Varying impact of lenvatinib or sorafenib therapy on skeletal muscle loss in patients with hepatocellular carcinoma.

BACKGROUND: Lenvatinib and sorafenib are key therapeutic agents for hepatocellular carcinoma. However, there are no useful biomarkers for selecting molecular-targeted agents (MTAs). Skeletal muscle volume is associated with the clinical outcomes in these patients. We investigated the effects of lenvatinib and sorafenib on the skeletal muscles of patients with HCC. METHODS: We evaluated the impact of skeletal muscle changes over a 3-month period for each MTA (n = 117; lenvatinib/sorafenib, 45/72). The skeletal muscle mass index (SMI) was measured at the third lumbar vertebra. Furthermore, we evaluated the direct effect of each MTA on primary human skeletal muscle cells by estimating muscle protein synthesis using western blot analysis. RESULTS: The median change in SMI was -0.7% (p = 0.959) and -5.9% (p <0.001) for the lenvatinib and sorafenib groups, respectively. Sorafenib had a greater effect on skeletal muscle loss than lenvatinib (p < 0.001). Additionally, SMI significantly decreased in the sorafenib group regardless of initial skeletal muscle volume (p < 0.001), whereas no significant differences were observed in the lenvatinib group. Sorafenib therapy (odds ratio [OR], 2.98; p = 0.023) and non-muscle depletion (OR, 3.31; p = 0.009) were associated with a decreased SMI. In vitro analysis showed that sorafenib negatively affected muscle synthesis compared to lenvatinib. CONCLUSIONS: Sorafenib may have a more negative effect on skeletal muscle than lenvatinib.

Double cancer of primary hepatic angiosarcoma and hepatocellular carcinoma treated with atezolizumab plus bevacizumab.

AIM: Primary hepatic angiosarcoma (PHA) is extremely rare, and its imaging findings are similar to those of other liver tumors including hepatocellular carcinoma (HCC). Here, we report a case of hepatitis C virus (HCV)-related HCC followed by PHA that showed remarkable clinical response to atezolizumab plus bevacizumab (Atezo/Bev) therapy. CASE PRESENTATION: A 78-year-old man with recurrent HCC had a liver tumor with lymphadenopathy. Although considered as HCC recurrence, microscopic examination of the resected liver and lymph node showed PHA. Three months later, a solitary lung nodule was newly detected and subsequently resected. The pathological diagnosis was poorly differentiated HCC. Therefore, the patient was finally diagnosed with double cancer of PHA and HCC. Thereafter, he developed a new liver tumor with lymphadenopathy and received Atezo/Bev therapy. Liver tumor biopsy was carried out before the treatment. The pathological diagnosis was angiosarcoma. The patient showed a partial response after two courses of Atezo/Bev therapy. CONCLUSION: To our best knowledge, this report is the first case to present HCV-related HCC followed by PHA and to show that Atezo/Bev therapy is beneficial for PHA.

Screening for portopulmonary hypertension using computed tomography-based measurements of the main pulmonary artery and ascending aorta diameters in patients with portal hypertension.

AIM: This study aimed to demonstrate the feasibility of identifying candidates of portopulmonary hypertension (PoPH) from general portal hypertension patients based on chest computed tomography (CT) results. METHODS: One hundred and thirty patients with portal hypertension who had undergone interventional radiology therapies at our hospital between August 2011 and July 2021 were included, and preoperative clinical data were collected. Suspicious PoPH was defined as main pulmonary artery diameter (mPA-D) ≥ 29 mm or the ratio of mPA-D to ascending aorta diameter (mPA-D/aAo-D) ≥ 1.0, and probable PoPH as mPA-D ≥ 33 mm based on the chest CT. Prevalence of suspicious and probable PoPH was evaluated, and the differences in clinical characteristics of each population were compared. RESULTS: Overall, 29 (22.3%) and 5 (3.8%) patients were categorized as suspicious and probable PoPH, respectively. Univariate analyses revealed that female sex, higher shortest diameter of inferior vena cava, presence of portosystemic shunts ≥ 5 mm, and lower blood urea nitrogen levels were significantly associated with suspicious PoPH (p < 0.05). Multivariate analyses identified all four factors as significantly independent determinants of suspicious PoPH (p < 0.05). In addition, among the population of suspicious PoPH, there were significant differences in seven parameters, including total bilirubin levels and spleen volume between patients with and without probable PoPH (p < 0.05). However, no significant independent indicators of probable PoPH were found. CONCLUSIONS: CT-based measurements of mPA-D and mPA-D/aAo-D have the potential to screen patients with suspicious PoPH in clinical practice focused on portal hypertension.

