We tested the hypothesis that therapeutic endoscopy using the Nd:YAG (neodymium:yttrium-aluminum-garnet) laser would benefit patients with acute peptic-ulcer bleeding. Over 43 months, 174 patients with active bleeding (n = 32) or stigmata of recent bleeding (n = 142) due to peptic ulcers were randomly assigned during endoscopy to either standard treatment with laser photocoagulation or therapy without photocoagulation. There were no significant differences in a number of outcomes between the group treated with laser photocoagulation and the control group. Continued bleeding or rebleeding was observed in 22 percent of the laser-treated group and in 20 percent of the control group. Urgent surgery was necessary in 16 percent of the laser-treated patients and in 17 percent of the controls. Laser-treated patients spent a mean of 41 hours in the intensive care unit, and controls spent a mean of 32 hours. The mean hospital stay was 12 days in the laser-treated group and 11 days in the control group. One death occurred in each group. When patients with active bleeding were analyzed separately, there was no significant difference in outcome, even though laser photocoagulation stopped active bleeding in 88 percent of cases. Among patients with visible vessels, rebleeding occurred in 5 of 14 (36 percent) who received laser treatment and 2 of 15 (13 percent) who did not. Laser treatment precipitated bleeding in four patients and duodenal perforation in one. We conclude that Nd:YAG-laser photocoagulation does not benefit patients with acute upper gastrointestinal bleeding from peptic ulcers.

The benefit of nonsurgical therapy in the treatment of active nonvariceal upper gastrointestinal tract hemorrhage is uncertain. I performed a prospective controlled trial of endoscopic multipolar electrocoagulation for active upper gastrointestinal hemorrhage. Patients were considered for entry if they had a bloody nasogastric aspirate, melena, or hematochezia, and any of the following: unstable vital signs, a requirement of greater than or equal to 2 units of blood per 12 hours, or a drop in hematocrit of greater than or equal to 6 percent in 12 hours. Forty-four patients were randomly assigned to receive multipolar electrocoagulation or sham multipolar electrocoagulation if endoscopy revealed active bleeding from an ulcer (24 patients), a Mallory-Weiss tear (17), or a vascular malformation (3). The group receiving multipolar electrocoagulation did significantly better in terms of hemostasis (90 percent vs. 13 percent, P less than 0.0001), mean (+/- SE) transfusion requirements (2.4 +/- 0.9 vs. 5.4 +/- 0.9 U; P = 0.002), mean number of hospital days (4.4 +/- 0.8 vs. 7.2 +/- 1.1, P = 0.02), and percentage needing emergency surgery or another intervention (14 vs. 57 percent, P = 0.01). Although mortality was lower in the group receiving multipolar electrocoagulation (0 vs. 13 percent), this difference was not statistically significant. The mean cost of hospitalization for treated patients was less than half that for the controls ($ 3,420 +/- 750 vs. $ 7,550 +/- 1,480, P = 0.001). I conclude that multipolar electrocoagulation markedly improves the hospital course in patients with major, nonvariceal upper gastrointestinal hemorrhage.

Patients with allergic rhinitis often have immediate symptoms after antigen challenge (the early-phase response), followed several hours later by a recurrence of symptoms (the late-phase response). Systemic glucocorticosteroids are known to inhibit the late-phase but not the early-phase response. We studied the effect of one week of pretreatment with topical (rather than systemic) glucocorticosteroids on the response to nasal challenge with antigen in a double-blind, randomized, placebo-controlled crossover study of 13 allergic patients who had previously had a dual response to nasal challenge. The patients were challenged with three 10-fold increments of allergen, producing an early response, and were then followed for 11 hours, encompassing the late response, before they were rechallenged with the lowest dose of allergen. We monitored their responses by means of symptom scores and measurements of the levels of histamine, tosyl-L-arginine methyl ester (TAME)-esterase activity, and kinins in nasal lavages. Topical glucocorticosteroids significantly reduced both the symptoms and the levels of histamine, TAME-esterase activity, and kinins in the early, late, and rechallenge allergic reactions. The fact that, in contrast to treatment with systemic glucocorticosteroids, prolonged pretreatment with topical glucocorticosteroids inhibited the early-phase response to antigen suggests that the route and duration of administration affect the mechanisms of action of the steroids. We conclude that inhibition of the early-phase as well as the late-phase response by topical glucocorticosteroids may provide an advantage over treatment with systemic glucocorticosteroids in patients with allergic rhinitis.

