We randomly assigned 230 patients with resected Stage II or III epidermoid (squamous-cell) lung cancer to receive postoperative adjuvant radiotherapy or no adjuvant treatment. Careful intraoperative staging had been performed in all patients. Before randomization, patients were stratified according to stage, weight loss, age, and institution. Prognostic variables, such as stage, weight loss, age, nodal-disease status, and tumor status, were equally distributed between the two groups. The mean time from randomization to analysis was 3.5 years among the 210 eligible patients. There was no evidence that radiotherapy improved survival, and although recurrence rates appeared to be somewhat reduced among patients assigned to radiotherapy, these decreases were not statistically significant. However, radiotherapy did produce a striking and significant reduction in recurrences to the ipsilateral lung and mediastinum. Moreover, overall recurrence rates were reduced by radiotherapy in patients with N2 disease (P less than 0.05), although even this subgroup had no evidence of improved survival. We conclude that radiotherapy can reduce local recurrences after resection of epidermoid carcinoma of the lung, but that it does not increase survival rates.

We conducted a randomized, double-blind, placebo-controlled trial to test the efficacy of the 14-valent pneumococcal capsular polysaccharide vaccine in 2295 high-risk patients (patients with one or more of the following: age above 55 years and the presence of chronic cardiac, pulmonary, renal, or hepatic disease, alcoholism, or diabetes mellitus). Seventy-one episodes of proved or probable pneumococcal pneumonia or bronchitis occurred among 63 of the patients (27 placebo recipients and 36 vaccine recipients). Vaccine-serotype Streptococcus pneumoniae strains were recovered in association with 11 infections in the placebo group and 14 infections in the vaccine group. Pneumococcal infections occurred most frequently among patients with chronic pulmonary, cardiac, or renal diseases. Among vaccine recipients who subsequently had vaccine-type pneumonia or bronchitis, the majority did not make or sustain serum antibodies against their infecting organism in concentrations that were twice as high as the base-line values, or more than 400 ng of antibody nitrogen per milliliter, although their base-line levels were higher than those in subjects in whom infection did not develop. We were unable to demonstrate any efficacy of the pneumococcal vaccine in preventing pneumonia or bronchitis in this population. Our data suggest that chronically ill patients, who are most susceptible to infection, may have an impaired immune response to the pneumococcal vaccine.

We treated 17 patients who had moderate to severe Alzheimer's disease with oral tetrahydroaminoacridine (THA), a centrally active anticholinesterase, in a three-phase study. In the nonblinded first phase of the study, significant improvement occurred in subjects who received the drug, as compared with their pretreatment status, on the global assessment (P = 0.001), the Orientation Test (P = 0.001), and the more sophisticated Names Learning Test (P = 0.001). During the second phase, the subjects served as their own controls in a double-blind, placebo-controlled, cross-over study in which the order of administration of the drug and placebo was randomly assigned. Among the 14 subjects completing Phase II, THA treatment produced significantly better results than placebo on the global assessment (P = 0.003), the Orientation Test (P = 0.004), the Alzheimer's Deficit Scale (P = 0.003), and the Names Learning Test (P = 0.001). Twelve subjects have entered Phase III, which involves long-term administration of oral THA. The average duration of treatment in these subjects at present is 12.6 months; symptomatic improvements have occurred, and no serious side effects attributable to THA have been observed. These encouraging initial results suggest that THA may be at least temporarily useful in the long-term palliative treatment of patients with Alzheimer's disease. We stress that further observations will be required before a clear assessment of the role of this agent can be made.

We performed a randomized double-blind trial comparing continuous intravenous heparin with intermittent subcutaneous heparin in the initial treatment of 115 patients with acute proximal deep-vein thrombosis. Intermittent subcutaneous heparin as administered in this trial was inferior to continuous intravenous heparin in preventing recurrent venous thromboembolism. The subcutaneous heparin regimen induced an initial anticoagulant response below the target therapeutic range in the majority of patients and resulted in a high frequency of recurrent venous thromboembolism (11 of 57 patients, 19.3 percent), which was virtually confined to patients with a subtherapeutic anticoagulant response. In contrast, continuous intravenous heparin induced a therapeutic anticoagulant response in the majority of patients and a low frequency of recurrent events (3 of 58 patients, 5.2 percent; P = 0.024); the recurrences were limited to patients with an initial subtherapeutic anticoagulant response. The results of this trial establish the efficacy of intravenous heparin in the treatment of proximal venous thrombosis and suggest a relation between the effectiveness of heparin and the levels of anticoagulation achieved; such a relation could explain the observed failure of the subcutaneous regimen.

