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Background/aim: Transcriptional factor prospero homeobox-1 (PROX-1) is crucial for the embryonic development of various organs and cell fate specification. It exhibits either an oncogenic or tumor suppressive activity depending on cancer types. However, the relationship between PROX-1 and hepatocellular carcinoma (HCC) remains obscure. This study was conducted to investigate the effect of PROX-1 on the invasive and oncogenic phenotypes of human HCC cells., Materials and Methods: The effect of PROX-1 on tumor cell behavior was investigated by using a pcDNA-myc vector and a small interfering RNA in HepG2 and Huh7 human HCC cell lines. Flow cytometry, migration, invasion, proliferation, and tube formation assays were performed. PROX-1 expression in human HCC cells was explored by western blotting., Results: PROX-1 overexpression enhanced tumor cell proliferation and inhibited apoptosis and cell cycle arrest by modulating the activities of caspase-3, PARP, and cyclin-dependent kinase inhibitors, including p21, p27, and p57 in HCC cells. After PROX-1 overexpression, the number of migrating and invading HCC cells significantly increased, and the expression levels of N-cadherin and Snail increased in HCC cells. PROX-1 overexpression enhanced angiogenesis through increased VEGF-A and VEGF-C expression and decreased angiostatin expression. PROX-1 overexpression also increased the phosphorylation of glycogen synthase kinase-3β (GSK-3β) and forkhead box O1 (FOXO1) in HCC cells. After PROX-1 knockdown, their phosphorylation was reversed., Conclusion: PROX-1 overexpression is associated with the invasive and oncogenic phenotypes of human HCC cells via GSK-3β and FOXO1 phosphorylation., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Transarterial chemoembolization (TACE) is a widely used hepatocellular carcinoma (HCC) treatment. Some cases of supraumbilical skin rash after TACE in patients with HCC have been reported. To the best of the authors' knowledge, there are no reports on atypical, generalized rashes caused by doxorubicin systemic absorption after TACE. This paper presents the case of a 64-year-old male with HCC who developed generalized macules and patches one day after a successful TACE procedure. A histology examination of a skin biopsy of a dark reddish patch on the knee revealed severe interface dermatitis. He was treated with a topical steroid, and all skin rashes improved within a week with no side effects. This report presents this rare case with a literature review on skin rash after TACE.

Background: Surgical resection is one of the most widely used modalities for the treatment of hepatocellular carcinoma (HCC). Early extrahepatic recurrence (EHR) of HCC after surgical resection is considered to be closely associated with poor prognosis. However, data regarding risk factors and survival outcomes of early EHR after surgical resection remain scarce., Aim: To investigate the clinical features and risk factors of early EHR and elucidate its association with survival outcomes., Methods: From January 2004 to December 2019, we enrolled treatment-naïve patients who were ≥ 18 years and underwent surgical resection for HCC in two tertiary academic centers. After excluding patients with tumor types other than HCC and/or ineligible data, this retrospective study finally included 779 patients. Surgical resection of HCC was performed according to the physicians' decisions and the EHR was diagnosed based on contrast-enhanced computed tomography or magnetic resonance imaging, and pathologic confirmation was performed in selected patients. Multivariate Cox regression analysis was performed to identify the variables associated with EHR., Results: Early EHR within 2 years after surgery was diagnosed in 9.5% of patients during a median follow-up period of 4.4 years. The recurrence-free survival period was 5.2 mo, and the median time to EHR was 8.8 mo in patients with early EHR. In 52.7% of patients with early EHR, EHR occurred as the first recurrence of HCC after surgical resection. On multivariate analysis, serum albumin < 4.0 g/dL, serum alkaline phosphatase > 100 U/L, surgical margin involvement, venous and/or lymphatic involvement, satellite nodules, tumor necrosis detected by pathology, tumor size ≥ 7 cm, and macrovascular invasion were determined as risk factors associated with early EHR. After sub-categorizing the patients according to the number of risk factors, the rates of both EHR and survival showed a significant correlation with the risk of early EHR. Furthermore, multivariate analysis revealed that early EHR was associated with substantially worse survival outcomes (Hazard ratio, 6.77; 95% confidence interval, 4.81-9.52; P < 0.001)., Conclusion: Early EHR significantly deteriorates the survival of patients with HCC, and our identified risk factors may predict the clinical outcomes and aid in postoperative strategies for improving survival., Competing Interests: Conflict-of-interest statement: The authors declare no competing interests., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Extrahepatic recurrence (EHR) after curative hepatectomy for hepatocellular carcinoma (HCC) is associated with a poor prognosis. We investigated the features of EHR and identified its predictive factors. This retrospective study included 398 treatment-naive patients who underwent curative hepatectomy for HCC at two tertiary hospitals. Multivariate Cox-regression analysis was performed to identify the variables associated with EHR. EHR was diagnosed in 94 patients (23.6%) over a median follow-up period of 5.92 years, most commonly in the lungs (42.6%). The 5-/10-year cumulative rates of HCC recurrence and EHR were 63.0%/75.6% and 18.1%/35.0%, respectively. The median time to EHR was 2.06 years. Intrahepatic HCC recurrence was not observed in 38.3% of patients on EHR diagnosis. On multivariate analysis, pathologic modified Union for International Cancer Control stage (III, IVa), surgical margin involvement, tumor necrosis, sum of tumor size > 7 cm, and macrovascular invasion were predictive factors of EHR. Four risk levels and their respective EHR rates were defined as follows: very low risk, 1-/5-year, 3.1%/11.6%; low risk, 1-/5-year, 12.0%/27.7%; intermediate risk, 1-/5-year, 36.3%/60.9%; and high risk, 1-year, 100.0%. Our predictive model clarifies the clinical course of EHR and could improve the follow-up strategy to improve outcomes.