Significant improvement in portal-systemic liver failure symptoms and successful management of portal-splenic venous hemodynamics by the combination of interventional radiology and pharmacotherapy.

This study describes a case of hepatitis C virus-related decompensated cirrhosis with portal-systemic liver failure and refractory encephalopathy. It was successfully managed with a combination of interventional radiology and pharmacotherapy, to improve hepatic function, including hyperammonemia and to control portal-splenic venous hemodynamics with hepatic venous pressure gradient (HVPG) monitoring. A man in his late 50s presented with a Child-Pugh score of 13, Model for End-Stage Liver Disease-sodium (MELD-Na) score of 19 and blood ammonia level of 185 µg/dL. He underwent balloon-occluded retrograde transvenous obliteration (BRTO) followed by partial splenic embolization (PSE) and non-selective beta-blocker (NSBB) administration. BRTO induced drastic changes in the portal-splenic venous hemodynamics, resulting in dramatically improved hepatic function and reduced hyperammonemia. However, the procedure resulted in increased HVPG from 13.6 mmHg at baseline to 23.5 mmHg at 1-month post-BRTO, accompanied by ascites retention and development of portal hypertensive gastropathy. Thereafter, PSE was performed, followed by NSBB administration, to control the elevated portal venous pressure following BRTO. Postoperatively, the patient's ascites and portal hypertensive gastrophy improved after splenic artery embolization, which eventually disappeared after the additional administration of NSBBs 1 month later. The HVPG finally decreased to 16.9 mmHg; the Child-Pugh score, MELD-Na score and blood ammonia level improved to 7, 11 and 22 µg/dL, respectively, after all therapies. BRTO significantly improved the symptoms of portal-systemic liver failure with refractory encephalopathy. PSE and NSBB administration could contribute to additional amelioration of hepatic function and successful management of complications induced by portal hemodynamic changes following BRTO.

Trans-portal hepatic infusion of cultured bone marrow-derived mesenchymal stem cells in a steatohepatitis murine model.

The incidence of nonalcoholic steatohepatitis-related liver cirrhosis is increasing. We used a steatohepatitis murine model fed a choline-deficient, l-amino acid-defined (CDAA) diet with a single injection of carbon tetrachloride (CCl4) to evaluate the efficacy of trans-portal hepatic infusion of bone marrow-derived mesenchymal stem cells (BMSCs) for liver fibrosis, liver steatosis, and oxidative stress. Mice were fed a CDAA diet and injected with a single intraperitoneal dose of CCl4 (0.5 ml/kg) after 4 weeks of CDAA diet. After 12 weeks of CDAA diet, 1 × 106 luciferase-positive syngeneic BMSCs (Luc-BMSCs) were infused into the animal spleen. An in vivo imaging system was used to confirm Luc-BMSC accumulation in the liver via the portal vein, and at 4 weeks after infusion, we compared liver fibrosis, liver steatosis, and oxidative stress. After the BMSC-infusion, serum albumin and serum total bilirubin were significantly improved. Liver fibrosis assessed by Sirius red staining, α-smooth muscle actin protein, and collagen 1A1 mRNA expression was significantly suppressed. Furthermore, liver steatosis area was significantly lower, the 8-hydroxy-2'-deoxyguanosine-positive cells were significantly fewer, and superoxide dismutase 2 protein expression of the liver was significantly increased. In conclusion, our data confirmed the efficacy of trans-portal hepatic infusion of BMSCs in a steatohepatitis murine model.

Liver stiffness measured by transient elastography as predictor of prognoses following portosystemic shunt occlusion.

