We conducted a double-blind, placebo-controlled study of acyclovir prophylaxis against infection with herpes simplex virus (HSV) in 20 seropositive recipients of bone-marrow transplants. Acyclovir or placebo was administered for 18 days, starting three days before transplantation. Culture-positive HSV lesions developed during the study in seven of the 10 patients who received placebo. In contrast, no such lesions appeared in the 10 patients who received acyclovir (P congruent to 0.003). None of the patients had evidence of drug toxicity. Five of the patients treated with acyclovir had mild culture-positive HSV infections after cessation of the drug, and two additional patients shed virus without having lesions. Acyclovir appears to be a potent inhibitor of HSV replication. Although acyclovir does no appear to eradicate latent infection, it can provide effective prophylaxis against reactivated infections.

From 1973 to 1980, we carried out a controlled study at the National Cancer Institute in Milan to consider the value of a conservative procedure in patients with breast cancer of small size. We randomized 701 patients with breast cancer measuring less than 2 cm in diameter and with no palpable axillary lymph nodes to Halsted radical mastectomy or to "quadrantectomy" with axillary dissection and radiotherapy to the ipsilateral residual breast tissue. We treated 349 patients with Halsted mastectomy and 352 with quadrantectomy. The two groups were comparable in age distribution, size and site of primary tumor, menopausal status, and frequency of axillary metastases. There were three local recurrences in the Halsted group and one in the quadrantectomy group. Actuarial curves showed no difference between the two groups in disease-free or overall survival. From these results, mastectomy appears to involve unnecessary mutilation in patients with breast cancer of less than 2 cm and no palpable axillary nodes.

We studied the possibility that the addition of tamoxifen to L-phenylalanine mustard combined with 5-fluorouracil enhances the benefit from the latter two drugs that has been observed in women with primary breast cancer and positive axillary nodes. Recurrence of disease was reduced at two years in patients given the three-drug regimen whose tumor estrogen-receptor levels were greater than or equal to 10 fmol. Among patients greater than or equal to 50 years old treatment failure was significantly reduced (P less than 0.001): by 51 per cent in those with one to three positive nodes and by 64 per cent in those with four or more. Higher receptor levels were associated with a greater probability of disease-free survival. Patients less than or equal to 49 years old were less responsive: those with one to three positive nodes received no benefit from tamoxifen at any receptor level, whereas those with four or more appeared to have reduced treatment failure associated with higher receptor levels. This adjuvant chemotherapy is not indicated in patients less than or equal to 49 years old whose tumor receptor levels are below 10 fmol; there is a suggestion of benefit in patients greater than or equal to 50 years old whose levels are low.

We designed a study to determine the relative analgesic potency of intramuscular heroin and morphine and to compare mood and side effects in 166 cancer patients with postoperative pain. Heroin was about twice as potent as morphine (95 per cent confidence limits, 1.6 to 2.6 times) in graded-dose, twin-crossover assays. Heroin provided an analgesic peak effect earlier than morphine (1.2 plus or minus 0.08 and 1.5 plus or minus 0.10 hours, respectively [mean plus or minus S.E.M.]). Doses with equal analgesic effects provided comparable improvements in various elements of mood, particularly feelings of peacefulness. Peak mood improvement occurred earlier after heroin than after morphine (1.2 plus or minus 0.10 and 1.8 plus or minus 0.13 hours, respectively). Both analgesia and mood improvement were less sustained after heroin at doses providing equal peak analgesic effects. The drugs shared the most common side effects, with no marked differences in their occurrence; sleepiness was the most frequent side effect after both drugs (46 per cent with each). Heroin has no apparent unique advantages or disadvantages for the relief pain in patients with cancer.

Although bromocriptine, a dopamine receptor agonist, is now widely used in the treatment of acromegaly, there have been no controlled trials of its biochemical or clinical effects on this disorder. We assessed its effects in a double-blind, crossover study. Eighteen patients with acromegaly were given bromocriptine and placebo alternately for three months per medication. Their responses to oral glucose-tolerance tests during the two regimens did not differ significantly. The number of patients noting amelioration of clinical symptoms during treatment with bromocriptine was almost identical to the number with clinical improvement during placebo. We conclude that it remains doubtful whether bromocriptine has a beneficial effect in acromegaly.

Fifty-three profoundly granulocytopenic patients with relapsed acute leukemia who were undergoing reinduction chemotherapy were prospectively randomized to receive either trimethoprim-sulfamethoxazole plus nystatin or gentamicin plus nystatin for prevention of infections. The acquisition of new organisms per patient during the total study period was similar in both groups. Thirty-five symptomatic infections (five of which were bacteremias) occurred in patients receiving trimethoprim-sulfamethoxazole plus nystatin, whereas 31 infections (eight bacteremias) occurred in patients receiving gentamicin plus nystatin. Four deaths related to infection occurred in patients taking trimethoprim-sulfamethoxazole, and eight occurred in patients taking gentamicin. We conclude that trimethoprim-sulfamethoxazole plus nystatin was approximately as effective as gentamicin plus nystatin for prophylaxis against infection in relapsed acute leukemia. Furthermore, side effects were fewer and compliance was better with trimethoprim-sulfamethoxazole plus nystatin.

