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Background: De principe transplantation is an attractive strategy for the treatment of patients with hepatocellular carcinoma (HCC). The most important issue for this strategy is how to predict the risk of early and extensive recurrence. The present study aimed to identify a molecule associated with early and extensive recurrence of HCC after resection., Methods: Differentially expressed genes were screened by DNA microarray analysis with the use of 12 HCC samples from patients who had different clinical courses based on the timing and extent of recurrence after operative resection. Furthermore, the obtained results were validated in 60 independent samples by quantitative real-time reverse transcription-polymerase chain reaction. Immunohistochemistry was performed to assess gene expression at the protein level., Results: Microarray analysis and quantitative reverse transcription-polymerase chain reaction revealed cytoskeleton-associated protein 2 (CKAP2) as a candidate gene associated with early and extensive recurrence of HCC after resection. This observation was confirmed through examination of independent set samples, in which patients with greater-level CKAP2 mRNA expression exhibited shorter recurrence-free survival. Immunohistochemistry showed CKAP2 protein expression was associated with early (≤3 years) and extensive recurrence (beyond Milan criteria) after operative resection., Conclusion: Immunohistochemical CKAP2 expression might be a potential biologic marker for identifying HCC patients at risk of early and extensive recurrence after operative resection., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Background: Although fibroblast growth factor 19 (FGF19) can promote liver carcinogenesis in mice, its involvement in human hepatocellular carcinoma (HCC) has not been well investigated. FGF19, a member of the FGF family, has unique specificity for its receptor FGFR4. This study aimed to clarify the involvement of FGF19 in the development of HCC., Methods: We investigated human FGF19 and FGFR4 expression in 40 hepatocellular carcinoma specimens using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) analysis and immunohistochemistry. Moreover, we examined the expression and the distribution of FGF19 and FGFR4 in 5 hepatocellular carcinoma cell lines (HepG2, HuH7, HLE, HLF, and JHH7) using RT-PCR and immunohistochemistry. To test the role of the FGF19/FGFR4 system in tumor progression, we used recombinant FGF19 protein and small interfering RNA (siRNA) of FGF19 and FGFR4 to regulate their concentrations., Results: We found that FGF19 was significantly overexpressed in HCCs as compared with corresponding noncancerous liver tissue (P < 0.05). Univariate and multivariate analyses revealed that the tumor FGF19 mRNA expression was an independent prognostic factor for overall and disease-free survival. Moreover, we found that the FGF19 recombinant protein could increase the proliferation (P < 0.01, n = 12) and invasion (P < 0.01, n = 6) capabilities of human hepatocellular carcinoma cell lines and inhibited their apoptosis (P < 0.01, n = 12). Inversely, decreasing FGF19 and FGFR4 expression by siRNA significantly inhibited proliferation and increased apoptosis in JHH7 cells (P < 0.01, n = 12). The postoperative serum FGF19 levels in HCC patients was significantly lower than the preoperative levels (P < 0.01, n = 29)., Conclusions: FGF19 is critically involved in the development of HCCs. Targeting FGF19 inhibition is an attractive potential therapeutic strategy for HCC.

Background/aims: Patients with both hepatocellular carcinoma and hypersplenic thrombocytopenia are occasionally seen and this condition can severely complicate liver resection. This study evaluated the usefulness of preoperative partial splenic embolization (PSE) as an alternative to splenectomy (SP)., Methodology: Twenty-eight patients with hypersplenic thrombocytopenia underwent hepatectomy for hepatocellular carcinoma. Five patients underwent preoperative PSE and 23 patients underwent concomitant splenectomy. The blood cell counts, laboratory chemistry data, and operative morbidity, prognosis were all examined., Results: There were no severe PSE-related complications such as splenic abscess seen after PSE. The platelet counts in the PSE group significantly increased in comparison to those in the SP group before the operation. The frequency of blood transfusion and postoperative complications in the PSE group was significantly less than that in the SP group. The duration of surgery, blood loss, and performance of PSE were significant factors to predict postoperative complications. The overall survival after liver resection was not significantly different between patients in the PSE and SP group., Conclusions: Preoperative PSE could be safely performed without severe adverse effects prior to liver resection and it was thus considered to be useful for increasing the number of platelets and reducing postoperative complications.

