• Asian Pacific Journal of Cancer Prevention
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• v.15 no.2
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• pp.775-780
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• 2014

Objectives: TCR-gamma-delta+T cells (${\gamma}{\delta}$ T cells) are non-conventional T lymphocytes that can recognize and eradicate tumor cells. Our previous studies showed that infiltration and function of ${\gamma}{\delta}$ T cells were substantially attenuated in hepatocellular carcinoma (HCC). However, their prognostic value was not clarified. Methods: The association between ${\gamma}{\delta}$ T cells and the clinical outcomes was determined by immunohistochemistry (IHC) in a HCC patient cohort (n = 342). Results:Immunohistochemistry showed decreased infiltration of ${\gamma}{\delta}$ T cells in tumoral tissues compared with paired peritumoral tissues. The counts of ${\gamma}{\delta}$ T cells in peritumoral tissues were negatively correlated with tumor size (P = 0.005). Survival analysis showed that the levels of peritumoral ${\gamma}{\delta}$T cells were related to both time to recurrence (TTR) and overall survival (OS) (P = 0.010 and P = 0.036, respectively) in univariate analysis, and related to TTR in multivariate analysis (P = 0.014, H.R. [95% CI] = 0.682 [0.502-0.927]). Furthermore, the level of peritumoral ${\gamma}{\delta}$ T cells showed independent prognostic value for TTR in Barcelona Clinic Liver Cancer (BCLC) stage A patients (P = 0.038, H.R. [95% CI] = 0.727 [0.537-0.984]). However, tumoral ${\gamma}{\delta}$ T cells did not show independent prognostic value for either TTR or OS in HCC patients. Conclusions: Low counts of ${\gamma}{\delta}$ T cells in peritumoral liver tissue are related to a higher incidence of recurrence in HCC and can predict postoperative recurrence, especially in those with early-stage HCC.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.24
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• pp.10949-10955
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• 2015

Liver cancer is one of leading digestive malignancies with high morbidity and mortality. There is an urgent need for the development of novel therapies for this deadly disease. It has been proven that asparagus polysaccharide, one of the most active derivates from the traditional medicine asparagus, possesses notable antitumor properties. However, little is known about the efficacy of asparagus polysaccharide as an adjuvant for liver cancer chemotherapy. Herein, we reported that asparagus polysaccharide and its embolic agent form, asparagus gum, significantly inhibited liver tumor growth with transcatheter arterial chemoembolization (TACE) therapy in an orthotopic hepatocellular carcinoma (HCC) tumor model, while significantly inhibiting angiogenesis and promoting tumor cell apoptosis. Moreover, asparagine gelatinous possessed immunomodulatory functions and showed little toxicity to the host. These results highlight the chemotherapeutic potential of asparagus polysaccharide and warrant a future focus on development as novel chemotherapeutic agent for liver cancer TACE therapy.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.24
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• pp.10713-10718
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• 2015

Purpose: To investigate the prognostic value of serum amyloid A (SAA) in patients with hepatocellular carcinoma (HCC) undergoing surgery. Materials and Methods: Preoperative serum samples of 328 patients with HCC who underwent curative resection and of 47 patients with benign liver lesion were assayed. Serum levels of SAA were measured by enzyme-linked immunosorbent assay and its correlations with clinicopathological characteristics and survival were explored. Results: Levels of SAA were significantly higher in patients with HCC than those with benign liver lesion. There were strong correlations between preoperative serum SAA level and tumor size and more advanced BCLC stage. On univariate analysis, elevated SAA was associated with reduced disease-free survival and overall survival (p=0.001 and 0.03, respectively). Multivariate analyses showed that serum SAA level was an independent prognostic factor for overall survival (hazard ratio 2.80, p=0.01). Conclusions: High SAA serum level is a novel biomarker for the prognosis of HCC patients.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.14
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• pp.5951-5957
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• 2014

Background: Traditional Chinese Medicine (TCM) possesses several advantages for treating patients with hepatocellular carcinoma (HCC). The theory of 'Jianpi Huayu Therapy' rooted from 'Jin Kui Yao Lue'is one of the most important therapies in this respect. This study was conducted to investigate the clinical effect and safety of hepatectomy combining with 'Jianpi Huayu Therapy' in the treatment of HCC. Materials and Methods: One hundred and twenty patients with HCC were randomized allocated into hepatectomy combined with 'Jianpi Huayu Therapy' group (treatment group, n=60) and hepatectomy alone group (control group, n=60). Disease- free survival (DFS) and overall survival (OS) were the primary end-points. Liver function at the end of one week after surgery, complications, average days of hospitalization as well as performance status (PS) at the end of one month post operation were also compared. Results: No significant differences existed between two groups on baseline analysis (p>0.05). No treatment related mortality occurred in either group. Post-operative complications were detected among 14 patients (23.3%) in the treatment group, and 12 (20.0%) in the control group (p=0.658). Alanine aminotransferase (ALT) at the end of one week after operation was lower in the treatment than control groups (p=0.042). No significant differences in other indexes of liver function were discovered between two groups. Average days of hospitalization reduced by 0.9 day in treatment group than in control (p=0.034). During follow-up, 104 patients (86.6%) developed recurrence. The rates of 1-, 3-, and 5-year DFS and median DFS for all patients were 77.4%, 26.3%, 9.0% and 25.6 months (range, 6.0~68.0), respectively (78.2%, 29.2%, 14.3% and 28.7 months for the 48 patients in the treatment group and 75.0%, 23.3%, 6.4%, and 22.6 months for the 56 patients in the control group (p=0.045)). 101 patients had died at the time of censor, with 1-, 3-, and 5-year overall survival rates and median survival for all patients of 97.5%, 76.4%, 40.5% and 51.2 months (range, 10.0~72.0), respectively (98.3%, 78.0%, 43.6% and 52.6 months, for treatment and 96.7%, 74.7%, 37.4%, and 49.8 months, for controls, respectively (p=0.048)). Conclusions: Hepatectomy combined with 'Jianpi Huayu therapy'was effective in the treatment of HCC, and reduced post-operative recurrence and metastasis and improved DFS and OS of HCC patients.

