title: Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan in patients with locally advanced soft tissue sarcomas: treatment response and clinical outcome related to changes in proliferation and apoptosis.
abstract: Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan (HILP-TM) with or without IFN-gamma is a promising local treatment in patients with locally advanced extremity soft tissue sarcomas (STSs), with response rates of up to 84%. The mechanisms of the treatment response are poorly understood. Here, we determined the HILP-TM-induced changes in mitotic activity, proliferation, and apoptosis in 37 STSs; the additional effect of IFN-gamma; and the association of HILP-TM with treatment response and clinical outcome. On archival material, obtained before and 6-8 weeks after HILP-TM with (n = 15) or without (n = 22) IFN-gamma, the number of mitoses was counted, and the proliferation fraction was determined by immunohistological staining for the proliferation associated Ki-67 antigen (MIB1). Apoptosis was visualized by enzymatic detection of DNA fragmentation (terminal deoxynucleotidyl transferase-mediated nick end labeling method). Clinical and histological response, follow-up status, and survival were recorded. The number of mitoses dropped 57% and proliferation rate decreased with 40% after HILP-TM, whereas the amount of apoptosis after HILP-TM more than doubled as before HILP-TM. The addition of IFN-gamma to HILP-TM did not influence the changes in tumor parameters and did not affect treatment response. A better clinical response to HILP-TM was correlated with high mitotic activity and low amount of apoptosis in tumor samples before HILP-TM. Patients with highly proliferative STS before and after HILP-TM had a relatively poor prognosis. Furthermore, patients who developed distant metastases after HILP-TM had a relatively high number of dividing cells in the tumor remnants after treatment.
authors.affiliation: Department of Pathology, University Hospital Groningen, The Netherlands. b.e.c.plaat@path.azg.nl
authors.forename: B E
authors.initials: BE
authors.lastname: Plaat
authors.forename: W M
authors.initials: WM
authors.lastname: Molenaar
authors.forename: M F
authors.initials: MF
authors.lastname: Mastik
authors.forename: J
authors.initials: J
authors.lastname: Koudstaal
authors.forename: E
authors.initials: E
authors.lastname: van den Berg
authors.forename: H S
authors.initials: HS
authors.lastname: Koops
authors.forename: H J
authors.initials: HJ
authors.lastname: Hoekstra
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis; D002455:Cell Division; D010478:Chemotherapy, Cancer, Regional Perfusion; D005260:Female; D005500:Follow-Up Studies; D005534:Foot Diseases / Q000188:drug therapy / Q000401:mortality; D006801:Humans; D006979:Hyperthermia, Induced; D007371:Interferon-gamma / Q000008:administration & dosage; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000627:therapeutic use*; D008875:Middle Aged; D012509:Sarcoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D008558:Melphalan