Effects of isolated limb perfusion with tumor necrosis factor-α on circulating levels of proinflammatory cytokines

P. Ferroni, F. Di Filippo, F. Martini, A. Spila, R. D'Alessandro, F. Cavaliere, M. Anzà, R. Garinei, S. Aloe, M. D. Carone, P. P. Gazzaniga, F. Guadagni

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Hyperthermic isolated limb perfusion (ILP) with tumor necrosis factor-α (TNFα) and cytotoxic drugs is currently used for treatment of melanoma and sarcoma of the limbs. Tumor necrosis factor-α 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 TNFα (n = 10). The results obtained demonstrated that ILP with TNFα was responsible for a leakage of TNFα in the systemic circulation, followed by a rise in interleukin (IL)-6 and IL-8 levels within 1 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 TNFα, 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 TNFα levels in the perfusion system (more than leakage of perfusate) in causing postoperative toxicity, although other ILP-related factors should not be excluded.

Original languageEnglish
Pages (from-to)354-362
Number of pages9
JournalJournal of Immunotherapy
Issue number4
Publication statusPublished - 2001


  • Cytokines
  • Isolated limb perfusion
  • Selectins
  • Systemic inflammatory response syndrome
  • TNFα

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Immunology


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