• Journal of the East Asian Society of Dietary Life
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• v.23 no.2
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• pp.197-202
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• 2013

The objective of this study is to evaluate the anti-cancer and anti-inflammatory activities of plum (Formosa, Oishiwase, Soldam) for the future development of functional food products. To determine the anti-inflammatory effect of different types of plums, the inhibitory effect of plum extracts on nitric oxide (NO) production were measured in lipopolysaccharide (LPS)-stimulated Raw 264.7 mouse macrophage cells and human cancer cell lines (A549, Ags, Hela, Hep3B). Among the three different plum cultivars, Oishiwase at a concentration of 1 mg/mL showed the highest inhibitory effects on NO production (%) in Raw 264.7 macrophage cells. Moreover, Oishiwase exhibited a higher anti-cancer activity against A549 (renal carcinoma, 50%), Ags (gastric carcinoma, 35%), HeLa (cervical carcinoma, 50%), and Hep3B (hepatocellular carcinoma, 31%) at a concentration on 1 mg/mL, respectively, compared to Formosa and Soldam. Our findings suggest Oishiwase plum extracts may serve as potential dietary sources of natural health promoting substances.

• Genomics & Informatics
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• v.6 no.4
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• pp.181-191
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• 2008

RAS guanyl-releasing protein 3 (RasGRP3), a member of the Ras subfamily of GTPases, functions as a guanosine triphosphate (GTP)/guanosine diphosphate (GDP)-regulated switch that cycles between inactive GDP- and active GTP-bound states during signal transduction. Various growth factors enhance hepatocellular carcinoma (HCC) proliferation via activation of the Ras/Raf-1/extracellular signal-regulated kinase (ERK) pathway, which depends on RasGRP3 activation. We investigated the relationship between polymorphisms in RasGRP3 and progression of hepatitis B virus (HBV)-infected HCC in a Korean population. Nineteen RasGRP3 SNPs were genotyped in 206 patients with chronic liver disease (CLD) and 86 patients with HCC. Our results revealed that the T allele of the rs7597095 SNP and the C allele of the rs7592762 SNP increased susceptibility to HCC (OR=1.55, p=0.04 and OR=1.81${\sim}$2.61, p=0.01${\sim}$0.03, respectively). Moreover, patients who possessed the haplotype (ht) 1 (A-T-C-G) or diplotype (dt) 1 (ht1/ht1) variations had increased susceptibility to HCC (OR=1.79${\sim}$2.78, p=0.01${\sim}$0.03). In addition, we identified an association between haplotype1 (ht1) and the age of HCC onset; the age of HCC onset are earlier in ht1 +/+ than ht1 +/- or ht1 -/- (HR=0.42${\sim}$0.66, p=0.006${\sim}$0.015). Thus, our data suggest that RasGRP3 SNPs are significantly associated with an increased risk of developing HCC.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.9
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• pp.3915-3920
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• 2014

Background: Hepatocellular carcinoma (HCC) is a dismal tumor with a high incidence, prevalence and poor prognosis and survival. Management of HCC necessitates multidisciplinary clinics due to the wide heterogeneity in its presentation, different therapeutic options, variable biologic behavior and background presence of chronic liver disease. We studied the different prognostic factors that affected survival of our patients to improve future HCC management and patient survival. Materials and Methods: This study is performed in a specialized multidisciplinary clinic for HCC in Kasr El Eini Hospital, Cairo University, Egypt. We retrospectively analyzed the different patient and tumor characteristics and the primary mode of management applied to our patients. Further analysis was performed using univariate and multivariate statistics. Results: During the period February 2009 till February 2013, 290 HCC patients presented to our multidisciplinary clinic. They were predominantly males and the mean age was $56.5{\pm}7.7years$. All cases developed HCC on top of cirrhosis that was mainly due to HCV (71%). Most of our patients were Child-Pugh A (50%) or B (36.9%) and commonly presented with small single lesions. Transarterial chemoembolization was the most common line of treatment used (32.4%). The overall survival was 79.9% at 6 months, 54.5% at 1 year and 22.4% at 2 years. Serum bilirubin, site of the tumor and type of treatment were the significant independent prognostic factors for survival. Conclusions: Our main prognostic variables are the bilirubin level, the bilobar hepatic affection and the application of specific treatment (either curative or palliative). Multidisciplinary clinics enhance better HCC management.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.1
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• pp.225-229
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• 2012

