title: Increased shedding of soluble TNF-receptor 1 during hyperthermic TNF-α-based isolated limb perfusion.
abstract: OBJECTIVE
  Hyperthermic isolated limb perfusion (HILP) with TNF-α and melphalan has high response rates in patients with soft tissue sarcomas (STS) or melanomas of the limbs. Its effectiveness is based on the destructive effect of TNF-α on the blood supply of the tumours. Shedding of soluble TNF-receptor (sTNF-R) negatively modulates the effects of TNF-α, whereas hyperthermia (HT) induces shedding. Here, we investigated whether sTNF-R shedding in response to HT occurs during HILP.
  
  
  METHODS
  The serum levels of sTNFR-1 were measured in 23 patients with HILP by obtaining serum from the extracorporeal and central circuits. The samples were taken from the patients under normothermic (37°C) and hyperthermic (39°C) conditions. Additionally, cell cultures of HUVEC, human fibrosarcoma cells and peripheral blood cells were used to confirm the effects of HT on sTNF-R1 shedding by ELISA and western blot.
  
  
  RESULTS
  Under HT, levels of sTNF-R1 increased 23.5% in the extracorporeal circuit, but this increase was not observed in the systemic circuit. However, we could not confirm this effect using the cell culture model, where cellular TNF-R1 and sTNF-R1 of culture supernatants, respectively, were not significantly different between NT and HT conditions.
  
  
  CONCLUSIONS
  HT is associated with an increase of sTNF-R1 in the extracorporeal circuit of perfused limbs. Interestingly, HT does not exhibit the same effect on cells cultured in vitro. Additional studies will be aimed at determining whether our findings have an impact in the clinic by analysing the relationship between TNF-R1 shedding and tumour response to HILP.
authors.affiliation: Institute of Pathology and Neuropathology, West German Cancer Center, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Grabellus
authors.forename: Lars E
authors.initials: LE
authors.lastname: Podleska
authors.forename: Saturnina
authors.initials: S
authors.lastname: Bjerlestam
authors.forename: Sien-Yi
authors.initials: SY
authors.lastname: Sheu
authors.forename: Sven
authors.initials: S
authors.lastname: Lendemans
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Schmid
authors.forename: Georg
authors.initials: G
authors.lastname: Taeger
mesh_terms: D000368:Aged; D002478:Cells, Cultured; D010478:Chemotherapy, Cancer, Regional Perfusion; D005121:Extremities / Q000473:pathology; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000628:therapy*; D008558:Melphalan / Q000627:therapeutic use*; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D012509:Sarcoma / Q000188:drug therapy / Q000628:therapy*; D012983:Soft Tissue Neoplasms / Q000188:drug therapy / Q000628:therapy*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
chemical_list: D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D008558:Melphalan