• YAKHAK HOEJI
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• v.55 no.1
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• pp.75-79
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• 2011

The replication competent adenoviral vector (AV), AdLPCDIRESE1A was generated and reported previously to have cytotoxic effects in some cell lines. In AdLPCDIRESE1A, the expression of cytosine deaminse (CD) and E1A genes are under the control of tumor-specific L-plastin promoter. CD enzyme can deaminate the nontoxic prodrug 5-fluorocytosine (5-FC) to the toxic 5-fluorouracil (5-FU). E1A gene is essential for viral replication. Primary liver cancer, most of which is hepatocellular carcinoma (HCC), is the third common leading cancer in Korea. Thus, we have conducted in vitro preclinical study to evaluate effectiveness of AdLPCDIRESE1A on HCC. The efficacy of cytotoxicity was measured by generation of cytopathic effect (CPE) and cell counting. We infected HepG2 cells with various MOI of vector alone or concurrent with 5-FC. Exposure of cells to AdLPCDIRESE1A generated a significant cytotoxic effect as compared to the control. Almost 83% of the cell had manifested the characteristic cytotoxic effect on day 9 after infection of cells with 10 MOI of vector. We also observed the additive cytotoxic effects when AdLPCDIRESE1A vector had been coadministrated with 5-FC. The results suggest that the use of AdLPCDIRESE1A/5FC may be value in treatment of liver cancer. Further animal studies are needed for clinical trial.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.13
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• pp.5155-5160
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• 2014

Aim: To investigate the efficacy and safety of lobaplatin-transcatheter arterial chemoembolization (TACE) combined with radioactive $^{125}I$ seed implantation in treatment of primary hepatocellular carcinoma (HCC). Methods: 75 patients with primary HCC were enrolled in the study, among them 43 receiving lobaplatin-TACE (TACE group) and 32 lobaplatin-TACE combined with $^{125}I$ seed implantation (TACE+$^{125}I$ group). After treatment, the local remission rates and postoperative complications of two groups were compared using the Pearson Chi-square test. Overall survival in the two groups was calculated using Kaplan-Meier survival curves and the differences were tested using Log-rank test. Results: There were 7 cases of complete response (CR), 13 of partial response (PR), 6 of stable disease (SD) and 17 of progressive disease (PD) in the TACE group, with 13 cases of CR, 9 of PR, 5 of SD and 5 of PD in the TACE+$^{125}I$ group. The disease control rates of TACE and TACE+$^{125}I$ group were 60.5% (26/43) and 84.4% (27/32), respectively, with a significant difference between them (P < 0.05). The survival rates at 6, 12 and 18 months in the TACE group were 100.0%, 81.8% and 50.0%, respectively, and those in TACE+$^{125}I$ group were 100.0%, 93.8% and 65.6%. The mean survival times in the TACE and TACE+$^{125}I$ groups were 19.5 and 22.9 months, respectively. There was a significant difference in the overall survival rate between two groups (P < 0.05). No serious complications were encountered in either group. Conclusion: Lobaplatin-TACE combined with $^{125}I$ seed implantation is favorable and safe for treatment of primary HCC.

• Molecules and Cells
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• v.38 no.3
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• pp.202-209
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• 2015

Hepatocellular carcinoma (HCC), a highly malignant disease and the third leading cause of all cancer mortalities worldwide, often responses poorly to current treatments and results in dismal outcomes due to frequent chemoresistance and tumor relapse. The heterogeneity of HCC is an important attribute of the disease. It is the outcome of many factors, including the cross-talk between tumor cells within the tumor microenvironment and the acquisition and accumulation of genetic and epigenetic alterations in tumor cells. In addition, there is accumulating evidence in recent years to show that the malignancy of HCC can be attributed partly to the presence of cancer stem cell (CSC). CSCs are capable to self-renew, differentiate and initiate tumor formation. The regulation of the stem cell-like properties by several important signaling pathways have been found to endow the tumor cells with an increased level of tumorigenicity, chemoresistance, and metastatic ability. In this review, we will discuss the recent findings on hepatic CSCs, with special emphasis on their putative origins, relationship with hepatitis viruses, regulatory signaling networks, tumor microenvironment, and how these factors control the stemness of hepatic CSCs. We will also discuss some novel therapeutic strategies targeted at hepatic CSCs for combating HCC and perspectives of future investigation.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.23
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• pp.10209-10215
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• 2015