Background: Males have a higher prevalence of hepatocellular carcinoma (HCC) than females in general, but the reasons for the sex disparity are still obscure. DNA copy number alteration (CNA) is a major feature of solid tumors including HCC, but whether CNA plays a role in sex-related differences in HCC development has never been evaluated. Methods: High-resolution array comparative genomic hybridization (CGH) was used to examine 17 female and 46 male HCC patients with chronic hepatitis B virus (HBV) infection in Shanghai, China. Two-tailed Fisher's exact or ${\chi}^2$ tests was used to compare CNAs between females and males. Results: The overall frequencies and patterns of CNAs in female and male cases were similar. However, female HCC tumors presented more copy number gains compared to those in males on 1q21.3-q22 (76.5% vs. 37.0%, P = 0.009), 11q11 (35.3% vs. 0.0%, P = 0.0002) and 19q13.31-q13.32 (23.5% vs. 0.0%, P = 0.004), and loss on 16p11.2 (35.3% vs. 6.5%, P = 0.009). Relative to females, male cases had greater copy number loss on 11q11 (63.0% vs. 17.6%, P = 0.002). Further analyses showed that 11q11 gain correlated with 19q13.31-q13.32 gain (P = 0.042), 11q11 loss (P = 0.011) and 16p11.2 loss (P = 0.033), while 1q21.3-q22 gain correlated with 19q13.31-q13.32 gain (P = 0.046). Conclusions: These findings suggest that CNAs may play a role in sex-related differences in HBVassociated HCC development.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.19
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• pp.8069-8073
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• 2014

Background: Hepatocellular carcinoma (HCC) is one of the most frequent cancers worldwide, with a high mortality. Most patients present with late stage disease, when the treatment options are limited to systemic chemotherapy. The purpose of our study was to evaluate the significance of p53 and EGFR expression in HCC, and to determine whether these two markers correlate with conventional parameters of prognosis. Materials and Methods: Our study included a total of 45 patients, diagnosed histopathologically with HCC. Clinicopathological data including sex, age, tumor necrosis, tumor size, histologic grading, tumor stage, the presence of cirrhosis and chronic hepatitis, were recorded from the Institute database. Three independent microscopic fields were selected for each sample and all the tumor cells within each microscopic field were counted, and then the positive percent of p53 cells were calculated. Three staining patterns were recognized: diffuse, heterogenous and focal. The intensity of EGFR staining was scored on a scale of 0-3+: 0 no staining; 1+ when a weak membrane staining was observed; 2+ when membrane staining is more intense than in 1+, but less than 3+, and 3+ when intense dark brown staining delineated the membrane. To determine the relationship between EGFR expression and p53, we performed double staining in the same HCC specimens. Results: By immunohistochemical staining, p53 protein was detected in tumor cell nuclei in 20 HCCs (44%). We found a significant correlation between the intensity of p53 expression and the histological grade (p=0.008). EGFR expression was detected in 17 (38%) cases, linked to histological grade (p=0.039). Moreover, the intensity of p53 expression was significantly correlated with EGFR intensity (p=0.014). Conclusions: Our results suggest that overexpression of p53 and EGFR plays an important role in hepatocarcinogenesis and contributes to more advanced disease. These markers are not only valuable predictors of prognosis in HCC, but they are also rational targets for new anti-tumor strategies.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.11
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• pp.4443-4448
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• 2014

