needed in the managerial decisions of patient care. For these decisions, the primary scientific goal is usually prediction rather than explication alone; the crucial data often involve "soft" information about clinical and personal phenomena; and the main creative challenge is to develop an improved methodology for getting adequate data and making unbiased comparisons. Although the experiments conducted as randomized clinical trials have been scientifically helpful, the improved methods will have to include evidence obtained in the often unplanned "experiments" of ordinary clinical practice.

Sham and real trials of peritoneal dialysis were carried out in a double-blind crossover study design to test the efficacy of peritoneal dialysis as a treatment for psoriasis. The criteria for patients included having severe plaque-type psoriasis unresponsive to all conventional therapy including methotrexate. Patients were randomly assigned to 4 weeks of sham or real dialysis, 8 weeks of observation, 4 weeks of alternative real or sham dialysis and 8 weeks of observation. Topical therapy was continued during the trial. Real dialysis was done for 48 hours weekly with 1.5-hour cycle times and 2-litre exchanges by machine. Sham peritoneal dialysis was done recycling the same 2 litres of 1.5% continuous ambulatory peritoneal dialysis fluid with 1.5-hour cycle times for 48 hours weekly. After real dialysis, two patients completely cleared, two patients had greater than 75% clearing, and one patient had no substantial response. None of the five patients had a response to the sham dialysis procedure (p less than 0.01).

During 1980 and 1981, we compared antibiotic regimens in 108 adult patients with early Lyme disease. Erythema chronicum migrans and its associated symptoms resolved faster in penicillin- or tetracycline-treated patients than in those given erythromycin (mean duration, 5.4 and 5.7 versus 9.2 days, F = 3.38, p less than 0.05). None of 39 patients given tetracycline developed major late complications (meningoencephalitis, myocarditis, or recurrent attacks of arthritis) compared with 3 of 40 penicillin-treated patients and 4 of 29 given erythromycin (chi square with 2 degrees of freedom = 5.33, p = 0.07). In 1982, all 49 adult patients were given tetracycline; again, none of them developed major complications. However, with all three antibiotic agents nearly half of the patients had minor late symptoms such as headache, musculoskeletal pain, and lethargy. These complications correlated significantly with the initial severity of illness. For patients with early Lyme disease, tetracycline appears to be the most effective drug, then penicillin, and finally erythromycin.

From 1969 to 1975, 53 patients with lupus nephritis took part in randomized trials comparing prednisone, oral azathioprine plus low-dose prednisone, and oral cyclophosphamide plus low-dose prednisone. After a mean follow-up of 85 months, cyclophosphamide appears marginally superior to prednisone for maintaining renal function (p = 0.03) and preventing end-stage renal failure (p = 0.07). Chronic change shown by renal biopsy assessed by a chronicity index was found useful in predicting renal function outcomes and response to immunosuppressive therapy. Three of 21 patients with a low chronicity index and 9 of 10 patients with a high chronicity index doubled their serum creatinine (p less than 0.00003). The probability of renal functional deterioration was not different among the treatments studied. However, in 14 patients with an intermediate chronicity index, 1 of 11 patients treated with azathioprine or cyclophosphamide doubled the serum creatinine level whereas all 3 patients treated with prednisone have progressed to end-stage renal failure (p = 0.005). The study suggests that single-drug oral immunosuppressive treatment combined with prednisone is most beneficial in lupus patients with intermediate chronic change shown by renal biopsy.

A critical review of the literature assessing the antiemetic efficacy of delta-9-tetrahydrocannabinol (THC) in patients receiving cancer chemotherapy showed considerable inconsistency in results. The equivocal nature of these results partly reflects the difficulty of doing research on antiemetic therapies, but also can be attributed to differences in the adequacy and nature of the research designs, procedures, and assessment instruments that have been used. Several factors were also identified that are seldom studied but may be important in determining whether THC will be effective: patient variables, such as chemotherapy regimen and age; pharmacologic variables, such as drug tolerance, dose, schedule, toxicity, route of administration, and drug interactions; and environmental variables associated with administration setting. The need to differentiate pharmacologically induced from conditioned nausea and vomiting was also pointed out. We believe that THC does have antiemetic efficacy, but the lack of controlled research does not allow precise knowledge of its true effectiveness and toxicity. Well-controlled trials are needed to help answer some of these questions.

Thirty-one patients with first episodes of genital herpes were randomized in a double-blind fashion to intravenous treatment with saline placebo or acyclovir, 5 mg/kg body weight at 8-hour intervals, for 5 days. The median duration of viral shedding from genital lesions after the onset of therapy was significantly shorter for patients given acyclovir (2 days) than for those given placebo (13 days), p less than 0.001. Viral shedding from the pharynx, cervix, urethra, and urine were also shorter in acyclovir-treated patients. (p less than or equal to 0.01 for each comparison). Local and systemic symptoms were shortened by a mean of 5 days and healing of genital lesions by a mean of 12 days in acyclovir-treated patients. (p less than 0.01). Complications during treatment, such as extragenital lesions or urinary retention requiring catheterization, developed in four patients given placebo and in none given acyclovir. (p less than 0.05). Intravenous acyclovir substantially decreases the symptoms, duration of lesions, and complications of primary genital herpes.