To assess the contribution of tumor necrosis factor $(TNF){\beta}$ +252 polymorphisms to risk and prognosis of hepatocellular carcinoma (HCC), we enrolled 150 pairs of sex- and age-matched patients with HCC, patients with cirrhosis alone, and unrelated healthy controls. $TNF{\beta}$ +252 genotypes were determined by polymerase chain reaction with restriction fragment length polymorphism. Multivariate analysis indicated that $TNF{\beta}$ G/G genotype [odds ratio (OR), 3.64; 95%CI, 1.49-8.91], hepatitis B surface antigen (OR, 16.38; 95%CI, 8.30-32.33), and antibodies to hepatitis C virus (HCV) (OR, 39.11; 95%CI, 14.83-103.14) were independent risk factors for HCC. There was an additive interaction between $TNF{\beta}$ G/G genotype and chronic hepatitis B virus (HBV)/HCV infection (synergy index=1.15). Multivariate analysis indicated that factors associated with $TNF{\beta}$ G/G genotype included cirrhosis with Child-Pugh C (OR, 4.06; 95%CI, 1.34-12.29), thrombocytopenia (OR, 6.55; 95%CI, 1.46-29.43), and higher serum ${\alpha}$-fetoprotein concentration (OR, 2.53; 95%CI, 1.14-5.62). Patients with $TNF{\beta}$ G/G genotype had poor cumulative survival (p=0.005). Cox proportional hazard model indicated that $TNF{\beta}$ G/G genotype was a biomarker for poor HCC survival (hazard ratio, 1.70; 95%CI, 1.07-2.69). In conclusion, there are independent and additive effects between $TNF{\beta}$ G/G genotype and chronic HBV/HCV infection on risk for HCC. It is a biomarker for poor HCC survival. Carriage of this genotype correlates with disease severity and advanced hepatic fibrosis, which may contribute to a higher risk and poor survival of HCC. Chronic HBV/HCV infected subjects with this genotype should receive more intensive surveillance for early detection of HCC.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.7
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• pp.2979-2986
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• 2014

Background: Recently, peroxiredoxin3 (PRDX3) was identified as a novel molecular marker for the progression of hepatocellular carcinoma (HCC). However, its potential clinical application as a serum marker for the early diagnosis and prognosis of HCC has not been investigated. Methods: PRDX3, alpha-fetaprotein (AFP), and other biochemical parameters were measured in serum samples from 297 Chinese patients, including 96 with HCC, 98 with liver cirrhosis (LC), and 103 healthy controls (HCs). Correlations between serum PRDX3 expression and clinicopathological variables and the relationship between serum PRDX3 expression and prognosis were analyzed. Results: Serum PRDX3 was significantly higher in HCC patients than in the LC and HC groups. The sensitivity and specificity of serum PRDX3 for the diagnosis of HCC were 85.9% and 75.3%, respectively, at a cutoff of 153.26 ng/mL, and the area under the curve was 0.865. Moreover, serum PRDX3 expression was strongly associated with AFP level, tumor diameter, TNM stage, and portal vein invasion. Kaplan-Meier curve analysis revealed that HCC patients with high serum PRDX3 expression had a shorter median survival time than those with low PRDX3 expression. Moreover, serum PRDX3 expression was an independent risk factor for overall survival. The inverse correlation between serum PRDX3 and patient survival remained significant in patients with early-stage HCC and in those with normal serum AFP levels. Conclusions: Serum PRDX3 can be used as a noninvasive biomarker for the diagnosis and/or prognosis of HCC.

