Twenty-eight patients with refractory rheumatoid arthritis completed a randomized 24-week double-blind crossover trial comparing oral methotrexate (2.5 to 5 mg every 12 hours for three doses weekly) with placebo. The methotrexate group had significant reductions (P less than 0.01 as compared with the placebo group) in the number of tender or painful joints, the duration of morning stiffness, and disease activity according to physician and patient assessments at the 12-week crossover visit; reductions in the number of swollen joints (P less than 0.05) and 15-m walking time (P less than 0.03) also occurred. These variables, as well as the grip strength and erythrocyte sedimentation rate, showed significant (P less than 0.01) improvement at 24 weeks in the population crossed over to methotrexate. A significantly increased frequency (P less than 0.03) of the HLA-DR2 haplotype occurred in the eight patients with the most substantial response to methotrexate. Adverse reactions during methotrexate therapy included transaminase elevation (21 per cent), nausea (18 per cent), and diarrhea (12 per cent); one patient was withdrawn from the trial because of diarrhea. One patient died while receiving the placebo. Methotrexate did not affect measures of humoral or cellular immunity. We conclude that this trial provides evidence of the short-term efficacy of methotrexate in rheumatoid arthritis, but the mechanism of action is unknown. Longer trials will be required to determine the ultimate safety and effectiveness of this drug.

Changes in potassium balance have been found to have variable effects on the blood pressure of animals, and the administration of potassium supplements has been reported to lower the blood pressure of normokalemic hypertensive patients. To assess the effect of potassium repletion in hypokalemic hypertension, we administered either potassium chloride, 60 mmol per day, or placebo tablets, each for six weeks, in a randomized, double-blind, crossover trial to 16 hypertensive patients who had diuretic-induced hypokalemia and who continued to take a constant amount of diuretic. We selected patients whose control serum potassium levels were below 3.5 mmol per liter. In association with an average rise in the serum potassium concentration of 0.56 mmol per liter, the mean blood pressure fell by an average of 5.5 mm Hg (P = 0.004), with at least a 4 mm Hg fall observed in 9 of the 16 patients. The fall in blood pressure correlated with a fall in plasma renin activity (r = 0.568, P = 0.043) but not with changes in plasma aldosterone levels or other variables. We conclude that short-term potassium supplementation that ameliorates diuretic-induced hypokalemia may induce a significant fall in blood pressure.

In 1971 we began a randomized trial to compare alternative local and regional treatments of breast cancer, all of which employ breast removal. Life-table estimates were obtained for 1665 women enrolled in the study for a mean of 126 months. There were no significant differences among three groups of patients with clinically negative axillary nodes, with respect to disease-free survival, distant-disease--free survival, or overall survival (about 57 per cent) at 10 years. The patients were treated by radical mastectomy, total ("simple") mastectomy without axillary dissection but with regional irradiation, or total mastectomy without irradiation plus axillary dissection only if nodes were subsequently positive. Similarly, no differences were observed between patients with clinically positive nodes treated by radical mastectomy or by total mastectomy without axillary dissection but with regional irradiation. Survival at 10 years was about 38 per cent in both groups. Our findings indicate that the location of a breast tumor does not influence the prognosis and that irradiation of internal mammary nodes in patients with inner-quadrant lesions does not improve survival. The data also demonstrate that the results obtained at five years accurately predict the outcome at 10 years. We conclude that the variations of local and regional treatment used in this study are not important in determining survival of patients with breast cancer.