Nineteen patients with advanced refractory metastatic breast cancer no longer responsive to chemotherapy were treated in the first phase II efficacy trial of recombinant leukocyte A interferon (IFL-rA), a highly purified single molecular species of alpha interferon prepared by recombinant DNA methods. Patients received a previously determined maximum tolerated dose for this agent (50 X 10(6) U/m2 body surface area) by intramuscular injection three times weekly for up to 3 months. The symptoms of toxicity observed in this trial resemble those previously reported for alpha interferons and include fever, chills, fatigue, anorexia, and leukopenia. All patients required dose reductions, most often for reasons of severe fatigue. Of the 17 patients evaluable for tumor response, one patient had stable disease and 16 had evidence of tumor progression. We conclude that IFL-rA is not an active agent in the treatment of advanced, refractory breast cancer when used at a maximum tolerated dose on this treatment schedule.

The clinical efficacy of clindamycin was compared with that of penicillin in a randomized study of the treatment of community-acquired putrid lung abscess. After starting therapy, patients treated with clindamycin had a shorter febrile period and fewer days of fetid sputum than patients treated with penicillin (mean 4.4 versus 7.6 days and 4.2 versus 8.0 days, respectively, p less than 0.05). Four of 20 patients treated with penicillin had clinically significant pulmonary or pleural extension of their infection within 10 days after starting therapy; this was not found in any of 19 patients treated with clindamycin (p less than 0.05). Penicillin treatment failed in two additional patients after 20 days of therapy. Within 1 month after treatment, 1 of 4 patients given penicillin for 3 weeks had relapse, but none of the 13 patients given clindamycin for 3 or 6 weeks, and none of the 5 patients given penicillin for 6 weeks had relapse. Overall, only 8 of 15 patients treated with penicillin who could be followed to the end of the study were cured, whereas all 13 patients treated with clindamycin who could be followed were cured (p less than 0.01). These results suggest that penicillin may not be optimal therapy for anaerobic lung abscess.

In a randomized placebo-controlled double-blind trial, we compared flecainide to quinidine for treatment of ventricular ectopic depolarizations in 19 patients. The mean percent suppression of total ventricular ectopic depolarizations was 95% for flecainide and 56% for quinidine (p less than 0.05). A greater than 80% reduction of total ventricular ectopic depolarizations was obtained in eight of nine patients given flecainide and in five of ten patients given quinidine (p = 0.09). After the randomized protocol, the patients who had received quinidine were given flecainide; 9 of the 10 patients had greater than 80% reduction of total ventricular ectopic depolarizations. Flecainide produced 100% suppression of nonsustained ventricular tachycardia and 99.5% suppression of paired ventricular depolarizations. Flecainide prolonged the PR and QRS intervals; quinidine prolonged the PR and JTC intervals. Side effects were commoner with quinidine than flecainide (p = 0.06). Three other patients failed to complete the protocol because of serious adverse experiences.

In an effort to prevent cytomegalovirus infection among seronegative patients having marrow transplants, a globulin with high antibody levels against cytomegalovirus was given before and for 11 weeks after transplantation in a randomized trial. Among 36 patients who received no prophylactic granulocyte transfusions, globulin recipients had significantly fewer infections than controls (2 of 17 versus 8 of 19, p = 0.05 by Fisher's exact test and p = 0.03 by Mantel-Cox test). Conversely, infection rates were high and unchanged by globulin use among patients who received granulocytes from seropositive donors (7 of 8 recipients versus 6 of 7 controls). The lack of effect of the globulin among patients receiving transfusions of granulocytes from seropositive donors may suggest that the dose of antibody was insufficient or that antibody is ineffective against virus transmitted in granulocytes. We conclude that cytomegalovirus infection can be prevented by immunoprophylaxis in seronegative patients having marrow transplants who are not given granulocyte transfusions.

From a group of 108 female patients with measurable and/or evaluable metastatic breast carcinoma, 52 were randomized to receive tamoxifen and 56 to receive tamoxifen and fluoxymesterone. The fluoxymesterone dose, given orally twice a day, was 7 mg/m2 body surface area. The tamoxifen dose per patient, also given orally twice a day, ranged from 2 to 100 mg/m2 body surface area. Eighty-five percent of the patients had received previous chemotherapy and 60% previous hormone therapy. The complete and partial remission rate was better with the tamoxifen and fluoxymesterone regimen (p = 0.016), with remission rates of 15% for tamoxifen alone and 38% for the combination. The tamoxifen and fluoxymesterone regimen appeared to have higher remission rates in all subsets of pretreatment variables. Duration of remission with each regimen was similar, but the overall time to treatment failure for tamoxifen and fluoxymesterone was longer than for tamoxifen alone (180 versus 64 days, p = 0.01). Median survival with the combination was 380 days compared to 330 days for tamoxifen. No significant dose-response relationships emerged. Side effects were not different between dose levels or regimens except for the androgen effects in the tamoxifen and fluoxymesterone combination. These results suggest that there is no major dose-response effect for doses ranging from 2 to 100 mg/m2 body surface area given twice daily in this largely (94%) postmenopausal pretreated patient group, and that the tamoxifen and fluoxymesterone regimen is superior to tamoxifen alone.

Eighty-five patients with Wegener's granulomatosis were studied for 21 years at the National Institutes of Health. Patients were treated with a protocol consisting of cyclophosphamide, 2 mg/kg body weight d, together with prednisone, 1 mg/kg body weight d, followed by conversion of the prednisone to an alternate-day regimen. Complete remissions were achieved in 79 of 85 patients (93%). The mean duration of remission for living patients was 48.2 (+/- 3.6) months. Twenty-three patients are off all therapy for a mean duration of 35.3 (+/- 6.3) months without therapy. This study provides a prospective experience with Wegener's granulomatosis and shows that long-term remissions can be induced and maintained in an extremely high number of patients by the combination of daily cyclophosphamide and alternate-day prednisone therapy.