• Korean Journal of Radiology
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• v.22 no.7
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• pp.1066-1076
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• 2021

Objective: To evaluate the performance of the 2018 Korean Liver Cancer Association-National Cancer Center (KLCA-NCC) Practice Guidelines (hereafter, PG) for the diagnosis of hepatocellular carcinoma (HCC) using gadoxetic acid-enhanced MRI, compared to the Liver Imaging-Reporting and Data System (LI-RADS) version 2018 (hereafter, v2018). Materials and Methods: From January 2013 to October 2015, treatment-naïve hepatic lesions (≥ 1 cm) on gadoxetic acid-enhanced MRI in consecutive patients with chronic hepatitis B or cirrhosis were retrospectively evaluated. For each lesion, three radiologists independently analyzed the imaging features and classified the lesions into categories according to the 2018 KLCA-NCC PG and LI-RADS v2018. The imaging features and categories were determined by consensus. Generalized estimating equation (GEE) models were used to compare the per-lesion diagnostic performance of the 2018 KLCA-NCC PG and LI-RADS v2018 using the consensus data. Results: In total, 422 lesions (234 HCCs, 45 non-HCC malignancies, and 143 benign lesions) from 387 patients (79% male; mean age, 59 years) were included. In all lesions, the definite HCC (2018 KLCA-NCC PG) had a higher sensitivity and lower specificity than LR-5 (LI-RADS v2018) (87.2% [204/234] vs. 80.8% [189/234], p < 0.001; 86.2% [162/188] vs. 91.0% [171/188], p = 0.002). However, in lesions of size ≥ 2 cm, the definite HCC had a higher sensitivity than the LR-5 (86.8% [164/189] vs. 82.0 (155/189), p = 0.002) without a reduction in the specificity (80.0% [48/60] vs. 83.3% [50/60], p = 0.15). In all lesions, the sensitivity and specificity of the definite/probable HCC (2018 KLCA-NCC PG) and LR-5/4 did not differ significantly (89.7% [210/234] vs. 91.5% [214/234], p = 0.204; 83.5% [157/188] vs. 79.3% [149/188], p = 0.071). Conclusion: For the diagnosis of HCC of size ≥ 2 cm, the definite HCC (2018 KLCA-NCC PG) had a higher sensitivity than LR-5, without a reduction in specificity. The definite/probable HCC (2018 KLCA-NCC PG) had a similar sensitivity and specificity to that those of the LR-5/4.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.14
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• pp.5721-5727
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• 2014

Objectives: To evaluate the performance of clustering methods used in the prognostic assessment of categorical clinical data for hepatocellular carcinoma (HCC) patients in China, and establish a predictable prognostic nomogram for clinical decisions. Materials and Methods: A total of 332 newly diagnosed HCC patients treated with hepatic resection during 2006-2009 were enrolled. Patients were regularly followed up at outpatient clinics. Clustering methods including the Average linkage, k-modes, fuzzy k-modes, PAM, CLARA, protocluster, and ROCK were compared by Monte Carlo simulation, and the optimal method was applied to investigate the clustering pattern of the indices including platelet count, platelet/lymphocyte ratio (PLR) and serum aspartate aminotransferase activity/platelet count ratio index (APRI). Then the clustering variable, age group, tumor size, number of tumor and vascular invasion were studied in a multivariable Cox regression model. A prognostic nomogram was constructed for clinical decisions. Results: The ROCK was best in both the overlapping and non-overlapping cases performed to assess the prognostic value of platelet-based indices. Patients with categorical platelet-based indices significantly split across two clusters, and those with high values, had a high risk of HCC recurrence (hazard ratio [HR] 1.42, 95% CI 1.09-1.86; p<0.01). Tumor size, number of tumor and blood vessel invasion were also associated with high risk of HCC recurrence (all p< 0.01). The nomogram well predicted HCC patient survival at 3 and 5 years. Conclusions: A cluster of platelet-based indices combined with other clinical covariates could be used for prognosis evaluation in HCC.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.10
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• pp.5995-6000
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• 2013

