Shintaro Kuroda

Ischemia–reperfusion injury in patients with fatty liver and the clinical impact of steatotic liver on hepatic surgery.

Hepatic steatosis is one of the most common hepatic disorders in developed countries. The epidemic of obesity in developed countries has increased with its attendant complications, including metabolic syndrome and non-alcoholic fatty liver disease. Steatotic livers are particularly vulnerable to ischemia/reperfusion injury, resulting in an increased risk of postoperative morbidity and mortality after liver surgery, including liver transplantation. There is growing understanding of the molecular and cellular mechanisms and therapeutic approaches for treating ischemia/reperfusion injury in patients with steatotic livers. This review discusses the mechanisms underlying the susceptibility of steatotic livers to ischemia/reperfusion injuries, such as mitochondrial dysfunction and signal transduction alterations, and summarizes the clinical impact of steatotic livers in the setting of hepatic resection and liver transplantation. This review also describes potential therapeutic approaches, such as ischemic and pharmacological preconditioning, to prevent ischemia/reperfusion injury in patients with steatotic livers. Other approaches, including machine perfusion, are also under clinical investigation; however, many pharmacological approaches developed through basic research are not yet suitable for clinical application.

Fatty liver creates a pro-metastatic microenvironment for hepatocellular carcinoma through activation of hepatic stellate cells

Fatty liver (FL) is associated with development of hepatocellular carcinoma (HCC). However, whether FL itself promotes the progression of HCC is unclear. We recently found that hepatic stellate cells (HSCs) were prominently activated in the steatotic liver. Here, we investigated whether steatotic livers promote HCC progression and whether HSCs of steatotic liver are associated with HCC progression. We implanted rat HCC cells into diet‐induced steatotic livers in rats via portal vein injection. Thereafter, HSCs and HCC cells were co‐implanted subcutaneously into nude rats. Migration and proliferation of HCC cells were measured, and activation of ERK and Akt in these cells was determined by western blotting. Chemokines secreted from HSCs and HCC cells were also evaluated by ELISA. Steatotic livers significantly promoted HCC metastasis compared with non‐steatotic livers. Additionally, co‐implantation of HCC cells with HSCs from steatotic livers produced significantly larger tumors in recipient rats as compared to those induced by HCC cells co‐implanted with HSCs from normal livers (NLs). HSCs isolated from steatotic livers, compared with HSCs isolated from NLs, secreted greater amounts of interleukin‐1α, vascular endothelial growth factor, and transforming growth factor‐β. These cytokines may enhance the proliferation and migration of HCC cells by increasing the phosphorylation of ERK and Akt in HCC cells. Moreover, we noted that the Rho‐kinase inhibitor deactivated activated HSCs and attenuated HCC progression. In conclusion, the rat steatotic liver microenvironment favors HCC metastasis, and this effect appears to be promoted by activated HSCs in the steatotic liver.

Treatment strategy for early hepatocellular carcinomas: Comparison of radiofrequency ablation with or without transcatheter arterial chemoembolization and surgical resection

The preferred choice between surgical treatment and radiofrequency ablation (RFA) for the treatment of small resectable hepatocelluar carcinoma (HCC) has become a subject for debate.

Rho inhibitor prevents ischemia–reperfusion injury in rat steatotic liver

BACKGROUND & AIMS Hepatic stellate cells are thought to play a role in modulating intrahepatic vascular resistance based on their capacity to contract via Rho signaling. We investigated the effect of a Rho-kinase inhibitor on ischemia-reperfusion injury in the steatotic liver. METHODS Steatotic livers, induced by a choline-deficient diet in rats, were subjected to ischemia-reperfusion injury. Hepatic stellate cells isolated from steatotic livers were analyzed for contractility and Rho signaling activity. The portal pressure of the perfused rat liver and the survival rate after ischemia-reperfusion were also investigated. RESULTS Hepatic stellate cells from steatotic livers showed increased contractility and upregulation of Rho-kinase 2 compared with those from normal livers. Furthermore, endothelin-1 significantly enhanced the contractility and phosphorylation level of myosin light chain and cofilin in hepatic stellate cells isolated from steatotic livers. A specific Rho-kinase inhibitor, fasudil, significantly suppressed the contractility and decreased the phosphorylation levels of myosin light chain and cofilin. Serum levels of endothelin-1 were markedly increased after IR in rats with steatotic livers, whereas fasudil significantly decreased endothelin-1 serum levels. Rats with steatotic livers showed a significant increase in portal perfusion pressure after ischemia-reperfusion and a significant decrease in survival rate; fasudil treatment significantly reduced these effects. CONCLUSIONS Activation of Rho/Rho-kinase signaling in hepatic stellate cells isolated from steatotic livers is associated with an increased susceptibility to ischemia-reperfusion injury. A Rho-kinase inhibitor attenuated the activation of hepatic stellate cells isolated from steatotic livers and improved ischemia-reperfusion injury in steatotic rats.

Significance of platelet count in the outcomes of hepatectomized patients with hepatocellular carcinoma exceeding the Milan criteria.

