LOXL2 is a prognosis biomarker and a potential therapeutic target in intrahepatic cholangiocarcinoma

E-AHPBA: FREE PRIZE PAPERS e FREE PAPERS 18 LIVER HCC TRANSPLANT F3C4 (FRIDAY 24TH APRIL 2015) LIVER 344 THE USE OF AN ABSORBABLE EMBOLIZATION MATERIAL FOR PORTAL VEIN EMBOLIZATION TO INDUCE LIVER REGENERATION IN A RABBIT MODEL F. Huisman, K. P. van Lienden, J. Verhei, J. C. M. Meijers and T. M. van Gulik Academic Medical Center, The Netherlands Aims: Unilateral portal vein embolization (PVE) is used to increase future remnant liver in patients requiring extended resections. Reversible PVE is of interest when generating sufficient hypertrophy while preserving embolized liver lobe. The concept of reversible PVE requires an absorbable embolization material. The aim of this study was to modulate lysis time of a fibrin-glue (FG) based embolization material (EM) while using different concentrations of Aprotinin (which inhibits fibrinolysis and thereby delays absorption of FG). Methods: We performed in vitro experiments to evaluate the clot lysis time under influence of different concentrations of aprotinin in combination with thrombin/fibrinogen. With these results, we performed PVE of the cranial liver lobe in 29 rabbits, divided into 6 groups with the following concentrations of Aprotinin: FG+1000KIU, 700KIU, 500KIU, 300KIU, 150 KIU and FG-Aprotinin. The rabbits were sacrificed after 7 (n = 19) and 49 days (n = 10), respectively. CT volumetry of non-embolized lobe (NELVol), liver damage parameters, liver-to-body weight ratio of NEL were evaluated. Results: The in vitro experiments showed a threshold concentration of 200 KIU Aprotinin above which the clot was permanent. Data were compared with series using a permanent EM, i.e. polyvinyl alcohol + coils (PVAc). FG-Aprot and FG+150KIU were completely absorbed in 7 days without an adequate hypertrophy response of the NEL. The FG+1000KIU and 700KIU groups behaved as a permanent EM. The hypertrophy response in these rabbits was not different from the PVAc group. The groups FG+500KIU and 300KIU were sacrificed at day 49. In the group FG+500KIU, 4 out of 5 animals showed recanalization of the embolized portal branches. In the group with FG+300KIU, 3 out of 5 animals showed recanalization. Both groups showed hypertrophy response rates not different from the PVAc group. Conclusions: Fibrin glue with the concentration of 500KIU Aprotinin resulted in 80% reversible embolization with a hypertrophy response comparable to permanent material.

BILIARY 442 LOXL2 IS A PROGNOSIS BIOMARKER AND A POTENTIAL THERAPEUTIC TARGET IN INTRAHEPATIC CHOLANGIOCARCINOMA D. Bergeat1, A. Fautrel2, B. Turlin1, A. Merdrignac1, M. Rayar1, B. Meunier1, B. Clement2, K. Boudjema1, C. Coulouarn2 and L. Sulpice1 1 Hospitalier Universitaire, Rennes, France; 2IUMR991 Liver Metabolisms and Cancer, USA

HPB 2016, 18 (S2), e863ee866

Aims: Intrahepatic cholangiocarcinoma (ICC) is associated with a poor prognosis related to early recurrence especially in the remnant liver following surgery. ICC exhibit a dense desmoplastic stroma which plays a pivotal role in ICC aggressiveness. Thus, analyzing gene deregulation in the stroma of ICC may help to identify new biomarkers and promising therapeutic targets. The aim of this study was to evaluate the clinical relevance of the matrix-remodeling enzyme lysyl oxidase-like 2 (LOXL2) expression in ICC. Methods: LOXL2 expression was evaluated at mRNA level in microdissected tumoral stroma (TS) and in non tumoral fibrous tissue (NFT): by gene expression profiling, n = 10 (testing set), and by qPCR, n = 6 (validating set). Secondly, LOXL2 expression was confirmed by immunohistochemistry (IHC) on a tissue micro array (TMA) containing an independent cohort, n = 80. The relationship between LOXL2 expression and survival was assessed by univariate and multivariate analyses. Results: LOXL2 was up regulated at mRNA level in TS, both in the testing set as in the validating set (P < 0.01). These results were confirmed at protein level, showing a significantly higher immunostaining in TS (P < 0.01). Univariate analysis revealed that LOXL2 staining was correlated with poor overall survival (OS) and disease free survival (DFS) (P < 0.01). Moreover, high expression of LOXL2 was an independent prognostic marker of OS (HR = 5.29, IC95%(1.71e16.3), P < 0.01) as well as DFS (HR = 5.55, IC95%(2.14e14.37), P < 0.01). Conclusions: Our study provides new arguments for the pivotal role of the stroma in ICC progression and reveals a new prognostic marker. LOXL2 over expression was directly correlated with the aggressiveness of ICC and should be now routinely performed by IHC. Moreover, targeting LOXL2 by neutralizing antibodies might represent an appealing strategy, which should be explorer in the context of personalized therapy.

BILIARY 612 DEVELOPMENT OF A PREOPERATIVE RISK SCORE FOR POSTOPERATIVE MORTALITY AFTER LIVER RESECTION FOR PRESUMED PERIHILAR CHOLANGIOCARCINOMA J. K. Wiggers1, B. Groot Koerkamp2, K. P. Cieslak1, A. Doussot3, P. J. Allen3, M. G. Besselink1, O. R. Busch1, M. I. D’Angelica3, R. P. DeMatteo3, D. J. Gouma1, T. P. Kingham3, T. M. van Gulik1 and W. R. Jarnagin3 1 Academic Medical Center Amsterdam; 2Erasmus Medical Center, The Netherlands; 3Memorial Sloan Kettering Cancer Center, USA Aims: Liver surgery for PHC is associated with postoperative mortality ranging from 5% to 18%. To develop a preoperative risk score to predict 90-day mortality after liver resection for presumed perihilar cholangiocarcinoma (PHC). Methods: Consecutive patients submitted to major liver resection for presumed PHC between 1997 and 2014 at two