The roles of chromatin remodelers and their underlying mechanisms of action in cancer remain unclear. In this study, SMARCB1, known initially as a bona fide tumor suppressor gene, was investigated in liver cancer. SMARCB1 was highly upregulated in patients with liver cancer and was associated with poor prognosis. Loss- and gain-of-function studies in liver cells revealed that SMARCB1 loss led to reduced cell proliferation, wound healing capacity, and tumor growth in vivo . Although upregulated SMARCB1 appeared to contribute to switch/sucrose nonfermentable (SWI/SNF) complex stability and integrity, it did not act using its known pathways antagonism with EZH2 or association between TP53 or AMPK. SMARCB1 knockdown induced a mild reduction in global H3K27 acetylation, and chromatin immunoprecipitation sequencing of SMARCB1 and acetylated histone H3K27 antibodies before and after SMARCB1 loss identified Nucleoporin210 (NUP210) as a critical target of SMARCB1, which bound its enhancer and changed H3K27Ac enrichment and downstream gene expression, particularly cholesterol homeostasis and xenobiotic metabolism. Notably, NUP210 was not only a putative tumor supporter involved in liver cancer but also acted as a key scaffold for SMARCB1 and P300 to chromatin. Furthermore, SMARCB1 deficiency conferred sensitivity to doxorubicin and P300 inhibitor in liver cancer cells. These findings provide insights into mechanisms underlying dysregulation of chromatin remodelers and show novel associations between nucleoporins and chromatin remodelers in cancer. SIGNIFICANCE: This study reveals a novel protumorigenic role for SMARCB1 and describes valuable links between nucleoporins and chromatin remodelers in cancer by identifying NUP210 as a critical coregulator of SMARCB1 chromatin remodeling activity., (©2020 American Association for Cancer Research.)

Background: Extrahepatic metastasis (EHM) of hepatocellular carcinoma (HCC) is associated with poor outcomes. However, the clinical features and risk factors of EHM of HCC after radiofrequency ablation (RFA) remain unclear., Aim: To elucidate the characteristics and risk factors of EHM after RFA for HCC., Methods: From January 2008 to December 2017, we retrospectively enrolled 661 patients who underwent RFA as first-line treatment for HCC at 2 tertiary hospitals. The inclusion criteria were age ≥ 18 years, a diagnosis of HCC, and treatment-naivety. Abdominal computed tomography (CT) or magnetic resonance imaging (MRI) and alpha-fetoprotein measurements were routinely performed at 1 mo after RFA and followed-up at intervals of 3-6 mo. Univariate analyses were performed using the chi-squared test or Student's t -test, and univariate and multivariate analyses were performed via logistic regression, as appropriate., Results: EHM was diagnosed in 44 patients (6.7%) during a median follow-up period of 1204 days. The 10-year cumulative rate of HCC recurrence and EHM was 92.7% and 33.7%, respectively. Initial recurrence was most often intrahepatic, and the rate of extrahepatic recurrence at initial recurrence was only 1.2%. The median time to the diagnosis of EHM was 2.68 years, and 68.2% of patients developed EHM within 2 years of the first recurrence, regardless of recurrence-free survival and 75.0% of patients developed EHM within 5 years after first recurrence. EHM was mostly diagnosed via abdominal CT/MRI in 33 (75.0%) and 38 of 44 patients (86.4%) with EHM had either positive abdominal CT scan results or serum AFP level elevation. In multivariate analysis, recurrence-free survival < 2 years, ablation zone/tumor size < 2, and alpha-fetoprotein level > 400 IU/mL were associated with a high EHM risk., Conclusion: EHM occurs following multiple intrahepatic recurrences after RFA and combined contrast-enhanced abdominal CT and serum AFP were useful for surveillance. Patients especially with high-risk factors require close follow-up for EHM., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Recent studies report a significant age-specific increase in hepatocellular carcinoma (HCC) development among persons over 75 years old. Therefore, there is an urgent need to determine the optimal treatment strategy in elderly patients with HCC. This systemic review examines the clinical characteristics, efficacy, and safety of first-line treatment modalities. The literature was searched regarding epidemiology and clinical outcomes in elderly patients (age ≥75 years) undergoing first-line treatment for HCC. Causative or comorbid conditions of HCC in elderly patients differed from those in younger patients. Radiofrequency ablation may be effective and safe in early stages. Surgical resection may also be feasible in the early stages for selected patients. Transarterial chemoembolization may be safe and effective for intermediate HCC, and sorafenib may be feasible in elderly patients with advanced HCC. Prospective randomized trials are needed to establish the treatment strategy for elderly patients with HCC., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The number of elderly patients diagnosed with hepatocellular carcinoma (HCC) has been increasing. But there is no proper management based on age stratification in elderly patients. Therefore, we evaluated the clinical characteristics and outcomes of elderly HCC patients more than 75 years old in South Korea., Patients and Methods: Five hundred and fifty elderly patients with HCC were enrolled and divided into the oldest-old (age ≥85 years), middle-old (age between 80 and 85 years), and young-old groups (age between 75 and 80 years)., Results: Fifty-one, 153, and 346 patients were included in the oldest-old (mean age: 87 years), middle-old (mean age: 82 years), and young-old groups (mean age: 77 years), respectively. There was a significantly lower rate of alcohol-related and hepatitis B virus-related diseases in the oldest-old group than in the other groups, whereas there was no significant difference in other characteristics. With increasing age, conservative treatment was predominantly performed. Transarterial chemoembolization was the main modality of active treatment in all groups. In multivariate analysis, the performance score, model for end-stage liver disease score, modified Union for International Cancer Control staging, Barcelona Clinic Liver Cancer staging, presence of portal vein tumor thrombosis, ruptured HCC, and active treatment were risk factors of overall survival., Conclusion: When the therapeutic approach is used in elderly patients with HCC, the patient's performance status, liver function, and stage of cancer should be considered, and its use should not be restricted to those of advanced age., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Rationale: Hepatocellular carcinomas (HCCs) with metastases to the right atrium (RA) and lungs are rare, with a poor prognosis. Furthermore, the treatment outcomes in patients with advanced HCCs remain unsatisfactory., Patient Concerns: A 46-year-old man presented to our hospital for dyspnea on exertion and abdominal pain., Diagnoses: HCC and extra-hepatic metastases to the lung and RA., Interventions: Multidisciplinary treatment including radiotherapy (RT), transarterial chemoembolization (TACE), and sorafenib. During a follow-up evaluation computed tomography, he experienced a radio-contrast-induced anaphylaxis. After the event, treatment such as RT, TACE, and sorafenib were continued., Outcomes: His tumor burden decreased, finally leading to a complete response as per the modified Response Evaluation Criteria in Solid Tumors. The patient is still alive, 30 months after the episode. Subsequent blood tests showed increased natural killer (NK) cell activity, which was significantly higher than that seen in other age-matched HCC patients with an identical stage of the tumor, receiving sorafenib. This suggests that the increase in NK cells induced by anaphylaxis influenced the tumor burden., Lessons: We report here a rare case of long-term survival of an HCC patient with multiple metastases treated with multidisciplinary modalities, in which high NK cell activity was observed after a radio-contrast-induced anaphylactic reaction during follow-up investigations.

