Real-time near infrared fluorescence (NIRF) intra-operative imaging in ovarian cancer using an α(v)β(3-)integrin targeted agent.

BACKGROUND In ovarian cancer, optimal cytoreductive surgery is of the utmost importance for long-term survival. The ability to visualize minuscule tumor deposits is important to ensure complete resection of the tumor. The purpose of our study was to estimate the in vivo sensitivity, specificity and diagnostic accuracy of an intra-operative fluorescence imaging system combined with an α(v)β(3)-integrin targeted near-infrared fluorescent probe. METHOD Tumor bearing mice were injected intravenously with a fluorescent probe targeting α(v)β(3) integrins. Fluorescent spots and non-fluorescent tissue were identified and resected. Standard histopathology and fluorescence microscopy were used as gold-standard for tumor detection. RESULTS Fifty-eight samples excised with support of intra-operative image-guided surgery were analyzed. The mean target to background ratio was 2.2 (SD 0.5). The calculated sensitivity of the imaging system was 95%, and the specificity was 88% with a diagnostic accuracy of 96.5%. CONCLUSION Near-infrared image-guided surgery in this model has a high diagnostic accuracy and a fair target to background ratio that supports the development towards clinical translation of α(v)β(3)-integrin targeted imaging.

[1]  Bryan Q. Spring,et al.  In vivo high-resolution fluorescence microendoscopy for ovarian cancer detection and treatment monitoring , 2009, British Journal of Cancer.

[2]  H. Hollema,et al.  Enhanced Antitumor Efficacy of a DR5-Specific TRAIL Variant over Recombinant Human TRAIL in a Bioluminescent Ovarian Cancer Xenograft Model , 2009, Clinical Cancer Research.

[3]  P. Choyke,et al.  Galactosyl human serum albumin-NMP1 conjugate: a near infrared (NIR)-activatable fluorescence imaging agent to detect peritoneal ovarian cancer metastases. , 2012, Bioconjugate chemistry.

[4]  Sylvain Gioux,et al.  Real-time, near-infrared, fluorescence-guided identification of the ureters using methylene blue. , 2010, Surgery.

[5]  J. Menéndez,et al.  αVβ3 integrin regulates heregulin (HRG)-induced cell proliferation and survival in breast cancer , 2005, Oncogene.

[6]  N. Kieffer,et al.  Integrin αvβ3 expression confers on tumor cells a greater propensity to metastasize to bone , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[7]  Vasilis Ntziachristos,et al.  Planar fluorescence imaging using normalized data. , 2005, Journal of biomedical optics.

[8]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[9]  Ralph Weissleder,et al.  Improved detection of ovarian cancer metastases by intraoperative quantitative fluorescence protease imaging in a pre-clinical model. , 2009, Gynecologic oncology.

[10]  Vasilis Ntziachristos,et al.  Multispectral imaging using multiple-bandpass filters. , 2008, Optics letters.

[11]  M. Golzio,et al.  Intraoperative fluorescence imaging of peritoneal dissemination of ovarian carcinomas. A preclinical study. , 2011, Gynecologic oncology.

[12]  M. Kéramidas,et al.  Intraoperative near‐infrared image‐guided surgery for peritoneal carcinomatosis in a preclinical experimental model , 2010, The British journal of surgery.

[13]  P. Low,et al.  Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results , 2011, Nature Medicine.

[14]  Vasilis Ntziachristos,et al.  Enhancing Surgical Vision by Using Real-Time Imaging of αvβ3-Integrin Targeted Near-Infrared Fluorescent Agent , 2011, Annals of Surgical Oncology.

[15]  L. Ngo,et al.  The FLARE™ Intraoperative Near-Infrared Fluorescence Imaging System: A First-in-Human Clinical Trial in Breast Cancer Sentinel Lymph Node Mapping , 2009, Annals of Surgical Oncology.

[16]  E Biganzoli,et al.  Vascular integrin alpha(v)beta3: a new prognostic indicator in breast cancer. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[17]  R. Tsien,et al.  Activatable cell penetrating peptides linked to nanoparticles as dual probes for in vivo fluorescence and MR imaging of proteases , 2010, Proceedings of the National Academy of Sciences.

[18]  Yusuke Inoue,et al.  Diet and Abdominal Autofluorescence Detected by in Vivo Fluorescence Imaging of Living Mice , 2008, Molecular imaging.

[19]  Richard O. Hynes,et al.  Integrins: A family of cell surface receptors , 1987, Cell.

[20]  G. Stamp,et al.  Integrins and their accessory adhesion molecules in mammary carcinomas: loss of polarization in poorly differentiated tumors. , 1992, Human pathology.

[21]  Sylvain Gioux,et al.  Real-time intra-operative near-infrared fluorescence identification of the extrahepatic bile ducts using clinically available contrast agents. , 2010, Surgery.

[22]  Vasilis Ntziachristos,et al.  Real-time intraoperative fluorescence imaging system using light-absorption correction. , 2009, Journal of biomedical optics.

[23]  D. Levine,et al.  What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC) , 2006 .

[24]  J. Ferlay,et al.  Global Cancer Statistics, 2002 , 2005, CA: a cancer journal for clinicians.