In 1976 we began a randomized trial to evaluate breast conservation by a segmental mastectomy in the treatment of Stage I and II breast tumors less than or equal to 4 cm in size. The operation removes only sufficient tissue to ensure that margins of resected specimens are free of tumor. Women were randomly assigned to total mastectomy, segmental mastectomy alone, or segmental mastectomy followed by breast irradiation. All patients had axillary dissections, and patients with positive nodes received chemotherapy. Life-table estimates based on data from 1843 women indicated that treatment by segmental mastectomy, with or without breast irradiation, resulted in disease-free, distant-disease-free, and overall survival at five years that was no worse than that after total breast removal. In fact, disease-free survival after segmental mastectomy plus radiation was better than disease-free survival after total mastectomy (P = 0.04), and overall survival after segmental mastectomy, with or without radiation, was better than overall survival after total mastectomy (P = 0.07, and 0.06, respectively). A total of 92.3 per cent of women treated with radiation remained free of breast tumor at five years, as compared with 72.1 per cent of those receiving no radiation (P less than 0.001). Among patients with positive nodes 97.9 per cent of women treated with radiation and 63.8 per cent of those receiving no radiation remained tumor-free (P less than 0.001), although both groups received chemotherapy. We conclude that segmental mastectomy, followed by breast irradiation in all patients and adjuvant chemotherapy in women with positive nodes, is appropriate therapy for Stage I and II breast tumors less than or equal to 4 cm, provided that margins of resected specimens are free of tumor.

To investigate the relation between blood glucose control on the one hand and an increased glomerular filtration rate and enlarged kidneys on the other, we studied 12 patients with insulin-dependent diabetes and an increased glomerular filtration rate for a year after they were randomly assigned either to continuous subcutaneous insulin infusion or to unchanged conventional therapy. Glycemic control, measured by mean plasma concentrations of glucose and glycosylated hemoglobin, was rapidly and significantly improved (P less than 0.001) in the pump group but did not change in the conventional-treatment group. In the pump group, the glomerular filtration rate fell significantly in the study period (P less than 0.001) and became normal in four of the six patients. It did not change in the conventional-treatment group. There was no change in kidney volume in either group. At the end of a year, a return to conventional insulin treatment in the pump group resulted in both metabolic deterioration and a significant rise in the mean glomerular filtration rate toward base-line values. We conclude that in patients with established insulin-dependent diabetes, strict glycemic control normalizes the glomerular filtration rate, although the kidneys may remain enlarged.

We performed a multicenter, randomized, controlled clinical trial of therapeutic peritoneal lavage (2 liters per hour for three days) in 91 patients with severe acute pancreatitis. Patients were entered into the study if severe pancreatitis was indicated by multiple laboratory criteria or diagnostic peritoneal lavage. All patients received full supportive treatment. The median time between the onset of symptoms and randomization was 38 hours. Forty-six patients were assigned to the control group and 45 to the lavage group. There were 13 deaths (28 per cent) and 16 patients with major complications (35 per cent) in the control group, as compared with 12 deaths (27 per cent) and 17 patients with major complications (38 per cent) in the lavage group. Lavage did not appear to modify the length of survival, the incidence of pancreatic collections (pseudocysts or abscesses), or the plasma amylase concentration. Considering the statistical power of the design, we conclude that the outcome of severe pancreatitis was not greatly, if at all, influenced by the regimen of peritoneal lavage used in this study.

It has been claimed that high-dose vitamin C is beneficial in the treatment of patients with advanced cancer, especially patients who have had no prior chemotherapy. In a double-blind study 100 patients with advanced colorectal cancer were randomly assigned to treatment with either high-dose vitamin C (10 g daily) or placebo. Overall, these patients were in very good general condition, with minimal symptoms. None had received any previous treatment with cytotoxic drugs. Vitamin C therapy showed no advantage over placebo therapy with regard to either the interval between the beginning of treatment and disease progression or patient survival. Among patients with measurable disease, none had objective improvement. On the basis of this and our previous randomized study, it can be concluded that high-dose vitamin C therapy is not effective against advanced malignant disease regardless of whether the patient has had any prior chemotherapy.