Barcelona clinic liver cancer-stage C (BCLC-C) encompasses a broad spectrum of tumor burdens, liver function statuses, patient prognoses, and treatment strategies. Currently, sorafenib is the only recommended treatment for patients with BCLC-C and outcomes remain suboptimal. The aims of this study were to assess the heterogeneity of BCLC-C hepatocellular carcinoma (HCC) cases, propose a novel subclassification for these cases, and suggest optimal treatment strategies other than sorafenib.We retrospectively analyzed 196 consecutive BCLC-C HCC patients who were diagnosed and treated between January 2008 and December 2015.All 196 patients were classified according to the modified Union for International Cancer Control (Stage I, 0.0%; Stage II, 8.2%; Stage III, 64.3%; Stage IVA, 21.9%; and Stage IVB, 5.6%) and American Joint Committee on Cancer TNM staging systems (Stage I, 0.0%; Stage II, 16.3%; Stage IIIA, 27.6%; Stage IIIB, 49.5%; Stage IIIC, 1.5%; Stage IVA, 1.0%; and Stage IVB, 4.1%). First-line treatment modalities included surgical resection (8.7%), transarterial chemoembolization (49.5%), hepatic arterial infusion therapy (5.6%), sorafenib therapy (9.2%), radiotherapy (9.2%), and best supportive care (10.7%). In univariate analysis, Child-Pugh score, tumor size, distant metastasis, multinodular or infiltrative/diffuse type of HCC, main portal vein invasion, hepatic vein invasion, and bile duct invasion were significantly associated with survival (P < .001). Tumor size, distant metastasis, HCC type, and bile duct invasion remained significantly associated with 1-, 3-, and 5-year survival rates in multivariate Cox regression analyses. Using these 4 characteristics, a novel subclassification of BCLC-C was developed and applied to the patient cohort. The subclassification included 5 substages (stages C0-C4), as defined based on the number of characteristics that were present in each HCC case (0-4). The subclassification showed significant associations with survival, with median survival times of 3026 days, 605 days, 224 days, 126 days, and 82 days for patients with Stage C0, C1, C2, C3, and C4 disease, respectively (P < .001). Additionally, diverse survival rates were observed when different treatment modalities were selected for cases within each substage.The proposed BCLC-C subclassification of HCC patients is effective in providing better prognostic subclassifications and more appropriate treatment strategies.

Background: Laparoscopic liver resection (LLR) has become an essential method for treating malignant liver tumors. Although the perioperative and oncologic outcomes of LLR in patients with hepatocellular carcinoma have been reported, there are few reports of LLR for intrahepatic cholangiocarcinoma (IHCC)., Methods: Patients who underwent liver resection for T1 or T2 IHCC between March 2010 and March 2015 in Gyeongsang National University Hospital were enrolled. They were divided into open (n = 23) and laparoscopic (n = 14) approaches, and the perioperative and oncologic outcomes were compared., Results: The Pringle maneuver was less frequently used (p = 0.015) and estimated blood loss was lesser (p = 0.006) in the laparoscopic group. There were no significant differences in complication rate (p = 1.000), hospital stay (p = 0.371), tumor size (p = 0.159), lymph node metastasis (p = 0.127), and the number of retrieved lymph nodes (p = 0.553). The patients were followed up for a median of 21 months. The 3-year overall survival (OS) and recurrence-free survival (RFS) rates were 74.7 and 55.2 %, respectively. No differences were observed in the 3-year OS (75.7 vs 84.6 %, p = 0.672) and RFS (56.7 vs 76.9 %, p = 0.456) rates between the open and laparoscopic groups, even after the groups were divided into patients that received liver resection with or without lymph node dissection., Conclusion: LLR for IHCC is a treatment modality that should be considered as an option alongside open liver resection in selected patients.

Objectives: This study aimed to investigate the effect of oral antiviral treatment on the prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after radiofrequency (RF) ablation., Methods: Between January 2003 and December 2010, 228 patients without a history of antiviral treatment were treated with RF ablation for a single HBV-related HCC. We divided the patients into two groups, patients who received (n=125) or did not receive antiviral treatment (n=103), based on whether oral antiviral treatment was administered after RF ablation. The median duration of antiviral treatment was 60.1 months. HCC recurrence and overall survival were compared in the two groups in the full cohort and the propensity score-matched cohort., Results: In the matched cohort, the probability of HCC recurrence at 5 years was 43.8% for the non-antiviral treatment group and 14.7% for the antiviral treatment group (p<0.001). The probability of overall survival at 5 years was 77.2% for the non-antiviral treatment group and 93.5% for the antiviral treatment group (p=0.002). Multivariable analysis showed that risk factors for HCC recurrence included large tumor size (hazard ratio (HR)=1.30, p=0.022), HBV DNA serum level (HR=1.11, p=0.005), and serum AFP level ≥20 ng/mL (HR=1.66, p=0.005). Overall survival was associated with larger tumor size (HR=1.86, p=0.001) and Child-Pugh Class B (HR=2.13, p=0.019). Oral antiviral treatment after RF ablation was significantly associated with a lower risk of tumor recurrence and death (HR=0.33, p<0.001, and HR=0.44, p=0.004)., Conclusion: Use of oral antiviral treatment after curative RF ablation was associated with favorable outcomes in terms of tumor recurrence and overall survival in patients with HBV-related HCC., Competing Interests: None of the authors have any conflicts of interest to declare.