We studied the development of tolerance to isosorbide dinitrate in 12 patients with chronic stable angina pectoris. The effect of 30 mg of isosorbide dinitrate on treadmill exercise performance was assessed before and at one, three, and five hours after a single dose. As compared with placebo, the drug increased treadmill walking time until the onset of angina and until the development of moderate angina over the five-hour observation period (P less than 0.05). The patients then received 30 mg of isosorbide dinitrate twice, three times, and four times daily for a period of one week, and exercise performance was assessed before and at one, three, and five hours after the final morning dose. During sustained treatment two and three times daily, treadmill walking time was longer throughout the five-hour testing period than during the placebo phase (P less than 0.05). In contrast, during treatment four times daily, treadmill walking time was prolonged at one hour (P less than 0.05) but not at three and five hours after the last dose. We conclude that tolerance to the clinical effects of isosorbide dinitrate develops with a sustained dosage of 30 mg four times daily, but not when the drug is given two or three times daily.

To evaluate the influence of the angiotensin-converting-enzyme inhibitor enalapril (2.5 to 40 mg per day) on the prognosis of severe congestive heart failure (New York Heart Association [NYHA] functional class IV), we randomly assigned 253 patients in a double-blind study to receive either placebo (n = 126) or enalapril (n = 127). Conventional treatment for heart failure, including the use of other vasodilators, was continued in both groups. Follow-up averaged 188 days (range, 1 day to 20 months). The crude mortality at the end of six months (primary end point) was 26 percent in the enalapril group and 44 percent in the placebo group--a reduction of 40 percent (P = 0.002). Mortality was reduced by 31 percent at one year (P = 0.001). By the end of the study, there had been 68 deaths in the placebo group and 50 in the enalapril group--a reduction of 27 percent (P = 0.003). The entire reduction in total mortality was found to be among patients with progressive heart failure (a reduction of 50 percent), whereas no difference was seen in the incidence of sudden cardiac death. A significant improvement in NYHA classification was observed in the enalapril group, together with a reduction in heart size and a reduced requirement for other medication for heart failure. The overall withdrawal rate was similar in both groups, but hypotension requiring withdrawal occurred in seven patients in the enalapril group and in no patients in the placebo group. After the initial dose of enalapril was reduced to 2.5 mg daily in high-risk patients, this side effect was less frequent. We conclude that the addition of enalapril to conventional therapy in patients with severe congestive heart failure can reduce mortality and improve symptoms. The beneficial effect on mortality is due to a reduction in death from the progression of heart failure.

Standard chemotherapy for disseminated germ-cell tumors includes a combination of cisplatin, vinblastine, and bleomycin, but this regimen produces substantial neuromuscular toxicity. In a randomized clinical trial in 261 men with disseminated germ-cell tumors, we substituted etoposide for the vinblastine in this regimen in half the patients to compare the efficacy and toxicity of the two treatments. Among 244 patients who could be evaluated for a response, 74 percent of those receiving the regimen including vinblastine and 83 percent of those receiving the regimen including etoposide became disease-free with or without subsequent surgery (P not significant). Among the 157 patients with high tumor volume, 61 percent became disease-free on the regimen that included vinblastine, as compared with 77 percent on the regimen that included etoposide (P less than 0.05). Survival among the patients who received etoposide was higher (P = 0.048). The regimens were similar in terms of myelosuppressive effects and pulmonary toxicity. However, the etoposide regimen caused substantially fewer paresthesias (P = 0.02), abdominal cramps (P = 0.0008), and myalgias (P = 0.00002). We conclude that etoposide with cisplatin and bleomycin is superior to vinblastine with cisplatin and bleomycin in the treatment of disseminated germ-cell tumors because of diminished neuromuscular toxicity and, among patients with advanced disease, better efficacy.

To evaluate the efficacy of dexamethasone for treatment of primary supratentorial intracerebral hemorrhage, we studied 93 patients 40 to 80 years old, using a double-blind randomized block design. After the subjects were stratified according to their level of consciousness (Glasgow Coma Scale), those with objectively documented primary supratentorial intracerebral hemorrhage were randomly assigned to either dexamethasone or placebo. For ethical reasons, three interim analyses were planned, to permit early termination of the trial if one study group did better than the other. During the third interim analysis, the death rate at the 21st day was identical in the two groups (dexamethasone vs. placebo, 21 of 46 vs. 21 of 47; chi-square = 0.01, P = 0.93). In contrast, the rate of complications (mostly infections and complications of diabetes) was much higher in the dexamethasone group (chi-square = 10.89, P less than 0.001), leading to early termination of the study. In the light of the absence of a demonstrable beneficial effect and the presence of a significant harmful effect, current practices of using dexamethasone for treatment of primary supratentorial hemorrhage should be reconsidered.

