Gi Hong Choi

Human Hepatocellular Carcinomas With ''Stemness''-Related Marker Expression: Keratin 19 Expression and a Poor Prognosis

There is a recently proposed subtype of hepatocellular carcinoma (HCC) that is histologically similar to usual HCC, but characterized by the expression of “stemness”‐related markers. A large‐scale study on two different cohorts of HCCs was performed to investigate the clinicopathologic features and epithelial‐mesenchymal transition (EMT)‐related protein expression status of this subtype of HCCs. The expression status of stemness‐related (e.g., keratin 19 [K19], cluster of differentiation [CD]133, epithelial cell adhesion molecule [EpCAM], and c‐kit) and EMT‐related markers (e.g., snail, S100A4, urokinase plasminogen activator receptor [uPAR], ezrin, vimentin, E‐cadherin, and matrix metalloproteinase [MMP]2) were examined using tissue microarrays from cohort 1 HCCs (n = 137). K19 protein expression in cohort 2 HCCs (n = 237) was correlated with the clinicopathologic parameters and messenger RNA (mRNA) levels of K19, uPAR, VIL2, Snail, Slug, and Twist. K19, EpCAM, c‐kit, and CD133 positivity were observed in 18.2%, 35.0%, 34.3%, and 24.8%, respectively. K19 was most frequently expressed in combination with at least one other stemness‐related marker (92.0%). K19‐positive HCCs demonstrated more frequent major vessel invasion and increased tumor size, compared to K19‐negative HCCs (P < 0.05). K19 was most significantly associated with EMT‐related protein expression (e.g., vimentin, S100A4, uPAR, and ezrin) (P < 0.05) and a poor prognosis (overall survival: P = 0.018; disease‐free survival: P = 0.007) in cohort 1. In cohort 2, HCCs with high K19 mRNA levels demonstrated higher mRNA levels of Snail, uPAR, and MMP2 (P < 0.05). K19‐positive HCCs demonstrated more frequent microvascular invasion, fibrous stroma, and less tumor‐capsule formation, compared to K19‐negative HCCs (P < 0.05). K19 expression was a significant independent predictive factor of poor disease‐free survival (P = 0.032). Conclusion: K19 was well correlated with clinicopathologic features of tumor aggressiveness, compared to other stemness‐related proteins. K19‐positive HCCs showed significantly increased EMT‐related protein and mRNA expression, suggesting that they may acquire more invasive characteristics, compared to K19‐negative HCCs through the up‐regulation of EMT‐associated genes. (HEPATOLOGY 2011;)

2014 Korean Liver Cancer Study Group-National Cancer Center Korea practice guideline for the management of hepatocellular carcinoma

The guideline for the management of hepatocellular carcinoma (HCC) was first developed in 2003 and revised in 2009 by the Korean Liver Cancer Study Group and the National Cancer Center, Korea. Since then, many studies on HCC have been carried out in Korea and other countries. In particular, a substantial body of knowledge has been accumulated on diagnosis, staging, and treatment specific to Asian characteristics, especially Koreans, prompting the proposal of new strategies. Accordingly, the new guideline presented herein was developed on the basis of recent evidence and expert opinions. The primary targets of this guideline are patients with suspicious or newly diagnosed HCC. This guideline provides recommendations for the initial treatment of patients with newly diagnosed HCC.

What are ‘true normal’ liver stiffness values using FibroScan®?: a prospective study in healthy living liver and kidney donors in South Korea

Aims: To identify the normal range of liver stiffness (LS) values by recruiting healthy living liver and kidney donors in South Korea.