Deregulation of the epigenome component affects multiple pathways in the cancer phenotype since the epigenome acts at the pinnacle of the hierarchy of gene expression. Pioneering work over the past decades has highlighted that targeting enzymes or proteins involved in the epigenetic regulation is a valuable approach to cancer therapy. Very recent results demonstrated that inhibiting the epigenetic reader BRD4 has notable efficacy in diverse cancer types. We investigated the potential of BRD4 as a therapeutic target in liver malignancy. BRD4 was overexpressed in three different large cohort of hepatocellular carcinoma (HCC) patients as well as in liver cancer cell lines. BRD4 inhibition by JQ1 induced anti-tumorigenic effects including cell cycle arrest, cellular senescence, reduced wound healing capacity and soft agar colony formation in liver cancer cell lines. Notably, BRD4 inhibition caused MYC-independent large-scale gene expression changes in liver cancer cells. Serial gene expression analyses with SK-Hep1 liver cancer cells treated with JQ1 to delineate the key player of BRD4 inhibition identified E2F2 as the first line of downstream direct target of BRD4. Further experiments including chromatin immunoprecipitation (ChIP) assay and loss of function study confirmed E2F2 as key player of BRD4 inhibition. Overexpressed E2F2 is a crucial center of cell cycle regulation and high expression of E2F2 is significantly associated with poor prognosis of HCC patients. Our findings reveal BRD4-E2F2-cell cycle regulation as a novel molecular circuit in liver cancer and provide a therapeutic strategy and innovative insights for liver cancer therapies., Competing Interests: The authors have declared that no competing interests exist.

Background/aims: To elucidate the role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) imaging as an independent prognostic factor in hepatocellular carcinoma (HCC)., Materials and Methods: A total of 104 patients with newly diagnosed HCC who underwent 18F-FDG-PET/CT imaging from 2009 to 2014 were reviewed retrospectively. The ratio of the maximal tumor standardized uptake value (SUV) to the mean mediastinum SUV (TSUVmax/MSUVmean) was evaluated as the predictive factor., Results: A high TSUVmax/MSUVmean ratio (≥3.1) was significantly associated with tumor burden indices, including α-fetoprotein (p<0.001), amino transaminase (AST) (p=0.007), tumor size (p=0.043), Tumor, Node, and Metastasis (TNM) stage (p<0.001), and Barcelona Clinic Liver Cancer (BCLC) staging (p<0.001). The mortality rate was higher (48.1% vs. 23.1%, p<0.001) in patients with a high TSUVmax/MSUVmean ratio (≥3.1). Among the 47 patients who underwent transarterial chemoembolization (TACE), patients with a high TSUVmax/MSUVmean ratio (≥3.1) were more likely to have recurrence following TACE (18/19 vs. 18/28, p=0.016)., Conclusion: A high TSUVmax/MSUVmean ratio on 18F-FDG-PET/CT imaging can serve as an independent prognostic factor in HCC and may predict tumor recurrence after TACE.

Intraductal tumor invasion of hepatocellular carcinoma (HCC) is considered rare. Transarterial chemoembolization (TACE) is effective for tumor thrombus of HCC in the bile duct. However, a few cases of obstructive jaundice caused by migration of a tumor fragment after TACE have recently been reported. The aim of this study was to identify factors that affect tumor migration after TACE. At this writing, a review of the medical literature disclosed seven reported cases of biliary obstruction caused by migration of a necrotic tumor cast after TACE. We, herein, report on an additional case of acute obstructive cholangitis complicated by migration of a necrotic tumor cast after TACE for intrabile duct invasion of HCC, in a 71-year-old man. The tumor cast in the common bile duct was removed successfully using a basket during ERCP and was pathologically confirmed to be a completely necrotic fragment of HCC. The patient's symptoms showed dramatic improvement. In summary, physicians should be aware of acute obstructive cholangitis complicated by tumor migration in a patient undergoing TACE. We suggest that an intrabile duct invasion would be a major predisposing factor of tumor migration after TACE and drainage procedures such as ERCP or percutaneous transbiliary drainage could be effective treatment modalities in these patients.

Purpose: To evaluate the risk factors of hepatocellular carcinoma (HCC) extension into the right atrium (RA) and determine poor prognostic factors for HCC extension to the heart., Materials and Methods: A total of 665 patients who were newly diagnosed with HCC were analyzed retrospectively from January 2004 to July 2012. The patients were divided into two groups: 33 patients with HCC extending into the RA and 632 HCC patients during the same period. The patients with HCC extending into the RA were subdivided into shorter survival group (<2 months) and longer survival group (≥2 months)., Results: The prevalence of HCC extending to the RA was 4.96%. In multivariate analysis, a modified Union Internationale Contre le Cancer (UICC) stage higher than IVA, hepatic vein invasion, concomitant inferior vena cava and portal vein invasion, and multinodular tumor type were risk factors for HCC extending to the RA. In multivariate analysis, Cancer of the Liver Italian Program (CLIP) score>3 (p=0.016, OR: 13.89) and active treatment (p=0.024, OR: 0.054) were associated with prognostic factors in patients HCC extending into the RA. Active treatment such as radiation (n=1), transcatheter arterial chemoembolization (TACE) (n=11), Sorafenib (n=1), and combined modalities (n=2) were performed., Conclusion: Modified UICC stage higher than IVA, vascular invasion and multinodular tumor type are independent risk factors for HCC extending to the RA. Active treatment may prolong survival in patients HCC extending into the RA.

Aim: To investigate the risk factors and characteristics of hepatocellular carcinoma (HCC) in the patients with drug-resistant chronic hepatitis B (CHB)., Methods: A total of 432 patients with drug-resistant CHB were analyzed retrospectively from January 2004 to December 2012. The patients were divided into two groups: the HCC group (n = 57) and the non-HCC group (n = 375). Two groups compared using logistic regression for various patients and viral characteristics in order to identify associated risk factors for HCC. Secondarily, patient and tumor characteristics of HCC patients with naïve CHB (N group, n = 117) were compared to the HCC group (R group, n = 57) to identify any difference in HCC characteristics between them., Results: A significant difference was found for age, platelet count, alpha-fetoprotein (AFP), positivity of HBeAg, seroconversion rate of HBeAg, virologic response, the Child-Pugh score, presence of rtM204I, and the duration of antiviral treatment in non-HCC and HCC group. Cirrhosis, age (> 50 years), HBeAg (+), virologic non-responder status, and rtM204I mutants were independent risk factors for the development of HCC. The R group had lower serum C-reactive protein (CRP) and AFP levels, earlier stage tumors, and a shorter mean tumor surveillance period than the N group. However, the total follow-up duration was not significantly different between the two groups., Conclusion: 13.2% of patients with drug-resistant CHB developed HCC. Age, cirrhosis, YIDD status, HBeAg status, and virologic response are associated with risk of HCC. Patients with drug-resistant CHB and these clinical factors may benefit from closer HCC surveillance.

