title: Acute-phase response patterns in isolated hepatic perfusion with tumour necrosis factor alpha (TNF-alpha) and melphalan in patients with colorectal liver metastases.
abstract: BACKGROUND
  In this study, we have evaluated hepatotoxicity, secondary cytokine production and hepatic acute-phase response (APR) in patients who underwent isolated hepatic perfusion (IHP) with tumour necrosis factor (TNF) alpha and melphalan for irresectable colorectal liver metastases.
  
  
  METHODS
  An extracorporeal veno-venous bypass was used to shunt blood from the lower body and intestines to the heart. Inflow catheters were placed in the hepatic artery and portal vein, and an outflow catheter in the inferior caval vein. The liver was perfused for 60 min with 0.4 mg of TNF-alpha plus 1 mg kg-1 melphalan (IHPTM group, n = 6) or 1 mg kg-1 melphalan (IHPM group, n = 3). The liver was washed with macrodex before restoring vascular continuity.
  
  
  RESULTS
  After the washout procedure, a TNF-alpha peak (169 +/- 38 pg mL-1) was demonstrated in the IHPTM group only. Both groups demonstrated peak levels of interleukin 6 (IL-6) in the perfusate as well as systemically. These were significantly higher in the IHPTM group. Acute-phase protein (APP) levels followed a similar pattern as has been demonstrated after major surgery, with no significant differences between both groups. The addition of TNF-alpha to the perfusate did not lead to a significant difference in APP levels and the time course between groups.
  
  
  CONCLUSIONS
  IHP with TNF and melphalan is followed by a transient systemic peak of TNF directly after liver washout. Secondary IL-6 induction was seen in the present study after IHP with and without TNF, which was highest when TNF was added. This phenomenon cannot be extrapolated to APP induction, which appeared unaffected by the addition of TNF, presumably because the surgical procedure itself already causes maximal stimulation of APP production.
authors.affiliation: The Department of Surgical Oncology, Dr Daniël den Hoed Cancer Centre,University Hospital Rotterdam, The Netherlands.
authors.forename: M R
authors.initials: MR
authors.lastname: De Vries
authors.forename: I H
authors.initials: IH
authors.lastname: Borel Rinkes
authors.forename: A J
authors.initials: AJ
authors.lastname: Swaak
authors.forename: C E
authors.initials: CE
authors.lastname: Hack
authors.forename: C J
authors.initials: CJ
authors.lastname: Van De Velde
authors.forename: T
authors.initials: T
authors.lastname: Wiggers
authors.forename: R A
authors.initials: RA
authors.lastname: Tollenaar
authors.forename: P J
authors.initials: PJ
authors.lastname: Kuppen
authors.forename: A M
authors.initials: AM
authors.lastname: Eggermont
mesh_terms: D000209:Acute-Phase Proteins / Q000096:biosynthesis*; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010478:Chemotherapy, Cancer, Regional Perfusion; D015179:Colorectal Neoplasms / Q000097:blood* / Q000188:drug therapy; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000556:secondary*; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D009961:Orosomucoid / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D013997:Time Factors; D014168:Transferrin / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D000515:alpha 1-Antitrypsin / Q000096:biosynthesis
chemical_list: D000209:Acute-Phase Proteins; D018906:Antineoplastic Agents, Alkylating; D015850:Interleukin-6; D009961:Orosomucoid; D011994:Recombinant Proteins; D014168:Transferrin; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; D008558:Melphalan