Ferroni P, Di Filippo F, Martini F, Spila A, D'Alessandro T, Cavaliere F, Anzà M, Garinei R, Aloe S, Carone M D, Gazzaniga P P, Guadagni F
Department of Experimental Medicine and Pathology, University of Rome La Sapienza, Italy.
J Immunother. 2001 Jul-Aug;24(4):354-62. doi: 10.1097/00002371-200107000-00011.
Hyperthermic isolated limb perfusion (ILP) with tumor necrosis factor-a (TNFalpha) and cytotoxic drugs is currently used for treatment of melanoma and sarcoma of the limbs. Tumor necrosis factor-alpha is involved in the systemic inflammatory response syndrome as a result of activation of inflammatory cells and production of bioactive substances. The goal of this study was to determine the circulating levels of proinflammatory cytokines and soluble adhesion molecules in 19 patients with limb melanoma or sarcoma undergoing ILP with (n = 9) or without TNFalpha (n = 10). The results obtained demonstrated that ILP with TNFalpha was responsible for a leakage of TNFalpha in the systemic circulation, followed by a rise in interleukin (IL)-6 and IL-8 levels within I h. Elevated soluble (s)P-selectin levels were found 1-3 h after ILP. Plasma sE-selectin peaked 6-9 h after ILP, and soluble vascular cell adhesion molecule (sVCAM) levels reached a maximum after 24 h. Significant correlations were observed among these variables, confirming the interdependence of all changes observed. On the other hand, ILP with cytotoxic drugs alone induced only a modest release of TNFalpha, which was not followed by an immediate rise in IL-6 and IL-8. Four of the 9 patients undergoing ILP with TNF had severe systemic toxicity. No association was found between systemic TNF levels and the clinical outcome, whereas elevated TNF perfusion levels as well as systemic IL-6 and IL-8 levels were constantly elevated in patients with severe toxicity. These results are suggestive of an important role of TNFalpha levels in the perfusion system (more than leakage of perfusate) in causing postoperative toxicity, although other ILP-related factors should not be excluded.
采用肿瘤坏死因子-α（TNFα）和细胞毒性药物进行热灌注隔离肢体灌注（ILP）目前用于治疗肢体黑色素瘤和肉瘤。肿瘤坏死因子-α由于炎症细胞的激活和生物活性物质的产生而参与全身炎症反应综合征。本研究的目的是测定19例接受ILP治疗的肢体黑色素瘤或肉瘤患者（其中9例使用TNFα，10例未使用TNFα）体内促炎细胞因子和可溶性黏附分子的循环水平。所得结果表明，使用TNFα的ILP导致TNFα漏入体循环，随后1小时内白细胞介素（IL）-6和IL-8水平升高。ILP后1 - 3小时发现可溶性（s）P-选择素水平升高。血浆sE-选择素在ILP后6 - 9小时达到峰值，可溶性血管细胞黏附分子（sVCAM）水平在24小时后达到最高。这些变量之间观察到显著相关性，证实了所有观察到的变化之间的相互依赖性。另一方面，单独使用细胞毒性药物的ILP仅诱导TNFα适度释放，随后IL-6和IL-8并未立即升高。9例接受含TNFα的ILP治疗的患者中有4例出现严重全身毒性。未发现全身TNF水平与临床结果之间存在关联，而严重毒性患者的TNF灌注水平以及全身IL-6和IL-8水平持续升高。这些结果表明，TNFα水平在灌注系统中（而非灌注液渗漏）在导致术后毒性方面起重要作用，尽管不应排除其他与ILP相关的因素。