Because of its safety and treatment effectiveness, the popularity of radiofrequency ablation (RFA) for the treatment of hepatocellular carcinoma (HCC) has gradually increased. However, some serious complications of RFA such as hepatic infarction, bowel perforation, and tumor seeding have been reported. Recently, we experienced a case of diaphragmatic hernia after RFA for HCC. A 61-year-old man with alcoholic cirrhosis was diagnosed with a 1.0 cm sized HCC in segment (S) 5 and a 1.3 cm sized HCC in S 8 of the liver. He was treated by transarterial chemoembolization and RFA. After RFA, an abdominal CT revealed a diaphragmatic defect with herniating mesentery. Twenty-two months after the RFA, the chest CT showed the diaphragmatic defect with herniating colon and mesentery. Because he had no symptoms, and surgical repair for the diaphragmatic hernia would be a high risk operation for him, we decided to treat the patient conservatively. For its great rarity, we report this case with a review of the literature.

Aim: To evaluate the factors predicting for recurrence and to analyze survival of patients with hepatocellular carcinoma (HCC)., Patients and Methods: A total of 743 patients who were consecutively diagnosed and treated with HCC were retrospectively analyzed from January 2004 to December 2012 at our institution. We analyzed their survival and tumor recurrence., Results: On multivariate analysis, age >50 years, CLIP score <3, ALP <120 U/l, LDH <450 IU/l, CRP <0.8 mg/dl, tumor size <6 cm, no distant metastasis, and curative treatment modality were predictors for 1-year survival. CRP <0.8 mg/dl, Child-Pugh score <7, curative treatment modality and tumor size <6 cm were predictors for 3-year survival. Absence of vascular invasion and uninodular tumor type were predictors for 5-year survival. Multinodular tumor, tumor size >4 cm, and palliative treatment were independent risk factors for 1-year recurrence after initial treatment., Conclusion: This large study provides a comprehensive overview of the survival outcomes and prognostic factors regarding HCC, according to clinical characteristics, various treatment modalities, and the results will help in the selection of effective treatment strategies future.

Objective: To compare the effectiveness of radiofrequency ablation (RFA) combined with transcatheter arterial chemoembolization (TACE) with surgical resection in patients with a single hepatocellular carcinoma (HCC) ranging from 2 to 5 cm., Materials and Methods: The study participants were enrolled over a period of 29 months and were comprised of 37 patients in a combined therapy group and 47 patients in a surgical resection group. RFA was performed the day after TACE, and surgical resection was performed by open laparotomy. The two groups were compared with respect to the length of hospital stay, rates of major complication, and rates of recurrence-free and overall survival., Results: Major complications occurred more frequently in the surgical resection group (14.9%) than in the combined therapy group (2.7%). However, there was no statistical significance (p = 0.059). The rates of recurrence-free survival at 1, 2, 3 and 4 years were similar between the combined therapy group (89.2%, 75.2%, 69.4% and 69.4%, respectively) and the surgical resection group (81.8%, 68.5%, 68.5% and 65%, respectively) (p = 0.7962, log-rank test). The overall survival rates at 1, 2, 3 and 4 years were also similar between groups (97.3%, 86.5%, 78.4% and 78.4%, respectively, in the combined therapy group, and 95.7%, 89.4%, 84.3% and 80.3%, respectively, in the surgical resection group) (p = 0.6321, log-rank test)., Conclusion: When compared with surgical resection for the treatment of a single HCC ranging from 2 to 5 cm, RFA combined with TACE shows similar results in terms of recurrence-free and overall survival rates.

Background/aims: The aim of this study was to determine the relationship between serum CRP levels and the prognosis of hepatocellular carcinoma (HCC) patients., Methods: HCC patients who underwent the first session of transcatheter arterial chemoembolization (TACE) between January 2005 and December 2009 (n=211) were analyzed retrospectively. The patients were divided into two groups: high C-reactive protein (CRP; ≥1 mg/dL, n=51) and low CRP (<1 mg/dL, n=160). They were followed for a mean of 22.44 months and their clinicoradiological variables and overall survival were compared., Results: There were significant differences between the two groups in regard to tumor type, tumor-progression-free survival, 10-month mortality, white blood cell (WBC) count, tumor size, and TNM stage. Multivariate analysis revealed that a high serum CRP level was independently associated with tumor size and tumor type. Subgroup analysis of CRP groups according to tumor size demonstrated that a high serum level of CRP was significantly associated with poorly defined (diffuse) tumor type in the tumor size <5 cm group [hazard ratio (HR)=4.81, P=0.018]. A Lipiodol dose exceeding 7 mL (HR=5.55, P=0.046) and the 10-month mortality (HR=7.693, P=0.004) were significantly associated with high serum CRP level in the group of patients with a tumor size of ≥5 cm. In addition, subgroup analysis of matched CRP according to TNM stage revealed that elevated serum CRP was independently associated with tumor type, WBC count, and tumorprogression-free survival., Conclusions: A high serum CRP level is associated with large tumors and a poorly defined tumor type, and is significantly associated with 10-month mortality in patients with large HCC (size ≥5 cm) who undergo TACE.

