Lymphopenia Is Associated with Gross Target Volumes and Fractions in Hepatocellular Carcinoma Patients Treated with External Beam Radiation Therapy and Also Indicates Worse Overall Survival.

Purpose: To investigate whether lymphocyte nadir induced by radiation is associated with survival and explore its underlying risk factors in patients with hepatocellular carcinoma (HCC). Methods: Total lymphocyte counts were collected from 184 HCC patients treated by radiotherapy (RT) with complete follow-up. Associations between gross tumor volumes (GTVs) and radiation-associated parameters with lymphocyte nadir were evaluated by Pearson/Spearman correlation analysis and multiple linear regression. Kaplan-Meier analysis, log-rank test, as well as univariate and multivariate Cox regression were performed to assess the relationship between lymphocyte nadir and overall survival (OS). Results: GTVs and fractions were negatively related with lymphocyte nadir (p < 0.001 and p=0.001, respectively). Lymphocyte nadir and Barcelona Clinic Liver Cancer (BCLC) stage were independent prognostic factors predicting OS of HCC patients (all p < 0.001). Patients in the GTV ≤55.0 cc and fractions ≤16 groups were stratified by lymphocyte nadir, and the group with the higher lymphocyte counts (LCs) showed longer survival than the group with lower LCs (p < 0.001 and p=0.006, respectively). Patient distribution significantly differed among the RT fraction groups according to BCLC stage (p < 0.001). However, stratification of patients in the same BCLC stage by RT fractionation showed that the stereotactic body RT (SBRT) group achieved the best survival. Furthermore, there were significant differences in lymphocyte nadir among patients in the SBRT group. Conclusions: A lower lymphocyte nadir during RT was associated with worse survival among HCC patients. Smaller GTVs and fractions reduced the risk of lymphopenia.

MicroRNA-146a-5p Attenuates Fibrosis-related Molecules in Irradiated and TGF-beta1-Treated Human Hepatic Stellate Cells by Regulating PTPRA-SRC Signaling.

MicroRNAs (miRNAs) have been shown to play a pivotal role in the pathogenesis and maintenance of liver fibrosis by altering expression of their downstream target genes. However, their role in radiation-induced liver fibrosis has not been assessed in detail. Here, we investigated the role of miR-146a-5p and the target gene in regulation of fibrosis-related markers in the human hepatic stellate cell line LX2. LX2 cells were stimulated with 8 Gy of X rays and various concentrations of TGF-ß1 (0-5 ng/ml). Expression of α-SMA, collagen 1 and miR-146a-5p was evaluated. The MiR-146a-5p target gene predictions were performed using bioinformatics analysis and confirmed by dual-luciferase reporter experiment. The effect of miR-146a-5p and the involved target gene on the expression of these fibrogenic molecules was also assessed. Expression of α-SMA and collagen 1 were upregulated in response to radiation and/or TGF-ß1 treatment and miR-146a-5p levels were altered in LX2 cells. Restoration of miR-146a-5p expression suppressed expression of α-SMA and collagen 1 in irradiated and TGF-ß1-treated LX2 cells. Subsequent mechanism experiments revealed that miR-146a-5p overexpression inhibited PTPRA expression by binding to its 3'-untrans-lated region and reduced SRC activation. In addition, enhancement of PTPRA partially reversed the suppressive effect of miR-146a-5p on α-SMA and collagen 1 expression in LX2 cells. In conclusion, miR-146a-5p may negatively regulate the PTPRA-SRC signaling to inhibit expression of fibrosis-related markers in irradiated and TGF-ß1-stimulated LX2 cells.

Benefit of adjuvant chemoradiotherapy in patients with pathological stage III gastric cancer.

BACKGROUND: For patients with locally advanced gastric cancer (LAGC) after D2 gastrectomy, the survival benefits of receiving adjuvant chemoradiotherapy versus adjuvant chemotherapy are unclear. This study aimed to compare the 5- and 7-year overall survival (OS) in the two groups and to identify which patients can benefit more from adjuvant chemoradiotherapy. METHODS: Retrospective data were collected from January 2009 to December 2014. The 5- and 7-year OS and disease-free survival (DFS) were compared between the two groups using the Chi-square test. The association of OS with prognostic factors was identified using the Cox's proportional hazard model, which was then adjusted for survival coparison using propensity score-matching (PSM) analysis. The association of OS with each clinical/demographic factor was compared between the two groups using the Kaplan-Meier analysis. RESULTS: A total of 415 eligible patients were identified (135 adjuvant chemoradiotherapy, 280 adjuvant chemotherapy). Significant 5- and 7-year OS and DFS benefits were found in the adjuvant chemoradiotherapy group versus chemotherapy group. Multivariate analysis showed that age, TNM stage, lymph node (LN) ratio, tumor deposits, and total/subtotal gastrectomy were independent prognostic factors. When the PSM analysis was adjusting by these factors, 135 patients were matched with an improved survival benefit from adjuvant chemoradiotherapy. Patients in the adjuvant chemoradiotherapy group had a lower locoregional relapse. Subset analysis also identified significant OS benefits of adjuvant chemoradiotherapy in patients with LN ratio <50%, pIIIA, and pIIIB stage disease, while OS benefits were not observed in patients with tumor deposits, pN3b classification, or pIIIC stage disease. CONCLUSION: Adjuvant chemoradiotherapy was shown to be superior in improving the OS in a certain population of patients compared with adjuvant chemotherapy. This finding may help to better guide the individualized treatments of patients with stage III LAGC after D2 gastrectomy.