BACKGROUND AND AIM: This study aimed to identify predictors of model for end-stage liver disease sodium score reductions and improvements in vital prognoses following portosystemic shunt occlusion in portal hypertension patients. METHODS: Seventy cirrhotic patients with major portosystemic shunts and a mean model for end-stage liver disease sodium score of 10.5 underwent balloon-occluded retrograde transvenous obliteration between February 2008 and March 2017. We calculated the scores before and 1 month after shunt occlusion. The long-term outcomes were monitored, and vital prognoses were analyzed. RESULTS: The model for end-stage liver disease sodium score did not change significantly 1 month post-balloon-occluded retrograde transvenous obliteration, and the score decreased postoperatively in 31 (44.3%) patients. Univariate analyses showed that decline in the score after portosystemic shunt occlusion was strongly associated with hepatic encephalopathy as a procedural indication, lower liver volumes, and lower liver stiffness levels measured by transient elastography before treatment (P < 0.05). Multivariate logistic regression analysis identified preoperative liver stiffness level as an independent predictor of model for end-stage liver disease sodium score amelioration following balloon-occluded retrograde transvenous obliteration (P < 0.05), and receiver operating characteristic curve analysis determined a liver stiffness cutoff value of 21.6 kPa, with a sensitivity of 76.0% and specificity of 69.6%. The Kaplan-Meier method determined that overall survival rates after treatment in patients with liver stiffness < 21.6 kPa were significantly higher than in patients with liver stiffness ≥ 21.6 kPa (P < 0.05). CONCLUSIONS: Liver stiffness measured by transient elastography may predict improvements in model for end-stage liver disease sodium scores and in survival rates after portosystemic shunt occlusion in portal hypertension patients.

Analysis of tolvaptan non-responders and outcomes of tolvaptan treatment of ascites.

BACKGROUND AND AIM: The goals of the study were to identify an effective treatment for ascites and to examine the influence of tolvaptan on outcomes by investigating non-responders to tolvaptan and comparing outcomes of hepatic cirrhosis in patients treated with and without tolvaptan. METHODS: In Study 1, of 145 patients with hepatic cirrhosis who were treated with tolvaptan between September 2013 and March 2018, 45 who did not achieve weight loss of ≥1.5 kg within one week were investigated. In Study 2, 83 patients who received tolvaptan for ascites between September 2013 and March 2017 were compared with 131 patients who were treated for ascites without use of tolvaptan between January 2006 and January 2012. RESULTS: In Study 1, the 45 patients were divided into three groups based on changes in dosing of diuretics. Renal function was retained in the dose reduction group compared with that in the other groups, and the rate of discharge with remission and the outcomes were also favorable in patients with dose reduction. In Study 2, survival was significantly more favorable in patients treated with tolvaptan. CONCLUSIONS: Dose reduction of diuretics may be effective for patients with reduced renal function for whom tolvaptan is ineffective or the effect is insufficient and may also improve outcomes of patients with hepatic cirrhosis by preventing a decline in renal function caused by an increased dose of diuretics.

[A Case of Multimodality Treatment Including Carbon Ion Radiotherapy to Multiple Distant Lymph Node Metastasis after a Surgery for Sigmoid Cancer].

We reported a case of a 30s woman who underwent Hartmann's surgery for sigmoid cancer. Her pathological stage was Stage Ⅳ(pT4b, N1b, M1b[liver and lung]). Postoperatively, 10 courses of systemic chemotherapy with FOLFOX plus cetuximab( Cmab)or bevacizumab(Bmab)were administered. After the chemotherapy, partial liver dissection and radiofrequency ablation(RFA)for multiple liver metastasis were performed. After 2 years of systemic chemotherapy with FOLFIRI plus ramucirumab(RAM), no liver or lung metastasis was observed; however, left supraclavicular lymph node and para-aortic lymph node metastases existed and gradually increased. For the purpose of local control, the para-aortic lymph node metastasis was treated with cervical dissection and carbon ion radiotherapy. Therefore, carbon ion radiotherapy was a useful treatment for local control.

Evaluation of the "assessment for continuous treatment with hepatic arterial infusion chemotherapy" scoring system in patients with advanced hepatocellular carcinoma.