Aim: To investigate tumor response and survival in patients with postembolization fever (PEF) and to determine the risk factors for PEF., Methods: Four hundred forty-three hepatocellular carcinoma (HCC) patients who underwent the first session of transcatheter arterial chemoembolization (TACE) between January 2005 and December 2009 were analyzed retrospectively. PEF was defined as a body temperature greater than 38.0 °C that developed within 3 d of TACE without evidence of infection. The tumor progression-free interval was defined as the interval from the first TACE to the second TACE based on mRECIST criteria. Clinical staging was based on the American Joint Committee on Cancer tumor, node, metastases (TNM) classification of malignant tumors. All patients were admitted before their 1(st) TACE treatment, and blood samples were obtained from all patients before and after treatment. Clinicoradiological variables and host-related variables were compared between two groups: patients with PEF vs patients without PEF. Additionally, variables related to 20-mo mortality and tumor progression-free survival were analyzed., Results: The study population comprised 370 (85.4%) men and 73 (14.6%) women with a mean age of 62.29 ± 10.35 years. A total of 1836 TACE sessions were conducted in 443 patients, and each patient received between 1 and 27 (mean: 4.14 ± 3.57) TACE sessions. The mean follow-up duration was 22.23 ± 19.6 mo (range: 0-81 mo). PEF developed in 117 patients (26.41%) at the time of the first TACE session. PEF was not associated with 20-mo survival (P = 0.524) or computed tomography (CT) response (P = 0.413) in a univariate analysis. A univariate analysis further indicated that diffuse-type HCC (P = 0.021), large tumor size (≥ 5 cm) (P = 0.046), lipiodol dose (≥ 7 mL, P = 0.001), poor blood glucose control (P = 0.034), alanine aminotransferase (ALT) value after TACE (P = 0.004) and C-reactive protein (CRP) value after TACE (P = 0.036) served as possible risk factors correlated with PEF. The ALT value after TACE (P = 0.021) and lipiodol dose over 7 mL (P = 0.011) were independent risk factors for PEF in the multivariate analysis. For the 20-mo survival, poor blood sugar control (P < 0.001), portal vein thrombosis (P = 0.001), favorable CT response after TACE (P < 0.001), initial aspartate aminotransferase (P = 0.02), initial CRP (P = 0.042), tumor size (P < 0.001), TNM stage (P < 0.001) and lipiodol dose (P < 0.001) were possible risk factors in the univariate analysis. Tumor size (P = 0.03), poor blood sugar control (P = 0.043), and portal vein thrombosis (P = 0.031) were significant predictors of survival in the multivariate analysis. Furthermore, the tumor progression-free interval was closely associated with CRP > 1 mg/dL (P = 0.003), tumor size > 5 cm (P < 0.001), tumor type (poorly defined) (P < 0.001), and lipiodol dose (> 7 mL, P < 0.001)., Conclusion: PEF has no impact on survival at 20 mo or radiologic response. However, the ALT level after TACE and the lipiodol dose represent significant risk factors for PEF.

Intrahepatic cholangiocarcinoma (ICC) is a rare primary malignant liver tumor with an extremely poor prognosis. Recently its incidence has increased, however, little attention has been directed to factors related to its molecular carcinogenesis, including oncogenes, tumor suppressor genes and cell cycle-related proteins. ICC is generally characterized by strong proliferation, invasion and early metastasis. These biological behaviors of ICC, with respect to the genetic and molecular aspects, remain to be clarified. In this study, we performed a proteomic analysis to identify the proteomic alterations associated with carcinogenesis of ICC. Protein expression profiles of sixteen cases of ICC were compared with those of adjacent non-involved bile duct tissue. Among the 151 protein spots that showed a statistically significant expression difference (P<0.05), there were 50 spots with significantly increased intensity (3-fold increase) and 17 spots with decreased intensity (3-fold decrease) in cancerous tissues. Of these, increased expression of fatty acid-binding protein 5 (FABP5) was further confirmed by western blot analysis and immunohistochemical analysis. Immunohistochemical analysis of FABP5 expression in tumor specimens obtained from 43 patients with mass-forming (MF) type ICC showed a positive correlation of FABP5 immunoreactivity with tumor size (P=0.047), lymph node metastasis (P=0.013), angioinvasion (P=0.032) and staging (P=0.007). In addition, silencing FABP5 with short hairpin RNA (shRNA) suppressed cell proliferation and invasiveness in HuCCT1 cells, and conversely, overexpression of FABP5 in FABP5-negative Hep3B cells increased cell proliferation and invasiveness. Our study shows that FABP5 is significantly overexpressed in ICC combined lymph node metastasis and is involved in cell proliferation and invasion in vitro. Our data suggest that FABP5 may be associated with tumor progression in ICC.

The recepteur d'origine nantais (RON) receptor tyrosine kinase is highly expressed in various cancers including human hepatocellular carcinoma (HCC) and involved in tumor progression. The aims of the current study were to evaluate whether RON affects tumor cell behavior and oncogenic signaling cascades in HCC cells. We investigated the biologic role of RON on tumor cell behavior and oncogenic signaling cascades including Akt, c-Raf and extracellular signal-regulated kinase (ERK) by using the small interfering RNA (siRNA) in HCC cell lines, chang, HepG2 and Huh7. Knockdown of RON suppressed tumor cell migration and invasion in all tested HCC cell lines. The proportion of apoptotic cells induced by knockdown of RON was greater than that induced by transfection of the scramble siRNA in all tested HCC cell lines. Knockdown of RON resulted in cell cycle arrest in the G2/M phase of chang and Huh7 cells, and sub G1 phase of HepG2 cells. Knockdown of RON activated cleaved caspase-3 and PARP, and down-regulated the expression of Bcl-2, Bcl-xL and survivin, leading to induction of apoptosis in all tested cell lines. Knockdown of RON negatively regulates the progression of the cell cycle by decreasing cyclin D1 and D3, and increasing p21 and p27 in all tested cell lines. The phosphorylation of Akt, c-Raf and ERK1/2 signal proteins was significantly blocked by knockdown of RON in all tested cell lines. These results suggest that RON is associated with invasive and oncogenic phenotypes such as tumor cell migration, invasion, resistance to apoptosis and cell cycle arrest through the modulation of Akt, c-Raf and ERK signaling cascades in HCC cells.

KITENIN promotes cancer cell migration and invasion in vitro and cancer metastasis in mouse cancer models, including colon and head and neck cancers. The purposes of this study were to observe the effect of KITENIN on tumor cell behaviors of human hepatocellular carcinoma (HCC) cells and to evaluate its expression in human HCC tissues. To functionally characterize KITENIN in human HCC, we depleted its expression in human HCC cell lines, HepG2 and Huh7, by using small interfering RNA (siRNA). Invasion and proliferation assays were performed. The activator protein-1 (AP-1) transcriptional activity and expression of AP-1 target genes were evaluated by AP-1 luciferase reporter assay and RT-PCR. The contribution of mitogen-activated protein kinase (MAPK) cascade signaling involved in AP-1 activation was assessed by Western blotting. We evaluated the expression of KITENIN and AP-1 target genes at mRNA levels by RT-PCR in human HCC tissues and paired normal hepatic mucosa of the same patients taken by surgery. Knockdown of KITENIN in HepG2 and Huh7 cells resulted in a significant reduction of tumor cell invasion. The tumor cell proliferation was significantly decreased in the KITENIN knocked down Huh7 cells compared to the negative control. The mRNA expressions of MMP-3 and COX-2 were decreased in KITENIN knocked down Huh7 cells. The mRNA expression of MMP-1 was decreased in KITENIN knocked down HepG2 cells. The AP-1 transcriptional activity in Huh7 cells was significantly decreased by knockdown of KITENIN. The JNK and ERK1/2 phosphorylations were decreased in KITENIN knocked down HepG2 and the p38 phosphorylation was decreased in KITENIN knocked down Huh7 cells. The mRNA expressions of KITENIN, MMP-1, and MMP-3 were significantly upregulated in human HCC tissues compared to paired normal mucosa. These results indicate that KITENIN is associated with activation of AP-1 target genes via MAPK cascades signaling in human HCC progression.