Current therapy for condylomata acuminata (genital warts) is not consistently effective. Therefore, we conducted a randomized, double-blind trial to compare interferon alpha-2b with placebo in the treatment of this disorder. Our rationale was that interferon has both antiproliferative and antiviral properties. The placebo or interferon (1 X 10(6) IU) was injected directly into one to three warts three times weekly for three weeks. The injections were well tolerated by both groups of patients. The side effects of fever, chills, myalgia, headache, fatigue, and leukopenia occurred more commonly in the interferon group than in the placebo group, but such effects rarely disrupted daily routines. Only 13 of 296 patients (4 percent) discontinued therapy because of side effects (11 in the interferon group and 2 in the placebo group). Twenty-six other patients were excluded from analysis because of a loss to follow-up or other deviations from protocol, thus leaving 257 patients in the final evaluation. At one week after the completion of therapy, interferon had produced a large and significantly greater reduction in mean wart area (a 62.4 percent decrease), as compared with placebo (a 1.2 percent increase in mean area) (P less than 0.001). At the conclusion of the study (13 weeks after the completion of therapy), the mean wart area was still decreased 39.9 percent below the initial size in the interferon group, whereas it had increased by 46 percent over base-line measurements in the placebo group (P less than 0.001). At the same time, all treated warts had completely cleared in 36 percent of the interferon recipients and in 17 percent of the placebo recipients (P less than 0.001), whereas treated warts progressed in 13 percent of the interferon recipients and in 50 percent of the placebo recipients (P less than 0.001). We conclude that injection of interferon alpha-2b directly into genital warts appears to be an effective and fairly well-tolerated form of therapy.

Bed rest is usually recommended for acute low back pain. Although the optimal duration of bed rest is uncertain, a given prescription may directly affect the number of days lost from work or other activities. In a randomized trial, we compared the consequences of recommending two days of bed rest (Group I) with those of recommending seven days (Group II). The subjects were 203 walk-in patients with mechanical low back pain; 78 percent had acute pain (less than or equal to 30 days), and none had marked neurologic deficits. Follow-up data were obtained at three weeks (93 percent) and three months (88 percent). Although compliance with the recommendation of bed rest was variable, patients randomly assigned to Group I missed 45 percent fewer days of work than those assigned to Group II (3.1 vs. 5.6 days, P = 0.01), and no differences were observed in other functional, physiologic, or perceived outcomes. For many patients without neuromotor deficits, clinicians may be able to recommend two days of bed rest rather than longer periods, without any perceptible difference in clinical outcome. If widely applied, this policy might substantially reduce absenteeism from work and the resulting indirect costs of low back pain for both patients and employers.

To determine the safety, efficacy, and cost savings of early hospital discharge of very-low-birth-weight infants (less than or equal to 1500 g), we randomly assigned infants to one of two groups. Infants in the control group (n = 40) were discharged according to routine nursery criteria, which included a weight of about 2200 g. Those in the early-discharge group (n = 39) were discharged before they reached this weight if they met a standard set of conditions. For families of infants in the early-discharge group, instruction, counseling, home visits, and daily on-call availability of a hospital-based nurse specialist for 18 months were provided. Infants in the early-discharge group were discharged a mean of 11 days earlier, weighed 200 g less, and were two weeks younger at discharge than control infants. The mean hospital charge for the early-discharge group was 27 percent less than that for the control group ($47,520 vs. $64,940; P less than 0.01), and the mean physician's charge was 22 percent less ($5,933 vs. $7,649; P less than 0.01). The mean cost of the home follow-up care in the early-discharge group was $576, yielding a net saving of $18,560 for each infant. The two groups did not differ in the numbers of rehospitalizations and acute care visits, or in measures of physical and mental growth. We conclude that early discharge of very-low-birth-weight infants, with follow-up care in the home by a nurse specialist, is safe and cost effective.

