Reversal of cyclosporine-induced mortality with a synthetic polymeric immunostimulant in a murine model of fecal peritonitis.

We have been investigating the effects of a synthetic immunostimulative polymer known as copovithane (Cpv). This agent appears to enhance humoral immunity in untreated and cyclosporine-immunosuppressed mice and is nontoxic in rodents and man. The purpose of this study was to determine whether cyclosporine (CsA) is deleterious to survival in a murine cecal ligation, puncture, and excision (CLPE) model of fecal peritonitis, and--if so--whether this effect could be ameliorated by Cpv without interfering with skin allograft acceptance. Cpv significantly prolongs survival in the CLPE model; the optimal dose for this effect was found to be 100 mg/kg. CsA was found to have a significant and deleterious effect on survival at several dosage levels when administrated 48 and 24 hr before cecal ligation, and immediately before and 16 hr after cecal ligation. Using a dose of CsA sufficient for skin allograft acceptance and the same schedule of administration outlined above, Cpv 100 mg/kg was administered 48 hr prior to cecal ligation. Mice treated with CsA plus Cpv had significantly longer survival than mice treated with CsA alone; furthermore, the survival of CsA-plus-Cpv-treated animals was not significantly different from that of saline-treated controls. Acceptance and survival of H-2 incompatible skin allografts in mice treated with CsA were not affected by Cpv 100 mg/kg/week. We conclude that CsA-induced mortality in the CLPE model can be abrogated by Cpv without adversely affecting skin allograft survival. It may eventually be possible to reduce the incidence of septic complications in clinical allotransplantation by prophylactically administering Cpv to patients on CsA immunosuppression.

Further experience with regional radiofrequency hyperthermia and cytotoxic chemotherapy for unresectable hepatic neoplasia.

The authors report on 178 patients with unresectable hepatic tumors who have been treated with 1 to 25 (median, 6) courses of radiofrequency hyperthermia (RFHT) and chemotherapy. In 137 patients, the hepatic tumors consisted of metastases from colorectal adenocarcinomas. For patients who had no previous therapy and who had colorectal metastases with no extraheptic disease, cumulative survival at 52 weeks' follow-up was 80.5% and partial tumor regression was seen in 78.4%. Among the 69 patients who previously had conventional treatment for their hepatic disease, partial regression was seen in 43.5%. We are no longer monitoring tumor core temperature routinely, as the invasive methods currently in use yield irreproducible results; the risks to the patient cannot be justified in view of the questionable relevance of the data obtained. A prospective randomized study of systemic chemotherapy with or without RFHT in patients with colorectal hepatic metastases is in progress.

Radiofrequency hyperthermia as adjuvant therapy following surgical resection of an experimental malignant neoplasm.

Local recurrence after radical surgery is a major problem with many primary solid cancers. The use of radiofrequency hyperthermia (RFHT) as adjuvant therapy to surgery was explored in the Fischer bladder carcinoma (FBCa)/F344 rat tumor system. After subcutaneous innoculation of 34 rats with 10(6) FBCa cells in suspension, RFHT was administered to 17 animals on days 1, 5, 8, and 12. The development of palpable tumors was delayed but not prevented, and tumor growth was retarded in RFHT-treated animals. In another experiment 40 rats were innoculated by subcutaneous trocar injection with a 1 mm3 piece of FBCa. After tumor excision on day 17, adjuvant therapy (untreated control, mitomycin C, RFHT, or RFHT plus mitomycin C) was started on day 20 (10 rats/treatment). The 20 RFHT-treated rats had only 1 incisional recurrence as compared to 9 recurrences in sham-heated rats (P less than 0.005). The authors conclude that RFHT has considerable value as adjuvant therapy to surgery in these tumors. Additional studies of RFHT as adjuvant treatment after surgical excision of tumors are planned.