Tsuyoshi Kobayashi

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.

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.

h-Prune is associated with poor prognosis and epithelial-mesenchymal transition in patients with colorectal liver metastases

The prognosis of patients with colorectal liver metastases (CRLM) remains low despite advances in chemotherapy and surgery. The expression of h‐prune (human homolog of Drosophila prune protein; HGNC13420), an exopolyphosphatase, is correlated with progression and aggressiveness in several cancers and promotes migration and invasion. We investigated the role of h‐prune in CRLM. To investigate the role of h‐prune, immunohistochemical analysis for h‐prune was performed in 87 surgically resected specimens of CRLM obtained between 2001 and 2009 at the Hiroshima University Hospital. Immunohistochemical analysis revealed positive staining for h‐prune in 24 (28%) cases. The overall survival rate was significantly lower in h‐prune‐positive cases than in h‐prune‐negative cases (pu2009=u20090.003). Multivariate analysis showed that h‐prune positivity was the only independent factor related to poor overall survival of patients after curative hepatectomy of CRLM. In vitro and in vivo, h‐prune‐knocked‐down and h‐prune‐overexpressing cells were analyzed. In vitro, h‐prune was associated with increased cell motility and upregulation of epithelial–mesenchymal transition (EMT) markers. In a mouse model, h‐prune was associated with invasion of the tumor and distant metastases. In summary, h‐prune expression is a useful marker to identify high‐risk patients for resectable colorectal liver metastasis. h‐Prune expression is necessary for cancer cell motility and EMT and is associated with liver and lung metastasis in colorectal cancer cells. h‐Prune could be a new prognostic marker and molecular target for CRLM.

Comparison of Anatomic and Non-anatomic Hepatic Resection for Hepatocellular Carcinoma

The aim of the present study was to compare the prognostic impact of anatomic resection (AR) versus non‐anatomic resection (NAR) on patient survival after resection of a single hepatocellular carcinoma (HCC).

Patients with early recurrence of hepatocellular carcinoma have poor prognosis

BACKGROUNDnEarly recurrence (ER) after hepatic resection (HR) is a poor prognostic factor for patients with hepatocellular carcinoma (HCC). This study aimed to identify the clinicopathological features, outcomes, and risk factors for ER after HR for small HCC in order to clarify the reasons why ER is a worse recurrence pattern.nnnMETHODSnWe retrospectively examined 130 patients who underwent HR for small HCC (≤30 mm). Recurrence was classified into ER (<2 years) and late recurrence (LR) (≥2 years). The clinicopathological features, outcomes, and risk factors for ER were analyzed by multivariate analysis.nnnRESULTSnER was observed in 39 patients (30.0%). The survival rate of the ER group was significantly lower than that of the LR group (P<0.005), and ER was an independent prognostic factor for poor survival (P=0.0001). The ER group had a significantly higher frequency (P=0.0039) and shorter interval (P=0.027) of development to carcinoma beyond the Milan criteria (DBMC) compared with the LR group, and ER was an independent risk factor for DBMC (P<0.0001). Multi-nodularity, non-simple nodular type, and microvascular invasion were independent predictors for ER (P=0.012, 0.010, and 0.019, respectively).nnnCONCLUSIONSnER was a highly malignant recurrence pattern associated with DBMC and subsequent poor survival after HR for small HCC. Multi-nodularity, non-simple nodular type, and microvascular invasion predict ER, and taking these factors into consideration may be useful for the decision of the treatment strategy for small HCC after HR.

