The impact of post-hepatectomy liver failure on long-term survival after liver resection for perihilar cholangiocarcinoma.

BACKGROUND: Although post-hepatectomy liver failure (PHLF) can accurately predict short-term mortality of liver resection for perihilar cholangiocarcinoma (pCCA), its significance in predicting long-term overall survival (OS) is still uncertain. METHODS: Retrospective analysis was performed on patients with pCCA who underwent liver resection between October 2013 and December 2018. The patients were divided into 3 groups; No PHF, PHLF (all grade) and grade B/C PHLF according to The International Study Group of Liver Surgery (ISGLS) criteria. RESULTS: A total of 177 patients were enrolled, 65 (36.7%) had PHLF; 25 (14.1%) had grade A, and 40 (22.6%) had grade B/C. Prior to surgery, patients with PHLF showed significantly greater bilirubin levels and CA 19-9 level than those without (11.5 vs 6.7 mg/dL, p = 0.002 and 232.4 vs 85.9 U/mL, p = 0.005, respectively). Additionally, pre-operative future liver remnant volume in PHLF group was lower than no PHLF group significantly (39.6% vs 43.5%, p = 0.006). Major complication and 90-day mortality were higher in PHLF group than no PHLF group (69.2% vs 20.5%, p < 0.001 and 29.2% vs 3.6%, p < 0.001, respectively). The OS in both grade A PHLF and grade B/C PHLF was significantly worse compared to no PHLF, with median survival times of 8.4, 3.3, and 19.2 months, respectively (p < 0.001 and p < 0.001, respectively). Multivariable analysis revealed that PHLF was independently prognostic factor for long-term survival. CONCLUSION: To achieve negative resection margin, the surgical resection in pCCA was aggressive, however this increased the risk of PHLF, which also affects the OS. Consequently, it is necessary for establishing a balance between aggressive surgery and PHLF.

Survival outcomes of surgical resection in perihilar cholangiocarcinoma in endemic area of O. Viverrini, Northeast Thailand.

BACKGROUND: Perihilar cholangiocarcinoma (pCCA) is an intractable malignancy and remains the most challenge for surgeon. This study aims to investigate survival outcomes and prognostic factors in pCCA patient. METHODS: From October 2013 to December 2018, 240 consecutive patients with pCCA underwent surgical exploration were retrospectively reviewed. The clinicopathological parameters and surgical outcomes were extracted. Patients were divided into two groups: unresectable and resectable group. The restricted mean survival time between two groups were analyzed. Factors associated with overall survival in resectable group were explored with multivariable Cox regression analysis. RESULTS: Of the 240 patients, 201 (83.75%) were received surgical resection. The survival outcomes of resectable group were better than unresectable group significantly. The restricted mean survival time difference were 0.5 (95%CI 0.22-0.82) months, 1.8 (95%CI 1.15-2.49) months, 4.7 (95%CI 3.58-5.87) months, and 9.1 (95%CI 7.40-10.78) months at four landmark time points of 3, 6, 12 and 24 months, respectively. The incidence of major complications and 90-day mortality in resectable group were 35.82% and 11.44%, respectively. Multivariable analysis revealed that Bismuth type IV (HR:4.43, 95%CI 1.85-10.59), positive resection margin (HR:4.24, 95%CI 1.74-10.34), and lymph node metastasis (HR:2.29, 95%CI 1.04-4.99) were all independent predictors of long-term survival. For pM0, R0 and pN0 patients, the median survival time was better than pM0, R1 or pN1/2 patients and pM0, R1 and pN1/2 patients (32.4, 10.4 and 4.9 months, respectively; p < 0.001) CONCLUSION: Surgical resection increased survival in pCCA. Bismuth type IV, positive resection margin and lymph node metastasis were independent factors for long-term survival.

Targeting FGFRs Using PD173074 as a Novel Therapeutic Strategy in Cholangiocarcinoma.

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.

Survival of Patients with Cholangiocarcinoma Receiving Surgical Treatment in an O. viverrini Endemic Area in Thailand: A Retrospective Cohort Study.

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) 1.09[1.03 - 1.15], 1.07[1.02 - 1.13], and 2.09 [1.28 - 3.39], respectively). In perihilar CCA patients, having positive lymph nodes and resection status were independently associated with mortality. Compared to R0 resection, R1, R2, and no resection of perihilar CCA were associated with a 2-, 8- and 4-fold increase in the risk of mortality (HR 2.17 (0.99 - 4.78), 7.97 (3.22 - 19.71), and 4.21 (0.51 - 34.82), respectively). CONCLUSION: CCA patients in this endemic area had fairly poor survival. Factors associated with mortality in intrahepatic CCA were number and size of tumors and perineural invasion. However, risk factors for perihilar CCA included positive lymph nodes and resection status.