Ming Kuang

Preoperative Aspartate Aminotransferase to Platelet Ratio is an Independent Prognostic Factor for Hepatitis B-Induced Hepatocellular Carcinoma After Hepatic Resection

BackgroundThere is conflicting evidence concerning platelet status and hepatocellular carcinoma (HCC) prognosis. We evaluated the prognostic value of platelet-based indices, including platelet count, platelet/lymphocyte ratio (PLR), and aspartate aminotransferase to platelet ratio index (APRI) in HCC after hepatic resection.MethodsWe retrospectively reviewed 332 patients with HCC treated with hepatectomy between 2006 and 2009. Preoperative platelet count, as well as demographic, clinical, and pathologic data, were analyzed.ResultsBoth disease-free survival (DFS) and overall survival (OS) were significantly improved for patients with low platelet count, PLR, and APRI compared to patients with elevated values. On multivariate analysis, APRI, tumor size ≥5xa0cm, noncapsulation, and multiple tumors were all associated with both poor DFS and OS. The 1-, 3-, and 5-year DFS rates were 52, 36, and 32xa0% for patients with APRI <0.62 and were 35, 22, and 19xa0% for patients with APRI ≥0.62. Correspondingly, the 1-, 3-, and 5-year OS rates were 77, 51, and 42, and 63, 35, and 29xa0% for both groups. Both DFS and OS of patients with APRI <0.62 were significantly better compared to patients with an elevated APRI (Pxa0=xa00.009 and 0.002, respectively). Patients with elevated APRI tended to have cirrhosis, hepatitis B virus (HBV) infection, surgical margin <1xa0cm, and noncapsulated tumors.ConclusionsElevated platelets based inflammatory indices, especially APRI, was associated with adverse characteristic features and poor prognosis in HCC, especially for patients with HBV infection or cirrhosis. Antiplatelet treatment may represent a potential therapy for HBV-induced HCC recurrence.

Risk factors and outcomes of postoperative pancreatic fistula after pancreatico-duodenectomy: an audit of 532 consecutive cases.

BackgroundPancreatic fistula (PF) remains the most challenging complication after pancreaticoduodenectomy (PD). The purpose of this study was to identify the risk factors of PF and delineate its impact on patient outcomes.MethodsWe retrospectively reviewed clinical data of 532 patients who underwent PD and divided them into PF group and no PF group. Risk factors and outcomes of PF following PD were examined.ResultsPF was found in 65 (12.2%) cases, of whom 11 were classified into ISGPF grade A, 42 grade B, and 12 grade C. Clinically serious postoperative complications in the PF versus no PF group were mortality, abdominal bleeding, bile leak, intra-abdominal abscess and pneumonia. Univariate and multivariate analysis showed that blood lossu2009≥u2009500xa0ml, pancreatic duct diameteru2009≤u20093xa0mm and pancreaticojejunostomy type were independent risk factors of PF after PD.ConclusionsBlood lossu2009≥u2009500xa0ml, pancreatic duct diameteru2009≤u20093xa0mm and pancreatico-jejunostomy type were independent risk factors of PF after PD. PF was related with higher mortality rate, longer hospital stay, and other complications.

Autocrine vascular endothelial growth factor signaling promotes cell proliferation and modulates sorafenib treatment efficacy in hepatocellular carcinoma.

