title: Cholangiocarcinoma: Validation of Surgical Selection and Prognostic Methodologies
Creators: name: Bird, Nicholas
Publisher: name: University of Liverpool Repository
Year: 2022

description: Background: Cholangiocarcinoma is a rare cancer with a poor prognosis. Radical surgical resection is the only option for curative treatment. Optimal determination of resectability is required so that patients can be stratified into operative or chemotherapeutic treatment cohorts. This thesis sought to validate and augment contemporaneous resectability systems in a large independent European validation cohort. Numerous putative prognostic histo-pathological and demographic characteristics have been reported to effect Overall Survival (OS). This thesis sought to validate a variety of histopathological, clinical and radiological systems and to determine the clinical prognostic utility of these systems. Improved prognostication through biomarkers has been suggested, and direct analysis of tumour may allow the development of a more personalised therapeutic approach. This thesis sought to define the utility of 2 potential prognostic biomarkers, hENT1 and Ki67, via direct immunohistochemical analysis of resected and biopsied patient specimens. Methods: Standardised meta-analytical methods were utilised to stratify clinical and biomarker prognostic co-variates. These clinical and biomarker co-variates were then assessed and validated within the context of a large, noncontinuous, European, contemporaneous registry of surgically resected cholangiocarcinoma patients at Aintree University Hospital between June 2006 – February 2017. Forty-four resected patient’s specimens and 58 non-matched biopsy specimens were acquired from CellNass. Two Tissue Matched Array’s (TMA’s) were constructed and immunohistochemical assessment of hENT1 and Ki67 abundance was undertaken. Results: Regression analyses identified that BC score, MSKCC score, age at diagnosis and left artery involvement were all significant independent predictor’s of resectability. The meta-analysis highlighted the significance of clinical prognostic variables affecting OS. The significant prognostic factors which had an effect upon OS were; ‘T’ status, lymph node involvement, microvascular invasion, peri-neural invasion, tumour differentiation and age. Numerous pre and post-operative co-variates retained prognostic utility when assessed within the validation cohort. Meta-analytical methods demonstrated that Ki67 and hENT1 biomarkers had significant prognostic effects for immunohistochemically assessed patients. Immunohistochemical assessment of the TMA specimens was undertaken. hENT1 and Ki67 abundance did not demonstrate significant survival correlates. However, an alternative commercially available hENT1 antibody was determined to demonstrate selectivity and utility in accurately assessing hENT1 abundance in resected peri-hilar cholangiocarcinoma specimens. 17 Conclusion: This thesis externally validated the utility of standardised scoring systems for pre-operatively stratifying patients for potential resection. It has also provided a potential novel anatomical co-variate which could be used to augment scoring systems to increase predictive accuracy. This thesis validated standardised clinical prognostic systems and provided novel and augmented alternative systems which explained variability in OS in the validation cohort. This thesis has validated an alternative commercially available hENT1 antibody which can accurately determine hENT1 abundance in resected peri-hilar cholangiocarcinoma specimens.