Background: A number of studies have reported the association of X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism with susceptibility to hepatocellular carcinoma (HCC). However, the results were inconsistent and inconclusive. The aim of this study was to comprehensively explore the association of XRCC1 Arg399Gln variant with HCC risk. Materials and Methods: Systematic searches of PubMed, Elsevier, Science Direct, CNKI and Chinese Biomedical Literature Database were performed. Pooled odds ratio (OR) with 95% confidence intervals (CI) was calculated to estimate the strength of association. Results: Overall, we observed an increased HCC risk among subjects carrying XRCC1 codon 399 Gln/Gln, Arg/Gln and Gln/Gln+Arg/Gln genotypes (OR=1.20, 95%CI: 1.05-1.38, OR=1.16, 95%CI: 1.05-1.28, and OR=1.14, 95%CI: 1.04-1.24, respectively) based on 20 studies including 3374 cases and 4633 controls. In subgroup analysis, we observed an increased risk of XRCC1 codon 399 Gln/Gln, Arg/Gln and Gln/Gln+Arg/Gln polymorphisms for HCC in hospital-based study (OR=1.25, 95%CI: 1.03-1.51, OR=1.21, 95%CI: 1.07-1.36 and OR=1.18, 95%CI: 1.06-1.31, respectively) and in Asian population (OR=1.19, 95%CI: 1.03-1.38, OR=1.17, 95%CI: 1.04-1.30 and OR=1.14, 95%CI: 1.04-1.25, respectively). Limiting the analysis to the studies with controls in agreement with Hardy-Weinberg equilibrium (HWE), we observed an increased HCC risk among Gln/Gln, Arg/Gln and Gln/ Gln+Arg/Gln genotype carriers (OR=1.17, 95%CI: 1.05-1.29, OR=1.12, 95%CI: 1.00-1.25 and OR=1.11, 95%CI: 1.02-1.21, respectively). Conclusions: This updated meta-analysis results suggest that XRCC1 Arg399Gln variants may contribute to HCC risk. Well-designed studies with larger sample size were required to further verify our findings.

• Radiation Oncology Journal
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• v.33 no.3
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• pp.179-187
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• 2015

Purpose: The purpose of this study was to investigate the predictable value of pretreatment $^{18}F$-fluorodeoxyglucose positron emission tomography-computed tomography ($^{18}F$-FDG PET-CT) in radiotherapy (RT) for patients with hepatocellular carcinoma (HCC) or portal vein tumor thrombosis (PVTT). Materials and Methods: We conducted a retrospective analysis of 36 stage I-IV HCC patients treated with RT. $^{18}F$-FDG PET-CT was performed before RT. Treatment target was determined HCC or PVTT lesions by treatment aim. They were irradiated at a median prescription dose of 50 Gy. The response was evaluated within 3 months after completion of RT using the Response Evaluation Criteria in Solid Tumors (RECIST). Response rate, overall survival (OS), and the pattern of failure (POF) were analyzed. Results: The response rate was 61.1%. The statistically significant prognostic factor affecting response in RT field was maximal standardized uptake value (maxSUV) only. The high SUV group (maxSUV ${\geq}5.1$) showed the better radiologic response than the low SUV group (maxSUV < 5.1). The median OS were 996.0 days in definitive group and 144.0 days in palliative group. Factors affecting OS were the %reduction of alpha-fetoprotein (AFP) level in the definitive group and Child-Pugh class in the palliative group. To predict the POF, maxSUV based on the cutoff value of 5.1 was the only significant factor in distant metastasis group. Conclusion: The results of this study suggest that the maxSUV of $^{18}F$-FDG PET-CT may be a prognostic factor for treatment outcome and the POF after RT. A %reduction of AFP level and Child-Pugh class could be used to predict OS in HCC.