We conducted a multicenter, randomized, prospective study comparing medical therapy alone with coronary-artery bypass surgery plus medical therapy in 468 men with unstable angina pectoris. Patients were entered in the study from June 1, 1976, to June 30, 1982. Among those assigned to surgery who received bypass grafts, operative mortality was 4.1 percent. Arteriography performed after one year of follow-up revealed that 74.8 percent of the grafts studied were patent. The cumulative rate of crossover from medical to surgical therapy after two years was 34 percent; the operative mortality among patients crossed over was 10.3 percent. Nonfatal myocardial infarction occurred in 11.7 percent of the patients treated surgically and 12.2 percent of those treated medically (no significant difference). Most of the nonfatal myocardial infarctions in the surgical group occurred in the perioperative period. Overall, the two-year survival rate computed by life-table analysis did not differ between the two groups. However, the curves reflecting mortality as a function of left ventricular ejection fraction were significantly different (P = 0.03); surgery was associated with a significantly reduced mortality among patients with lower ejection fractions. We conclude that patients with unstable angina pectoris have a similar outcome after two years whether they receive medical therapy alone or coronary bypass surgery plus medical therapy. However, patients with reduced left ventricular ejection fractions may have a better two-year survival rate after coronary bypass surgery.

We conducted a prospective, randomized study to clarify the role of radiotherapy of the primary tumor in limited small-cell cancer of the lung. After stratification for sex and for performance score based on the ability to ambulate, patients were randomly assigned to receive initial radiotherapy plus chemotherapy, delayed radiotherapy plus chemotherapy, or chemotherapy alone. The chemotherapy consisted of cyclophosphamide, etoposide (VP-16-213), and vincristine, with doxorubicin subsequently replacing etoposide in alternate cycles 7 through 18. Chemotherapy was given every three weeks for 18 months. The radiotherapy comprised 4000 rad in four weeks, followed by a 1000-rad "boost" directed against residual disease. All patients received prophylactic whole-brain radiation. The patients enrolled totaled 426, and 399 were evaluable. There was a statistically significant difference in the frequency of complete responses in favor of the two radiotherapy regimens (P = 0.0013). Failure-free survival was also longer with these two regimens (P less than 0.001), as was the interval before treatment failure in the chest (P less than 0.001) and overall survival (P = 0.0099). As expected, toxic effects--chiefly neutropenia--were also increased. The addition of radiotherapy of the primary tumor to combination chemotherapy improved both complete-response rates and survival, with increased but acceptable toxicity.

In patients with nephropathic cystinosis, corneal crystals develop by one year of age; they progressively accumulate and eventually cause recurrent corneal erosions and photophobia. After an in vitro study of cystinotic corneal stromal cells showed cystine depletion by cysteamine and after topical cysteamine was determined to be nontoxic in rabbits, we performed a controlled double-blind clinical trial of 10 mM cysteamine eyedrops in young patients with cystinosis, using one eye for treatment and the other as the control. Two children begun on the protocol before two years of age had a striking decrease in the number of corneal crystals in the cysteamine-treated eye within four to five months of entering the study. Cysteamine eyedrops appear to be safe and efficacious in the short-term treatment of patients with cystinosis who are under two years of age. The long-term value of such treatment and its effectiveness in older patients remain to be determined.

We randomly assigned 20 patients with progressively worsening generalized myasthenia gravis of recent onset whose illness was not controlled by anticholinesterase therapy to treatment with either cyclosporine (6 mg per kilogram of body weight per day) or placebo. Patients who had been treated with thymectomy, steroids, or other immunosuppressive agents were excluded. The duration of treatment was 12 months. Disease activity was assessed by quantified strength testing and by measurements of antihuman acetylcholine-receptor antibody. Patients were assessed at 6 months and 12 months, or at the following early end points: drug failure (doubling of creatinine), treatment failure (respiratory or swallowing difficulty), or protocol violation (stopping medication for more than five days). At six months, patients in the cyclosporine group had had significantly more objective improvement in strength; one early end point had been reached (drug failure; no treatment failures). In the placebo group, three early end points had been reached (all treatment failures). The decline in titers of acetylcholine-receptor antibody was larger in the treated group, although the difference was not statistically significant. At the end of the study (after 12 months of treatment or arrival at an earlier end point), improvement in strength and reduction in titers of anti-receptor antibody continued to be greater in the cyclosporine group. Nephrotoxicity occurred in three patients receiving cyclosporine but was nonprogressive with a reduction in dosage and reversible with discontinuation of the drug. These results are preliminary and need confirmation, but we conclude that cyclosporine is probably an effective therapy in some patients with myasthenia gravis.