AIM: Sorafenib is the recommended standard of care for advanced hepatocellular carcinoma (HCC) patients. However, hepatic arterial infusion chemotherapy (HAIC) is a treatment option in Asia. We recently developed the assessment for continuous treatment with HAIC (ACTH) score to guide decision-making for continuous HAIC treatment. The purpose of this study was to validate the utility of the ACTH score in a dedicated cohort. METHODS: One hundred and thirty-one patients with advanced HCC were enrolled in this study (90 in the training group and 41 in the validation group). The point score (range, 0-3) was calculated as follows: Child-Pugh score before HAIC (A = 0, B = 1), α-fetoprotein (AFP) response (yes = 0, no = 1), and des-γ-carboxy prothrombin (DCP) response (yes = 0, no = 1). The AFP and DCP responses were assessed 2 weeks after HAIC induction; a positive response was defined as a reduction of ≥20% from the baseline. RESULTS: The DCP response in the validation group was significantly associated with treatment response, and the median survival time (MST) was longer in patients with an ACTH score ≤1 (15.9 months) than in those with a score ≥2 (7.0 months; P = 0.002). Survival in all patients showed significant stratification according to the ACTH score; the MSTs associated with scores of 0, 1, 2, and 3 points were 21.7, 14.4, 9.5, and 3.8 months, respectively. CONCLUSION: The ACTH score can aid in the therapeutic assessment and continued treatment planning of HCC patients receiving HAIC.

Comparison of patients with hepatic encephalopathy and those with gastric varices before and after balloon-occluded retrograde transvenous obliteration.

AIM: To compare the clinical characteristics of patients with hepatic encephalopathy (HE) and those with gastric varices (GV) before and after balloon-occluded retrograde transvenous obliteration (BRTO). METHODS: Eighty cirrhotic patients who underwent BRTO, including 42 men and 38 women, and whose mean age was 68 years, comprised the HE (n = 18) and GV (n = 62) groups. The patients' data before and 1 month after BRTO were analyzed. RESULTS: Before BRTO, the groups did not differ in their portal flow volume (PFV) or hepatic venous pressure gradient (HVPG). The portal vein (PV) was narrower and the splenic vein (SpV) was wider in the HE group than in the GV group. The SpV flow was hepatofugal in 75.0% of HE patients and hepatopetal in 92.6% of GV patients. The Child-Pugh (CP) score of the HE group was significantly higher than that of the GV group pre-BRTO. After BRTO, the PFV and HVPG increases in the HE group equaled those in the GV group, and the PV dilation was similar in both groups. Conversely, the SpV was significantly contracted for HE patients, but significantly dilated for GV patients. Postoperatively, the SpV flow was hepatopetal in all patients. Compared to that in the GV group, the CP score decreased markedly in the HE group, and no significant increases in complications occurred post-BRTO for HE patients. CONCLUSIONS: The HE patients showed distinct portal-splenic hemodynamics before and after BRTO. Balloon-occluded retrograde transvenous obliteration markedly improved hepatic function in the HE group compared with the GV group.

Hemobilia immediately after transcatheter arterial chemoembolization using drug-eluting beads for hepatocellular carcinoma with intrahepatic bile duct invasion.

Transcatheter arterial chemoembolization (TACE) is used as a palliative treatment for unresectable hepatocellular carcinoma (HCC) worldwide. Recently, a novel drug delivery-embolic agent, the drug-eluting bead (DEB), was introduced for TACE. There are a few reports of tumor hemorrhage after TACE using DEB (DEB-TACE) for HCC. However, there have not been any reports of hemobilia immediately after DEB-TACE for HCC with intrahepatic bile duct invasion. Here, the first such case is reported. A 71-year-old woman was admitted to our hospital to undergo DEB-TACE for multiple HCCs with worsening left intrahepatic bile duct dilatation. She was diagnosed with HCC that extensively invaded the left hepatic duct. After DEB-TACE through the left hepatic artery, a hepatic arteriogram showed extra flow of the contrast agent to the left hepatic and common bile ducts. Therefore, transcatheter arterial embolization (TAE) of the responsible vessel was carried out using coils, and no extra flow of the contrast agent was identified. The patient was discharged 14 days after TAE without deterioration of liver function. Although hemobilia immediately after DEB-TACE is rare, there may be increased potential for hemobilia when DEB-TACE is carried out for HCC with extensive bile duct invasion. We suggest that DEB-TACE may be contraindicated for such cases.

Plasma Glucose Level Is Predictive of Serum Ammonia Level After Retrograde Occlusion of Portosystemic Shunts.

