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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]

This study was conducted to assess the efficacy and toxicity of nimotuzumab combined with radiotherapy (RT) in elderly patients with esophageal squamous cell carcinoma. The clinical data of 16 esophageal squamous cell carcinoma patients, aged >70 years, who were initially treated with nimotuzumab combined with RT, were collected and retrospectively reviewed. The overall response and treatment toxicity were analyzed using SPSS software. All the patients completed the treatment schedule. The response to treatment was assessed at treatment completion and reassessed after 1-2 months: 1 patient achieved complete response (CR), 10 patients achieved partial response (PR), 4 patients exhibited stable disease and 1 patient developed disease progression and succumbed to radiation pneumonitis (RP) 1 month later. The overall response rate (CR+PR) was 68.8%. All 16 patients experienced grade 1-2 radiation esophagitis; no grade 3-4 toxicities were reported. There was one case of treatment-related mortality due to RP during the study. One patient developed a rash on the forearm. No hematological, gastrointestinal, hepatic or renal toxicities were observed. In conclusion, the toxicity of combined nimotuzumab with RT in elderly patients with esophageal cancer was tolerable. However, due to limitations associated with the retrospective nature of this study, the limited number of enrolled cases and the epidermal growth factor receptor expression determination prior to treatment, the efficacy of this treatment modality requires further investigation. [ABSTRACT FROM AUTHOR]

Background: To validate a gradient-based segmentation method for gross tumor volume(GTV) delineation on 8F-fluorothymidine (FLT)positron emission tomography (PET)/ computer tomography (CT) in esophageal squamous cell cancer through pathologic specimen, in comparison with standardized uptake values (SUV) threshold-based methods and CT. The corresponding impact of this GTV delineation method on treatment planning was evaluated. Methods and materials: Ten patients with esophageal squamous cell cancer were enrolled. Before radical surgery, all patients underwent FLT-PET/CT. GTVs were delineated by using four methods. GTVGRAD, GTV1.4 and GTV30%max were segmented on FLT PET using a gradient-based method, a fixed threshold of 1.4 SUV and 30% of SUVmax, respectively. GTVCT was based on CT data alone. The maximum longitudinal tumor length of each segmented GTV was compared with the measured tumor length of the pathologic gross tumor length (LPath). GTVGRAD, GTV1.4 and GTV30%max were compared with GTVCT by overlap index. Two radiotherapy plannings (planGRAD) and (planCT) were designed for each patient based on GTVGRAD and GTVCT. The dose-volume parameters for target volume and normal tissues, CI and HI of planGRAD and planCT were compared. Results: The mean ± standard deviation of LPath was 6.47 ± 2.70 cm. The mean ± standard deviation of LGRAD, L1.4, L30%max and LCT were 6.22 ± 2.61, 6.23 ± 2.80, 5.95 ± 2.50,7.17 ± 2.28 cm, respectively. The Pearson correlation coefficients between LPath and each segmentation method were 0.989, 0.920, 0.920 and 0.862, respectively. The overlap indices of GTVGRAD, GTV1.4, GTV30%max when compared with GTVCT were 0.75 ± 0.12, 0.71 ± 0.12, 0.57 ± 0.10, respectively. The V5, V10, V20, V30 and mean dose of total-lung, V30 and mean dose of heart of planGRAD were significantly lower than planCT. Conclusions: The gradient-based method provided the closest estimation of target length. The radiotherapy plannings based on the gradient-based segmentation method reduced the irradiated volume of lung, heart in comparison to CT. [ABSTRACT FROM AUTHOR]

Background To validate a gradient-based segmentation method for gross tumor volume(GTV) delineation on 8F-fluorothymidine (FLT)positron emission tomography (PET)/ computer tomography (CT) in esophageal squamous cell cancer through pathologic specimen, in comparison with standardized uptake values (SUV) threshold-based methods and CT. The corresponding impact of this GTV delineation method on treatment planning was evaluated. Methods and materials Ten patients with esophageal squamous cell cancer were enrolled. Before radical surgery, all patients underwent FLT-PET/CT. GTVs were delineated by using four methods. GTVGRAD, GTV1.4 and GTV30%max were segmented on FLT PET using a gradient-based method, a fixed threshold of 1.4 SUV and 30% of SUVmax, respectively. GTVCT was based on CT data alone. The maximum longitudinal tumor length of each segmented GTV was compared with the measured tumor length of the pathologic gross tumor length (LPath). GTVGRAD, GTV1.4 and GTV30%max were compared with GTVCT by overlap index. Two radiotherapy plannings (planGRAD) and (planCT) were designed for each patient based on GTVGRAD and GTVCT. The dose-volume parameters for target volume and normal tissues, CI and HI of planGRAD and planCT were compared. Results The mean ± standard deviation of LPath was 6.47 ± 2.70cm. The mean ± standard deviation of LGRAD,L1.4, L30%max and LCT were 6.22 ± 2.61, 6.23 ± 2.80, 5.95 ± 2.50,7.17 ± 2.28cm, respectively. The Pearson correlation coefficients between LPath and each segmentation method were 0.989, 0.920, 0.920 and 0.862, respectively. The overlap indices of GTVGRAD, GTV1.4, GTV30%max when compared with GTVCT were 0.75 ± 0.12, 0.71 ± 0.12, 0.57 ± 0.10, respectively. The V5, V10, V20, V30 and mean dose of total-lung, V30 and mean dose of heart of planGRAD were significantly lower than planCT. Conclusions The gradient-based method provided the closest estimation of target length. The radiotherapy plannings based on the gradient-based segmentation method reduced the irradiated volume of lung, heart in comparison to CT. [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]