There is experimental evidence that low-molecular-weight fractions of heparin are as effective as the standard form but cause less bleeding. We therefore performed a double-blind, randomized trial comparing PK10169 low-molecular-weight heparin with placebo for the prevention of venous thrombosis in patients undergoing elective hip surgery. Prophylactic treatment with a fixed dose was begun postoperatively and continued for 14 days. Fifty patients in each treatment group underwent surveillance with [125I]fibrinogen leg scanning and impedance plethysmography. In the first 24 patients, venography was performed only if either surveillance test was positive. Because the rate of venous thrombosis detected in those patients was unexpectedly low, venography was requested in the remaining 76 patients, even if the screening tests were negative. In this latter group, venous thrombosis occurred in 4 patients (10.8 percent) given PK10169 heparin and 20 patients (51.3 percent) given placebo (P = 0.0002); the corresponding rates for proximal-vein thrombosis were 5.4 percent and 23.1 percent, respectively (P = 0.029). In the entire group of 100 patients, venous thrombosis occurred in 12 percent of those given PK10169 heparin and 42 percent of those given placebo (P = 0.0007), and the corresponding rates for proximalvein thrombi were 4 percent and 20 percent, respectively (P = 0.014). The observed hemorrhagic rate was 4 percent in each treatment group. We conclude that prophylaxis with fixed-dose PK10169 heparin is effective and safe for patients undergoing elective hip replacement.

We conducted a double-blind, placebo-controlled trail in which 40 patients who had undergone long-term therapy with benzodiazepines were switched to placebo or to diazepam in a dose approximately equivalent to their usual dose of the benzodiazepine; the dose of diazepam was then tapered during an eight-week period. Patients were assessed clinically and psychologically and had weekly sessions of behavioral therapy. The subjects who received placebo had more symptoms, assessed their symptoms as more severe, and stopped taking the study drug at a higher rate than those receiving the tapering doses of diazepam. The subjects in the placebo group also had symptoms shortly after being switched to placebo, whereas those in the diazepam group had symptoms much later. Some withdrawal symptoms were distinct from those of anxiety (e.g., tinnitus, involuntary movement, and perceptual changes). Withdrawal symptoms occurred earlier in patients who had received short-acting benzodiazepines than in those who had received long-acting benzodiazepines. Symptoms gradually disappeared over a four-week period in both the placebo and the diazepam groups. Serial determination of plasma benzodiazepine concentrations was a useful way to assess compliance, treatment outcome, and relapse during withdrawal. We conclude that a clinically important, mild, but distinct withdrawal syndrome occurs after discontinuation of long-term therapeutic use of benzodiazepines.

To evaluate the concept that long duration of action is an advantageous property of angiotensin-converting enzyme inhibitors in the treatment of severe heart failure, we randomly assigned 42 patients to therapy with either a short-acting inhibitor (captopril, 150 mg daily) or a long-acting inhibitor (enalapril, 40 mg daily) for one to three months while concomitant therapy with digoxin and diuretics was kept constant. The treatment groups had similar hemodynamic and clinical characteristics at base-line evaluation and similar initial responses to converting-enzyme inhibition. During long-term therapy, captopril and enalapril produced similar decreases in systemic blood pressure, but the hypotensive effects of enalapril were more prolonged and persistent than those of captopril. Consequently, although the patients in both groups improved hemodynamically and clinically during the study, serious symptomatic hypotension (syncope and near syncope) was seen primarily among those treated with enalapril. Sustained hypotension also probably accounted for the decline in creatinine clearance (P less than 0.05) and the notable retention of potassium (P less than 0.05) observed in the patients treated with enalapril but not in those treated with captopril. We conclude that when large, fixed doses of converting-enzyme inhibitors are used in the treatment of patients with severe chronic heart failure, long-acting agents may produce prolonged hypotensive effects that may compromise cerebral and renal function, and thus they may have disadvantages in such cases, as compared with short-acting agents.

