Although wide surgical excision is the accepted treatment for thin malignant melanomas, there is reason to believe that narrower margins may be adequate. We conducted a randomized prospective study to assess the efficacy of narrow excision (excision with 1-cm margins) for primary melanomas no thicker than 2 mm. Narrow excision was performed in 305 patients, and wide excision (margins of 3 cm or more) was performed in 307 patients. The major prognostic criteria were well balanced in the two groups. The mean thickness of melanomas was 0.99 mm in the narrow-excision group and 1.02 mm in the wide-excision group. The subsequent development of metastatic disease involving regional nodes and distant organs was not different in the two groups (4.6 and 2.3 percent, respectively, in the narrow-excision group, as compared with 6.5 and 2.6 percent in the wide-excision group). Disease-free survival rates and overall survival rates (mean follow-up period, 55 months) were also similar in the two groups. Only three patients had a local recurrence as a first relapse. All had undergone narrow excision, and each had a primary melanoma with a thickness of 1 mm or more. The absence of local recurrence in the group of patients with a primary melanoma thinner than 1 mm and the very low rate of local recurrences indicate that narrow excision is a safe and effective procedure for such patients.

We conducted a study of the effectiveness of an educational intervention designed to modify risk factors associated with coronary heart disease among 3388 children in 37 schools in two demographically dissimilar areas (the Bronx and Westchester County) in and around New York City. Schools within each area were randomly assigned to either intervention or nonintervention groups. In schools targeted for intervention, children in the fourth through eighth grades were taught a teacher-delivered curriculum focusing on diet, physical activity, and cigarette smoking. Risk-factor levels were measured in all schools at base line and at four follow-up points. A total of 1769 of the children qualified for analysis of the intervention effect. After five years, the net mean change in plasma levels of total cholesterol was -1.7 mg per deciliter per year (-0.04 mmol per liter) (95 percent confidence interval, -2.7 to -0.7 mg per deciliter [-0.07 to -0.02 mmol per liter]) in the Westchester County schools, or -8.5 mg per deciliter (-0.22 mmol per liter) (5.1 percent) over a period of five years. In the schools in the Bronx, the net mean change was -1.0 mg per deciliter per year (-0.03 mmol per liter) (95 percent confidence interval, -2.3 to +0.3 mg per deciliter [-0.06 to +0.01 mmol per -2.3 to +0.3 mg per deciliter [-0.06 to +0.01 mmol per liter]), or -5.0 mg per deciliter (-0.13 mmol per liter) (2.9 percent) over a period of five years. Favorable trends in dietary intake and health knowledge were also observed, whereas the other targeted risk factors were not significantly altered. If these findings can be replicated, this will suggest that educational programs to modify coronary risk factors are feasible and may have a favorable (albeit small) effect on blood levels of cholesterol in children.

To evaluate the feasibility and cost savings of hospital discharge three days after acute myocardial infarction, we screened 507 consecutive patients prospectively for clinical complications and exercise-test performance. Of 179 patients whose condition was classified as uncomplicated (no angina, heart failure, or arrhythmia 72 hours after admission), 126 underwent early exercise testing and 90 had no provocable myocardial ischemia. Eighty of these patients were randomly assigned to early (day 3) or conventional (days 7 to 10) hospital discharge. Seventy-six of them had received coronary reperfusion therapy (thrombolysis, angioplasty, or both). At six months of follow-up, there were no deaths or new ventricular aneurysms, and the early-discharge and conventional-discharge groups had similar numbers of hospital readmissions (6 and 10), reinfarctions (none and 5), and patients with angina (3 and 8). In the early-discharge group, 25 of 29 previously employed patients returned to work 40.7 +/- 21.9 days (mean +/- SD) after admission, as compared with 25 of 27 patients in the conventional-discharge group, who returned to work after a mean of 56.9 +/- 30.3 days (P = 0.054). The mean cumulative hospital and professional charges were $12,546 +/- 3,034 in the early-discharge group, as compared with $17,868 +/- 3,688 in the conventional-discharge group (P less than 0.0001). In carefully selected patients with uncomplicated myocardial infarction, hospital discharge after three days is feasible and leads to a substantial reduction in hospital charges. Before this strategy can be widely recommended, however, its safety must be confirmed in larger prospective clinical trials.

