title: Modified In Vivo Lung Perfusion for Local Chemotherapy: A Preclinical Study With Doxorubicin.
abstract: BACKGROUND
  In vivo lung perfusion (IVLP) is a promising adjuvant treatment of lung metastases, allowing the localized delivery of drugs to the lungs without systemic exposure. Previous experimental and clinical data resulted in variable efficacy and frequent toxicity. Our objectives were to demonstrate the feasibility and safety of a novel protective IVLP technique coupled with the delivery of sarcoma-based chemotherapy to the lung.
  
  
  METHODS
  The left pulmonary artery and veins in pigs were cannulated and clamped. Left lung IVLP was performed for 4 hours. Doxorubicin (Dox) at a standard clinical dose of 75 mg/m(2) was used, followed by 150 and 225 mg/m(2). Dox 75 mg/m(2) combined with ifosfamide (Ifos) 6 g/m(2) was also tested. After IVLP, blood reperfusion was allowed for 4 hours. Lung physiology was assessed and biopsy samples were obtained for histologic assessment of acute lung injury (ALI), inflammatory profile, and cell death. Lung tissue levels, perfusate, and plasma levels of Dox were measured during the procedure.
  
  
  RESULTS
  Lungs treated with Dox 75 mg/m(2) alone or combined with Ifos showed stable function throughout the procedure, without evidence of ALI (p = 0.12 and p = 0.36, respectively). Tissue levels of Dox were 70.3 μg/g homogeneously distributed in the lung (p = 0.12). No drug was detected systemically. Dox 150 mg/m(2) and 225 mg/m(2) showed incremental ALI.
  
  
  CONCLUSIONS
  IVLP for 4 hours with Dox 75 mg/m(2) alone or combined with Ifos was well tolerated, without measurable ALI. High drug levels in perfusate and lung tissue were found without systemic leakage. A dose-related toxicity was observed with increases in Dox doses.
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; and Division of Thoracic Surgery, Department of Surgery, University of Toronto, University Health Network, Toronto, Ontario, Canada.
authors.forename: Pedro
authors.initials: P
authors.lastname: Reck Dos Santos
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; and Division of Thoracic Surgery, Department of Surgery, University of Toronto, University Health Network, Toronto, Ontario, Canada.
authors.forename: Jin
authors.initials: J
authors.lastname: Sakamoto
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; and Division of Thoracic Surgery, Department of Surgery, University of Toronto, University Health Network, Toronto, Ontario, Canada.
authors.forename: Manyin
authors.initials: M
authors.lastname: Chen
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; and Division of Thoracic Surgery, Department of Surgery, University of Toronto, University Health Network, Toronto, Ontario, Canada.
authors.forename: Virginia
authors.initials: V
authors.lastname: Linacre
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; and Division of Thoracic Surgery, Department of Surgery, University of Toronto, University Health Network, Toronto, Ontario, Canada.
authors.forename: Chantel
authors.initials: C
authors.lastname: Arce
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; and Division of Thoracic Surgery, Department of Surgery, University of Toronto, University Health Network, Toronto, Ontario, Canada.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; and Division of Thoracic Surgery, Department of Surgery, University of Toronto, University Health Network, Toronto, Ontario, Canada.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Waddell
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; and Division of Thoracic Surgery, Department of Surgery, University of Toronto, University Health Network, Toronto, Ontario, Canada.
authors.forename: Shaf
authors.initials: S
authors.lastname: Keshavjee
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; and Division of Thoracic Surgery, Department of Surgery, University of Toronto, University Health Network, Toronto, Ontario, Canada. Electronic address: marcelo.cypel@uhn.ca.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Cypel
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D004317:Doxorubicin / Q000008:administration & dosage*; D005240:Feasibility Studies; D007069:Ifosfamide / Q000008:administration & dosage*; D007150:Immunohistochemistry; D008168:Lung / Q000098:blood supply / Q000187:drug effects*; D023421:Models, Animal; D010477:Perfusion / Q000379:methods*; D011652:Pulmonary Circulation / Q000502:physiology; D011659:Pulmonary Gas Exchange; D018570:Risk Assessment; D013552:Swine
chemical_list: D004317:Doxorubicin; D007069:Ifosfamide