Caspase 8 and survivin are known as key molecules of apoptosis in hepatocellular carcinoma (HCC). The purpose of the present study was to investigate the relationship between promoter methylation and expression and apoptotic function of caspase 8 and survivin in HCC. Promoter methylation of the caspase 8 and survivin gene was analyzed in 73 primary HCC using methylation-specific polymerase chain reaction. The relationship between immunohistochemical expression of gene products and proliferative/apoptotic indices, and clinicopathological parameters was also investigated. Twenty-five (34%) and 24 (33%) patients had promoter methylation of caspase 8 and survivin gene. Immunohistochemical staining of caspase 8 and survivin was observed in 35 (48%) and 32 (44%). The methylation of caspase 8 and survivin demonstrated a negative correlation with immunohistochemical expression of gene products (P= 0.049 and P= 0.001). Methylation of caspase 8 and positive expression of its gene product was significantly correlated with high apoptotic indices (P= 0.032 and P= 0.026). Nuclear survivin expression was significantly correlated with high proliferative index (P= 0.001). On survival analysis, positive nuclear survivin expression was associated with a poor prognosis in HCC (P= 0.043). In conclusion, epigenetic alteration by promoter methylation of caspase 8 and survivin may constitute an important regulatory mechanism for expression of those genes in HCC.

Transcatheter arterial chemoembolization (TACE) is the mainstay of treatment for unresectable hepatocellular carcinoma (HCC). Although various complications of TACE have been reported, cerebral lipiodol embolism after TACE is rare. We report a 67-year-old man, who had patent foramen ovale and developed cerebral lipiodol embolism after TACE via the inferior phrenic artery. At 20 months after third TACE of 3 cm sized HCC in the left hepatic lobe, computed tomography (CT) revealed about 1.6 cm newly developed HCC in the anterior superior segment of right hepatic lobe. The angiogram revealed the HCC was supplied from the right inferior phrenic artery. Toward the end of TACE, there were accumulations of the iodized oil in the pulmonary vasculature. Immediately after TACE, he complained of weakness in right upper and lower limbs and sensory decrease in right limbs and right hemitrunk. Magnetic resonance imaging revealed a cerebral lipiodol embolism. Transesophageal echocardiography revealed no visible thrombi but contrast-echocardiography using hand agitated saline revealed an intracardiac right to left shunt consistent with patent foramen ovale. Motor weakness and sensory decrease were gradually improved, and all neurological symptoms disappeared over 4 weeks.

Background/aims: Spontaneous rupture of hepatocellular carcinoma (HCC) is a rare but life-threatening complication. Although the prevalence rate and mortality of HCC has been reportedly high in Korea, studies on ruptured HCC are limited. The aim of this study was to determine the clinical characteristics and prognostic factors of ruptured HCC., Methods: Among 886 cases with HCC that had been diagnosed at Chonnam National University Hospital from January 2002 to December 2007, 62 cases (7.0%) with ruptured HCC were studied retrospectively regarding their clinical characteristics and prognostic factors., Results: Transarterial embolization was performed in 56 cases (90.3%) to control bleeding, with a hemostasis success rate of 89.3%. The survival time after the rupture of HCC was 8.0+/-1.7 months (mean+/-SD), although it was longer in HCC cases that were first diagnosed in a ruptured state or ruptured with a small amount of bleeding than in those that ruptured during follow-up after diagnosis or with a large amount of bleeding, respectively. The 30-day mortality rate in patients with a ruptured HCC was 43.5%, and the early deaths were independently associated with the presence of hepatic encephalopathy (odds ratio, OR=44.7; 95% confidence interval, CI=1.9-1051.1; P=0.018), serum bilirubin >3.0 mg/dL (OR=36.7; 95% CI=1.3-1068.5; P=0.036), and the massive or diffuse type of tumor morphology (OR=53.5; 95% CI=3.0-964.2; P=0.007)., Conclusions: The prognosis in patients with ruptured HCCs was poor with a 30-day mortality of 43.5%. The early deaths after the rupture of HCC were associated with elevated serum bilirubin levels, hepatic encephalopathy, and the massive or diffuse type of tumor morphology.

Loss or reduced E-cadherin expression and aberrant expression of N-cadherin have been associated with invasiveness of human carcinoma cells and poor prognosis. The role of E- and N-cadherin, however, in hepatocellular carcinoma (HCC) has not yet been elucidated. The aim of the present study was to investigate the expression pattern of E- and N-cadherin in surgically resected HCC specimens according to their relationship with clinicopathological features. The expression patterns of E- and N-cadherin were evaluated on immunohistochemistry in 68 specimens of HCC and adjacent non-tumor tissue. The most different expression pattern between HCC and non-tumor tissue was the decreased staining intensity of E-cadherin (n = 37, 54%) and the dot-like discontinuous staining of N-cadherin (n = 35, 55%). Decreased intensity of E-cadherin and discontinuous staining of N-cadherin in HCC was correlated with advanced stage. The risk factors for expression patterns related to recurrence were loss of E-cadherin expression (odds ratio (OR) = 3.6; 95% confidence interval (CI): 1.1-12.4) and discontinuous staining of N-cadherin (OR = 1.6; 95% CI: 0.8-3.2). In conclusion, discontinuous staining of N-cadherin and loss of E-cadherin expression in HCC predicts a high risk of recurrence after surgical treatment.