We discontinued anticonvulsant drugs in 92 patients who had been free of seizures during two years of treatment with a single drug. All the patients had epilepsy that had previously been untreated, and had been randomly assigned to receive carbamazepine, phenytoin, or sodium valproate. Thirty-one patients relapsed, and 61 remained free of seizures. The mean duration of the follow-up in the patients remaining free of seizures was 35 months (range, 6 to 62). There was no significant difference between the relapse rate among adults (35 percent) and that among children (31 percent). Our results suggest that the number of seizures a patient had before control was achieved, the number of drugs tried as single-drug therapy, and the type of treatment withdrawn all influenced the outcome. Among the various types of seizures, complex partial seizures with secondary generalization carried the worst prognosis. In comparison, the risk of relapse was 65 percent lower in patients with generalized seizures and 97 percent lower in patients with complex or simple partial seizures in the absence of secondary generalized attacks. Among the four electroencephalographic classes, class 4 (abnormal before treatment and unchanged before withdrawal) carried the worst prognosis. The risk of relapse was 94 to 99 percent lower in patients in the other three electroencephalographic classes. Among the three anticonvulsants, withdrawal of sodium valproate carried the worst prognosis. In comparison, the odds of relapsing were 28 percent lower after withdrawal of phenytoin and 85 percent lower after withdrawal of carbamazepine. We conclude that withdrawal of anticonvulsant medication should be considered in patients free of seizures for two years.

We randomly assigned 95 patients with large esophageal varices (Grade 3 or 4) who had not previously had upper gastrointestinal tract bleeding to two groups: 49 received intravariceal sclerotherapy, and 46 were followed as controls. Over a mean follow-up of 13 months there was no difference between the sclerotherapy group and the control group in mortality (24.4 percent) or any significant difference in average hospital stay per month (3.0 vs. 2.6 days). Sclerotherapy was associated with significantly more episodes of upper gastrointestinal bleeding (26 vs. 10 episodes, P less than 0.05); 75 percent of deaths in the sclerotherapy group were related to bleeding, as compared with 18 percent in the control group. An additional 54 patients with cirrhosis who did not qualify for the study were also followed--20 with small varices and 34 with none. Mortality was 20 and 15 percent, respectively; no deaths were due to bleeding. We conclude that prophylactic sclerotherapy does not provide clinical benefit to patients with large esophageal varices.

Legislatively mandated programs for early intervention on behalf of handicapped infants often stipulate the inclusion of physical therapy as a major component of treatment for cerebral palsy. To evaluate the effects of physical therapy, we randomly assigned 48 infants (12 to 19 months of age) with mild to severe spastic diplegia to receive either 12 months of physical therapy (Group A) or 6 months of physical therapy preceded by 6 months of infant stimulation (Group B). The infant-stimulation program included motor, sensory, language, and cognitive activities of increasing complexity. Masked outcome assessment was performed after both 6 and 12 months of therapy to evaluate motor quotient, motor ability, and mental quotient. After six months, the infants in Group A had a lower mean motor quotient than those in Group B (49.1 vs. 58.1, P = 0.02) and were less likely to walk (12 vs. 35 percent, P = 0.07). These differences persisted after 12 months of therapy (47.9 vs. 63.3, P less than 0.01, and 36 vs. 73 percent, P = 0.01, respectively). We noted no significant differences between the groups in the incidence of contractures or the need for bracing or orthopedic surgery. Group A also had a lower mean mental quotient than Group B after six months of therapy (65.6 vs. 75.5, P = 0.05). The routine use of physical therapy in infants with spastic diplegia offered no short-term advantage over infant stimulation. Because of the limited scope of the trial, our conclusions favoring infant stimulation are preliminary. The results suggest that further study of the effects of both physical therapy and infant stimulation is indicated.

