Improved detection of ovarian cancer metastases by intraoperative quantitative fluorescence protease imaging in a pre-clinical model.
OBJECTIVE
Cytoreductive surgery is a cornerstone of therapy in metastatic ovarian cancer. While conventional white light (WL) inspection detects many obvious tumor foci, careful histologic comparison has shown considerable miss rates for smaller foci. The goal of this study was to compare tumor detection using WL versus near infrared (NIR) imaging with a protease activatable probe, as well as to evaluate the ability to quantify NIR fluorescence using a novel quantitative optical imaging system.


METHODS
A murine model for peritoneal carcinomatosis was generated and metastatic foci were imaged using WL and NIR imaging following the i.v. administration of the protease activatable probe ProSense750. The presence of tumor was confirmed by histology. Additionally, the ability to account for variations in fluorescence signal intensity due to changes in distance between the catheter and target lesion during laparoscopic procedures was evaluated.


RESULTS
NIR imaging with a ProSense750 significantly improved upon the target-to-background ratios (TBRs) of tumor foci in comparison to WL imaging (minimum improvement was approximately 3.5 fold). Based on 52 histologically validated samples, the sensitivity for WL imaging was 69%, while the sensitivity for NIR imaging was 100%. The effects of intraoperative distance changes upon fluorescence intensity were corrected in realtime, resulting in a decrease from 89% to 5% in signal variance during fluorescence laparoscopy.


CONCLUSIONS
With its molecular specificity, low background autofluorescence, high TBRs, and quantitative signal, optical imaging with NIR protease activatable probes greatly improves upon the intraoperative detection of ovarian cancer metastases.
Sheth
Rahul Anil
RA
Center for Molecular Imaging Research, Massachusetts General Hospital, Simches 8226, 185 Cambridge St., Boston, MA 02114, USA.
Upadhyay
Rabi
R
Stangenberg
Lars
L
Sheth
Rucha
R
Weissleder
Ralph
R
Mahmood
Umar
U
D000465:Algorithms; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000201:enzymology / Q000473:pathology* / Q000601:surgery; D010447:Peptide Hydrolases / Q000378:metabolism; D010534:Peritoneal Neoplasms / Q000175:diagnosis* / Q000201:enzymology / Q000556:secondary*; D019265:Spectroscopy, Near-Infrared / Q000379:methods*
D005456:Fluorescent Dyes; D010447:Peptide Hydrolases