Purpose: The purpose of this study was to explore the correlation between the respiration-induced target motion and volume variation with the dosimetric variance on breast and organ at risk (OAR) during free breathing. Methods and materials: After breast-conserving surgery, seventeen patients underwent respiration-synchronized 4DCT simulation scans during free breathing. Treatment planning was constructed using the end inspiration scan, then copied and applied to the other phases and the dose distribution was calculated separately to evaluate the dose-volume histograms (DVH) parameters for the planning target volume (PTV), ipsilateral lung and heart. Results: During free breathing, the treated breast motion vector was 2.09 ± 0.74 mm, and the volume variation was 3.05 ± 0.94%. There was no correlation between the breast volume and target/OAR dosimetric variation (∣r∣ = 0.39 ∼ 0.48). In the anteroposterior, superoinferior and vector directions, breast movement correlated well with the mean PTV dose, conformal index, and the lung volume receiving high dose (∣r∣ = 0.651-0.975); in the superoinferior and vector directions, breast displacement only correlated with the heart volume receiving >5 Gy (V5) (r=-0.795, 0.687). The lung volume and the lung volume receiving high dose correlated reasonably well (r = 0.655 ∼ 0.882), and a correlation only existed between heart volume and V5 (r = -0.701). Conclusion: Target movement correlated well with the target/OAR dosimetric variation in certain directions, indicating that whole breast IMRT assisted by breathing control or respiratory-adapted gated treatment promotes the accuracy of dose delivery during radiotherapy. During free breathing, the effect of breast volume variation can be ignored in whole breast IMRT. [ABSTRACT FROM AUTHOR]

Background: To investigate the feasibility of contouring the planning risk organ volume (PRV) for the heart, and to determine the probability of evaluating radiation dose to the heart using kilovoltage-cone beam computed tomography (kV-CBCT) in early-stage non-small-cell lung cancer (NSCLC) patients, who received stereotactic body radiotherapy (SBRT).Materials and Methods: Seventeen NSCLC patients who received SBRT (5Gy/f × 10f dose) were enrolled and subjected to CBCT and CT imaging analyses to plan treatment. Sequential planning CBCT images of individual patient's hearts were analyzed for reproducibility of heart contouring and volume. Comparative analyses were made between the planning CT- and CBCT-detected heart margins and dose-volume indices for treatment.Results: The heart volume from planning CT images was significantly smaller than that from CBCT scans (p < 0.05), and the volumes based on the different series of CBCT images were similar (p > 0.05).The overlap of the heart region on the same anatomical section between the first series of CBCT scans and other scans reached 0.985 ± 0.020 without statistically significant differences (p > 0.05). The mean margins of the heart from planning CT and CBCT scans were 10.5 ± 2.8 mm in the left direction, 5.9 ± 2.8 mm in the right direction, 2.2 ± 1.6 mm in the direction of the head, 3.3 ± 2.2 mm in the direction of the foot, 6.7 ± 1.1 mm in the anterior direction, and 4.5 mm ± 2.5 mm in the posterior direction. All relative and absolute dose-volume indices obtained from CBCT images were significantly larger than those from planning CT scans (p < 0.05), with the exception of the volume in the 5Gy region.Conclusion: The PRV of heart contouring based on kV-CBCT is feasible with good reproducibility. More accurate and objective dose-volume indices may be obtained for NSCLC patients by using kV-CBCT, instead of CT, to plan SBRT. [ABSTRACT FROM AUTHOR]

Background Lung radiation injury is a critical complication of radiotherapy (RT) for thoracic esophageal carcinoma (EC). Therefore, the goal of this study was to investigate the feasibility and dosimetric effects of reducing the lung tissue irradiation dose during RT for thoracic EC by applying volumetric modulated arc radiotherapy (VMAT) combined with active breathing control (ABC) for moderate deep inspiration breath-hold (mDIBH). Methods Fifteen patients with thoracic EC were randomly selected to undergo two series of computed tomography (CT) simulation scans with ABC used to achieve mDIBH (representing 80% of peak DIBH value) versus free breathing (FB). Gross tumor volumes were contoured on different CT images, and planning target volumes (PTVs) were obtained using different margins. For PTV-FB, intensity-modulated radiotherapy (IMRT) was designed with seven fields, and VMAT included two whole arcs. For PTV -DIBH, VMAT with three 135° arcs was applied, and the corresponding plans were named: IMRT-FB, VMAT-FB, and VMAT-DIBH, respectively. Dosimetric differences between the different plans were compared. Results The heart volumes decreased by 19.85%, while total lung volume increased by 52.54% in mDIBH, compared to FB (p < 0.05). The mean conformality index values and homogeneity index values for VMAT-DIBH (0.86, 1.07) were slightly worse than those for IMRT-FB (0.90, 1.05) and VMAT-FB (0.90, 1.06) (p > 0.05). Furthermore, compared to IMRT-FB and VMAT-FB, VMAT-DIBH reduced the mean total lung dose by 18.64% and 17.84%, respectively (p < 0.05); moreover, the V5, V10, V20, and V30 values for IMRT-FB and VMAT-FB were reduced by 10.84% and 10.65% (p > 0.05), 12.5% and 20% (p < 0.05), 30.77% and 33.33% (p < 0.05), and 50.33% and 49.15% (p < 0.05), respectively. However, the heart dose-volume indices were similar between VMAT-DIBH and VMAT-FB which were lower than IMRT-FB without being statistically significant (p > 0.05). The monitor units and treatment time of VMAT-DIBH were also the lowest (p < 0.05). Conclusions VMAT combined with ABC to achieve mDIBH is a feasible approach for RT of thoracic EC. Furthermore, this method has the potential to effectively reduce lung dose in a shorter treatment time and with better targeting accuracy. [ABSTRACT FROM AUTHOR]