We evaluated the use of silver nitrate drops and tetracycline ointment for the prophylaxis of ophthalmia neonatorum in a controlled trial involving 2732 newborns in Nairobi, Kenya. The overall rates of prevalence of intrapartum maternal gonococcal and chlamydial infection were 6.4 and 8.9 percent, respectively. After prophylaxis with silver nitrate, the incidence rates of gonococcal, chlamydial, and nongonococcal, nonchlamydial ophthalmia neonatorum were 0.4, 0.7, and 6.2 percent, respectively, whereas after prophylaxis with tetracycline, the rates were 0.1, 0.5, and 4.5 percent. The attack rates of gonococcal ophthalmia neonatorum in newborns exposed to Neisseria gonorrhoeae at birth were 7.0 percent in those receiving silver nitrate and 3.0 percent in those receiving tetracycline (95 percent confidence interval for the difference in rates, -3.4 to 11.4 percent). As compared with historical controls, the incidence of gonococcal ophthalmia neonatorum decreased 83 percent among infants treated with silver nitrate and 93 percent among those treated with tetracycline. Failure of prophylaxis was associated with postpartum maternal endometritis (P = 0.05). Among newborns exposed to maternal infection with Chlamydia trachomatis, chlamydial conjunctivitis developed in 10.1 percent given silver nitrate and in 7.2 percent given tetracycline (95 percent confidence interval for the difference in rates, -4.7 to 10.5 percent), yielding reductions in the incidence of chlamydial ophthalmia of 68 and 77 percent, respectively, as compared with the historical controls. We conclude that tetracycline is as effective as silver nitrate in preventing gonococcal ophthalmia neonatorum.

To test our previous observation that methotrexate reduces corticosteroid requirements of patients with severe asthma, we studied 14 patients with corticosteroid-dependent bronchial asthma in a 24-week randomized double-blind crossover trial comparing a low dosage of methotrexate (15 mg per week) with placebo. At base line the mean dosage of prednisone was 173.5 mg per week (range, 70 to 420). On the average, 36.5 percent less prednisone was required when patients received methotrexate than when they received placebo (P = 0.01). Measurement of forced vital capacity and forced expiratory volume in one second showed that there was no deterioration in the condition of patients in whom the dosage of prednisone was reduced. The patients' subjective assessment of breathing ability indicated significant improvement (P = 0.01). The adverse effects of methotrexate were limited to transient nausea in three patients and an evanescent rash in one patient. Nine patients are still receiving methotrexate 3 to 10 months after the study's conclusion. The dosages of steroids have been further reduced in each of these patients, and prednisone has been discontinued in four. We conclude from this preliminary study that the use of methotrexate allows a significant reduction in the use of corticosteroids in patients with severe asthma without deterioration of pulmonary function.

Treatment with nafarelin, a gonadotropin-releasing hormone agonist, reversibly inhibits ovarian function and induces hypoestrogenemia. To determine the efficacy of such hormonal manipulation in the treatment of endometriosis, we randomly assigned 213 patients with laparoscopically confirmed endometriosis to receive, for six months, either nafarelin by nasal spray (400 or 800 micrograms per day) or oral danazol (800 mg per day). Placebo nasal spray and placebo tablets were used to double blind the study. Pretreatment and post-treatment laparoscopies were compared by means of the American Fertility Society's scoring system. More than 80 percent of the patients in each treatment group had a reduction in the extent of disease as assessed by laparoscopy. The mean laparoscopic scores decreased from 21.9 to 12.6 with 800 micrograms of nafarelin, from 20.4 to 11.7 with 400 micrograms of nafarelin, and from 18.4 to 10.5 with danazol (P = 0.0001 within each group; there were no statistically significant differences between the groups). The percentage of women with severely painful symptoms of endometriosis decreased from about 40 percent to 5 to 10 percent, whereas the percentage with no or minimal discomfort rose from 25 to 70 percent. Of the 149 patients who tried to become pregnant, 58 (39 percent) succeeded after the completion of treatment; similar rates of pregnancy applied to the three treatment groups. Danazol use decreased high-density lipoprotein levels and increased low-density lipoprotein levels. These changes were not observed in nafarelin users, but a higher percentage of them reported hot flashes and decreased libido. We conclude that nafarelin is an effective agent for treating endometriosis and has few side effects other than hypoestrogenism.

Thromboembolic disease has long been recognized as a complication of cancer. Recent reports have suggested that drugs used in the treatment of cancer, including chemotherapeutic agents and hormones, may contribute to this risk, but it has not been possible to separate the effect of these drugs from that of the cancer. We performed a randomized trial comparing 12 weeks of chemohormonal therapy (using cyclophosphamide, methotrexate, fluorouracil, vincristine, prednisone, doxorubicin, and tamoxifen) with 36 weeks of chemotherapy (using cyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone) in patients with Stage II breast cancer. Among 205 patients randomly assigned to treatment, there were 14 episodes of thrombosis (6.8 percent). These 14 episodes occurred during 979 patient-months of chemotherapy; by comparison, there were no events during 2413 patient-months without therapy. During the first 12 weeks of the study, five patients in the 12-week group and four patients in the 36-week group had thrombosis. During the subsequent 24 weeks, when only patients in the 36-week group were still receiving chemotherapy, there was no thrombosis in the 12-week group, but there were five additional events in the 36-week group (P = 0.03). These findings suggest that chemotherapy contributes to thrombosis in patients with breast cancer.

