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Virally-Directed Fluorescent Imaging (VFI) Improves Diagnostic Sensitivity in the Detection of Minimal Residual Disease Following Potentially Curative Cytoreductive Surgery
Prasad S. Adusumilli, David P. Eisenberg, Yun Shin Chun, Keun-Won Ryu, Christopher Riedl, Karen Hendershott, Mei-Ki Chan, Leah Ben-Porat, Memorial Sloan-Kettering Cancer Center, New York, NY; Yuman Fong, Memorial Sloan_kettering Cancer Center, New York, NY

Background:
Completeness of cytoreduction is an independent prognostic factor following cure-intended surgery for peritoneal carcinomatosis (PC). Intraoperative detection of the minimal residual disease (MRD) may aid in achieving complete cytoreduction. NV1066, an attenuated herpes simplex virus carrying a gene for green fluorescent protein (GFP) selectively infects cancer cells. NV1066 infected cancer cells express GFP that can be detected by fluorescence laparoscopy. We sought to determine the feasibility of herpes virus-directed fluorescent imaging (VFI) in the intraoperative detection of MRD following cytoreductive surgery for PC.

Methods:
In vitro, gastric (OCUM-2MD3), colon (HT-29), and eleven malignant mesothelioma cell lines were infected with NV1066 at MOIs (multiplicity of infection; ratio of viral particles per cancer cells) of 0.01, 0.1 and 1. Viral infectivity was determined by flow cytometry for GFP, and immunohistochemistry for herpes viral antigen. A PC model was developed in mice (n=24) by injection of OCUM cells into the peritoneal cavity. In mice with established disease, 48 hours following intraperitoneal injection of NV1066, two experienced surgeons resected all visible disease and identified 15 mice free of disease. Four independent observers examined these mice by fluorescent laparoscopy and documented lesions as per the peritoneal cancer index. Selective expression of GFP in tumor tissue was evaluated by histology and RT-PCR for viral gene.

Results:
In vitro, in all cell lines, NV1066 infected and expressed GFP at all MOIs. GFP signal was detected as early as 4-6 hours following infection. GFP signal intensity of infected cells was significantly higher than the autofluorescence of normal cells (170 - 540 fold). In vivo, tumor nodules < 1 mm were identified by GFP fluorescence. Following resection of all visible disease, 13/15 mice were found to have MRD identified by green fluorescence in more than two sites; the most common sites being intestinal serosa and mesentery (45%), pelvis (43%), stomach (37%), and peritoneal surface (27%) (p<0.01). Specificity of NV1066 infection of tumor nodules was confirmed by histology and by RT-PCR.

Conclusion:
We have demonstrated that virally-directed fluorescent imaging (VFI), a novel molecular imaging technology, can be used for real-time visualization of macroscopically undetectable tumor nodules following cytoreductive surgery, thereby improving the completeness of cure-intended resection.


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