title: The Value of Intraoperative Near-Infrared Fluorescence Imaging Based on Enhanced Permeability and Retention of Indocyanine Green: Feasibility and False-Positives in Ovarian Cancer.
abstract: OBJECTIVE
  In ovarian cancer, two of the most important prognostic factors for survival are completeness of staging and completeness of cytoreductive surgery. Therefore, intra-operative visualization of tumor lesions is of great importance. Preclinical data already demonstrated tumor visualization in a mouse-model using near-infrared (NIR) fluorescence imaging and indocyanine green (ICG) as a result of enhanced permeability and retention (EPR). The aim of this study was to determine feasibility of intraoperative ovarian cancer metastases imaging using NIR fluorescence imaging and ICG in a clinical setting.
  
  
  METHODS
  Ten patients suspected of ovarian cancer scheduled for staging or cytoreductive surgery were included. Patients received 20 mg ICG intravenously after opening the abdominal cavity. The mini-FLARE NIR fluorescence imaging system was used to detect NIR fluorescent lesions.
  
  
  RESULTS
  6 out of 10 patients had malignant disease of the ovary or fallopian tube, of which 2 had metastatic disease outside the pelvis. Eight metastatic lesions were detected in these 2 patients, which were all NIR fluorescent. However, 13 non-malignant lesions were also NIR fluorescent, resulting in a false-positive rate of 62%. There was no significant difference in tumor-to-background ratio between malignant and benign lesions (2.0 vs 2.0; P=0.99).
  
  
  CONCLUSIONS
  This is the first clinical trial demonstrating intraoperative detection of ovarian cancer metastases using NIR fluorescence imaging and ICG. Despite detection of all malignant lesions, a high false-positive rate was observed. Therefore, NIR fluorescence imaging using ICG based on the EPR effect is not satisfactory for the detection of ovarian cancer metastases. The need for tumor-specific intraoperative agents remains.
  
  
  BACKGROUND
  ISRCTN Registry ISRCTN16945066.
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Quirijn R J G
authors.initials: QR
authors.lastname: Tummers
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Charlotte E S
authors.initials: CE
authors.lastname: Hoogstins
authors.affiliation: Department of Gynecology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Alexander A W
authors.initials: AA
authors.lastname: Peters
authors.affiliation: Department of Gynecology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Cor D
authors.initials: CD
authors.lastname: de Kroon
authors.affiliation: Department of Gynecology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: J Baptist M Z
authors.initials: JB
authors.lastname: Trimbos
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: van de Velde
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America; Department of Radiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America; Curadel, LLC, Worcester, Massachusetts, United States of America.
authors.forename: John V
authors.initials: JV
authors.lastname: Frangioni
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Vahrmeijer
authors.affiliation: Department of Gynecology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Katja N
authors.initials: KN
authors.lastname: Gaarenstroom
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D005456:Fluorescent Dyes; D006801:Humans; D007208:Indocyanine Green; D008875:Middle Aged; D016343:Monitoring, Intraoperative; D009362:Neoplasm Metastasis / Q000175:diagnosis*; D061848:Optical Imaging / Q000379:methods; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D010539:Permeability
chemical_list: D005456:Fluorescent Dyes; D007208:Indocyanine Green