Background: The prognosis of patients with hepatocellular carcinoma (HCC) invading the main trunk of the portal vein and the inferior vena cava is dismal. The best strategy for treatment is not well known., Study Design: We retrospectively reviewed the medical records of 641 patients treated for HCC between 1990 and June 2009. Eighty-four (13%) of these patients had HCC, with a tumor thrombus invading the main trunk or the first-order branch of the portal vein, or the inferior vena cava. Thirty-four patients underwent hepatectomy and 50 patients underwent transcatheter arterial chemoembolization (TACE). We specifically focused on these 34 patients to describe our results of surgical treatment for advanced HCC., Results: Among the 34 patients who underwent hepatectomy, preoperative TACE was performed in 15 patients. Six patients were identified as having a tumor size reduction or necrosis of 50% or higher (TE3) by TACE. The median operative duration was 355 minutes. Postoperative morbidity and mortality rates were 44% and 2.9%, respectively. The 5-year survival rate after hepatectomy was 20%, which was better than that of patients after TACE alone. The response after preoperative TACE (hazard ratio 4.65; 95% CI, 1.39 to 15.5) and tumor diameter (hazard ratio 2.78; 95% CI, 1.16 to 6.64) were identified as significant favorable preoperative prognostic factors for survival using the multivariable Cox model. Patients with tumors smaller than 10 cm and TE3 effect had a more favorable survival than patients with tumors 10 cm or larger and who did not have a good TACE outcome., Conclusions: A combination of aggressive surgical treatment and effective preoperative TACE treatment for HCC with major vascular invasion may be beneficial for selected patients., (Copyright © 2011. Published by Elsevier Inc.)

A 50-year-old man having an advanced hepatocellular carcinoma (HCC) was admitted to our institution. An abdominal computed tomogram showed infiltrative mass in the right liver with tumor thrombus invading into the main trunk and contralateral branch of the portal vein. Repetitive transcatheter arterial chemoembolization reduced a tumor size and shrunken portal vein tumor thrombus. The tumor marker levels such as AFP and PIVKA-II decreased. During follow-up, he was diagnosed as having an impending rupture of HCC with acute abdominal pain. He was successfully treated with interventional technique. He died of liver failure 66 months after the first treatment. Although he had a highly advanced HCC with tumor thrombus of the portal vein, repetitive transcatheter arterial chemoembolization therapy may prolong survival.

Heterogeneous biological characteristics of hepatocellular carcinoma may be attributed to the cellular origin of the tumor. Patients with hepatocellular carcinoma probably derived from hepatic progenitor cells had early tumor recurrence after surgical resection or liver transplantation, suggesting that these tumors have aggressive characteristics. Ezrin, a member of the ERM (ezrin-radixin-moesin) cytoskeleton-associated protein family, is highly expressed in several types of human cancers and correlations between its immunoreactivity and patient outcome have been shown. In this study, ezrin expression, as well as cytokeratin19 and cytokeratin 7 expression, which are regarded as progenitor cell/ductular markers were immunohistochemically assessed in cases of hepatocellular carcinoma. In normal livers, ezrin expression was not found in any cell types, whereas cytokeratin 7 and cytokeratin 19 were exclusively stained in bile duct cells. In contrast, in livers with chronic hepatitis or cirrhosis, positive ezrin expression was observed in ductular reactions with strong intensity and intermediate hepatobiliary cells with various intensity. Of 77 cases of hepatocellular carcinoma, 28 (36%) had positive ezrin expression, 32 (42%) had cytokeratin 7 expression, and 11 (14%) had cytokeratin 19 expression. Ezrin expression in hepatocellular carcinoma was significantly associated with cytokeratin 19 expression, but not with cytokeratin 7 expression. Patients with ezrin-positive hepatocellular carcinoma had a significantly higher prevalence of elevated serum alpha-fetoprotein. Patients with immunohistochemical ezrin-positive hepatocellular carcinoma demonstrated significantly shorter recurrence-free and overall survival compared to patients with ezrin-negative hepatocellular carcinoma. Multivariate analysis revealed positive ezrin expression and multiple tumors to be independently associated with early recurrence in patients with hepatocellular carcinoma after curative surgical resection. These results suggested that hepatocellular carcinoma with ezrin expression might be at least partly derived from hepatic progenitor cells. Measurement of ezrin expression might be used to identify patients with an increased risk of early recurrence.