In a randomized, double-blind, placebo-controlled trial involving 518 infants and children who had otitis media with effusion ("secretory" otitis media), we evaluated the efficacy of a two-week course of amoxicillin (40 mg per kilogram of body weight per day) with and without a four-week course of an oral decongestant-antihistamine combination. Among the 474 subjects who were evaluated at the four-week end point, the rate of resolution of middle-ear effusion was twice as high in those treated with amoxicillin, either with or without the decongestant-antihistamine, as in those who received placebo (P less than 0.001), but 69.8 percent of the amoxicillin-treated subjects still had effusion. Among both the amoxicillin-treated subjects and the placebo-treated subjects, resolution was more likely in those with initially unilateral effusion, in those who had had effusion for eight weeks or less, and in those without an upper respiratory tract infection at the four-week end point. Side effects were reported more often in subjects who received decongestant-antihistamine than in those who did not. Among the subjects without effusion at the four-week end point, recurrent effusion developed in approximately half those in both the amoxicillin and placebo groups during the subsequent three months. We conclude that in infants and children with otitis media with effusion, amoxicillin treatment increases to some extent the likelihood of resolution.

In a continuation of a trial for which preliminary results were reported in the Journal two years ago, a total of 64 patients with Child Class C cirrhosis and variceal hemorrhage requiring six or more units of blood were randomly assigned to receive either a portacaval shunt (32 patients) or endoscopic sclerotherapy (32 patients). The duration of initial hospitalization and the total amount of blood transfused during hospitalization were significantly less in the patients receiving sclerotherapy (P less than 0.001). There was no difference in short-term survival (50 percent of the sclerotherapy group were discharged alive, as compared with 44 percent of the shunt-surgery group). Both groups were followed for a mean of 530 days after randomization. Rebleeding from varices, the duration of rehospitalization for hemorrhage, and transfusions received after discharge were all significantly greater in the sclerotherapy group (P less than 0.001). Forty percent of the sclerotherapy-treated patients discharged alive (7 of 16 patients) ultimately required surgical treatment for bleeding varices, despite a mean of 6.1 treatment sessions. Health care costs and long-term survival did not differ significantly between the groups (P greater than 0.05). We conclude that although endoscopic sclerotherapy is as good as surgical shunting for the acute management of variceal hemorrhage in poor-risk patients with massive bleeding, sclerotherapy-treated patients in whom varices are not obliterated and bleeding continues should be considered for elective shunt surgery.

13-cis-Retinoic acid has been reported to be effective in treating oral leukoplakia. We randomly assigned 44 patients with this disease to receive 13-cis-retinoic acid (24 patients) or placebo (20), 1 to 2 mg per kilogram of body weight per day for three months, and followed them for six months. There were major decreases in the size of the lesions in 67 percent (16 patients) of those given the drug and in 10 percent (2 patients) of those given placebo (P = 0.0002); dysplasia was reversed in 54 percent (13 patients) of the drug group and in 10 percent (2 patients) of the placebo group (P = 0.01). The clinical response to the drug correlated with the histologic response in 56 percent (9 of 16) of the patients evaluated. Relapse occurred in 9 of 16 patients two to three months after treatment ended. The toxic effects of the drug were acceptable in all but two patients. Cheilitis, facial erythema, and dryness and peeling of the skin were common; conjunctivitis and hypertriglyceridemia also occurred. All adverse reactions could be reversed by reducing the dose or temporarily discontinuing the drug. We conclude that 13-cis-retinoic acid, even in short-term use, appears to be an effective treatment for oral leukoplakia and has an acceptable level of toxicity.

In a prospective, placebo-controlled study, 74 women with recurrent vulvovaginal candidiasis were treated with oral ketoconazole (400 mg daily for two weeks) and were then randomly assigned to receive placebo (Group A), prophylactic ketoconazole, 400 mg daily for five days beginning with the onset of menses for six menstrual cycles (Group B), or low-dose ketoconazole, 100 mg daily for six months (Group C). Within a six-month follow-up period, 15 of 21 women (71.4 percent) treated with placebo had symptomatic recurrence of candidal vaginitis. In contrast, candidal vaginitis recurred in 6 of 21 (28.6 percent) and in 1 of 21 (4.8 percent) women in Groups B and C (P less than 0.01; P less than 0.001). After the prophylaxis was discontinued, the recurrence rates of candidal vaginitis were high in women in Groups B and C. At the end of 12 months of follow-up, 23.8 percent of the women in Group A remained asymptomatic and attack-free, in contrast to 42.9 percent of the women in Group B (P greater than 0.05) and 52.4 percent in Group C (P less than 0.05). It appears that maintenance prophylactic therapy with oral ketoconazole is effective in preventing recurrent episodes of vulvovaginal candidiasis, but that relapse is common after withdrawal of the drug. Because of the risk of hepatotoxicity, caution is essential in selecting patients for long-term ketoconazole therapy and in following patients undergoing such treatment.