OBJECTIVE: The purpose of this study was to evaluate predictors of reduction in ammonia levels by occlusion of portosystemic shunts (PSS) in patients with cirrhosis. MATERIALS AND METHODS: Forty-eight patients with cirrhosis (21 women, 27 men; mean age, 67.8 years) with PSS underwent balloon-occluded retrograde transvenous obliteration (BRTO) at one institution between February 2008 and June 2014. The causes of cirrhosis were hepatitis B in one case, hepatitis C in 20 cases, alcohol in 15 cases, nonalcoholic steatohepatitis in eight cases, and other conditions in four cases. The Child-Pugh classes were A in 24 cases, B in 23 cases, and C in one case. The indication for BRTO was gastric varices in 40 cases and hepatic encephalopathy in eight cases. Testing was conducted before and 1 month after the procedure. Statistical analyses were performed to identify predictors of a clinically significant decline in ammonia levels after BRTO. RESULTS: Occlusion of PSS resulted in a clinically significant decrease in ammonia levels accompanied by increased portal venous flow and improved Child-Pugh score. Univariate analyses showed that a reduction in ammonia levels due to BRTO was significantly related to lower plasma glucose levels, higher RBC counts, and higher hemoglobin concentration before the treatment. Furthermore, multivariate logistic regression identified preoperative plasma glucose level as the strongest independent predictor of a significant ammonia reduction in response to BRTO. In addition, although BRTO resulted in significantly declined ammonia levels in patients with normal glucose tolerance before the procedure, ammonia levels were not significantly decreased after shunt occlusion in patients with diabetes mellitus or impaired glucose tolerance before BRTO, according to 75-g oral glucose tolerance test results. CONCLUSION: Preoperative plasma glucose level is a useful predictor of clinically significant ammonia reduction resulting from occlusion of PSS in patients with cirrhosis. Even if PSS are present, control of blood ammonia levels by BRTO alone may be difficult in patients with glucose intolerance.

Serum transferrin as a predictor of prognosis for hepatic arterial infusion chemotherapy in advanced hepatocellular carcinoma.

AIM: We recently reported that the iron chelator deferoxamine (DFO) is efficacious in advanced hepatocellular carcinoma (HCC) patients. Iron regulation may thus have an important impact in HCC therapy. Because transferrin is a native chelator that regulates iron homeostasis, it may act as an anticancer agent in a similar manner as DFO. The objective of this study was to evaluate serum transferrin as a prognostic predictor in advanced HCC patients undergoing hepatic arterial infusion chemotherapy (HAIC). METHODS: We retrospectively studied 44 patients receiving HAIC and analyzed various parameters for their possible use as prognostic predictors. RESULTS: The 1-, 2- and 3-year cumulative survival rates were 36.4%, 18.2% and 8.5%, respectively, and the median survival time (MST) was 7.0 months. The survival rates of patients who had serum transferrin of 190 mg/dL or more (MST, 12.0 months) were significantly better than those of patients who had serum transferrin of less than 190 mg/dL (MST, 4.9 months). Multivariate analysis identified serum transferrin of 190 mg/dL or more (hazard ratio [HR], 0.282; 95% confidence interval [CI], 0.132-0.603; P = 0.001) and Child-Pugh score B (HR, 1.956; 95% CI, 1.034-3.700; P = 0.039) as independent prognostic predictors. There was a significant correlation between serum transferrin level and therapeutic effect (P < 0.001). CONCLUSION: Serum transferrin could be useful as a prognostic predictor in advanced HCC patients before HAIC treatment.

Association of tyrosine with insulin resistance in hepatitis C virus-related chronic liver disease.

AIM: Insulin resistance (IR) increases during the early stages of hepatitis C virus (HCV)-related chronic liver disease and is a sign of poor prognosis as well as a risk factor for hepatic fibrosis and hepatocellular carcinoma. We aimed to determine the factors affecting IR in HCV-related chronic liver disease. METHODS: We retrospectively examined 71 patients with HCV-related chronic liver disease and analyzed various parameters, including amino acids, as possible predictors of IR. IR was assessed using the Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR). Amino acids were assayed by examining branched-chain amino acids (BCAA), tyrosine level, and the ratio of BCAA to tyrosine level (BTR). RESULTS: HOMA-IR was significantly correlated with body mass index, platelet count, prothrombin time, hemoglobin, total bilirubin, total protein, albumin, total cholesterol, fasting glucose, BTR (r = -0.46, P = 0.0001) and tyrosine (r = 0.55, P < 0.0001). However, BCAA were not significantly correlated with HOMA-IR (r = -0.21, P = 0.082). In multivariate analysis, only two factors were identified as independent parameters contributing to a HOMA-IR of 2.5 or more: total cholesterol (odds ratio [OR], 6.511; 95% confidence interval [95% CI], 1.554-27.284; P = 0.010) and tyrosine (OR, 4.839; 95% CI, 1.087-21.549; P = 0.039). CONCLUSION: Serum tyrosine levels may be associated with IR in patients with HCV-related chronic liver disease.

