Low miR-10b-3p associated with sorafenib resistance in hepatocellular carcinoma.

BACKGROUND: Sorafenib is one of the standard first-line therapies for advanced hepatocellular carcinoma (HCC). Unfortunately, there are currently no appropriate biomarkers to predict the clinical efficacy of sorafenib in HCC patients. MicroRNAs (miRNAs) have been studied for their biological functions and clinical applications in human cancers. METHODS: In this study, we found that miR-10b-3p expression was suppressed in sorafenib-resistant HCC cell lines through miRNA microarray analysis. RESULTS: Sorafenib-induced apoptosis in HCC cells was significantly enhanced by miR-10b-3p overexpression and partially abrogated by miR-10b-3p depletion. Among 45 patients who received sorafenib for advanced HCC, those with high miR-10b-3p levels, compared to those with low levels, exhibited significantly longer overall survival (OS) (median, 13.9 vs. 3.5 months, p = 0.021), suggesting that high serum miR-10b-3p level in patients treated with sorafenib for advanced HCC serves as a biomarker for predicting sorafenib efficacy. Furthermore, we confirmed that cyclin E1, a known promoter of sorafenib resistance reported by our previous study, is the downstream target for miR-10b-3p in HCC cells. CONCLUSIONS: This study not only identified the molecular target for miR-10b-3p, but also provided evidence that circulating miR-10b-3p may be used as a biomarker for predicting sorafenib sensitivity in patients with HCC.

Inflammasome Priming Mediated via Toll-Like Receptors 2 and 4, Induces Th1-Like Regulatory T Cells in De Novo Autoimmune Hepatitis.

De novo autoimmune hepatitis (DAIH) is an important cause of late allograft dysfunction following liver transplantation, but its cause and underlying pathogenesis remains unclear. We sought to identify specific innate and adaptive immune mechanisms driving the pro-inflammatory cytokine secreting regulatory T cell (Treg) phenotype in DAIH and determine if modulation of these pathways could resolve the inflammatory milieu observed in the livers of patients with DAIH. Here, we demonstrate toll-like receptors (TLRs) 2- and 4-mediated inflammasome activation in CD14++ monocytes, a finding that is key to maintaining dysfunctional Tregs in patients with DAIH. Furthermore, silencing of TLR 2 and 4 in CD14++ monocytes prevented activation of the inflammasome and significantly decreased IFN-γ production by FOXP3+ Tregs. We also observed significantly increase in expression of tumor necrosis factor α-induced protein 3 (TNFAIP3), a negative regulator of the NLRP3 Inflammasome, in monocytes/macrophages of liver transplant subjects who have normal allograft function and do not have DAIH. TNFAIP3 expression was virtually absent in monocytes/macrophages of patients with DAIH. Our findings suggest that autoimmunity in DAIH is promoted by CD14++ monocytes predominantly through activation of inflammatory signaling pathways.

Late small bowel toxicity after aggressive abdominopelvic intensity modulated radiation therapy.

PURPOSE: We retrospectively analyzed late small bowel toxicity in patients who received abdominal or pelvic intensity modulated radiation therapy (IMRT) to the small bowel with a maximum dose greater than the generally accepted maximal tolerable dose of 45 Gy. METHODS AND MATERIALS: All patients (N = 94) who received IMRT with a point dose of at least 45 Gy to tightly contoured small bowel between 2005 and 2014 at our institution were included. The median prescribed treatment dose was 70.2 Gy. The median follow-up was 20.1 months. Late small bowel toxicity was assessed using the Common Terminology Criteria for Adverse Events Version 3.0. Dosimetric variables and clinical factors were assessed for their relationship to small bowel toxicity. RESULTS: The median maximal small bowel point dose (Dmax) was 6546.5 cGy. The estimated 5-year rates of freedom from at least grade 1, at least grade 2, and at least grade 3 late small bowel toxicity were 72.4% (95% confidence interval [CI], 60.7%-86.5%), 91.9% (95% CI, 84.1%-100%), and 93.6% (95% CI, 86.2%-100%), respectively. One patient (1.1%) developed grade 3 late toxicity, and 2 patients (2.1%) developed grade 4 late toxicity. Use of capecitabine/5-fluorouracil treatment was a significant predictor (P < 0.001) of at least grade 1 and at least grade 2 small bowel toxicity. No other clinical factors were associated with toxicity. None of the dose-volume parameters were significant predictors of small bowel toxicity. CONCLUSION: It may be possible with IMRT to deliver high doses to small volumes of small bowel with low rates of significant long-term complications. Further studies should explore tolerable dose-volume relationships in cases in which aggressive abdominal or pelvic treatment may be warranted to treat the underlying malignancy.

Combined hepatectomy and hepatic pedicle lymphadenectomy in colorectal liver metastases is justified.

BACKGROUND: The aim of this study was to describe the outcome of patients with colorectal liver metastases (CRLM) and radiological or clinical evidence of metastatic hepatic lymph node involvement who underwent combined hepatectomy and hepatic pedicle lymphadenectomy. METHODS: Retrospective analysis of a prospectively maintained audit of 2082 patients undergoing liver resection for CRLM between 1994 and 2014. Age, type of resection, CT/MRI/PET detection, location, disease recurrence and survival were analysed. RESULTS: Combined hepatectomy and hepatic pedicle lymphadenopathy was performed on 76 patients who met the inclusion criteria. 46% of enlarged lymph nodes were located in the hepatic ligament, with 38% retroportal, 38% common hepatic and 33% coeliac nodes. 50% of lymph node resections were positive for metastatic tumour. Pre-operative CT, MRI and CT/PET failed to detect histologically proven lymph node disease in 25/38 patients. Patients with negative nodal histology had a significant overall (44 vs 20 months, p = 0.008) and disease free (20 vs 11 months, p < 0.001) survival advantage. CONCLUSION: Combined hepatectomy and lymph node resection for CRLM in the setting of enlarged or suspicious lymphadenopathy is justified as imaging and operative findings are poor guides in determining positive lymph node disease.