Early Experience With Laparoscopic Common Bile Duct Exploration at a Non-Academic Teaching Hospital

Abstract

The emergence of contrast-enhanced ultrasound (CEUS) and microbubble (MB) platforms capable of delivering payloads to solid cancers has expanded the arena of targeted molecular therapies. Tumour vascular endothelial ligands are an integral component of this approach to target MBs to tumour vasculature. With its aggressive nature and lack of effective adjunctive treatments, we evaluated Perihilar Cholangiocarcinoma (PH-CCA) as a candidate for this approach. The expression and impact of a panel of vascular endothelial markers in PH-CCA was assessed and CD105 based MB targeting analysed in a preclinical model. Methods: CD31, CD105 and Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) expression was assessed by tumour Immunohistochemistry (IHC) using microvessel density (MVD) measurements in a cohort of 54 patients who underwent PH-CCA resection from 2000e2010. Invitro flow assays were conducted to quantify CD105-MB targeting on SVR endothelial cells. CD105-MB tumour binding in-vivo was analysed using CEUS in BALB/c nude mice bearing subcutaneous extra-hepatic CCA (TFK-1 and EGI-1) xenografts. Results: Median patient age was 57.6 years and median tumour size 65 mm. T2 tumours formed the majority (54%). Nodal metastases occurred in 54% cases. None of the endothelial markers were significantly associated with nodal/systemic metastases. Cox regression analysis identified tumour size >47 mm and CD105 MVD >31 as independent predictors of overall survival (p <0.0001 and 0.003 respectively). CD105 was however expressed by hepatic sinusoids. Flow assay data revealed significantly higher endothelial cell binding of CD105-MB compared to isotype control (p = 0.019). Targeted molecular imaging in human CCA xenografts showed higher tumour endothelial binding of CD105-MB compared to control MBs. Conclusions: CD105 holds promise as a prognostic endothelial marker in PH-CCA. Further validation of these pre-clinical CCA models using CD105-MB is underway towards potential translation into clinical application.