Background: Nausea and vomiting after transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) are common in clinical practice, but few studies have reported the incidence and risk factors of such events. Objective: The purpose of this study was to analyze the incidence and risk factors of nausea and vomiting after TACE for HCC. Methods: This study was a single-center retrospective analysis of a prospectively maintained database. Between May 2010 and October 2012, 150 patients with HCC were analyzed for incidence and preprocedural risk factors. Results: The incidence of postembolization nausea and vomiting was 38.8% and 20.9%, respectively, in patients with HCC. Patients who developed nausea had lower levels (<100 IU/L) of serum alkaline phosphatase (ALP) compared to those without nausea ($123.04{\pm}69.38$ vs. $167.41{\pm}138.95$, respectively, p=0.044). Female gender correlated to a higher incidence of nausea as well (p=0.024). Patients who developed vomiting, compared to those who did not, also had lower levels (<100 IU/L) of serum ALP ($112.52{\pm}62.63$ vs. $160.10{\pm}127.80$, respectively, p=0.010), and serum alanine transferase (ALT) ($35.61{\pm}22.87$ vs. $4.97{\pm}29.62$, respectively, p=0.045). There were no statistical significances in the incidences of nausea and vomiting between male patients over 50 years old and female patients who have entered menopause (p=0.051 and p=0.409, respectively). Multivariate analysis by logistic regression analysis demonstrated that female gender and ALP>100 IU/L were the most independent predictive factors of postembolization nausea (odds ratio (OR): 3.271, 95% CI: 1.176-9.103, p=0.023 and OR: 0.447, 95% CI: 0.216-0.927, p=0.030, respectively). ALP>100 IU/L was also the most independent predictive risk factor of postembolization vomiting (OR: 0.389, 95% CI: 0.159-0.952, p=0.039). Conclusions: Postembolizaiton nausea and vomiting are common in patients with HCC. Recognition of the risk factors presented above before TACE is important for early detection and proper management of postembolization nausea and vomiting. Nevertheless, future studies are required.

• Journal of Life Science
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• v.30 no.5
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• pp.460-467
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• 2020

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers in the word. Although radiation and chemotherapy are generally effective, there are various side effects that greatly limit the effectiveness of these treatments. Therefore, traditional herbs may have potential as important resources for the discovery of liver cancer therapeutics. In this study, we selected three Korean herbal medicine formulas from the Donguibogam, namely Bigihwan (BGH), Daechilgithang (DCGT), and Mokwhyangbinranghwan (MHBRH), and evaluated their anti-cancer effects on HCC cells. According to our results of three ethanol extracts, BGH was more effective at suppressing HCC growth than DCGT or MHBRH. Furthermore, flow cytometry analysis showed that inhibition of HCC proliferation by the three extracts was associated with the induction of apoptosis and autophagy. In particular, BGH significantly increased mitochondrial impairment and showed the possibility of inducing mitophagy in comparison with the other two extracts. BGH prominently upregulated the levels of microtubule-associated protein light chain-3 which was accompanied by a decrease in the expression of anti-apoptotic Bcl-2 without altering the expression of pro-apoptotic Bax. In addition, the levels of PTEN-induced kinase 1 were also markedly increased in BGH-treated HCC cells. Moreover, autophagy blocking improved cell viability and reduced apoptosis after the three treatments, indicating that autophagy by these extracts enhances HCC cells against cytotoxicity. In conclusion, our findings show that BGH demonstrates the highest anti-cancer activity among the three formulas and inhibits the proliferation of HCC cells through autophagy induction.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.15
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• pp.6387-6390
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• 2014

Background: The prognostic significance of the circulating absolute monocyte count (AMC) in patients with locally advanced hepatocellular carcinoma (HCC) is uncertain. This study was designed to assess the association of circulating AMC with survival outcomes in patients diagnosed with locally advanced or metastatic HCC receiving systemic chemotherapy. Materials and Methods: Between January 1, 2005 and December 30, 2012, locally advanced or metastatic HCC patients who had Child-Pugh stage A or B disease and received systemic chemotherapy were retrospectively enrolled. Patient features including gender, age, extrahepatic metastasis, Child-Pugh stage, serum alpha-fetoprotein(AFP) level and AMC were collected to investigate their prognostic impact on overall survival(OS). Results: A total of 216 patients were eligible for the study. The optimal cut-off value of AMC for OS analysis was $0.38{\times}10^9/L$. Median OS was 5.84 months in low-AMC group (95% confidence interval [CI], 5.23 to 6.45), and 5.21 months in high-AMC group (95% CI, 4.37 to 6.04; p=0.003). In COX multivariate analysis, elevated AMC remained as an independent prognostic factor for worse OS (HR, 1.578; 95% CI, 1.120 to 2.223, p=0.009). Conclusions: Our results indiicate that circulating AMC is confirmed to be an independent prognostic factor for OS in patients with locally advanced or metastatic HCC receiving systemic chemotherapy.