Background and Aim: Hepatocellular carcinoma is one of the most common cancers. alpha-Fetoprotein is strongly expressed in most patients with hepatocellular carcinoma, and high levels of alpha-fetoprotein expression have been reported as an independent prognostic factor. However, there have been few reports on the reasons for poor prognosis., Methods: We analyzed the correlation between serum alpha-fetoprotein levels and clinicopathological findings in 37 hepatocellular carcinoma patients undergoing curative surgery. alpha-Fetoprotein mRNA expression in tissue samples was analyzed by quantitative reverse transcription-polymerase chain reaction (RT-PCR), while protein expression was assessed by immunohistochemistry. To assess the mechanistic correlations between alpha-fetoprotein and tumor progression, we further analyzed cell proliferation (Ki-67), angiogenesis (CD34), and apoptosis (TdT-mediated dUTP-biotin nick end labeling [TUNEL] assay)., Results: Post-operative serum alpha-fetoprotein levels were correlated with disease-free and overall survival, and were an independent prognostic factor for survival. alpha-Fetoprotein expression, as assessed by immunohistochemistry, was strong and heterogeneous in hepatocellular carcinoma. Control livers did not express alpha-fetoprotein and there was weak expression of alpha-fetoprotein in adjacent regions in hepatocellular carcinoma patients. The Ki-67 labeling index in the high serum alpha-fetoprotein cases was significantly higher than in alpha-fetoprotein-negative cases (P = 0.042). The alpha-fetoprotein-positive cases also showed a significantly higher microvessel density than alpha-fetoprotein-negative cases (P = 0.035), whereas hepatocellular carcinoma without alpha-fetoprotein overexpression had a higher apoptotic index when compared to hepatocellular carcinoma with alpha-fetoprotein overexpression (P = 0.033)., Conclusion: These results indicate that the poor prognosis associated with high alpha-fetoprotein is due to high cell proliferation, high angiogenesis, and low apoptosis.

Background and Aim: Hepatocellular carcinoma (HCC) is characteristically a hypervascular tumor and its progression is known to be closely related to angiogenesis. In this study, we investigated angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) levels in the hepatic vein draining from HCC, as well as in the peripheral vein, to evaluate their relation to clinicopathological features and prognosis., Methods: To obtain hepatic venous blood samples, a catheter was placed into the main branch of the hepatic vein draining from HCC in 21 patients. The Ang-2 and VEGF levels in both the hepatic and peripheral veins were investigated. Furthermore, Ang-2 mRNA expression in surgically resected HCC was evaluated by quantitative reverse-transcription polymerase chain reaction (RT-PCR), as well as microvessel density (MVD) by CD34 immunostaining., Results: Ang-2 levels in the hepatic vein significantly correlated with Ang-2 mRNA expression in HCC, but Ang-2 levels in the peripheral vein did not correlate. Furthermore, a significant correlation was found between hepatic venous Ang-2 and MVD levels, whereas there was no significant correlation with hepatic venous VEGF levels. When hepatic venous Ang-2 levels were compared with clinicopathological features, a significant relationship was found between high Ang-2 levels and portal vein invasion. The survival for patients in the high hepatic venous Ang-2 group was significantly poorer when compared with the low group., Conclusion: Preoperative hepatic venous Ang-2 levels may be a good predictor for portal vein invasion and also prognosis in patients with HCC.

A 71-year-old man was admitted to our institution having a HCC with tumor thrombus extending to the inferior vena cava. He simultaneously had a sigmoid colon cancer. S8 segmentectomy combined with a removal of tumor thrombus in the IVC and sigmoidectomy was performed. He had an uneventful postoperative course. He had a recurrence to the lung 46 months after the surgery, and underwent a pulmonary partial resection. Hepatic recurrence was found in 59 months after the initial surgery. Transcatheter arterial chemoembolization was performed for the treatment. The patient died of esophageal variceal rupture 78 months after the surgery. Although this case was a highly advanced hepatocellular carcinoma with tumor thrombus in the inferior vena cava and synchronous sigmoid colon cancer, a surgical treatment and multidisciplinary therapy may contribute to a long-term survival.

