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Background: Hepatocellular carcinoma (HCC), a primary liver malignancy, is the most common cancer in males and fourth common cancer in females in Taiwan. HCC patients usually have a poor prognosis due to late diagnosis. It has been classified as a complex disease because of the heterogeneous phenotypic and genetic traits of the patients and a wide range of risk factors. Micro (mi)RNAs regulate oncogenes and tumor suppressor genes that are known to be dysregulated in HCC. Several studies have found an association between downregulation of miR-122, a liver-specific miRNA, and upregulation of paternally expressed gene 10 (PEG10) in HCC; however, the correlation between low miR-122 and high PEG10 levels still remains to be defined and require more investigations to evaluate their performance as an effective prognostic biomarker for HCC.Methods: An in silico approach was used to isolate PEG10, a potential miR-122 target implicated in HCC development. miR-122S binding sites in the PEG10 promoter were evaluated with a reporter assay. The regulation of PEG10 by miR-122S overexpression was examined by quantitative RT-PCR, western blotting, and immunohistochemistry in miR-122 knockout mice and liver tissue from HCC patients. The relationship between PEG10 expression and clinicopathologic features of HCC patients was also evaluated.Results: miR-122 downregulated the expression of PEG10 protein through binding to 3'-untranslated region (UTR) of the PEG10 transcript. In miR-122 knockout mice and HCC patients, the deficiency of miR-122 was associated with HCC progression. The expression of PEG10 was increased in 57.3 % of HCC as compared to paired non-cancerous tissue samples. However, significant upregulation was detected in 56.5 % of patients and was correlated with Okuda stage (P = 0.05) and histological grade (P = 0.001).Conclusions: miR-122 suppresses PEG10 expression via direct binding to the 3'-UTR of the PEG10 transcript. Therefore, while PEG10 could not be an ideal diagnostic biomarker for HCC but its upregulation in HCC tissue still has predictive value for HCC prognosis. [ABSTRACT FROM AUTHOR]

Background: The decrease in peripheral blood lymphocytes induced by radiation lessens the antitumour effect of the immune response, which might cause immunosuppression. We aimed to investigate the correlation between the decrease in peripheral blood lymphocytes during radiotherapy (RT) and the spleen irradiation dose in patients with hepatocellular carcinoma (HCC).Methods: The subjects were 59 patients with HCC who had received RT from 2005 to 2014. The Min ALC (minimum value of absolute counts for peripheral blood lymphocytes) was collected from the routine workup for each patient prior to RT and weekly during RT. Spleen dose-volume variables, including the percentage of the organ volume receiving ≥ n Gy (Vn) and the mean spleen dose (MSD), were calculated using Eclipse treatment planning. Potential associations between dosimetric variables and the Min ALC were assessed by multiple linear regression analysis.Results: Peripheral lymphocytes decreased during RT (P < 0.001). The Min ALC correlated with the MSD (P = 0.005), spleen V5 (P = 0.001), spleen V25 (P = 0.026) and spleen V30 (P = 0.018). Controlling for the Karnofsky performance status (KPS), sex, age, Child-Pugh grade, total dose and tumour stage, a multiple linear regression model with bootstrap analysis of 1000 replicates showed that only the spleen V5 was correlated with the decrease in the Min ALC (P < 0.05). According to the receiver-operating characteristic (ROC) curve analysis, the predictive cutoff values of the MSD, V5, V25 and V30 of the spleen for the Min ALC were 227.72 cGy, 17.84, 0.98 and 0.42%, respectively (P = 0.002, P = 0.004, P = 0.007 and P = 0.002, respectively). Furthermore, an MSD ≥ 227.72 cGy (OR = 14.39; 95% CI, 12.18 to 16.60) and V5 (OR = 7.99; 95% CI, 6.91 to 9.07) of the spleen significantly predicted the Min ALC.Conclusions: Higher spleen irradiation doses were significantly correlated with lower Min ALC during RT for HCC. V5 should be limited in clinical practice. Maximum sparing for spleen irradiation during RT is recommended to preserve peripheral blood lymphocytes, which may decrease immunosuppression. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the safety of CyberKnife stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) patients and identify the treatment-related risk factors of hepatic toxicity. Materials and methods: One hundred and four HCC patients treated with CyberKnife SBRT were included in this study between August 2009 and December 2012. The average dose of prescribed radiation was 42.81±4.78 Gy (28-55 Gy) with the average fraction size of 8-16 Gy to the planning target volume. The average fractions were 3.31±0.81 (2-6 fractions). Response rates were determined, and the Child-Pugh (CP) score and class following CyberKnife SBRT were obtained to evaluate hepatic toxicity. Results: Seventeen patients experienced progression in CP class and 24 patients experienced CTCAE V. 4.0 grade 2-3 hepatic toxicity during the five-month follow-up period, while no patient experienced grade 4 liver toxicity. Multivariate analysis indicated that only V25 was an independent factor in grade 2-3 hepatic toxicity (P=0.029, <0.05). Radiation-induced hepatic toxicity (RIHT), defined as an increase of at least two points within three months following CyberKnife SBRT, occurred in 13 of the 104 patients (13/104, 12.5%), and only the normal liver tissue was found to be associated with RIHT (P=0.008, <0.05). Conclusion: CyberKnife SBRT is a feasible and safe treatment for HCC with regard to hepatic toxicity, while V25 and normal liver volume may be an independent factor of grade 2-3 hepatic toxicity and RIHT, respectively. [ABSTRACT FROM AUTHOR]

Objective To study the feasibility and the potential benefits of defining the internal gross tumor volume (IGTV) of hepatocellular carcinoma (HCC) using contrast-enhanced 4D CT images obtained by combining arterial-phase (AP) contrast-enhanced (CE) 3D CT and non-contrast-enhanced (NCE) 4D CT images using deformable registration (DR). Methods Ten HCC patients who had received radiotherapy beforehand were selected for this study. The following CT simulation images were acquired sequentially: NCE 4D CT in free breathing, NCE 3D CT and APCE 3D CT in end-expiration breath holding. All 4D CT images were sorted into ten phases according to breath cycle (CT00 ~ CT90). Gross tumor volumes (GTVs) were contoured on all CT images and the IGTV-1 was obtained by merging the GTVs in each phase of 4D CT images. The GTV on the APCE 3D CT image was deformably registered to each 4D CT phase image according to liver shape using RayStationTM 3.99.0.7 version treatment planning system. The IGTV-DR was obtained by merging the GTVs after DR on the 4D CT images. Volume differences among the GTVs and between the IGTV-1 and the IGTV-DR were compared. Results The edge of most lesions could be definitively identified using APCE 3D CT images compared to NCE 4D and 3D CT images. The GTV volume on APCE 3D CT images increased by an average of 34.79% (P < 0.05). There was no significant difference among the GTV volumes obtained using NCE 4D and 3D CT images (P > 0.05). The GTV volumes after DR on 4D CT different phase images increased by an average of 36.29% (P < 0.05) as was observed using the APCE 3D CT image (P > 0.05). Lastly, the volume of IGTV-DR increased by an average of 19.91% compared to that of IGTV-1 (P < 0.05). Conclusion NCE 4D CT imaging alone has the potential risk of missing a partial volume of the HCC. The combination of APCE 3D CT and NCE 4D CT images using the DR technique improved the accuracy of the definition of the IGTV in HCC. [ABSTRACT FROM AUTHOR]