BackgroundThe appropriate treatment strategy for advanced hepatocellular carcinoma (HCC) that does not meet the Milan criteria (MC) is unclear. The aim of this study was to determine the significance of surgical treatment for such patients.Study designFrom January 1990 to December 2007, 151 patients with HCC exceeding MC who underwent curative surgical treatment were enrolled. Survival and recurrence data and clinicopathological factors were examined. Prognostic factors were analyzed to identify those that contributed to improved surgical outcomes retrospectively.ResultsAfter the initial hepatectomy, the overall 3-, 5-, and 10-year survival rates were 73%, 55%, and 33%, respectively, for the 151 patients in this study; the corresponding disease-free survival rates were 36%, 30%, and 17%, respectively. A platelet count under 105/mm3, multiple tumors, and liver cirrhosis of noncancerous tissue were adverse survival and disease-free survival factors by univariate analysis. Platelet count was an independent prognostic factor by multivariate analysis. The 3-, 5-, and 10-year overall survival rates of HCC exceeding MC in patients whose platelet count was 105/mm3 or greater reached 76%, 65%, and 44%, respectively, and were comparable with those that met MC (86%, 68%, and 37%, respectively).ConclusionsHepatectomy for patients with advanced HCC exceeding MC improves survival, especially for patients with a sufficiently high platelet count, although recurrence rates after initial hepatectomy are high.

Suppression of hepatocellular carcinoma recurrence after rat liver transplantation by FTY720, a sphingosine-1-phosphate analog.

Background. Although the outcome of liver transplant patients with hepatocellular carcinoma (HCC) has improved with the introduction of strict criteria, tumor recurrence still remains a significant problem. Sphingosine-1-phosphate (S1P) is a phospholipid mediator that can induce diverse cellular responses, such as proliferation, migration, adhesion, and cell-rounding, in cancer cells. We investigated whether FTY720, a S1P analog, suppresses tumor recurrence after experimental liver transplantation in a rat HCC model. Methods. HCC-bearing rats were subjected to orthotropic liver transplantation. HCC cells were analyzed for cell migration, proliferation, and S1P receptors. Results. FTY720 induced the down-regulation of the S1P-1 receptor of HCC cells and suppressed both cancer cell migration and proliferation. FTY720 also suppressed mitogen-activated protein kinase phosphorylation. The suppression of tumor recurrence after liver transplantation and a significant prolongation of survival were observed in the FTY720-treated rats, in comparison with FTY720-untreated rats. Conclusion. FTY720 suppresses the invasiveness and proliferation of HCC through a down-regulating S1P-1 receptor to suppress the recurrence of HCC after liver transplantation; FTY720 may be used as a new antimetastatic agent for the prevention of tumor recurrence after liver transplantation.

Prediction of long-term survival by using the Glasgow Prognostic Score in patients with hepatocellular carcinoma after liver transplantation.

This study aimed to validate the prognostic value of the Glasgow Prognostic Score (GPS) in patients who underwent living donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC).

Evaluation of the risk factors and prognostic factors of hepatectomy for hepatocellular carcinoma in patients aged 80 years or more

The risk factors of postoperative complications and prognostic factors of hepatocellular carcinoma in patients aged ≥80 years have not yet been defined. We aimed to identify these factors in this patient population.

Rho‐kinase inhibitor targeting the liver prevents ischemia/reperfusion injury in the steatotic liver without major systemic adversity in rats

Rho‐kinase (ROCK) inhibitors improve liver blood flow after ischemia/reperfusion (IR) injury, especially in the setting of steatosis, by decreasing the resistance of intrahepatic microcirculation through hepatic stellate cell (HSC) relaxation. However, the systemic administration of ROCK inhibitors causes severe hypotension; therefore, liver‐specific ROCK inhibition is required. Here, we tested vitamin A (VA)–coupled liposomes carrying the ROCK inhibitor Y‐27632 for targeted HSCs in steatotic rats. Rat livers with steatosis induced by a choline‐deficient diet were subjected to IR injury. The delivery site and effect of the ROCK inhibitor were investigated. After liposomal Y‐27632 injection, the survival rate after IR, the liver blood flow, the portal perfused pressure, and the hemodynamics were investigated. Immunohistochemical studies showed VA–coupled liposome accumulation in livers. Liposomal Y‐27632 was 100‐fold more effective in inhibiting HSC activation than free Y‐27632. Liposomal Y‐27632 improved the survival rate after IR injury, the liver blood flow, and the portal perfusion pressure without severe hypotension. In contrast, untargeted Y‐27632 elicited severe systemic hypotension. We conclude that VA–coupled liposomes carrying the ROCK inhibitor yield enhanced drug accumulation in the liver and thus mitigate IR injury in the steatotic liver and reduce major systemic adversity. Liver Transpl 21:123‐131, 2015.

External Validation of Two Nomograms for Predicting Patient Survival After Hepatic Resection for Metastatic Colorectal Cancer

BackgroundTwo nomograms are available for predicting patient survival after hepatic resection for metastatic colorectal cancer (CRC). However, they have not been externally validated using other databases, and so their universal applicability has not been established. We aimed to examine the validity of these nomograms for predicting patient survival after hepatic resection for metastatic CRC in different institutions.MethodsWe analyzed the cases of 113 patients who underwent hepatic resection for metastatic CRC at Hiroshima University Hospital between 1995 and 2006. In this patient set, we assessed the predictive value of the Kattan nomogram of the Memorial Sloan-Kettering Cancer Center (MSKCC) (United States) and the Kanemitsu nomogram from the Aichi Cancer Center (Japan). The concordance index was used as an accuracy measure for comparing these two nomograms. The predictive accuracy of these nomograms was compared with that of conventional predictive models.ResultsThe 3-, 5-, and 10-year overall survival rates in our cohort were 66.3%, 52.4%, and 42.7%, respectively. The concordance indexes of the pre- and postoperative Kanemitsu nomogram and that of the Kattan nomogram were 0.70, 0.69, and 0.68, respectively. These values were higher than those obtained using other models for hepatic metastatic CRC, including the clinical risk score of the MSKCC and the grading system of the Japanese Society for Cancer of the Colon and Rectum.ConclusionsThe high predictive accuracy of both nomograms shows that these predictive tools can be used in different institutions. Patient counseling and adjuvant therapy decision-making should benefit from use of these nomograms.