We randomly assigned frail elderly inpatients with a high probability of nursing-home placement to an innovative geriatric evaluation unit intended to provide improved diagnostic assessment, therapy, rehabilitation, and placement. Patients randomly assigned to the experimental (n = 63) and control (n = 60) groups were equivalent at entry. At one year, patients who had been assigned to the geriatric unit had much lower mortality than controls (23.8 vs. 48.3 per cent, P less than 0.005) and were less likely to have initially been discharged to a nursing home (12.7 vs. 30.0 per cent, P less than 0.05) or to have spent any time in nursing home during the follow-up period (26.9 vs. 46.7 per cent, P less than 0.05). The control-group patients had substantially more acute-care hospital days, nursing-home days, and acute-care hospital readmissions. Patients in the geriatric unit were significantly more likely to have improvement in functional status and morale than controls (P less than 0.05). Direct costs for institutional care were lower for the experimental group, especially after adjustment for survival. We conclude that geriatric evaluation units can provide substantial benefits at minimal cost for appropriate groups of elderly patients, over and above the benefits of traditional hospital approaches.

At the time of their first hemorrhage from esophageal varices, 187 unselected patients with cirrhosis were randomly assigned to medical treatment including balloon tamponade or to medical treatment supplemented with intensive, paravariceal sclerotherapy. Follow-up period ranged from 9 to 52 months. The overall mortality in the sclerotherapy group (hazard) was 76 per cent (95 per cent confidence limits, 54 to 107 per cent) of that in the medical-regimen group. The relative mortality in the sclerotherapy group, determined by stratifying according to degree of encephalopathy and ascites, was 63 per cent of that in the medical-regimen group (95 per cent confidence limits, 44 to 91 per cent). The main effect of sclerotherapy may be a reduction of long-term mortality, which after Day 40 was only 43 per cent (95 per cent confidence limits, 23 to 79 per cent) of that in the medical-regimen group. Sclerotherapy had no significant influence on the initial hemorrhage as judged from the duration of bleeding or of balloon tamponade, the number of blood transfusions needed, or immediate mortality. Forty-five patients in the sclerotherapy group had 64 episodes of recurrent hemorrhage, as compared with 138 episodes among 51 patients in the medical-regimen group. This difference was due to a pronounced reduction of rebleeding after Day 40 in the sclerotherapy group. We recommend sclerotherapy for patients with cirrhosis who have bleeding from esophageal varices.

Fifty-two patients with severe cirrhosis (Child Class C) and variceal hemorrhage requiring six or more units of blood were randomly assigned to either sclerotherapy or portacaval shunt. Of 38 pretreatment characteristics, only the frequency of active alcoholism differed significantly between the groups. During the initial hospitalization, the patients in the shunt group required significantly more blood (21.5 +/- 3.1 units) than did those in the sclerotherapy group (12.3 +/- 1.3 units), although the latter had significantly more rebleeding during hospitalization after the procedure (14 of 28 vs. 5 of 24 patients). There was no difference in short-term survival, with 13 patients in the sclerotherapy group discharged alive, as compared with 10 patients in the shunt group. Patients were followed for a mean of 263 days after the initial discharge (range, 8 to 1117). The sclerotherapy group required significantly more days of hospitalization for rebleeding, but we failed to demonstrate any significant difference in long-term survival between the sclerotherapy and shunt groups. Total health-care costs per patient were significantly higher for the shunt group (+23,957 +/- +3,111) than for the sclerotherapy group (+15,364 +/- +2,220). We conclude that sclerotherapy is less costly than portacaval shunt and as effective for the treatment of esophageal varices associated with severe cirrhosis.