• Radiation Oncology Journal
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• v.33 no.4
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• pp.276-283
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• 2015

Purpose: We evaluated the efficacy and toxicity of repeated high dose 3-dimensional conformal radiation therapy (3D-CRT) for patients with unresectable hepatocellular carcinoma. Materials and Methods: Between 1998 and 2011, 45 patients received hepatic re-irradiation with high dose 3D-CRT in Samsung Medical Center. After excluding two ineligible patients, 43 patients were retrospectively reviewed. RT was delivered with palliative or salvage intent, and equivalent dose of 2 Gy fractions for ${\alpha}/{\beta}=10Gy$ ranged from $31.25Gy_{10}$ to $93.75Gy_{10}$ (median, $44Gy_{10}$). Tumor response and toxicity were evaluated based on the modified Response Evaluation Criteria in Solid Tumors criteria and the Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0. Results: The median follow-up duration was 11.2 months (range, 4.1 to 58.3 months). An objective tumor response rate was 62.8%. The tumor response rates were 81.0% and 45.5% in patients receiving ${\geq}45Gy_{10}$ and $<45Gy_{10}$, respectively (p = 0.016). The median overall survival (OS) of all patients was 11.2 months. The OS was significantly affected by the Child-Pugh class as 14.2 months vs. 6.1 months (Child-Pugh A vs. B, p < 0.001), and modified Union for International Cancer Control (UICC) T stage as 15.6 months vs. 8.3 months (T1-3 vs. T4, p = 0.004), respectively. Grade III toxicities were developed in two patients, both of whom received ${\geq}50Gy_{10}$. Conclusion: Hepatic re-irradiation may be an effective and tolerable treatment for patients who are not eligible for further local treatment modalities, especially in patients with Child-Pugh A and T1-3.

• Radiation Oncology Journal
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• v.36 no.1
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• pp.25-34
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• 2018

Purpose: This study aimed to evaluate the initial outcomes of proton beam therapy (PBT) for hepatocellular carcinoma (HCC) in terms of tumor response and safety. Materials and Methods: HCC patients who were not indicated for standard curative local modalities and who were treated with PBT at Samsung Medical Center from January 2016 to February 2017 were enrolled. Toxicity was scored using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Tumor response was evaluated using modified Response Evaluation Criteria in Solid Tumors (mRECIST). Results: A total of 101 HCC patients treated with PBT were included. Patients were treated with an equivalent dose of $62-92GyE_{10}$. Liver function status was not significantly affected after PBT. Greater than 80% of patients had Child-Pugh class A and albumin-bilirubin (ALBI) grade 1 up to 3-months after PBT. Of 78 patients followed for three months after PBT, infield complete and partial responses were achieved in 54 (69.2%) and 14 (17.9%) patients, respectively. Conclusion: PBT treatment of HCC patients showed a favorable infield complete response rate of 69.2% with acceptable acute toxicity. An additional follow-up study of these patients will be conducted.

• Journal of Veterinary Clinics
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• v.28 no.6
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• pp.549-554
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• 2011

FK506 is a widespread immunosuppressive drug after liver transplantion in patients with advanced-stage hepatocellular carcinoma. Dexamethasone is frequently used as co-treatment in cytotoxic cancer therapy, e.g. to prevent nausea, to protect normal tissue or for other reasons. Our aim was to investigate antitumor effects of FK506 in Hep3B cells, one of differentiated human hepatocellular carcinoma cell lines and inhibitory effects of dexamethsone on FK506- induced antitumor effects. Cell injury was evaluated by biochemical assays as cell viability, lactate dehydrogenase (LDH) and reactive oxygen species (ROS) in Hep3B cells. Intracellular calcium concentration ([$Ca^{2+}$]i) and the level of activation of the c-Jun-N-terminal kinase (JNK) and the Bax protein in cultured Hep3B cells was measured. Exposure of 0.1 ${\mu}M$ FK506 to Hep3B cells led to cell death accompanied by a decrease in cell viability and an increase in LDH, ROS and [$Ca^{2+}$]i. FK506 induced an increase in activity of Bax and JNK protein but inhibited the activity of Bcl-2 protein. Treatment of dexamethsone, per se, had no effects on cell viability, LDH and ROS. However, co-treatment of FK506 and dexamethasone diminished the FK506-induced LDH release, ROS generation and JNK activation. These results demonstrate that FK506 has antitumor effect in Hep3B cells but the combination of FK506 and dexamethasone antagonizes the FK506-induced antitumor effects.