We undertook a randomized, controlled trial to determine whether human surfactant administered endotracheally at birth to very premature infants (gestational age, 24 to 29 weeks) would prevent the respiratory distress syndrome or reduce its severity. Thirty-one treated infants (birth weight, 938 +/- 286 g) were compared in a blinded fashion with 29 control infants (birth weight, 964 +/- 174 g). The lecithin/sphingomyelin ratio was less than 2 in all infants, and phosphatidylglycerol was not present in amniotic fluid or tracheal fluids at birth, indicating a deficiency of surfactant in the lungs. The principal dependent variables were neonatal death, the incidence of bronchopulmonary dysplasia, and the infant's requirement for respiratory support (and its complications). The surfactant-treated group had significantly fewer deaths than the control group (16 percent vs. 52 percent, P less than 0.001), fewer cases of bronchopulmonary dysplasia (16 percent vs. 31 percent), and significantly fewer cases of pulmonary interstitial emphysema (P less than 0.001) and pneumothorax (P less than 0.02). Prophylactic treatment with human surfactant also substantially reduced the period of neonatal intensive care. We conclude that treatment with human surfactant offers promise for improving the survival of very premature infants with a surfactant deficiency and for reducing the pulmonary sequelae of the respiratory distress syndrome.

The reversibility of thyroid dysfunction in children with endemic cretinism treated with supplemental iodine is unknown. To study this question we conducted a five-month follow-up of 51 patients with cretinism (age 14 and below), who were randomly assigned to treatment (0.5 ml of intramuscular iodized oil) and control groups. The geometric mean initial serum level of thyrotropin (223 microU per milliliter; SD, 97 to 513) and the mean (+/- SD) initial serum level of thyroxine (1.0 +/- 1.2 micrograms per deciliter) indicated that all patients had severe hypothyroidism. Within one month after receiving the iodized oil, 13 of 14 of the younger patients (less than 4 years) and 1 of 9 of the older patients (4 to 14 years; P less than 0.001) had thyrotropin values below 20 microU per milliliter. Five months after treatment, the levels of thyrotropin had decreased and those of thyroxine had increased in all children, but greater changes occurred in the 13 younger patients than in the 14 older patients. The mean levels of thyrotropin were 2 microU per milliliter (SD, 0.6 to 6) vs. 38 microU per milliliter (SD, 11 to 132; P less than 0.001), and the mean (+/- SD) levels of thyroxine were 13.1 +/- 2.8 vs. 8.1 +/- 4.6 micrograms per deciliter (P less than 0.001). In the untreated group, 3 of the 9 younger patients and none of the 15 older patients recovered normal thyroid function within five months. We conclude that iodine supplementation restored a biochemically euthyroid state in all younger children with cretinism but only some of the older children. In addition, some younger patients became euthyroid without iodine supplementation.

Bleeding is a major complication of uremia. Both cryoprecipitate and desmopressin effectively shorten the prolonged bleeding time and favorably influence clinical bleeding, but the former carries the risk of transmitting blood-borne infectious diseases, and both cryoprecipitate and desmopressin have a short duration of action. Preliminary evidence has suggested that estrogens may be useful, and we therefore performed a randomized, double-blind, crossover trial comparing the effect of conjugated estrogens with that of placebo on hemorrhagic tendencies and the bleeding time in six patients with uremia who were on maintenance hemodialysis. Five daily infusions of placebo or conjugated estrogens were administered at the beginning of one-month trial periods. Estrogen shortened the bleeding time in all six patients. The effect was detectable six hours after the first infusion, reached its maximum in all patients between days 5 and 7, and lasted for 14 days. By day 16 after the last infusion, the bleeding time had returned to base line in four of the six patients. No side effects were noted during or after estrogen infusion. Estrogens did not influence the circulating level of von Willebrand factor or change its multimeric structure. Moreover, the defective platelet aggregation and thromboxane formation observed in the patients were not corrected by estrogens. We conclude that conjugated estrogens are an adequate alternative to cryoprecipitate or desmopressin for the treatment of bleeding associated with renal failure, especially when a longer duration of action is needed and immediate onset of the effect is not essential. The mechanism of action of estrogens remains to be clarified.

We evaluated the effect of anticholinergic and beta-adrenergic inhaled bronchodilators, alone or in sequence, in 11 patients with chronic obstructive pulmonary disease. We compared the agents albuterol and ipratropium bromide when each was used as a single aerosol in the maximal dose. After giving a maximal dose of one agent, we compared the effect of adding the other with that of adding a placebo. When used alone, both bronchodilators significantly increased airflow and relieved hyperinflation, and there was no significant difference between the two. After the improvement with the initial bronchodilator, the subsequent effect of a second inhaled bronchodilator was not greater than that of placebo. These results suggest that in the treatment of chronic obstructive pulmonary disease, these two aerosols are usually equipotent in maximal doses and the addition of a second agent is of no practical value. The data support the prescription of a single inhaled agent in most cases but do not rule out the value of combinations of agents under special circumstances.