Background and Aim: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Recently, abnormal activation of the Wnt pathway has been found to be involved in the carcinogenesis of HCC. However, the relationship between genetic changes in the Wnt pathway-associated genes and its protein expression has not been studied in patients with HCC and cirrhotic nodules. The purpose of this study is to explore the contribution of inappropriate activation of the Wnt pathway in liver carcinogenesis., Methods: Somatic mutation in exons 3-5 of AXIN1 and exon 3 of beta-catenin were analyzed by direct sequencing and expression of axin and beta-catenin proteins by immunohistochemistry in a series of 36 patients with HCC and cirrhosis., Results: The AXIN1 and beta-catenin gene mutations were observed in 25% (9/36) and 2.8% (1/36) of HCCs, respectively. All mutations detected in AXIN1 and beta-catenin genes were missense point mutations. Abnormal nuclear expression of beta-catenin was observed in 11 of 36 cases of HCCs (30.6%), but not in cirrhotic nodules. Reduced or absent expression of axin was seen in 24 of 36 HCCs (66.7%). The abnormal expression of beta-catenin and axin proteins was closely correlated with mutations of AXIN1 and beta-catenin (P < 0.0001 and P = 0.008, respectively)., Conclusions: These data suggest that mutation of AXIN1 gene is a frequent and late event for HCC associated with cirrhosis, and is correlated significantly with abnormal expression of axin and beta-catenin. Therefore, activation of Wnt signaling through AXIN1 rather than beta-catenin mutation might play an important role in liver carcinogenesis.

Background/aims: Epigenetic silencing of DNA repair genes, O6-methylguanine-DNA methyltransferase (MGMT), hMLH1 and hMSH3, by promoter hypermethylation have been observed in various cancers. However, the relationship between hypermethylation of DNA mismatch repair genes and microsatellite instability (MSI) has not been studied in hepatocellular carcinoma (HCC) associated with cirrhosis., Methods: We investigated the methylation pattern of CpG islands of 3 genes using methylation-specific PCR (MSP) and MSI in 40 patients with paired hepatocellular carcinoma and associated cirrhosis., Results: hMSH3 and MGMT were the most methylated genes in both cirrhosis (70% and 68%, respectively) and HCC (75% and 73%, respectively). The methylation of hMLH1 was rarely found in both cirrhosis (8%) and HCC (5%). Gene promoters methylated in cirrhosis were also methylated in HCC with the exception of 9 cases found to be methylated either in cirrhosis or HCC. Of 40 cases of HCC associated with cirrhosis, three had MSI-positive phenotype in which two were MSI-low and one was MSI-high. One MSI-positive phenotype was present both in cirrhosis and in HCC, while two were only in HCC. There was no significant correlation between aberrant DNA methylation of mismatch repair genes and MSI status in HCC associated with cirrhosis. Immunohistochemical expressions of hMLH1, MGMT, and hMSH3 proteins were present in 16 (40%), 6 (15%), and 11 (28%) of 40 cases of HCC respectively. There was no significant correlaton between the aberrant DNA methylation of mismatch repair genes and clinical characteristics such as histological differentiation, postoperative recurrence and mortality., Conclusions: The methylation of MGMT and hMSH3 among DNA repair genes are frequent, but those of hMLH1 and MSI is very rare in both cirrhosis and HCC. There is no significant correlation between the methylation of DNA repair genes and clinical characteristics of HCC.

Ileovesical fistula is a very rare clinical entity, the most frequent cause of which is Crohn's disease. Furthermore, it is an exceptionally rare complication of malignancies. We experienced one case of ileovesical fistula which had been caused by hepatocellular carcinoma (HCC) arising from the noncirrhotic liver. A 27-year-old man was diagnosed with HCC in a noncirrhotic liver. Despite treatment with transarterial chemoembolization (TACE), the disease status became more aggravated. The patient complained of dysuria, fecaluria, and intermittent lower abdominal pain. Pelvic CT scan showed a soft tissue mass of 6 cm abutting on the distal ileum which was downwardly displaced. Barium study of the small bowel showed a fistula between the small bowel loop and the urinary bladder. Upon operation, adhesion and fistula were found between the ileum and the urinary bladder. The microscopic findings of the surgical specimen were compatible with metastatic HCC. We confirmed that ileovesical fistula had been caused by metastatic HCC.

Despite septic arthritis is increasingly being reported in elderly patients with diabetes or alcoholism, reported cases of spontaneous bacterial arthritis in cirrhotic patients are extremely rare. We present the first reported case of K. pneumoniae septic arthritis and spontaneous bacterial peritonitis in a cirrhotic patient with hepatocellular carcinoma. K. pneumoniae, one of the most common causative organisms of spontaneous bacterial peritonitis in cirrhotic patients, was isolated from both the blood and the joint fluid, which suggests that the route of infection was hematogenous. After the treatment with cefotaxime and closed tube drainage, the condition of the patient was improved, and subsequently, the joint fluid became sterile and the blood cultures were proved negative. Therefore, this case provides further evidence for the mode of infection being bacteremia in cirrhotic patients and suggests that the enteric bacteremia in cirrhotics may cause infection in different organ systems., (Copyright The Korean Academy of Medical Sciences)

Background: Matrix metalloproteinases (MMPs) have been implicated in the remodelling of extracellular matrix (ECM), including basement membrane. ECM remodelling is associated with pathological processes, including hepatic fibrosis, tumor invasion and metastasis. Tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 were known to inhibit MMP-9 and MMP-2, respectively. In the present study, we examined the expression of TIMP-1 and TIMP-2 in surgical specimen pairs of hepatocellular carcinoma and nontumoral liver and the correlation between their expression and clinicopathological characteristics., Methods: The localization of both transcripts and protein of TIMP-1 and TIMP-2 was studied by using in situ hybridization and immunohistochemistry., Results: TIMP-1 and TIMP-2 mRNA transcripts were found in tumor cells, hepatocyte, sinusoidal cells, endothelial cells and stromal cells. Signal intensity of TIMP-1 was stronger than that of TIMP-2. The results of immunohistochemical stainings were concordant with those obtained by in situ hybridization. Expression of TIMP-1 and TIMP-2 was observed in tumorous tissue, in nontumorous tissue and in the portions of the tumors adjacent to the capsules. However, a clear difference in TIMP-1 and TIMP-2 mRNA expression was not observed among the three tissue types. The intensity of TIMP-2 expression was generally weaker than that of TIMP-1, and the intensity of TIMP-1 and TIMP-2 mRNA expression did not correlate with variable clinicopathological characteristics., Conclusion: TIMPs was expressed in tumor cells and many cell types of the nontumoral liver. Further investigations for TIMPs' unknown functional role are needed.