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Eighteen patients received a continuous intravenous infusion of adriamycin for 14-60 days in a phase I study in which the dose rates were escalated from 2 mg/sq m/day to 5 mg/sq m/day to establish the optimal dose to be delivered over a 30-day period. The drug was delivered via a tunneled subclavian catheter by a portable infusion pump (Cormed model ML-6) primed to provide a volume of diluted drug of 10 cc/day. Leukopenia and stomatitis were observed at 4 mg/sq m/day doses or greater in 50% of courses. At doses less than 4 mg/sq m/day, only 3/17 courses (18%) were associated with stomatitis. Partial alopecia developed in all patients, but less than 50% of scalp hair was affected. The cumulative dose of continuous infusion adriamycin at 30 days is comparable to the dose delivered by standard bolus intermittent schedules (60-90 mg/sq m g 21 days), but the adverse drug effects are eliminated or substantially reduced. Cardiac toxicity was assessed in selected patients treated to 450 mg/sq m or greater by cardiac biopsy and/or gated pool studies. No histopathologic lesions were noted in 3 patients receiving 450 mg/sq m or greater. The recommended daily dose rate of adriamycin in this protracted infusion regimen is 3 mg/sq m/day. The phase II study of this schedule and dose rate in 38 additional patients (a total of 52 evaluable patients) demonstrated objective responses in 1/9 soft tissue sarcoma, 1/3 mesothelioma, 1/3 hepatoma, and 2/13 breast cancer. Phase III studies of the protracted continuous infusion schedule for adriamycin are indicated in that clinical activity is demonstrated at a substantial reduction in toxicity. Pharmacologic studies expanding the existing data base are also necessary.

Granuloma formation has been the concern of many investigators at both the research and clinical levels. The procedures used to study granulomatous inflammation have included morphological observation ( 1 ), analysis of cell migration patterns (2-4), and measurement of granuloma size in terms of granuloma diameter ( S ) , volume ( 6 ) , and weight ( 7 ). These methods, however, lack the capacity to quantitate the actual number of each cell type involved in the formation of a granuloma.Our laboratory has been particularly concerned with quantitation procedures for the study of the inflammatory exudate in the peritoneal cavity (8). In the course of these studies, it was noted that granulomatous tissue was subsequegtly formed at the site of inflammation (9, lo). Our investigations were then extended to determine if it would be possible to develop a technique for quantitating the cells in the granuloma. This study describes a procedure for dispersing experimentally induced granulomas into their cellular components. Also presented are the results obtained when this procedure was applied at different stages of granuloma formation following the injection of antigenic and nonantigenic substances.ulomas. In this investigation, 3 types of granulomas were induced by subcutaneous injections into the inguinal region of adult female BDFl hybrid mice. Type I (primary granuloma) consisted of granulomas formed in response to a priming injection of 0.4 ml of tetanus toxoid adsorbed onto aluminum phosphate (APTT) (Parke Davis). Type I1 (secondary granuloma) consisted of granulomas formed in response to a challenging injection of 0.4 ml of APTT in mice which had been primed subcutaneously in the dorsal neck 5 weeks previously with 0.2 ml of APTT mixed with 0.2 ml of pertussis vaccine (PV) (Eli Lilly) adjuvant diluted 1 : 10 with saline. Type I11 (alum granuloma) consisted of granulomas formed in response to an injection of 0.4 ml of a nonantigenic substance, aluminum phosphate (AP), ( 5 mg/ml of saline) into mice which had been primed with PV-APTT as above. In order to facilitate location of the granulomas, activated sterile carbon (C) (Merck and Co.) was mixed with AP, APTT and PV-APTT solutions in a concentration of 2 mg/ml.Processing of granulomas. Mice were killed by cervical dislocation, dipped quickly into a solution of pHisoHex (Winthrop Laboratory, New York), and the skin was peeled back to reveal the subcutaneous granulomas.Each granuloma was freed of any adherent connective tissue and then subjected to dispersion and digestion procedures in a siliconized tube containing 1 ml of a cold, freshly prepared solution of collagenase.Collagenase, from Clostridium histo2yticum (General Biochemical Corp.) was prepared at a concentration of 4 mg of collagenase/ml of Hanks' balanced salt solution (pH 7.1-7.2). After 1-3 hr of incubation at 37", the stroma dissolved; and the granuloma fell 1090

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