• Radiation Oncology Journal
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• v.36 no.2
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• pp.129-138
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• 2018

Purpose: This study was conducted to compare clinical outcomes and treatment-related toxicities after stereotactic body radiation therapy (SBRT) with two different dose regimens for small hepatocellular carcinomas (HCC) ${\leq}3cm$ in size. Materials and Methods: We retrospectively reviewed 44 patients with liver-confined HCC treated between 2009 and 2014 with SBRT. Total doses of 45 Gy (n = 10) or 60 Gy (n = 34) in 3 fractions were prescribed to the 95% isodose line covering 95% of the planning target volume. Rates of local control (LC), intrahepatic failure-free survival (IHFFS), distant metastasis-free survival (DMFS), and overall survival (OS) were calculated using the Kaplan-Meier method. Results: Median follow-up was 29 months (range, 8 to 64 months). Rates at 1 and 3 years were 97.7% and 95.0% for LC, 97.7% and 80.7% for OS, 76% and 40.5% for IHFFS, and 87.3% and 79.5% for DMFS. Five patients (11.4%) experienced degradation of albumin-bilirubin grade, 2 (4.5%) degradation of Child-Pugh score, and 4 (9.1%) grade 3 or greater laboratory abnormalities within 3 months after SBRT. No significant difference was seen in any oncological outcomes or treatment-related toxicities between the two dose regimens. Conclusions: SBRT was highly effective for local control without severe toxicities in patients with HCC smaller than 3 cm. The regimen of a total dose of 45 Gy in 3 fractions was comparable to 60 Gy in efficacy and safety of SBRT for small HCC.

• Korean Journal of Veterinary Research
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• v.39 no.3
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• pp.593-601
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• 1999

This study was designed to evaluate the effect of cyclophosphamide(CY) on diethylnitrosamine(DEN)-induced hepatic tumors in rats. Thirty five male or female Sprague Dawley rats were continiously given water containing 0.01% DEN for 10 weeks and then were given with CY 25mg/rat/day in water for 3, 5, 7 or 9 days. The livers of rats were removed and fixed in 10% buffered neutral formalin. he appearances of positive cells by immunohistochemical methods using proliferating cell nuclear antigen (PCNA) antibody, p53 antibody and apoptotic kit were investigated. The livers of rats given with CY were grossly brilliant, red-brown color, flexible, and thin border, and stainability of the liver cells were restored microscopically, and the vaccuolated and degenerated regions were differentiated from restored regions. These restored findings also were advanced in control group because of no DEN treatment but tended to be less avanced. In immunohistochemistry, positive cells to PCNA antibody appeared more numerous in control groups than that of CY treated groups. Appearance of positive cells in CY-treated group for 7 days and for 9 days were more numerous than those of CY-treated groups for 3 days and for 5 days, respectively. So these findings suggested that CY suppressed cell proliferations and effects of these action were decreased with CY-treated days. The numbers of positive cells to PCNA antibody were more prominent in hepatocellular carcinoma regions and cholangiocarcinoma regions, and then were ranked as order of large liver cell regions and normal liver cell regions. Also the numbers of the positive cells by apoptotic kit tended to be higher in hepatocellular carcinoma regions and cholangiocarcinoma regions but not uniformly in order in all regions and were much less numbers than those of PCNA positive cells. So immunohistochemical methods using PCNA antibody together than using apoptotic kit alone when anti-carcinogen experiments. Rats with positive cells by p53 antibody were 11 of 15 rats(73.4%) in control groups and 12 of 18 rats(66.7%) in CY treated group, respectively. These positive cells appeared focally in early vacuole-occurring regions and were very low in numbers.

• Molecules and Cells
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• v.41 no.9
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• pp.830-841
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• 2018

Recent studies have indicated that microRNAs (miRNAs) play an important role in hepatocellular carcinoma (HCC) progression. In this study, we showed that miR-766-3p was decreased in approximately 72% of HCC tissues and cell lines, and its low expression level was significantly correlated with tumour size, TNM stage, metastasis, and poor prognosis in HCC. Ectopic miR-766-3p expression inhibited HCC cell proliferation, colony formation, migration and invasion. In addition, we showed that miR-766-3p repressed Wnt3a expression. A luciferase reporter assay revealed that Wnt3a was a direct target of miR-766-3p, and an inverse correlation between miR-766-3p and Wnt3a expression was observed. Moreover, Wnt3a up-regulation reversed the effects of miR766-3p on HCC progression. In addition, our study showed that miR-766-3p up-regulation decreased the nuclear ${\beta}-catenin$ level and expression of Wnt targets (TCF1 and Survivin) and reduced the level of MAP protein regulator of cytokinesis 1 (PRC1). However, these effects of miR-766-3p were reversed by Wnt3a up-regulation. In addition, PRC1 upregulation increased the nuclear ${\beta}-catenin$ level and protein expression of TCF1 and Survivin. iCRT3, which disrupts the ${\beta}-catenin-TCF4$ interaction, repressed the TCF1, Survivin and PRC1 protein levels. Taken together, our results suggest that miR-766-3p down-regulation promotes HCC cell progression, probably by targeting the Wnt3a/PRC1 pathway, and miR-766-3p may serve as a potential therapeutic target in HCC.

