Hirotaka Tashiro

Overexpression of Hypoxia Inducible Factor-1 Alpha is an Independent Risk Factor for Recurrence After Curative Resection of Colorectal Liver Metastases

BackgroundHypoxia inducible factor-1α (HIF-1α) is a major regulator of tumorigenesis in hypoxic conditions and therefore represents a potential therapeutic target in colorectal cancer (CRC). Clinical significance of HIF-1α expression in liver metastases has not been elucidated. Therefore, this study aimed to clarify the clinical significance of HIF-1α expression in colorectal liver metastasis (CRLM).MethodsWe retrospectively analyzed 64 patients who underwent curative resection of CRLM from 2000 to 2008. We evaluated HIF-1α expression by immunohistochemical staining and analyzed its association with several clinicopathological characteristics, including vascular endothelial growth factor (VEGF) expression. We analyzed the mutation status of genes involved in CRC (p53, KRAS, BRAF, and PIK3CA). Finally, we compared HIF-1α expression between the primary tumor and the corresponding liver metastases.ResultsWe found a significant positive correlation between HIF-1α expression in liver metastases and PIK3CA mutation status (pxa0=xa00.019). A significant correlation was also observed between the expressions of HIF-1α and VEGF in liver metastases and primary tumors (pxa0=xa00.015, 0.024, respectively). High HIF-1α expression in liver metastases was an independent risk factor for recurrence (pxa0=xa00.031).ConclusionsOur results suggest a possible induction of HIF-1α expression by mutant PIK3CA. The expressions of HIF-1α and VEGF in liver metastases significantly correlated with those in the corresponding primary tumor. Overexpression of HIF-1α was an independent risk factor for recurrence after curative resection of CRLM, suggesting that HIF-1α represents an important candidate for the treatment of CRLM in a subset of patients with high HIF-1α expression.

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.

Risk Factors for Development of New-Onset Diabetes Mellitus and Progressive Impairment of Glucose Metabolism After Living-Donor Liver Transplantation

BACKGROUNDnNew-onset diabetes mellitus (NODM) has a negative impact on graft and patient survivals. Hepatitis C virus (HCV) infection, high body mass index, increased donor and recipient ages, and calcineurin inhibitor (CNI) type have been identified as risk factors for the development of NODM. We aimed to elucidate the risk factors for the development of NODM and those for progressive glucose intolerance in adult living-donor liver transplant (LDLT) recipients.nnnMETHODSnWe collected data from 188 primary liver transplant recipients (age > 16 years) who underwent LDLT from June 1991 to December 2011 at Hiroshima University Hospital. Risk factors for NODM and progressive impairment of glucose metabolism in pre-transplantation diabetes mellitus (DM) recipients were examined.nnnRESULTSnPre-transplantation DM was diagnosed in 32 recipients (19.3%). The overall incidence of NODM was 6.0% (8/134 recipients). Multivariate analysis revealed that old recipient age (≥55 years) is a unique predictive risk factor for developing NODM. The incident of pre-transplantation DM was significantly higher in recipients with HCV infection than in those without HCV. A high pre-transplantation triglyceride level was an independent risk factor for progressive impairment of glucose tolerance among 32 LDLT recipients with pre-transplantation DM. All of the NODM patients were being treated with tacrolimus at the time of diagnosis. Switching the CNI from tacrolimus to cyclosporine allowed one-half of the patients (4/8) to withdraw from insulin-dependent therapy. NODM and post-transplantation glucose intolerance had no negative impact on patient and graft outcomes.nnnCONCLUSIONSnOlder age of the recipient (≥55 years) was a significant risk factor for NODM. Hypertriglyceridemia in the recipients with DM is an independent risk factor for post-transplantation progressive impairment of glucose metabolism. NODM had no negative impact on outcomes in the LDLT recipients.

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.

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).

Clinical Efficacy of Simultaneous Splenectomy in Liver Transplant Recipients With Hepatitis C Virus

BACKGROUNDnInterferon (IFN) therapy is a well-established antiviral treatment for hepatitis C virus (HCV)xa0- infected patients. However, susceptibility to thrombocytopenia is a major obstacle in its initiation or continuation, particularly in patients with HCV who underwent liver transplantation (LT). We previously showed that the coexistence of splenomegaly and thrombocytopenia could result in persistent thrombocytopenia after LT. Here we retrospectively evaluated the validity of this criterion for simultaneous splenectomy in recipients with HCV.nnnPATIENTS AND METHODSnSubjects included 36 recipients with HCV who received LT between January 2006 and February 2012 at Hiroshima University. We analyzed the spleen volume, body surface area, platelet (PLT) count, and rate of completion or continuation with IFN therapy in these recipients.nnnRESULTnOf these recipients, 30 did not require simultaneous splenectomy according to the criterion, and 24 actually did not receive simultaneous splenectomy. In this group, 21 (87.5%) started IFN therapy. Fifteen (71.4%) of these recipients completed or continued IFN therapy, whereas 13 (61.9%) achieved either a sustained virological response (SVR) or an end-of-treatment response. The PLT count increased to >100,000/mm(3) 1 month after LT in 16 (66.7%) recipients from this group.nnnCONCLUSIONnOur criterion detected the PLT count outcome after LT in recipients with HCV and achieved a better SVR result after IFN therapy.

New suture: Tail clinch knot for transabdominal preperitoneal hernia repair

There is some controversy regarding the proper surgical method for inguinal hernia repair and whether transabdominal preperitoneal or totally extraperitoneal repair should be used. The greatest difference between these procedures is the need for absorbable sutures to close the peritoneal incision.