Heterotopic prosthetic ventricles were used to support the circulation in 29 candidates for heart transplantation who were expected to die before procurement of a donor heart. Twenty-one of these patients (average age, 36 years) underwent successful transplantation after 8 hours to 31 days of circulatory support. The other eight patients died because their condition could not be stabilized for transplantation, despite restoration of blood flow. Fourteen patients received biventricular support; 15 received only left ventricular support, with pharmacologic assistance of right heart function. Before transplantation, blood flow from the left prosthetic ventricle averaged 2.8 +/- 0.4 liters per minute per square meter of body-surface area, and from the right prosthesis 2.4 +/- 0.4 liters, as compared with an average flow of 1.6 +/- 0.5 liters per minute per square meter before implantation. Of the 21 patients who received heart transplants, 20 were discharged from the hospital after a median of 31 days. Nineteen patients were alive at 7 to 39 months, and 11 of the first 12 were alive at one year. We conclude that heterotopic placement of prosthetic ventricles as a bridge to transplantation provides an effective method of temporarily supporting cardiac function in critically ill patients without removing the natural heart. The early survival rate after transplantation is similar to that with elective cardiac transplantation.

Recent investigations suggest that increased cellular calcium concentrations may be implicated in neuronal death after ischemia. To determine whether treatment with a calcium-channel blocker would improve survival and neurologic outcome in acute ischemic stroke, we enrolled 186 patients in a prospective, double-blind, randomized, placebo-controlled trial of nimodipine (30 mg every six hours), begun within 24 hours of the onset of symptoms of an acute ischemic stroke. During the four-week treatment period, mortality from all causes was significantly reduced with nimodipine as compared with placebo (8 deaths [8.6 percent] vs. 19 [20.4 percent]). The improvement in survival was restricted to men. During the follow-up period of six months, an additional eight patients in each group died. A significantly better neurologic outcome, as assessed by the Mathew scale of neurologic deficit, was also observed in the nimodipine group. The improvement in neurologic status was greatest in patients with a moderate to severe deficit at base line. There were no important side effects except for one episode of reversible azotemia that may have been related to treatment with nimodipine. Our data suggest that patients with acute ischemic stroke may benefit from early treatment with nimodipine, but this therapeutic effect appears to be limited to men.

Coronary heart disease is an important cause of death in patients with non-insulin-dependent diabetes mellitus (NIDDM) and is particularly common in diabetic populations that have relatively high levels of plasma cholesterol. To determine whether plasma cholesterol levels in patients with NIDDM could be reduced by drug therapy, we assessed the effect of lovastatin, a potent inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, in a randomized double-blind placebo-controlled manner in 16 white patients with NIDDM and mild to moderate elevations of plasma cholesterol. Lovastatin (20 mg twice daily) or a placebo was given for four weeks, during which blood glucose concentrations remained controlled. As compared with the placebo, lovastatin reduced total cholesterol by 26 percent, low-density lipoprotein (LDL) cholesterol by 28 percent, and LDL apolipoprotein B by 26 percent. Lovastatin therapy also reduced plasma triglycerides and very-low-density lipoprotein cholesterol by 31 percent and 42 percent, respectively. Although there was no change in the plasma level of high-density lipoprotein (HDL) cholesterol, the ratio of total cholesterol to HDL cholesterol fell by 29 percent. No side effects or abnormalities in serum values were noted during short-term lovastatin therapy. The beneficial effects of lovastatin on plasma lipid levels in patients with NIDDM could decrease the risk of the development of coronary heart disease.

