Fluorescence Guided Surgery: Intra-Operative Fluorescent Imaging in Laparoscopic Colonic Tumour Resection and Laparoscopic Cholecystectomy Surgery

Introduction: Fluorescence-guided surgery could improve the operative decision-making process. Near Infrared Cholangiography (NIR-FC) with Indocyanine Green (ICG) in laparoscopic cholecystectomy (LC) may aid visualisation of bile duct anatomy. The c-met transmembrane protein is over-expressed in colorectal cancer (CRC). EMI-137 is a c-Met specific peptide coupled to fluorophore. Methods: Twenty-two participants requiring LC were allocated to four dosing subgroups and received a single intravenous (I.V) dose of ICG before surgery. Biliary anatomy was assessed with NIR-FC and surgeon satisfaction was evaluated. c-Met transcription in HT-29 CRC cells was silenced with targeted SiRNA to demonstrate specificity of EMI-137. A HT-29 xenograft model was developed in female BALB/C mice. EMI-137 (0.18mg/kg) was injected into tail veins and biodistribution analysed by fluorescent imaging. c-Met immunopositivity was graded in matched normal and CRC tissue TMA samples obtained from the MRC CLASICC trial. Nine participants with colon cancer, received IV EMI-137 1-3 hours before laparoscopic tumour resection surgery. Tumour and lymph node (LN) fluorescence were assessed with a fluorescent laparoscope. Immunohistochemistry analysed c-Met expression. Results: A prolonged ICG dosing interval consistently increased structure identification at LC and was preferred by the operating surgeon. c-Met was consistently overexpressed in CRC relative to normal tissue and could be visualised with EMI-137, comparable to indirect c-Met identification methods. EMI-137 uptake in tumour xenografts was observed for 6 hours post-administration. At clinical trial, no serious adverse events related to EMI-137 were reported. Marked background fluorescence was observed in all participants; 4/9 showed mild increase in tumour fluorescence over background; 5/9 had histological LN metastases; no fluorescent LN were detected intraoperatively. All primary tumours (8/8) and malignant LN (15) exhibited moderate-high c-Met protein expression. Conclusion: Prolonged ICG dosing improves visualisation of structures with NIR-FC at LC. EMI-137, binds specifically to the human c-Met protein, is safe but its intra-operative utility is limited by insufficient tumour-to-background ratios.