We entered 60 patients with primary biliary cirrhosis in a double-blind randomized controlled trial to determine whether colchicine is therapeutically effective. Thirty patients had early disease (Stages 1 and 2), and 30 had advanced disease (Stages 3 and 4). Fifteen patients with early disease and 15 with advanced disease received colchicine (0.6 mg twice daily), and the remainder received placebo. Patients were studied about every two months; those remaining in the blind phase at two years underwent repeat liver biopsy and were then placed on open-label colchicine (0.6 mg twice daily). With a few exceptions, the results in patients with early disease were similar to those in patients with advanced disease; hence, data on patients in all stages were combined in the main analysis. During the two-year study period the colchicine-treated patients, as compared with the placebo-treated patients, had improvement in levels of serum albumin, serum bilirubin, alkaline phosphatase, cholesterol, and aminotransferases. However, there was no such improvement in the severity of symptoms or physical findings; moreover, there was no significant difference in the histologic changes noted at liver biopsy in the two treatment groups. At four years after entry, the cumulative mortality from liver disease was 21 percent in patients given colchicine and 47 percent in those given placebo (P = 0.05). The only side effect of colchicine was diarrhea, noted in three patients. The consistent and significant improvement in a number of markers of liver disease and the apparent decreased mortality from liver disease suggest that colchicine may provide some long-term clinical benefit in patients with primary biliary cirrhosis. However, the failure of colchicine to reduce hepatic inflammation and fibrosis leaves uncertain the effect of the drug on the longterm outcome of this disease.

In a double-blind study, we examined the efficacy of allopurinol in the prevention of recurrent calcium oxalate calculi of the kidney. Sixty patients with hyperuricosuria and normocalciuria who had a history of calculi were randomly assigned to receive either allopurinol (100 mg three times daily) or a placebo. After the study, the placebo group had 63.4 percent fewer calculi (P less than 0.001), whereas the allopurinol group had 81.2 percent fewer calculi (P less than 0.001). During the study period, the mean rate of calculous events was 0.26 per patient per year in the placebo group and 0.12 in the allopurinol group. When the treatment groups were compared by actuarial analysis, the allopurinol group was found to have a significantly longer time before recurrence of calculi (P less than 0.02). We conclude that allopurinol is effective in the prevention of calcium oxalate stones in patients with hyperuricosuria. The large reduction in the frequency of calculi in the placebo group underscores the positive treatment bias that regularly occurs in trials of prophylaxis against renal calculi when historical controls are used.

We conducted a randomized clinical trial comparing a single intramuscular dose of 125 mg of ceftriaxone with a single intramuscular dose of 75 mg of kanamycin followed by topical gentamicin for seven days, and with a single intramuscular dose of 75 mg of kanamycin followed by topical tetracycline for seven days, in the treatment of gonococcal ophthalmia neonatorum in Nairobi, Kenya. Of 122 newborns with culture-proved gonococcal ophthalmia neonatorum, 105 returned for follow-up. Sixty-one infants (54 percent) received ceftriaxone, 32 received kanamycin plus topical gentamicin, and 29 received kanamycin plus topical tetracycline. Sixty-six (54 percent) of the Neisseria gonorrhoeae isolates were penicillinase producing. All 55 newborns who received ceftriaxone and returned for follow-up were clinically and microbiologically cured. One of 26 returning newborns who received kanamycin plus tetracycline and 2 of 24 returning newborns who received kanamycin plus gentamicin had persistent or recurrent gonococcal conjunctivitis. Ceftriaxone also eradicated oropharyngeal gonococcal infection in 18 newborns, whereas oropharyngeal infection persisted in 2 of 8 newborns who had received kanamycin (P not significant). We conclude that 125 mg of ceftriaxone as a single intramuscular dose is very effective therapy for gonococcal ophthalmia neonatorum, with marked efficacy against extraocular infection and without the need for concomitant topical antimicrobial therapy.

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.