In an effort to clarify the role of immunosuppressive drugs in the management of lupus nephritis, we pooled data from all published clinical trials in which patients had been randomly assigned to receive either prednisone alone or prednisone plus cyclophosphamide or azathioprine. The pooled analysis showed that patients receiving immunosuppressive drugs had less renal deterioration (P = 0.006), were less likely to have end-stage renal disease (P = 0.023), and were less likely to die from kidney disease (P = 0.024) than patients receiving steroids alone. There were no significant differences with respect to deaths from nonrenal causes or overall mortality. When cyclophosphamide and azathioprine were considered separately, both were associated with a 40 per cent reduction in the rates of adverse renal outcomes, although because the treatment groups were smaller, many of these differences were not statistically significant. A power analysis showed that a study of 100 high-risk patients (development of renal insufficiency in 50 per cent) would be needed to prove that an immunosuppressive agent is 50 per cent superior to steroids alone in preventing renal deterioration. We conclude that immunosuppressive drugs and steroids together are more effective than steroids alone in treating lupus nephritis and that published trials have reached false negative conclusions because of small sample sizes.

We randomly assigned patients with a clinical diagnosis of acute myocardial infarction to one of four treatment groups: intracoronary streptokinase, intracoronary nitroglycerin, intracoronary streptokinase and intracoronary nitroglycerin, or conventional therapy without initial angiography. Of 124 patients 122 sustained acute myocardial infarction. Initial angiography revealed total occlusion of the coronary artery responsible for infarction in 67 per cent (61 of 91). Acute recanalization occurred in 74 per cent (32 of 43) of patients receiving streptokinase but in only 6 per cent (1 of 18) of patients treated with nitroglycerin alone (P less than 0.01). At angiography of all four groups on Day 10 to 14 the vessel responsible for acute myocardial infarction was patent in 77 per cent (71 of 92) of patients; there was no difference among groups, indicating gradual, endogenous thrombolysis in patients not treated with streptokinase. Patients with subtotal obstruction initially had significant improvement in left ventricular function, significantly lower peak creatine kinase levels, and a trend toward lower mortality than patients with total occlusion initially. Mortality at six months in patients receiving streptokinase (21 per cent, 13 of 62) did not differ significantly from that in patients not treated with streptokinase (10 per cent, 6 of 61). Additional studies will be necessary to assess treatment effects in the angiographic subsets identified by this trial.

A cooperative study was conducted to determine the efficacy of 30 days of treatment with either a glucocorticosteroid (prednisolone) or an anabolic steroid (oxandrolone) in moderate or severe alcoholic hepatitis. One hundred thirty-two patients with moderate disease and 131 with severe disease were randomly assigned to one of three treatments: prednisolone, oxandrolone, or placebo. During the 30 days, mortality in the groups receiving steroid therapy was not significantly different from mortality in the placebo group. Thirteen per cent of the moderately ill patients and 29 per cent of the severely ill patients died. Although neither steroid improved short-term survival, oxandrolone therapy was associated with a beneficial effect on long-term survival. This was especially true in patients with moderate disease: among those who survived for one or two months after the start of treatment the conditional six-month death rate was 3.5 per cent after oxandrolone and 19 to 20 per cent after placebo (P = 0.02). No consistent long-term effect was associated with prednisolone therapy.