Thromboxane A2 (TxA2), an arachidonic acid metabolite causing vasoconstriction and platelet aggregation, is a putative mediator of coronary-artery vasospasm. To determine whether platelet-released TxA2 causes coronary arterial vasospasm, we measured plasma thromboxane B2 (TxB2, the inactive hydration product of TxA2) in the radial-artery and coronary-sinus blood of seven patients and performed therapeutic trials of antiplatelet agents in nine. Although coronary-sinus TxB2 levels rose from the base line approximately fivefold with spontaneous ischemia, samples drawn early in ischemia showed no rise over base-line values. Although a 150 mg dose of aspirin reduced urinary dinor-TxB2 levels by over 75 per cent, it had no effect on the course of the chronic recurrent form of angina pectoris due to vasospasm ("vasotonic angina"). Similarly, indomethacin had no effect on the frequency or duration of ischemia. TxA2 is unlikely to cause vasotonic angina, but it may be released during coronary vasospasm.

Anticoagulation during hemodialysis is necessary to prevent clotting of the blood on contact with the dialysis membrane. Heparin is the usual anticoagulant used, but systemic anticoagulation may persist for hours, and hemorrhage is common. We successfully used an infusion of prostacyclin, which has an in vitro half-life of three to five minutes, as the sole anticoagulant in 10 patients on long-term hemodialysis and in one patient undergoing dialysis for acute renal failure (this patient bled severely on three occasions when heparin was used). Prostacyclin was infused intravenously for 10 minutes before dialysis and into the arterial line of the dialyzer during dialysis. We adjusted the rate of infusion into the dialyzer to prevent prostacyclin-induced hypotension. Each patient completed 240 minutes of dialysis and received a total of 423 +/- 91 ng of prostacyclin per kilogram of body weight (mean +/- S.E.M.; range, 56 to 780). Prostacyclin caused no clinically important changes in the intrinsic clotting system, and there were no hemorrhages or clotting of the coil. We conclude that prostacyclin can safely replace heparin as the sole antithrombotic agent during hemodialysis and may be more advantageous if anticoagulation is contraindicated.

To determine whether routine early endoscopy is beneficial to patients with upper-gastrointestinal-tract bleeding that ceases during hospitalization, we randomly assigned 206 patients to routine endoscopy (100 patients) or no routine endoscopy (106). Patients in the latter group underwent endoscopy only if recurrent bleeding occurred during hospitalization or if x-ray films disclosed gastric ulcer or suggested neoplasia. All patients were initially treated with an empiric antacid regimen. When the two groups were compared (experimental versus control), there were no significant differences in overall hospital deaths (11 versus eight), recurrence of bleeding (33 versus 32), number of transfusions required to treat recurrent bleeding (mean +/- S.E.M., 7.4 +/- 1.2 versus 6.3 +/- 0.7 units), deaths after recurrent bleeding (eight versus five), or duration of hospital stay. During the 12 months after discharge, there were also no significant differences in frequency of readmission to the hospital, incidence of further gastrointestinal bleeding, number of hemorrhage-related deaths, or frequency of gastrointestinal surgery. We conclude that endoscopy should not be a routine procedure in patients with upper-gastrointestinal-tract bleeding that ceases during treatment.

To compare the erythropoietic effects of nandrolone decanoate, testosterone enanthate, oxymetholone, and fluoxymesterone, we performed a randomized clinical trial in patients with anemia who were receiving maintenance hemodialysis (the women were not given testosterone enanthate). After a control period of at least two months, patients received one of the drugs for six months and then returned to control status; a second and third drug were administered in a similar fashion. Seventy-seven patients completed the first drug period, 56 the second, and 35 the third. The response to nandrolone and testosterone enanthate, the two drugs given by injection, was clearly superior to the response to oxymetholone or fluoxymesterone, given by mouth, in terms of the percentage of patients responding and the mean rise in hematocrit. Approximately half the patients had an increase of at least 5 percentage points in hematocrit after an injectable androgen was given; more than half the women responded. Patients who required transfusions regularly and those who had bilateral nephrectomies did not respond.

To assess the efficacy and safety of verapamil in variant angina pectoris, we entered 16 patients in a double-blind, randomized trial of nine months, duration. During treatment with verapamil, the frequency of angina fell substantially (12.6 +/- 25.9 chest pains per week with placebo, 1.7 +/- 2.8 pains per week with verapamil, mean +/- S.D.; P less than 0.01), as did the use of nitroglycerin tablets (14.4 +/- 34.4 tablets per week with placebo, 2.1 +/- 3.3 tablets per week with verapamil; P less than 0.05). The number of hospitalizations for clinical instability was significantly lower with verapamil (P less than 0.01). The number of episodes of transient ST-segment deviation during treatment with verapamil was reduced (33.1 +/- 39.3 ST-segment deviations per week with placebo, 7.7 +/- 11.7 deviations per week with verapamil; P less than 0.01). Verapamil caused no side effects forcing a reduction in dosage or a discontinuation. We conclude that verapamil is safe and effective in the therapy of variant angina pectoris.

A multicenter double-blind randomized study was carried out to compare the effect of timolol (10 mg twice daily) with that of placebo in patients surviving acute myocardial infarction. Treatment was started seven to 28 days after infarction in 1884 patients (945 taking timolol, and 939 placebo), who represented 52 per cent of those evaluated for entry; the patients were followed for 12 to 33 months (mean, 17). There were 152 deaths in the placebo group and 98 in the timolol group. When deaths that occurred during treatment or within 28 days of withdrawal were considered, the cumulated sudden-death rate over 33 months was 13.9 per cent in the placebo group and 7.7 per cent in the timolol group--a reduction of 44.6 per cent (P = 0.0001). The cumulated reinfarction rate was 20.1 per cent in the placebo group and 14.4 per cent in the timolol group (P = 0.0006). We conclude that long-term treatment with timolol in patients surviving acute myocardial infarction reduces mortality and the rate of reinfarction.