Tumor cells express vascular endothelial growth factor (VEGF) that can activate VEGF receptors (VEGFRs) on or within tumor cells to promote growth in an angiogenesis‐independent fashion; however, this autocrine VEGF pathway has not been reported in hepatocellular carcinoma (HCC). Sorafenib, an angiogenic inhibitor, is the only drug approved for use in advanced HCC patients. Yet the treatment efficacy is diverse and the mechanism behind it remains undetermined. Our aims were to study the molecular mechanisms underlying autocrine VEGF signaling in HCC cells and evaluate the critical role of autocrine VEGF signaling on sorafenib treatment efficacy. By immunohistochemistry, we found robust nuclear and cytoplasmic staining for active, phosphorylated VEGF receptor 1 (pVEGFR1) and phosphorylated VEGF receptor 2 (pVEGFR2), and by western blotting we found that membrane VEGFR1 and VEGFR2 increased in HCC tissues. We showed that autocrine VEGF promoted phosphorylation of VEGFR1 and VEGFR2 and internalization of pVEGFR2 in HCC cells, which was both pro‐proliferative through a protein lipase C‐extracellular kinase pathway and self‐sustaining through increasing VEGF, VEGFR1, and VEGFR2 mRNA expressions. In high VEGFR1/2‐expressing HepG2 cells, sorafenib treatment inhibited cell proliferation, reduced VEGFR2 mRNA expression in vitro, and delayed xenograft tumor growth in vivo. These results were not found in low VEGFR1/2‐expressing Hep3B cells. In an advanced HCC population on sorafenib treatment for postoperative recurrence, we found that the absence of VEGFR1 or VEGFR2 expression in resected tumor tissues before sorafenib treatment was associated with poorer overall survival. Conclusion: Autocrine VEGF signaling directly promotes HCC cell proliferation and affects the sorafenib treatment outcome in vitro and in vivo, which may enable better stratification for clinical treatment decisions. (Hepatology 2014;60:1264–1277)

Identification of Dermcidin as a novel binding protein of Nck1 and characterization of its role in promoting cell migration.

A distinct feature of hepatocellular carcinoma (HCC) is the tendency of tumor cells to disperse throughout the liver. Nck family adaptor proteins function to couple tyrosine phosphorylation signals to regulate actin cytoskeletal reorganization that leads to cell motility. In order to explore the role of Nck in HCC development, we performed GST pull-down assay using the SH2 domain of Nck1 as bait. The resulting precipitates were separated by 2-DE. Mass spectrometry analysis revealed a group of Nck1 SH2 domain-binding proteins that were differentially expressed in HCC. One of these proteins, dermcidin (DCD), and its interaction with Nck1, was further validated in vitro. GST pull-down assay revealed that Nck1 SH2 domain binds to the phosphotyrosine residue at position 20 (Y20) of the DCD. Pervandate treatment significantly enhanced the interaction between DCD and Nck1. Moreover, we demonstrated that forced expression of DCD could activate Rac1 and Cdc42 and promoted cell migration. Taken together, these data suggest a role of DCD in tumor metastasis.

Mcl-1 Is a Novel Target of miR-26b That Is Associated with the Apoptosis Induced by TRAIL in HCC Cells

Aim. To investigate the role of miR-26b and Mcl-1 in TRAIL-inducing cell death in hepatocellular carcinoma. Methods. The expression of miR-26b and Mcl-1 in HCC was detected by RT-qPCR and western blot. The regulation of Mcl-1 by miR-26b was determined by luciferase reporter assay. MTT and flow cytometry were employed to detect the cell viability and apoptosis. Results. miR-26b is commonly downregulated in HCC cell lines compared with the LO2 cell line. In contrast, the Mcl-1 expression is upregulated in HCC cell lines. Bioinformatic analysis identified a putative target site in the Mcl-1 mRNA for miR-26b and luciferase reporter assay showed that miR-26b directly targeted the 3′-UTR (3′-Untranslated Regions) of Mcl-1 mRNA. Transfection of miR-26b mimics suppressed Mcl-1 expression in HCC cells and sensitized the cancer cells to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) cytotoxicity. In addition, transfection of HCC cells with Mcl-1 expression plasmid abolished the sensitization effect of miR-26b to TRAIL-inducing apoptosis. Conclusions. Our study showed that miR-26b was a negative regulator of Mcl-1 gene and sensitized TRAIL-inducing apoptosis in HCC cells, suggesting that the miR-26b-Mcl-1 pathway might be a novel target for the treatment of HCC.

Foxp3+ regulatory T cells and the formation of portal vein tumour thrombus in patients with hepatocellular carcinoma.