• Korean Journal of Community Nutrition
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• v.2 no.5
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• pp.735-744
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• 1997

The effect of green tea drinking on the hepatocellular chemical cacinogenesis have been studied. Placental glutathione S-transferase(GST-P) positive foci area in a liver tissue, contents of thiobarbituric acid reactive substances(TBARS), total cytochrome P450 and glucose 6-phospphatase(G6P) activity in hepatic microsomes were investigated. Weaning Sprague-Dawley male rats were fed AIN-76A diet with deionized water or green tea infusion, Rats of CTR and CTR+ groups were provided deionized water while GTI and GTI+ groups were provided green tea instead of deionized water for the entire experimental period of 13weeks. Rats of GTP and GTP + groups had deionized water for the first 6 weeks and switched to green tea for the last 7weeks of the experimental period. CTR+, GTI +, and GTP + groups were carcinogen treated groups, Diethylnitrosamine(DEN) was injected as a single dose of 200mg/kg body weight intraperitoneally after 4 weeks of feeding. 2-Acetyla-minofluorene(AAF) was used as a carcinogen proliferater and suppled in the diets of carcinogen treated rats as 0.02% content for the last 6weeks starting from 2weeks after DEN injection. Rats were sacrificed after 13week weeks of feeding. The area and number of GST-P positive foci detected in carcinogen treated rats were decreased by green tea ingestion but when timing and duration of green tea ingestion was delayed after promotion period as in GTP + group, GST-P positive foci were not decreased as much as in GTI+ group. TBARS contents of carcinogen treated rats decreased by 13weeks of green tea ingestion but GTP groups did not show statiscally significant differences. G6P activities tended to decrease by carcinogen treatment but changes were not statiscally significant by green tea ingestion. Total cytochrome P450 contents were increased by carcinogen treatment. Thirteen weeks of green tea ingestion (GTI) also increased to total cytochrome P450 contents while 7weeks of green tea ingestion(GTP) did show any effects. These results suggest that green tea has suppressive effects on hepatocellular chemical carcinogenesis probably through the activities of antioxidant compounds. (Korean J Community utrition 2(5) : 735∼744, 1997)

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.6
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• pp.2857-2860
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• 2016

Background: Chronic hepatitis B (CHB) infection is one of the important causes of hepatocellular carcinoma (HCC) in Thailand, involved in the pathogenesis and leading to a development of HCC with or without cirrhotic changes of the liver. This study was aimed to investigate the predictive factors for HCC among CHB patients in a tertiary care center in Thailand. Materials and Methods: We conducted a retrospective study of CHB patients with or without HCC during the period of January 2009 and December 2014 at Thammasat University Hospital, Pathumthani, Thailand. Data on clinical characteristics, biochemical tests and radiologic findings were collected from review of medical records. Results: A total of 266 patients were diagnosed with CHB in Thammasat university hospital during the study period. However, clinical information of only 164/266 CHB patients (98 males, 66 females with mean age of 49.4 years) could be completely retrieved in this study. The prevalence of HCC in CHB infection in this study was 38/164 (23.2%). CHB patients with HCC had a mean age older than those without HCC (59.5 vs 47 years, P-value = 0.01). Furthermore, history of upper GI bleeding, tattooing, blood transfusion, and chronic alcoholism were significantly more common in CHB patients with HCC than patients without HCC (13.2% vs 3.2% P-value 0.03, OR = 4.6, 95%CI = 1.2-18.1, 20% vs 3.9%, P-value = 0.01, OR= 6.1, 95% CI= 1.6-23.6, 20% vs 6.3%, P-value = 0.03, OR = 3.8, 95%CI =1.1-12.7, 62.2% vs 30.3%, P-value <0.0001, OR = 3.7, 95%CI= 1.7-8.1 respectively). Interestingly, more CHB patients with HCC had evidence of cirrhosis than those without HCC (78.9% vs 20.4%, P-value <0.0001, OR = 14.6, 95%CI = 5.8-36.7). In CHB patients with HCC, surgical therapy provided longer survival than radiofrequency ablation (RFA) (72 vs 46.5 months, P-value= 0.04). The mean survival time after HCC diagnosis was 17.2 months. Conclusions: HCC remains a major problem among patients with CHB infection in Thailand. Possible risk factors are male gender, history of upper GI bleeding, chronic alcoholism, tattooing, blood transfusion and evidence of cirrhosis. For early stage HCC patients, surgical treatment provided longer survival time than RFA. Most HCC patients presented with advanced disease and had a grave prognosis. Appropriate screening of CHB patients at risk for HCC might be an appropriate approach for early detection and improvement of long-term outcomes.