We studied the effectiveness of chewing gum containing nicotine, in combination with group counseling, for subjects who were attempting to stop smoking. We used the Horn-Russell scale, based on a smoking questionnaire, to measure dependence on cigarettes; 173 smokers were grouped as highly dependent on nicotine or as having medium to low degrees of dependence. In a randomized double-blind study, the 60 highly dependent smokers were given gum containing 4 mg of nicotine (n = 27) or 2 mg of nicotine (n = 33), and the 113 smokers with medium or low dependence were given gum containing 2 mg of nicotine (n = 60) or a placebo gum (n = 53). All smokers took part in group counseling. In the highly dependent group, abstinence from cigarettes was chemically verified after six weeks, one year, and two years; 81.5 percent, 44.4 percent, and 33.3 percent of the subjects given gum containing 4 mg of nicotine were abstinent after those follow-up periods; the rates of abstinence were 54.5 percent, 12.1 percent, and 6.1 percent, respectively, for the subjects given gum containing 2 mg of nicotine. In the group with medium or low dependence, the rates of abstinence after the same periods were 73.3 percent, 38.3 percent, and 28.3 percent for the subjects given gum containing 2 mg of nicotine and 41.5 percent, 22.6 percent, and 9.4 percent for those given placebo gum. The differences in outcomes were significant at the 5 percent level for all comparisons, with the exception of the 2-mg nicotine gum versus the placebo gum at one year. This study indicates that the effectiveness of nicotine gum is not due to a placebo effect and that it is related to dose. The use of nicotine gum in appropriate doses should be helpful to persons who are attempting to stop smoking.

There is controversy over whether therapy to prevent ventricular tachyarrhythmias should be selected noninvasively (by trying drugs and monitoring the patient electrocardiographically) or invasively (by selecting a drug that prevents induction of the arrhythmia by programmed stimulation). We randomly assigned 57 patients with symptomatic and demonstrable ventricular tachyarrhythmias to therapy selected either noninvasively or invasively. The tachyarrhythmias involved were sustained ventricular tachycardia (35 patients), nonsustained ventricular tachycardia with hypotension (15 patients), and ventricular fibrillation (7 patients). The noninvasive approach sought reduction of ventricular premature beats by more than 80 percent and of couplets by more than 90 percent, with elimination of three or more successive ventricular beats on ambulatory monitoring and exercise testing. The invasive approach sought to prevent the induction of five or more repetitive beats by programmed stimulation. The noninvasive approach required fewer drug trials (3.2 +/- 1.8 [mean +/- SD] vs. 5.5 +/- 2.8, P less than 0.001) and fewer hospital days (20 +/- 15 vs. 33 +/- 24, P = 0.01) and identified a therapy predicted to be effective for more patients than did the invasive approach (29 of 29 vs. 15 of 28, P less than 0.001). When a predicted effective therapy was not found, amiodarone was prescribed despite persisting inducibility of ventricular tachycardia. Patients randomly assigned to the noninvasive approach had more symptomatic recurrences of tachyarrhythmia than those treated by the invasive approach (two-year actuarial probabilities of 0.50 +/- 0.10 vs. 0.20 +/- 0.08, P = 0.02). Similar differences were observed when amiodarone recipients were excluded. There were only three deaths from recurrent ventricular tachyarrhythmias--two in the group whose treatment was selected noninvasively and one in the group whose treatment was selected invasively (not significant). We conclude that therapy selected by the invasive approach prevents recurrences of ventricular tachyarrhythmias better than that selected by the noninvasive approach.

To determine whether combination antibiotic therapy including a short course of an aminoglycoside was as effective and less toxic than a conventional long course of the combination for the empirical therapy of gram-negative bacteremia in patients with cancer and granulocytopenia, we conducted a randomized multicenter trial comparing ceftazidime plus a short course (three days) of amikacin, ceftazidime plus a long course (nine days) of amikacin, and azlocillin plus a long course (nine days) of amikacin. Single-organism gram-negative bacteremia occurred in 129 of 872 evaluable patients. Without a change in antibiotics, the response rates were 81 percent with ceftazidime and long-course amikacin, 48 percent with ceftazidime and short-course amikacin (P = 0.002), and 40 percent with azlocillin and long-course amikacin (P less than 0.001). Among patients with fewer than 100 granulocytes per cubic millimeter throughout therapy, the response rates were 6 percent with ceftazidime and short-course amikacin and 50 percent with ceftazidime and long-course amikacin (P = 0.03). Linear logistic-regression analysis showed that therapy with ceftazidime and long-course amikacin was the most favorable prognostic factor of the response to infection, whereas the presence of leukemia or shock was the least favorable. We conclude that ceftazidime should be given in combination with a conventional full course of an aminoglycoside (amikacin) when used for the empirical treatment of gram-negative bacteremia in cancer patients with granulocytopenia.