Systemic gemcitabine combined with hepatic arterial infusion chemotherapy with cisplatin, 5-fluorouracil, and isovorin for the treatment of advanced intrahepatic cholangiocarcinoma: a pilot study.

BACKGROUND/AIMS: Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis and usually presents as advanced disease. Hepatic arterial infusion chemotherapy (HAIC) is a promising option for advanced hepatocellular carcinoma; however, there have been few reports on the use of HAIC in patients with ICC. In the present study, we investigated the efficacy of treatment with systemic gemcitabine (GEM) combined with HAIC with cisplatin (CDDP), 5-fluorouracil (5-FU), and isovorin in patients with advanced ICC. METHODOLOGY: Seven patients with advanced ICC, who received systemic GEM combined with HAIC with CDDP, 5-FU, and isovorin were studied. RESULTS: The response rate after the first chemotherapy cycle was 57.1% (partial response, 4; stable disease, 2; progressive disease, 1). The cumulative survival rates at 1 and 2 years were 85.7% and 28.6%, respectively, and the median survival time was 22.3 months. With regard to grade 3 or 4 adverse reactions, the percentages of patients developing leukopenia, neutropenia, thrombocytopenia, anemia, and anorexia were 28.6%, 28.6%, 42.9%, 14.3%, and 14.3%, respectively. Na treatment-related deaths were encountered. CONCLUSIONS: Although this is a pilot study, we suggest that systemic GEM combined with HAIC with CDDP, 5-FU, and isovorin, may be a useful therapy for patients with advanced ICC.

Hepatocyte growth factor/c-met signaling is required for stem-cell-mediated liver regeneration in mice.

UNLABELLED: Hepatocyte growth factor (HGF)/c-Met supports a pleiotrophic signal transduction pathway that controls stem cell homeostasis. Here, we directly addressed the role of c-Met in stem-cell-mediated liver regeneration by utilizing mice harboring c-met floxed alleles and Alb-Cre or Mx1-Cre transgenes. To activate oval cells, the hepatic stem cell (HSC) progeny, we used a model of liver injury induced by diet containing the porphyrinogenic agent, 3,5-diethocarbonyl-1,4-dihydrocollidine (DDC). Deletion of c-met in oval cells was confirmed in both models by polymerase chain reaction analysis of fluorescence-activated cell-sorted epithelial cell adhesion molecule (EpCam)-positive cells. Loss of c-Met receptor decreased the sphere-forming capacity of oval cells in vitro as well as reduced oval cell pool, impaired migration, and decreased hepatocytic differentiation in vivo, as demonstrated by double immunofluorescence using oval- (A6 and EpCam) and hepatocyte-specific (i.e. hepatocyte nuclear factor 4-alpha) antibodies. Furthermore, lack of c-Met had a profound effect on tissue remodeling and overall composition of HSC niche, which was associated with greatly reduced matrix metalloproteinase (MMP)9 activity and decreased expression of stromal-cell-derived factor 1. Using a combination of double immunofluorescence of cell-type-specific markers with MMP9 and gelatin zymography on the isolated cell populations, we identified macrophages as a major source of MMP9 in DDC-treated livers. The Mx1-Cre-driven c-met deletion caused the greatest phenotypic impact on HSCs response, as compared to the selective inactivation in the epithelial cell lineages achieved in c-Met(fl/fl); Alb-Cre(+/-) mice. However, in both models, genetic loss of c-met triggered a similar cascade of events, leading to the failure of HSC mobilization and death of the mice. CONCLUSION: These results establish a direct contribution of c-Met in the regulation of HSC response and support a unique role for HGF/c-Met as an essential growth-factor-signaling pathway for regeneration of diseased liver.