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Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. There is increasing interest in developing specific markers to serve as predictors of response to sorafenib and to guide targeted therapy. Using a sequencing platform designed to study somatic mutations in a selection of 112 genes (HepatoExome), we aimed to characterize lesions from HCC patients and cell lines, and to use the data to study the biological and mechanistic effects of case-specific targeted therapies used alone or in combination with sorafenib. We characterized 331 HCC cases in silico and 32 paired samples obtained prospectively from primary tumors of HCC patients. Each case was analyzed in a time compatible with the requirements of the clinic (within 15 days). In 53% of the discovery cohort cases, we detected unique mutational signatures, with up to 34% of them carrying mutated genes with the potential to guide therapy. In a panel of HCC cell lines, each characterized by a specific mutational signature, sorafenib elicited heterogeneous mechanistic and biological responses, whereas targeted therapy provoked the robust inhibition of cell proliferation and DNA synthesis along with the blockage of AKT/mTOR signaling. The combination of sorafenib with targeted therapies exhibited synergistic anti-HCC biological activity concomitantly with highly effective inhibition of MAPK and AKT/mTOR signaling. Thus, somatic mutations may lead to identify case-specific mechanisms of disease in HCC lesions arising from multiple etiologies. Moreover, targeted therapies guided by molecular characterization, used alone or in combination with sorafenib, can effectively block important HCC disease mechanisms., Competing Interests: CONFLICTS OF INTEREST MV: Advisory boards, conferences, travel grants from Bayer. MAP has the following COI: Takeda-advisory board. Novartis, Amgen and Roche: Speaker bureau. CRL: Bayer HealthCare advisory board. JC: advisory board and conferences ABBVIE, MBS, GILEAD, JANSSEN, MSD and ROCHE. The other authors declare no conflicts of interest.

The presence of large spontaneous splenorenal shunts (SSRSs) is a risk factor for poor portal vein flow and liver dysfunction. The disconnection of splenorenal shunts by left renal vein (LRV) ligation has been suggested as a potential solution for improving portal flow. We reviewed the hemodynamic consequences of splenorenal shunts in deceased donor liver transplantation and investigated the role of LRV ligation. In 10 patients who underwent liver transplantation at our institution between January 2006 and April 2010, an SSRS was diagnosed preoperatively. Intraoperative portal and hepatic artery flows were measured with a transit time flowmeter. The shunt was disconnected in 6 patients for whom the portal flow after reperfusion was less than or equal to 1200 mL/minute. LRV ligation resulted in significant increases in the portal flow. There were no differences in renal function for the patients who underwent renal vein ligation and the patients who did not undergo ligation. In conclusion, LRV ligation disconnects splenorenal shunts and modulates the portal inflow without any detrimental effects on renal function., (Copyright © 2011 American Association for the Study of Liver Diseases.)