BACKGROUNDnMost patients with hepatocellular carcinoma (HCC) have advanced-stage disease at diagnosis. The prognosis for patients with HCC is very poor, especially for those with portal vein tumour thrombi (PVTT). The purpose of our study was to observe the prognostic value of PVTT and tumour-infiltrating regulatory T cells (Tregs) and the correlation between them.nnnMETHODSnWe examined 76 HCC specimens by immunohistochemistry for CD4+, CD8+ T cells and Foxp3+ Tregs. The survival of patients was prospectively followed up. Patients with HCC were grouped according to the formation of PVTT or Treg infiltration status. We performed a Kaplan-Meier survival analysis to observe the difference in prognosis between the groups. We analyzed the correlation of Treg expression with clinical and pathologic features.nnnRESULTSnSurvival analysis revealed that both the disease-free survival rate and total survival rate after hepatic resection were significantly lower in patients in the PVTT group than those in the non-PVTT group (p=0.026 and p=0.022, respectively). Likewise, both the disease-free survival rate and the total survival rate were significantly lower in patients in the high Treg group than those in the low Treg group (p=0.012 and p=0.023, respectively). We found that intratumoural Tregs were associated with PVTT formation (p=0.001) and that patients with high Treg infiltration had a higher percentage of PVTT formation.nnnCONCLUSIONnPatients with PVTT formation or high intratumoural Treg infiltration tended to have a poor prognosis. Intratumoural Treg was associated with formation of PVTT in patients with HCC.

Elevated preoperative peripheral blood monocyte count predicts poor prognosis for hepatocellular carcinoma after curative resection.

BackgroundPeripheral blood monocyte count is an easily assessable parameter of systemic inflammatory response. The aim of this study was to determine whether monocyte count was prognostic in hepatocellular carcinoma (HCC) following hepatic resection.MethodsWe retrospectively reviewed 351 patients with HCC treated with hepatic resection from 2006 to 2009. Preoperative absolute peripheral monocyte count, demographics, and clinical and pathological data were analyzed.ResultsOn univariate and multivariate analysis, elevated monocyte counts (≥545/mm3), tumor size ≥5xa0cm, non-capsulation, and multiple tumors were associated with poor disease-free survival (DFS) and overall survival (OS). The 1-, 3- and 5-year DFS rates were 58%, 41% and 35%, respectively, for patients with monocyte counts <545/mm3, and 36%, 23% and 21% for patients with monocyte counts ≥545/mm3. Correspondingly, the 1-, 3- and 5-year OS rates were 79%, 53% and 46% for monocyte counts <545/mm3, and 64%, 36% and 29% for monocyte counts ≥545/mm3. Subgroup analysis indicated that DFS after hepatic resection in hepatitis B virus (HBV)-infected patients was significantly better in those with a peripheral blood monocyte counts <545/mm3, but it did not differ between patients without HBV infection. In addition, DFS was significantly better for patients with a peripheral blood monocyte count <545/mm3, whether or not cirrhosis was present. Patients with elevated monocyte counts tended to have larger tumors.ConclusionsElevated preoperative monocyte count is an independent predictor of worse prognosis for patients with HCC after hepatic resection, especially for those with HBV infection. Postoperative adjuvant treatment might be considered for patients with elevated preoperative monocyte counts.

Percutaneous thermal ablation for the treatment of colorectal liver metastases and hepatocellular carcinoma: a comparison of local therapeutic efficacy

Abstract Aim: This study aimed to compare the local therapeutic efficacy of percutaneous thermal ablation for colorectal liver metastases (CRLM) and hepatocellular carcinoma (HCC). Methods: One hundred sixty-one CRLM nodules in 101 patients and 122 HCC nodules in 97 patients were treated with thermal ablation. Complications and local efficacy were retrospectively compared. Results: Major complications were observed in two (2.0%) patients in the CRLM group and one (1.0%) in the HCC group (pu2009=u20091.000). The complete ablation (CA) rate of lesions ≤u20093u2009cm was lower in the CRLM group than in the HCC group (pu2009=u20090.018). After a mean follow-up period of 21.1u2009±u200920.7 months in the CRLM group and 22.1u2009±u200917.6 months in the HCC group, the local tumour progression (LTP) rate of lesions >u20093u2009cm was higher in the CRLM group than in the HCC group (pu2009=u20090.036). The multivariate analysis revealed that only safety margin (≤u20090.5u2009cm/>u20090.5u2009cm) was a significant predictor of LTP in both CRLM and HCC. Conclusions: To achieve better local tumour control, thermal ablation should be more aggressive for CRLM than for HCC, especially for large tumours in clinical.