Prognostic Factors and Optimal Treatment Strategy for Intrahepatic Nodular Recurrence After Curative Resection of Hepatocellular Carcinoma

BackgroundIntrahepatic recurrence is a major problem after curative resection of hepatocellular carcinoma. However, the most effective treatments for patients with intrahepatic recurrence still remain unclear. In addition, the selection of various treatment modalities such as repeat resection, local ablation therapy, and transarterial chemoembolization is only applicable to patients with intrahepatic nodular recurrence.MethodsOf 353 patients who underwent curative resection, 97 patients with intrahepatic nodular recurrence were retrospectively studied. The prognostic factors for survival after recurrence and treatment modalities were analyzed. The patients were divided into two groups, a control group and a progression group, according to their response to initial treatment for recurrent tumors.ResultsThe 1-, 3-, and 5-year overall survival rates after recurrence in patients with intrahepatic nodular recurrence were 91.0%, 71.0%, and 37.5%, respectively. Multivariate analysis revealed that early recurrence (≤12 months), Child-Pugh class B or C at diagnosis of recurrence, and serum albumin level of ≤3.5 g/dL at diagnosis of recurrence were poor prognostic factors for survival after recurrence. With regard to the response to the initial treatment, time to recurrence of ≤12 months was found to be the only statistically significant risk factor for progression of disease in multivariate analysis.ConclusionsTime to recurrence, which usually corresponds with the cellular origin of recurrence, seems to be more important when determining the prognosis of patients with recurrent disease and treatment response than treatment modality. Therefore, different treatment methods should be selected according to the time to recurrence of intrahepatic nodular recurrence.

Normal liver elasticity values using acoustic radiation force impulse imaging: A prospective study in healthy living liver and kidney donors

Background and Aim:  Although several studies have investigated the normal range of liver elasticity using acoustic radiation force impulse (ARFI) elastography in healthy volunteers, they could not strictly exclude the morphological and functional liver abnormalities. The aim of this study was to identify the normal range of ARFI velocity by recruiting healthy living liver and kidney donors who passed the full laboratory tests and imaging studies.

Revisiting the Role of Nonanatomic Resection of Small (≤4 cm) and Single Hepatocellular Carcinoma in Patients With Well-Preserved Liver Function

BACKGROUND Anatomic resection of the liver in patients with hepatocellular carcinoma (HCC) is generally recommended. Several previous reports have described the potential superiority of anatomic resection. However, no clear evidence of long-term survival or other advantages compared with those achieved with limited resection exist. We evaluated the oncologic outcomes of nonanatomic resection performed as a primary treatment for small (<or=4 cm) and single HCC in patients with well-preserved liver function (Child-Pugh class A). MATERIALS AND METHODS From March 1998 to January 2005, 353 consecutive patients underwent resection of HCC. Among them, 167 patients with single and small (<or=4 cm) HCC and well-preserved liver function (Child-Pugh class A) were selected. Twenty-one patients (12.6%) underwent nonanatomic resection (Group NA) and 146 (82.4%) underwent anatomic resection (Group A). Patient factors, tumor factors, surgery factors, disease-free survival, and recurrence patterns were compared between the two groups. RESULTS There were no significantly different preoperative clinical characteristics between the two groups (Group NA versus Group A). Only the resection margin width (0.8 +/- 0.6 cm versus 2.0 +/- 1.4 cm, P < 0.001) and operative time (211.9 +/- 72.9 min versus 251 +/- 80.0 min, P = 0.036) were significantly different between the two groups. There was no difference in disease-free survival between the two groups, and platelet counts of less than 100,000/microL (P = 0.038), satellite nodules (P = 0.0164), and microscopic portal vein invasion (P < 0.001) were significant prognostic factors predicting disease-free survival in univariate analysis. Subsequent Cox-proportional hazards models revealed that both microscopic portal vein invasion (Exp {beta} = 3.281, P < 0.001) and platelet counts of less than 100,000/microL (Exp {beta} = 1.913, P = 0.012) adversely affected disease-free survival. Nonanatomic resection did not have adverse effects on early recurrence compared to anatomic resection (P = 0.805). CONCLUSION Our study showed that nonanatomic resection has no adverse effects on the oncologic outcomes of single and small (<or=4 cm) HCC in patients with well-preserved liver function (Child-Pugh class A).

