A phase II study of alpha-difluoromethylornithine (DFMO) for the treatment of metastatic melanoma.

Difluoromethylornithine (DFMO) is an irreversible enzyme-activated inhibitor of ornithine decarboxylase, a key enzyme in polyamine synthesis. We have screened for potential anti-cancer activity of DFMO using a clonogenic assay, which suggested that melanoma might have sensitivity to this agent. Accordingly, we have performed a phase II trial of DFMO (2 g/m2 po q 8 h) in 24 patients, 21 of whom were evaluable for response. One patient achieved a complete response of a large subcutaneous mass for 11 months. Although stabilization is frequently difficult to measure, seven patients appeared to stabilize previously active disease, with a median duration of response of eight weeks. Toxicity was significant and DFMO was discontinued in five patients due to side effects - hearing loss alone in four and hearing loss associated with thrombocytopenia in the fifth patient. Hearing changes occurred in ten patients. Other side effects were mild. These data indicate that DFMO as a single agent may be an effective therapy for melanoma. A phase II trial of DFMO in previously untreated patients using a different schedule to decrease hearing loss is warranted. Additionally, several in vitro and animal models suggest that DFMO plus interferon are synergistic, and this combination might be used for a clinical trial as well.

Atrial coronary hyperemia and ischemia in response to variations in atrial pressure in dogs.

We altered the mechanical activity of the atrial myocardium in open-chest dogs and measured changes in coronary blood flow distribution, using the radioactive microsphere technique. When left and right atrial pressures were decreased to 2 mm Hg by hypovolemia, atrial coronary blood flow fell to values nearly 50% below baseline. Acute left atrial hypertension was induced by creating mitral valvular incompetence. Progressive increases in left atrial pressure from 8 to 12 to 20 mm Hg caused increases in left atrial coronary blood flow from 47 to 54 to 75 ml/100 gm X min (mean values). Severe left atrial hypertension (32 mm Hg) caused a fall in left atrial blood flow to 30 ml/100 gm X min. The P wave in lead II of the ECG widened by a mean value of 18 msec, suggesting ischemic impairment of left atrial depolarization.

Serial cardiac function tests in myocarditis.

Sixteen patients (mean age 27 years, range 16 to 39 years) with the diagnosis of myopericarditis established by strict clinical criteria were evaluated following recovery 0.7 to 4.0 years (mean 2.7 years) later. Evidence of an acute viral infection was present in 44%. During the acute illness, the major clinical manifestations consisted of pericarditis in 10 patients, acute myocardial infarction in 5, right ventricular dysfunction in 5, bundle branch or hemiblock in 4, ventricular arrhythmias in 3, congestive heart failure in 3 and cardiogenic shock and inappropriate sinus tachycardia in one patient each. Holter monitoring, echophonocardiography and radionuclide ventriculography results were abnormal in 57, 67 and 64% of patients respectively. At follow-up, these tests were abnormal in 67, 7 and 73%. Focal wall motion abnormalities were present in five. Seventy-five percent of patients had one or more abnormal tests at last follow-up. Although 8 patients had improved by a scoring system, 5 patients had an increase in the number of abnormal tests, including one who died. These findings indicate that persistent abnormalities following recovery from myopericarditis are not rare and support the hypothesis that the syndrome of dilated cardiomyopathy may be a sequel of myopericarditis.