• Molecules and Cells
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• v.44 no.9
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• pp.658-669
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• 2021

Enhancers have been conventionally perceived as cis-acting elements that provide binding sites for trans-acting factors. However, recent studies have shown that enhancers are transcribed and that these transcripts, called enhancer RNAs (eRNAs), have a regulatory function. Here, we identified putative eRNAs by profiling and determining the overlap between noncoding RNA expression loci and eRNA-associated histone marks such as H3K27ac and H3K4me1 in hepatocellular carcinoma (HCC) cell lines. Of the 132 HCC-derived noncoding RNAs, 74 overlapped with the eRNA loci defined by the FANTOM consortium, and 65 were located in the proximal regions of genes differentially expressed between normal and tumor tissues in TCGA dataset. Interestingly, knockdown of two selected putative eRNAs, THUMPD3-AS1 and LINC01572, led to downregulation of their target mRNAs and to a reduction in the proliferation and migration of HCC cells. Additionally, the expression of these two noncoding RNAs and target mRNAs was elevated in tumor samples in the TCGA dataset, and high expression was associated with poor survival of patients. Collectively, our study suggests that noncoding RNAs such as THUMPD3-AS1 and LINC01572 (i.e., putative eRNAs) can promote the transcription of genes involved in cell proliferation and differentiation and that the dysregulation of these noncoding RNAs can cause cancers such as HCC.

• The Korean journal of internal medicine
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• v.33 no.6
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• pp.1093-1102
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• 2018

Background/Aims: The aim of this study was to investigate parameters that predict radiation-induced liver disease (RILD) following stereotactic body radiotherapy (SBRT) in patients with hepatocellular carcinoma (HCC) and to identify the clinical significance of RILD. Methods: We retrospectively reviewed the medical records of 117 HCC patients who were treated by SBRT from March 2011 to February 2015. RILD was defined as elevated liver transaminases more than five times the upper normal limit or a worsening of Child-Pugh (CP) score by 2 within 3 months after SBRT. All patients were assessed at 1 month and every 3 months after SBRT. Results: Median follow-up was 22.5 months (range, 3 to 56) after SBRT. RILD was developed in 29 of the 117 patients (24.7%). On univariate analysis, significant predictive factors of RILD were pretreatment CP score (p < 0.001) and normal liver volume (p = 0.002). Multivariate analysis showed that CP score was a significant predictor of RILD (p < 0.001). The incidence of RILD increased above a CP score of 6 remarkably. The rate of recovery from RILD decreased significantly above a CP score of 8. Survival analysis showed that CP score was an independent prognostic factor of overall survival (p = 0.001). Conclusions: CP score is a significant factor to predict RILD in patients with chronic liver disease. RILD can be tolerated by patients with a CP score ${\leq}7$. However, careful monitoring of liver function is needed for patients with a CP score 7 after SBRT.

• Journal of the Korea Academia-Industrial cooperation Society
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• v.20 no.3
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• pp.188-193
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• 2019

Transarterial chemoembolization (TACE) is a commonly used and rapidly evolving non-invasive treatment for hepatocellular carcinoma (HCC). It is important that understanding individual anatomical variants and planning for tumor-feeding artery access to acquire adequate treatment effectiveness. In this study, we will report acquired arteriovenous malformation which interferes with TACE for HCC. A 72-year-old man with persistent abdominal pain for 2 days visited our hospital. The patient was chronic hepatitis B carrier and had a history of HCC treated with conventional TACE 10 years ago. Hypervascular nodular HCC in the liver segment 8 and aberrant right hepatic artery from the superior mesenteric artery were detected on computed tomography (CT). When first TACE was performed, the tumor-feeding artery originating from the left hepatic artery was found and embolized. There was no tumor-feeding artery from the right hepatic artery but arteriovenous malformation was found. After a month, follow up CT showed necrotic lesion and residual HCC and we performed secondary TACE. On secondary TACE, we selected the right hepatic artery and passed through arteriovenous malformation. Superselective-angiogram showed remnant tumoral staining and remnant tumor was embolized using drug-eluting bead and Adriamycin. Final angiogram showed no remnant tumoral staining and the patient was discharged without complication. We found the rare case of arteriovenous malformation adjacent to HCC, and we performed superselective TACE beyond arteriovenous malformation to treat HCC.