Notch1 differentially regulates oncogenesis by wildtype p53 overexpression and p53 mutation in grade III hepatocellular carcinoma

The tumor suppressor p53 is a key prognostic factor in hepatocellular carcinoma (HCC), yet only 35% of grade III tumors exhibit mutation of p53. Several other pathways have been implicated in HCC and, among these, the role of the Notch1/Snail pathway remains unclear. Therefore, we investigated the expression of p53, Notch1, and Snail proteins in HCC with regard to both clinical grade and p53 mutational status. Immunoblotting for p53 revealed that, whereas in many tumors increased p53 was a result of p53 mutation, wildtype p53 (p53WT) expression was also frequently elevated in HCCs. Coordinated evaluation of p53, Notch1, and Snail expression suggests that grade III HCC can be subdivided based on the expression of these three proteins. We found that Notch1 expression in HCC tissues and cell lines is differentially affected by p53WT and mutant p53 (p53Mut). Notch1 expression was correlated with p53 expression in cells expressing p53WT, but was not elevated in p53Mut‐expressing cells. Virally mediated expression or silencing of p53WT or p53Mut confirmed that p53WT overexpression causes Notch1 up‐regulation in HCC. Surprisingly, the consequence of Notch1 overexpression for the proliferative and invasive capacity of HCC cells depends on both the p53 mutational status and activation of the Snail pathway. Conclusion: In the presence of p53WT, Snail/Notch1 activation increased the invasiveness of HCC cells. In contrast, in the absence of p53WT, Notch1 decreased the invasiveness of HCC. Taken together, these findings shed new light on the complex role of the Notch1/Snail axis in HCC and provide a framework for further classifying HCC based on the expression and mutational status of p53 and the expression of Notch1 and Snail. (HEPATOLOGY 2011;53:1352‐1362)

Invasion and EMT-associated genes are up-regulated in B viral hepatocellular carcinoma with high expression of CD133-human and cell culture study☆

Hepatocellular carcinomas (HCCs) with expression of stem/progenitor cell markers including CD133 have been reported to have more aggressive biological behavior, and epithelial-mesenchymal transition (EMT), closely related invasion, has been suggested to generate cancer stem cells. To elucidate biological characteristics of HCCs expressing CD133, we evaluated migration assay and the mRNA expression levels of CD133, invasion-associated genes [urokinase plasminogen activator receptor (uPAR), villin 2 (VIL2), and MMP1 and MMP2], and EMT regulators (Snail, Slug, Twist, E-cadherin, and N-cadherin) by real-time PCR in HCC cell lines including HepG2, Hep3B, Huh7, PLC/RFP/6, SNU423, SNU449, and SNU475. Same genes and pathological features were also investigated in 49 samples of hepatitis B virus-related human HCCs. In all HCC cell lines studied, CD133-positive cells showed higher cell migration activity and up-regulated invasion- and EMT-associated genes with increased N-cadherin and decreased E-cadherin expressions compared to CD133-negative cells. The human HCCs were divided into the CD133-high group (top 40%) and the CD133-low group (bottom 40%) according to the level of CD133 mRNA. The CD133-high group showed relatively frequent vascular invasion and significantly higher expression of invasion-associated genes [uPAR (p=0.002), MMP1 (p=0.01), and MMP2 (p=0.003)] and EMT regulators [Snail (p=0.002) and Twist (p=0.0003)] compared to the CD133-low group. In conclusion, our results suggest that there is a subtype of HCC with high expression of CD133, which might have more invasive characteristics by up-regulation of invasion-associated genes and EMT-associated genes.

Detection of liver metastases using gadoxetic-enhanced dynamic and 10- and 20-minute delayed phase MR imaging

To assess the incremental value of hepatobiliary phase images in gadoxetate disodium‐enhanced magnetic resonance imaging (MRI), and to compare diagnostic accuracy and lesion conspicuity on 10‐ and 20‐minute delayed images for preoperative detection of hepatic metastases with subgroup analysis according to size and history of chemotherapy.

Predictive factors for long-term survival in patients with clinically significant portal hypertension following resection of hepatocellular carcinoma

Background: Hepatic resection for hepatocellular carcinoma (HCC) is not currently recommended for patients with clinically significant portal hypertension (PHT); however, recent studies have shown similar post‐operative outcomes between patients with and without clinically significant PHT.