• 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.9
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• pp.5527-5531
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• 2013

Background and Aim: Increasing evidence correlates the presence of systemic inflammation with poor survival in patients with hepatocellular carcinoma (HCC). The aim of this study was to investigate the prognostic significance of the blood neutrophil-to-lymphocyte ratio (NLR) in patients with advanced HCC who received sorafenib monotherapy. Methods: A total of sixty-five patients with advanced HCC, not eligible for locoregional therapy, treated with sorafenib were enrolled. Potential prognostic factors such as age, gender, tumoral characteristics, performance status and NLR were analyzed. Results: Median OS and TTP for the entire cohort were 10.0 months (95%CI, 7.6-12.3 months) and 4.5 months (95% CI, 4.0-4.9 months). The mean NLR at baseline was 2.89. The median OS of patients with a high NLR (>4) was 6.5 months (95%CI, 5.2-7.7 months) compared with 12.5 months (95%CI, 9.9-15.0) for patients with a normal NLR (${\leq}4$) (P=0.01). Age ${\leq}65$, NLR>4, extrahepatic metastases and vascular invasion were all predictors of poorer overall survival. Multivariate analysis showed that NLR > 4, vascular invasion and extrahepatic metastases were independent predictors of poorer overall survival. The median TTP of patients with a high NLR was 2.5 months (95%CI, 1.4-3.6 months) compared with 4.5 months (95%CI, 3.9-5.1 months) for patients with a normal NLR (P=0.012). Conclusions: High baseline NLR was associated with worse OS and TTP for patients with advanced HCC treated with sorafenib.

• The Journal of the Korean Society for Microbiology
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• v.21 no.2
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• pp.233-241
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• 1986

Patients of chronic hepatic diseases(n=107) including chronic hepatitis caused by hepatitis B virus infections(n=31), liver cirrhosis(n=53), and hepatocellular carcinoma(n=23) were examined to ascertain genetic relationship between chronic hepatic diseases and histocompatibility antigen. Peripheral blood lymphocytes were separated from whole blood by the method of Ficoll/Hypaque gradient. Total 54 histocompatibility antigens(class I antigens: 41, class II antigens: 13) were analysed by performing of complement dependent microlymphocytotoxicity method using Terasaki's and Catholic Medical College tissue typing plates. HLA antigen frequencies were compared with those of 661 normal controls. The following results were obtained: 1. HLA antigen frequencies of HLA-Bw46, -Bw76, -Cw1, -Cw6, and HLA-DR8 in chronic hepatitis patients were shown to be higher than those in controls(P<0.01). 2. HLA antigen frequencies of HLA-Bw46, -Cw7(P<0.01), and HLA-B37, -Bw58, -Cw1, -MT1(P < 0.05) in liver cirrhosis patients were shown relatively higher frequencies than those in controls. 3. In patients with hepatocellular carcinoma, antigens of HLA-A1, -A26, -Cw3, -Cw7 and HLA-DR6 were dominantly detected. 4. There were negative associations with HLA-Cw4, and -DR4 in patients of chronic hepatic diseases(P < 0.05).

• Reproductive and Developmental Biology
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• v.31 no.3
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• pp.145-152
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• 2007

Transgenic mice were generated by microinjecting a plasmid DNA containing the SV40 (simian virus 40) large T antigen (Tag) gene fused with mouse albumin promoter/enhancer sequences into fertilized one-cell mouse embryos. Among eleven founder transgenic animals, four developed hepatocellular carcinoma, two showed kidney cancer and one developed skin and brain tumors. Three stable transgenic lines, #1-2, #1-6 and #1-11 were established. Members of the lines #1-6 and #1-11 reproducibly developed liver tumors by 8 to 10 weeks of age but did not exhibit any phenotypic changes in other tissues. Histological changes loading to liver tumor formation occurred with predictable kinetics and could be classified into three distinct stages; (a) newborn to 3 weeks of age, characterized by hyperplastic hepatocytes with reduced amounts of cytoplasm without any nuclear alterations, (b) between 4 to 8 weeks of age, characterized by diffuse liver cell dysplasia without observable tumor nodules, and (c) 9 weeks of age and thereafter, characterized by hepatocellular carcinomas in the background of extensive liver dysplasia. Metastasis to the lung from a liver carcinoma was observed in #1-11 founder animal. This transgenic mouse system displays similarities with human liver cancers in a number of aspects and provides a useful model for the study of molecular events involved in hepatocarcinogenesis.

• 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.