Hyperprolactinemia occurs in 25 to 30 percent of young women with amenorrhea, and this condition is known to be associated with osteopenia. To determine whether the osteopenia is affected by treatment of hyperprolactinemia, we studied 32 women with hyperprolactinemic amenorrhea prospectively for 12 to 72 months to investigate the effects of sustained hyperprolactinemia or return of gonadal function on bone mass. We studied 18 patients using direct photon absorptiometry before and after normalization of serum prolactin levels. Initial bone densities ranged from 0.55 to 0.77 g per square centimeter (mean +/- 1 SD, 0.64 +/- 0.05)--densities significantly lower (P less than 0.001) than those of controls (0.71 +/- 0.04 g per square centimeter). After therapy, bone density increased significantly (P less than 0.001), to 0.67 +/- 0.05 g per square centimeter, but remained lower (P less than 0.05) than normal. Fourteen patients were followed without therapy. Their initial bone densities ranged from 0.62 to 0.75 g per square centimeter (mean, 0.67 +/- 0.04)--values significantly lower (P less than 0.02) than those in controls. There was a significant decrease (P less than 0.002) in bone density over time in this group. We conclude that (1) treatment of hyperprolactinemia increases bone mass in most amenorrheic women with osteopenia, (2) normalization of serum prolactin levels in such women is associated with prevention of bone loss, and (3) a subset of untreated women with hyperprolactinemia have progressive osteopenia, which could have adverse long-term health consequences.

To assess the efficacy of single-agent therapy relative to standard combination antibiotic therapy for the initial management of fever and neutropenia in cancer patients, we conducted a randomized trial comparing ceftazidime alone with a combination of cephalothin, gentamicin, and carbenicillin. Of 550 evaluable episodes of fever and neutropenia, 282 were treated with ceftazidime alone and 268 with the combination. All episodes were evaluated for responses at 72 hours after the start of treatment and at resolution of the neutropenia. Of the patients with unexplained fever who were given ceftazidime alone, 99 percent were alive at 72 hours and 98 percent were alive when the neutropenia resolved, as compared with 100 percent and 98 percent, respectively, of those given combination therapy. Of the patients with documented infection who were given ceftazidime alone, 98 percent were alive at 72 hours and 89 percent when the neutropenia resolved, as compared with 98 percent and 91 percent, respectively, of those given combination therapy. The majority of episodes of documented infection in both treatment groups necessitated additional antimicrobial treatment or other modifications of the initial regimen, as compared with only 22 percent of the episodes of unexplained fever. We conclude that initial single-agent therapy with certain beta-lactam antibiotics is a safe alternative to standard combination antibiotic therapy, although patients with documented infection or protracted neutropenia are likely to require additional or modified treatment.

We performed a multicenter, double-blind, randomized study to evaluate the effect of diltiazem on reinfarction after a non-Q-wave myocardial infarction. Nine centers enrolled 576 patients: 287 received diltiazem (90 mg every six hours) and 289 received placebo. Treatment was initiated 24 to 72 hours after the onset of infarction and continued for up to 14 days. The primary end point, reinfarction, was defined as an abnormal reelevation of MB creatine kinase in plasma within 14 days. Reinfarction occurred in 27 patients in the placebo group (9.3 percent) and in 15 in the diltiazem group (5.2 percent)--a 51.2 percent reduction in cumulative life-table incidence (P = 0.0297; 90 percent confidence interval, 7 to 67 percent). Diltiazem reduced the frequency of refractory postinfarction angina (a secondary end point) by 49.7 percent (P = 0.0345; 90 percent confidence interval, 6 to 73 percent). Mortality was similar in the two groups (3.1 and 3.8 percent, respectively, in the placebo and diltiazem groups), but adverse drug reactions (most of which were mild) were more common in the diltiazem group. Nevertheless, the drug was well tolerated, despite concurrent treatment with beta-blockers in 61 percent of the patients. We conclude that diltiazem was effective in preventing early reinfarction and severe angina after non-Q-wave infarction and that it was also safe and generally well tolerated.