Liver resection for liver tumors located in deep positions in segment VIII remains a technical challenge. We successfully resected a hepatocellular carcinoma located in deep position in segment VIII and extended into the paracaval portion of the right caudate lobe, using an anterior transhepatic approach. The patient was a 73-year-old man with chronic hepatitis C. Preoperative ultrasonography and dynamic computed tomography revealed that the tumor was about 3.0 cm in diameter and close to the roots of the middle and right hepatic veins and the paramedian Glissonian pedicle. The right anterior artery was supplying the tumor. The liver was opened along the right side of the middle hepatic vein. The dorsal Glissonian pedicle of segment VIII was easily exposed, ligated, and divided. The dorsal part of segment VIII was removed, along with the paracaval portion of the right caudate lobe. The postoperative course was uneventful. The patient was disease-free 17 months after surgery. This anterior transhepatic approach provides a wide operating field and easy hemostasis, and could preserve the liver parenchyma as much as possible in a patient with liver dysfunction.

Surgical treatment of hepatocellular carcinoma (HCC) has developed remarkable for several reasons. The surgical mortality rates of patients with HCC after hepatectomy have decreased due to appropriate criteria for surgery, refined surgical techniques and improvement in the pre- and postoperative management. In preoperative management, refinements in liver function tests and strategies for esophageal varices, and the induction of preoperative portal vein embolization have contributed favorably to the outcome after hepatectomy for HCC. Furthermore, hepatectomy has been technically refined by various vascular control methods and liver transection devices based on the realization that surgical anatomical information also plays a major role in improving surgical outcome. Also concomitant splenectomy with hepatectomy might extend the criteria for surgery in HCC patients with hypersplenism. Therefore, hepatectomy is a safe therapeutic approach that could bring about a favorable outcome in patients with HCC. Nowadays transplantation is one of the therapeutic options for HCC patients, even in Japan. Herein the surgical treatment of HCC in Japan is reviewed and current issues in the surgical treatment of HCC are discussed., ((c) 2007 S. Karger AG, Basel.)

We describe a 66-year-old man having hepatocellular carcinoma with tumor thrombus extending into the inferior vena cava and synchronous pulmonary metastasis. He was referred to Chiba University Hospital on May, 2000, complaining of emaciation. Radiological findings showed a huge hepatocellular carcinoma in the entire right lobe and tumor thrombus extended into the intrapericardial inferior vena cava. He also had a solitary pulmonary metastasis in the left pulmonary lobe (stage IVB). Right hemihepatomy was performed under total hepatic vascular exclusion without cardiopulmonary bypass, and tumor thrombus was completely removed. Thoracoscopic wedge resection of pulmonary metastasis was also performed. The patient had an uneventful postoperative course. Histopathological examination revealed that the tumor was moderately differentiated hepatocellular carcinoma The patient is still alive after 26 months with pulmonary recurrence, but without hepatic recurrence. To our knowledge, there has been no reported case of resection for both hepatocellular carcinoma invading the inferior vena cava and synchronous pulmonary metastasis. In conclusion, aggressive surgical resection for advanced hepatocellular carcinoma concomitant with pulmonary resection may bring about better prognosis in highly selected patients.

Human hepatocellular carcinoma (HCC) is a hypervascular tumor but the mechanisms underlying the process of angiogenesis are not fully understood. Angiopoietins (Ang) have been recently identified as ligands for Tie-2 receptor and are thought to be important factors in vascular maturation and stability during angiogenesis. In this study, we investigated the expression of Ang-1, Ang-2, Tie-2, and vascular endothelial growth factor (VEGF) in surgically resected specimens from 46 patients with HCC to determine their potential role in tumor angiogenesis and its progression. VEGF messenger RNA (mRNA) was significantly up-regulated in HCC compared to normal liver tissue from patients with hepatic metastases. No differences were found between HCC and adjacent liver tissue. Meanwhile, Ang-2 mRNA expression in HCC was significantly increased when compared to adjacent liver tissue. On the other hand, Ang-1 and Tie-2 mRNA expression in HCC was not different from that in adjacent liver tissue. Immunohistochemical staining also showed increased Ang-2 protein in HCC. Furthermore, a high Ang-2/1 mRNA ratio in HCC was closely associated with tumor portal vein invasion, tumor diameter, and the microvessel density level as assessed by CD34 immunostaining. With regard to prognosis, the survival time for patients in the high Ang-2/1 mRNA ratio group was significantly poorer when compared with the low Ang-2/1 mRNA ratio group. In conclusion, an increased expression of Ang-2/1 in the presence of VEGF may play a critical role in promoting tumor angiogenesis and progression in human HCC.