Obstructive jaundice caused by a giant liver hemangioma with Kasabach-Merritt syndrome: a case report

Hemangioma is the most common benign tumor of the liver. Liver hemangioma (LH) usually remains asymptomatic, but the most common symptoms associated with LH are abdominal pain and discomfort. LH is an uncommon cause of bile duct dilatation and obstructive jaundice. An 83-year-old Japanese woman who received hemodialysis at another hospital was referred to our hospital because of abnormal liver function and obstructive jaundice. Abdominal computed tomography and magnetic resonance imaging revealed a 13-cm tumor in liver segments IV–V and intrahepatic bile duct dilatation. Endoscopic retrograde cholangiopancreatography revealed extrinsic compression of the bile duct at the hepatic hilar region. Laboratory tests showed that the patient had low platelet counts and low fibrinogen levels. Because the patient had hyperbilirubinemia and Kasabach-Merritt syndrome, we performed a segmentectomy of liver segments IV and V. Histological examination showed hemangioma of the liver. The patient’s thrombocytopenia and coagulopathy improved immediately after surgery. In conclusion, LH is a very rare cause of obstructive jaundice. LH has the potential to compress the bile duct and cause obstructive jaundice.

Prognostic evaluation of mucin-5AC expression in intrahepatic cholangiocarcinoma, mass-forming type, following hepatectomy

AIMnThis study aimed to investigate the clinicopathological predictors of survival in patients with intrahepatic cholangiocarcinoma, mass-forming type (ICC-MF), following curative intent hepatectomy.nnnMETHODSnClinical characteristics and outcomes were analyzed in a series of 42 patients who underwent curative hepatectomy for ICC-MF between February 1987 and December 2012. The relationship between immunohistochemical expression profiles of mucin (MUC) core proteins (MUC2, MUC5AC, and MUC6) and surgical outcomes was examined.nnnRESULTSnThe overall median follow-up period was 2.6 years (0.2-17.9). Bile duct reconstruction (pxa0=xa00.017), lymph node metastasis (pxa0=xa00.049), maximal mass diameter ≥5.0xa0cm (pxa0=xa00.002), and MUC5AC expression (pxa0=xa00.003) were identified as significant adverse predictors of overall survival by univariate analysis. Bile duct reconstruction (pxa0=xa00.048), maximal mass diameterxa0≥5.0xa0cm (pxa0=xa00.002), and MUC5AC expression (pxa0=xa00.005) were found to be independent predictors of poor prognosis by multivariate analysis. Maximal mass diameter ≥5.0xa0cm (pxa0=xa00.011) was found to be an independent predictor for the tumor recurrence. There was a strong correlation between MUC5AC expression and lymph node metastasis (pxa0=xa00.021). MUC6 expression was more frequent in patients with concurrent MUC5AC expression (pxa0=xa00.019).nnnCONCLUSIONSnMUC5AC expression was significantly related to long-term prognosis and aggressive tumor development, and may be a useful prognostic marker.

Treatment of hepatic amyloid light-chain amyloidosis with bortezomib and dexamethasone in a liver transplant patient.

Hepatic amyloid light‐chain (AL) amyloidosis is characterized by abnormal deposition of amyloid fibrils in the liver. As this precursor protein is produced by a proliferative plasma cell clone in the bone marrow, liver transplantation (LT) does not affect the diseases progression. Here, we describe the successful treatment using bortezomib‐ and dexamethasone‐based chemotherapy, following LT, of hepatic AL amyloidosis in a 65‐year‐old woman with progressive liver failure. The patient presented with progressive hepatic dysfunction accompanied by hepatorenal syndrome requiring hemodialysis, and living donor LT was successfully performed. Histology revealed amyloid deposits in the liver and stomach, and serum immunofixation revealed AL amyloidosis (κ‐type). The patient began chemotherapy on day 45 after the LT, and remission was achieved after one course. She was subsequently discharged 83u2009days after the LT, with normal liver and renal function, and no clinical evidence of recurrent disease was observed at the latest follow up (22u2009months post‐LT).

Methotrexate-associated primary hepatic malignant lymphoma following hepatectomy: A case report

Highlights • Primary hepatic lymphoma is difficult to diagnose preoperatively.• MTX use encouraged MTX-related ML.• In MTX-related MLs, withdrawing MTX had a therapeutic effect.