Objective: To investigate risk factors associated with mortality in cholangiocarcinoma patients receiving surgical treatment in Thailand's endemic area and their survival rate. Materials and Methods: Medical records of patients with histologically confirmed cholangiocarcinoma, who underwent surgical treatment at Sanpasitthiprasong Regional Hospital from October 1, 2013 to October, 31 2015, were retrospectively included. Patients' vital status (death/alive) and date of death were obtained from the Interior Ministry's death certificate. Cox proportional hazard regression was used to examine factors associated with mortality. Results: Out of 295 patients with cholangiocarcinoma (CCA), 180(58%) were intrahepatic CCA, 86(28%) were perihilar CCA, and 29 (9%) were distal CCA. Three groups were homogenous in terms of age and gender. Most of our patients referred with abdominal pain (63%), especially those who were intrahepatic CCA (77%). However, almost 80% of the perihilar CCA and distal CCA patients came with jaundice. Tumor markers (CEA and CA19-9) were not different between groups p=0.74 and p=0.43 respectively. Median survival of patients with intrahepatic CCA, perihilar CCA, and distal CCA patients was 14.6, 14.2, and 14.0 months, respectively. Factors independently associated with mortality in intrahepatic CCA patients were number and size of tumors and presence of perineural invasion (Hazard ratio (HR) 1.
Background: Resection margin status is the most important prognostic factor in resected perihilar cholangiocarcinoma (pCCA). Although the impact of ductal margin (DM) was reported in many studies, the influence of radial margin (RM) is unclear. This study aims to investigate the incidence and the effect of positive RM on survival. Methods: Patients with pCCA who underwent curative resection between October 2013 to December 2018 were retrospectively reviewed. Resection margin status were divided into negative resection margin (R0) and positive resection margin (R1); positive RM alone (RM+) and positive DM with or without positive RM (DM+). Results: Of the 170 pCCA patients, 63 (37%) had R1 margin. Among 63 R1 patients; 18 (28.6%) had positive DM alone, 20 (31.7%) had positive RM alone and 25 (39.7%) had both positive DM and RM. The R1 patients had a significantly greater number of LN metastases and advanced tumor staging than R0 patients, however, there was no difference between the RM+ and DM+ patients. In contrast, the RM+ patients had more combined vascular resection than the DM+ patients. The median survival time of patients with RM+ was significantly poorer than R0 patients (13.8 vs. 24.7 months; p < 0.001, respectively) and similar to the DM+ patients (9.1 months, p = 0.561). In multivariable analysis, positive resection margin and LN metastasis were independent prognostic factors. Conclusions: Positive resection margin remains the most important prognostic factors and positive RM is common in these patients. Positive RM also had a comparable effect on survival as positive DM. As a result, in pCCA, surgical resection should target both RM and DM.
Cholangiocarcinoma (CCA) is an architecturally complex tumour with high heterogeneity. Discovery at later stages makes treatment challenging. However, the lack of early detection methodologies and the asymptomatic nature of CCA make early diagnosis more difficult. Recent studies revealed the fusions in Fibroblast Growth Factor Receptors (FGFRs), a sub-family of RTKs, as promising targets for targeted therapy for CCA. Particularly, FGFR2 fusions have been of particular interest, as translocations have been found in approximately 13% of CCA patients. Pursuing this, Pemigatinib, a small-molecule inhibitor of FGFR, became the first targeted therapy drug to be granted accelerated approval by the FDA for treating CCA patients harbouring FGFR2 fusions who have failed first-line chemotherapy. However, despite the availability of Pemigatinib, a very limited group of patients benefit from this treatment. Moreover, as the underlying mechanism of FGFR signalling is poorly elucidated in CCA, therapeutic inhibitors designed to inhibit this pathway are prone to primary and acquired resistance, as witnessed amongst other Tyrosine Kinase Inhibitors (TKIs). While acknowledging the limited cohort that benefits from FGFR inhibitors, and the poorly elucidated mechanism of the FGFR pathway, we sought to characterise the potential of FGFR inhibitors in CCA patients without FGFR2 fusions. Here we demonstrate aberrant FGFR expression in CCA samples using bioinformatics and further confirm phosphorylated-FGFR expression in paraffinised CCA tissues using immunohistochemistry. Our results highlight p-FGFR as a biomarker to guide FGFR-targeted therapies. Furthermore, CCA cell lines with FGFR expression were sensitive to a selective pan-FGFR inhibitor, PD173074, suggesting that this drug can be used to suppress CCA cells irrespective of the FGFR2 fusions. Finally, the correlation analysis utilising publicly available cohorts suggested the possibility of crosstalk amongst the FGFR and EGFR family of receptors as they are significantly co-expressed. Accordingly, dual inhibition of FGFRs and EGFR by PD173074 and EGFR inhibitor erlotinib was synergistic in CCA. Hence, the findings from this study provide support for further clinical investigation of PD173074, as well as other FGFR inhibitors, to benefit a larger cohort of patients. Altogether, this study shows for the first time the potential of FGFRs and the importance of dual inhibition as a novel therapeutic strategy in CCA.
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