SYSTEMIC RELEASE OF SOLUBLE TNF RECEPTORS AFTER HIGH-DOSE TNF IN ISOLATED LIMB PERFUSION

Isolated limb perfusion (ILP) with high-dose tumour necrosis factor (T NF), interferon gamma and melphalan (TIM) is an efficient treatment fo r patients with regionally advanced melanoma and sarcoma. In 44 patien ts, we determined the kinetics of soluble TNF receptors (sTNF-RI and R II) plasma concentrations, and correlated them with systemic TNF and i nterleukin 6 (IL-6) levels and shock. Seven patients treated conventio nally by ILP without cytokine served as controls. Elevated levels of b oth sTNF-Rs were observed within 30 min after begining of the TIM-ILP. A first peak of sTNF-Rs levels was observed 3 h after ILP and was fol lowed by a rapid decrease reaching a nadir at 12-14 h post ILP. This f irst peak was followed by a second, long-lasting elevation of both sTN F-Rs levels persisting for 4 to 5 days after TIM-ILP. Patients treated by ILP without TNF/interferon gamma (IFN-gamma) had no detectable inc rease in either sTNF-Rs or in circulating TNF, demonstrating that the release of TNF-Rs was dependent upon the administration of TNF/IFN-gam ma. High plasma levels of TNF and IL-6, were observed in patients that had more than 5% leakage during the TIM-ILP, but no significant corre lation between TNF levels and the peak values of both sTNF-Rs,vas obse rved. The levels of TNF and IL-6 were, however, significantly related to each other. TNF systemic levels, but not sTNF-Rs concentrations, co rrelated significantly with the severity of the shock observed after T IM-ILP. Patients in which sTNF-RII concentration was in excess over ci rculating TNF, had no shock or grade I shock only, suggesting that sTN F-RII may play a protective, although limited, role in inhibiting acti vity of circulating TNF. (C) 1997 Academic Press Limited.