A proof-of-concept methodology to validate the in situ visualization of residual disease using cancer-targeted molecular agents in fluorescence-guided surgery

摘要

Introduction: The clinical need for improved intraoperative tumor visualization has led to thedevelopment of targeted contrast agents for fluorescence-guided surgery (FGS). A keycharacteristic of these agents is their high tumor specificity, which could enable detection of residuallesions that would likely be missed by visual inspection. Here, we examine the utility of a promisingsomatostatin receptor subtype-2 (SSTR2)-targeted fluorescent agent for detecting residual diseasein mouse xenografts using FGS and post-operative histopathological validation.Methods: Mice (n=2) implanted with SSTR2 overexpressing tumors were injected with 2 nmol ofthe dual-labeled somatostatin analog, ~(67)Ga-MMC(IR800)-TOC, and tumors were resected 48 hpost-injection using traditional white light reflectance and palpation. Tumors underwent gammacounting and histopathology analysis. The wide-field FGS imaging platform (OnLume) was used toevaluate residual disease in situ under ambient light representative of an operating room.Results: The tumor was resected with grossly negative margins using conventional inspection andpalpation; however, additional in situ residual disease was found in the tumor cavity using FGSimaging. In situ fluorescent tumor contrast-to-noise ratios (CNRs) were 3.0 and 5.2. Agentaccumulation was 7.72 and 8.20 %ID/g in tumors and 0.27 and 0.20 %ID/g in muscle. Fluorescencepixel values and gamma counts were highly correlated (r = 0.95, P < 0.048). H&E and IHC stainingconfirmed cancer positivity and SSTR2-overexpression, respectively.Conclusion: Our findings demonstrate that the use of clinically relevant fluorescence imaginginstrumentation enhances the evaluation of promising FGS agents for in situ visualization ofresidual disease.