• Korean Journal of Radiology
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• v.22 no.12
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• pp.1974-1984
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• 2021

Objective: This study aimed to compare the efficacy between no-touch (NT) radiofrequency ablation (RFA) and conventional RFA using twin internally cooled wet (TICW) electrodes in the bipolar mode for the treatment of small hepatocellular carcinomas (HCC). Materials and Methods: In this single-center, two-arm, parallel-group, prospective randomized controlled study, we performed a 1:1 random allocation of eligible patients with HCCs to receive NT-RFA or conventional RFA between October 2016 and September 2018. The primary endpoint was the cumulative local tumor progression (LTP) rate after RFA. Secondary endpoints included technical conversion rates of NT-RFA, intrahepatic distance recurrence, extrahepatic metastasis, technical parameters, technical efficacy, and rates of complications. Cumulative LTP rates were analyzed using Kaplan-Meier analysis and the Cox proportional hazard regression model. Considering conversion cases from NT-RFA to conventional RFA, intention-to-treat and as-treated analyses were performed. Results: Enrolled patients were randomly assigned to the NT-RFA group (37 patients with 38 HCCs) or the conventional RFA group (36 patients with 38 HCCs). Among the NT-RFA group patients, conversion to conventional RFA occurred in four patients (10.8%, 4/37). According to intention-to-treat analysis, both 1- and 3-year cumulative LTP rates were 5.6%, in the NT-RFA group, and they were 11.8% and 21.3%, respectively, in the conventional RFA group (p = 0.073, log-rank). In the as-treated analysis, LTP rates at 1 year and 3 years were 0% and 0%, respectively, in the NT-RFA group sand 15.6% and 24.5%, respectively, in the conventional RFA group (p = 0.004, log-rank). In as-treated analysis using multivariable Cox regression analysis, RFA type was the only significant predictive factor for LTP (hazard ratio = 0.061 with conventional RFA as the reference, 95% confidence interval = 0.000-0.497; p = 0.004). There were no significant differences in the procedure characteristics between the two groups. No procedure-related deaths or major complications were observed. Conclusion: NT-RFA using TICW electrodes in bipolar mode demonstrated significantly lower cumulative LTP rates than conventional RFA for small HCCs, which warrants a larger study for further confirmation.

• Korean Journal of Radiology
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• v.22 no.11
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• pp.1786-1796
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• 2021

Objective: To evaluate the prognostic implications of preoperative magnetic resonance imaging (MRI) features of hepatocellular carcinoma (HCC) with a focus on those with targetoid appearance based on the Liver Imaging Reporting and Data System (LI-RADS), as well as known microvascular invasion (MVI) features. Materials and Methods: This retrospective study included 242 patients (190 male; mean age, 57.1 years) who underwent surgical resection of a single HCC (≤ 5 cm) as well as preoperative gadoxetic acid-enhanced MRI between January 2012 and March 2015. LI-RADS category was assigned, and the LR-M category was further classified into two groups according to rim arterial-phase hyperenhancement (APHE). The imaging features associated with MVI were also assessed. The overall survival (OS), recurrence-free survival (RFS), and their associated factors were evaluated. Results: Among the 242 HCCs, 190 (78.5%), 25 (10.3%), and 27 (11.2%) were classified as LR-4/5, LR-M with rim APHE, and LR-M without rim APHE, respectively. LR-M with rim APHE (vs. LR-4/5; hazard ratio [HR] for OS, 5.48 [p = 0.002]; HR for RFS, 2.09 [p = 0.042]) and tumor size (per cm increase; HR for OS, 6.04 [p = 0.009]; HR for RFS, 1.77 [p = 0.014]) but not MVI imaging features (p > 0.05) were independent factors associated with OS and RFS. Compared to the 5-year OS and RFS rates in the LR-4/5 group (93.9% and 66.8%, respectively), the LR-M with rim APHE group had significantly lower rates (68.0% and 45.8%, respectively, both p < 0.05), while the LR-M without rim APHE group did not significantly differ in the survival rates (91.3% and 80.2%, respectively, both p > 0.05). Conclusion: Further classification of LR-M according to the presence of rim APHE may help predict the postoperative prognosis of patients with a single HCC.