miR-500a-3p promotes cancer stem cells properties via STAT3 pathway in human hepatocellular carcinoma

BackgroundmiR-500a-3p has been demonstrated to be involved in the development, progression and metastasis in several human cancers. Constitutive activation of JAK/STAT3 signaling pathway has been reported to play an important role in the development and progression of hepatocellular carcinoma (HCC).The purpose of this study was to determine the biological roles and clinical significance of miR-500a-3p in HCC and to identify whether miR-500a-3p has an effect on the activity of JAK/STAT3 signaling in HCC.MethodsmiR-500a-3p expression was examined by real-time PCR in 8 paired HCC tissues and individual 120 HCC tissues respectively. Statistical analysis was performed to explore the clinical correlation between miR-500a-3p expression and clinicopathological features and overall and relapse-free survival in HCC patients. In vitro and in vivo assays were performed to investigate the biological roles of miR-500a-3p in HCC. The bioinformatics analysis, real-time PCR, western blot and luciferase reporter assay were performed to discern and examine the relationship between miR-500a-3p and its potential targets. Clinical correlation of miR-500a-3p with its targets was examined in HCC tissues.ResultsmiR-500a-3p is dramatically elevated in HCC tissues and cells and high expression of miR-500a-3p correlates with poor overall and relapse-free survival in HCC patients. Upregulating miR-500a-3p enhances, while silencing miR-500a-3p suppresses, the spheroid formation ability, fraction of side population and expression of cancer stem cell factors in vitro and tumorigenicity in vivo in HCC cells. Our findings further reveal miR-500a-3p promotes the cancer stem cell characteristics via targeting multiple negative regulators of JAK/STAT3 signaling pathway, including SOCS2, SOCS4 and PTPN11, leading to constitutive activation of STAT3 signaling. Moreover, the inhibitory effects of anti-miR-500a-3p on cancer stem cell phenotypes and activity of STAT3 signaling were reversed by silencing SOCS2, SOCS4 and PTPN11 in miR-500a-3p-downexpressing cells, respectively. Clinical correlation of miR-500a-3p with the targets was examined in human HCC tissues.Conclusionour results uncover a novel mechanism by which miR-500a-3p promotes the stemness maintenance of cancer stem cell in HCC, suggesting that silencing miR-500a-3p may serve as a new therapeutic strategy in the treatment of hepatocellular carcinoma.

Combined vascular resection and analysis of prognostic factors for hilar cholangiocarcinoma.

BACKGROUNDnHilar cholangiocarcinoma (HCCA) is a devastating malignancy arising from the bifurcation of the hepatic duct, whether combined vascular resection benefits HCCA patients is controversial. This study was undertaken to assess the effect of combined vascular resection in HCCA patients and to analyze the prognostic factors.nnnMETHODSnClinical data of 154 HCCA patients who had been treated from January 2005 to December 2012 were retrospectively analyzed. The patients were divided into three groups based on vascular resection: those without vascular resection; those with portal vein resection alone and those with hepatic artery resection. The survival and complication rates were compared among the three groups. Multivariate analysis was made to determine prognostic factors.nnnRESULTSnNo significant differences were found in survival and complication rates among the three groups (P>0.05). Multivariate analysis showed that 3 factors were related to survival: lymph node metastasis, tumor size (>2.5 cm), and positive resection margin.nnnCONCLUSIONSnVascular resection improved the survival rate of patients with HCCA involving the hepatic artery or portal vein. Lymph node metastasis, tumor size (>2.5 cm) and positive resection margin were poor prognostic factors in patients with HCCA.