We evaluated long-term survival after coronary-artery bypass grafting in 686 patients with stable angina who were randomly assigned to medical or surgical treatment at 13 hospitals and followed for an average of 11.2 years. For all patients and for the 595 without left main coronary-artery disease, cumulative survival did not differ significantly at 11 years according to treatment. The 7-year survival rates for all patients were 70 per cent with medical treatment and 77 per cent with surgery (P = 0.043), and the 11-year rates were 57 and 58 per cent, respectively. For patients without left main coronary-artery disease, the 7-year rates were 72 and 77 per cent in medically and surgically treated patients, respectively (P = 0.267), and the 11-year rates were 58 per cent in both groups. A statistically significant difference in survival suggesting a benefit from surgical treatment was found in patients without left main coronary-artery disease who were subdivided into high-risk subgroups defined angiographically, clinically, or by a combination of angiographic and clinical factors: (1) high angiographic risk (three-vessel disease and impaired left ventricular function)--at 7 years, 52 per cent in medically treated patients versus 76 per cent in surgically treated patients (P = 0.002); at 11 years, 38 and 50 per cent, respectively (P = 0.026); (2) clinically defined high risk (at least two of the following: resting ST depression, history of myocardial infarction, or history of hypertension)--at 7 years, 52 per cent in the medical group versus 72 per cent in the surgical group (P = 0.003); at 11 years, 36 versus 49 per cent, respectively (P = 0.015); and (3) combined angiographic and clinical high risk--at 7 years, 36 per cent in the medical group versus 76 per cent in the surgical group (P = 0.002); at 11 years, 24 versus 54 per cent, respectively (P = 0.005). Survival among patients with impaired left ventricular function differed significantly at 7 years (63 per cent in the medical group versus 74 per cent in the surgical group [P = 0.049]) but not at 11 years (49 versus 53 per cent). The surgical treatment policy resulted in a nonsignificant survival disadvantage throughout the 11 years in subgroups with normal left ventricular function, low angiographic risk, and low clinical risk, and a statistically significant disadvantage at 11 years in patients with two-vessel disease.(ABSTRACT TRUNCATED AT 400 WORDS)

We compared the efficacy and safety of the gonadotropin-releasing hormone analogue, leuprolide (1 mg subcutaneously daily), with diethylstilbestrol (DES, 3 mg by mouth daily) in patients with prostate cancer and distant metastases (Stage D2) who had not previously received systemic treatment. Initial therapy (leuprolide or DES) was continued for as long as an objective response was noted; cross-over to the alternative arm occurred at the time of disease progression or intolerable adverse reactions. Ninety-eight patients were randomly assigned to leuprolide, and 101 to DES. Suppression of testosterone and dihydrotestosterone and decreases in acid phosphatase were comparable in the two groups. Patients receiving DES experienced more frequent painful gynecomastia (P less than 0.00001), nausea and vomiting (P = 0.02), edema (P = 0.008), and thromboembolism (P = 0.065) than those receiving leuprolide. The leuprolide group reported more "hot flashes" (P = 0.00001). Overall, 86 per cent of the leuprolide group had an objective response (complete response, 1 per cent; partial response, 37 per cent; stable disease, 48 per cent), as compared with 85 per cent of the DES group (complete, 2 per cent; partial, 44 per cent; stable, 39 per cent). Actual survival rates at one year were 87 per cent for the leuprolide group and 78 per cent for the DES group (P = 0.17). We conclude that leuprolide offers an important alternative treatment that is therapeutically equivalent to and causes fewer side effects than DES for the initial systemic management of metastatic prostate cancer.

To determine whether corticosteroids are efficacious in severe septic shock, we conducted a prospective study of 59 patients randomly assigned to a methylprednisolone, dexamethasone, or control group. Patients were treated 17.5 +/- 5.4 hours (mean +/- S.E.M.) after the onset of shock, and 55 patients required vasopressor agents. Early in the hospital course, reversal of shock was more likely in patients who received corticosteroids than in those who did not. Four (19 per cent) of 21 methylprednisolone-treated, 7 (32 per cent) of 22 dexamethasone-treated, and none of 16 control patients had reversal of shock 24 hours after drug administration (corticosteroid groups vs. control group, P less than 0.05). Patients treated with corticosteroids within four hours after the onset of shock had a higher incidence of shock reversal (P less than 0.05). At 133 hours after drug administration, 17 (40 per cent) of 43 corticosteroid-treated patients had died, and 11 (69 per cent) of 16 control patients had died (P less than 0.05). However, these differences in reversal of shock and survival disappeared later in the course. Overall, 16 (76 per cent) of 21 patients receiving methylprednisolone, 17 (77 per cent) of 22 patients receiving dexamethasone, and 11 (69 per cent) of 16 controls in the hospital died. We conclude that corticosteroids do not improve the overall survival of patients with severe, late septic shock but may be helpful early in the course and in certain subgroups of patients.