Jun-Hua Lu

Hepatectomy for bilateral primary hepatolithiasis: a cohort study.

Objective:This study aimed to evaluate the perioperative and long-term results of partial hepatectomy for patients with complicated bilateral primary hepatolithiasis. Summary Background Data:Hepatolithiasis is best managed by a multidisciplinary approach. Definitive treatment can be offered using endoscopic, percutaneous, laparoscopic, or open surgical approaches. Partial hepatectomy is only indicated for recurrent, troublesome, localized, and severe disease affecting the liver. Methods:From January 2000 to December 2006, 136 consecutive patients who underwent bilateral (n = 54) or unilateral (n = 82) hepatectomy for biliary strictures and bilateral primary hepatolithiasis in our center were included in this study. All patients had concomitant bile duct exploration. Their perioperative and long-term outcomes were analyzed. Results:The immediate stone clearance rates after bilateral and unilateral hepatectomy were 81.5% and 65.9%, respectively. Additional postoperative choledochoscopic lithotripsy raised the clearance rates to 85.2% and 81.7%, respectively. The hospital mortality rates were 5.6% and 0%, respectively, and the complication rates were 46.3% and 46.3%, respectively. The 5-year overall survival rates were 98% and 91.5%, respectively. Conclusion:In selected patients with biliary strictures and bilateral hepatolithiasis, partial hepatectomy associated with choledochoscopic lithotripsy is a safe and efficacious treatment, with a high immediate stone clearance rate, a low long-term stone recurrence rate and good long-term survival.

High viral load is associated with poor overall and recurrence-free survival of hepatitis B virus-related hepatocellular carcinoma after curative resection: A prospective cohort study

PURPOSE The aim of this prospective cohort study was to investigate the impact of preoperative hepatitis B viral load, as well as postoperative antiviral therapy, on the risk of long-term survival after curative resection of hepatitis B virus-related hepatocellular carcinoma (HCC). METHODS A prospective cohort of hepatitis B virus-related HCC patients undergoing curative resection from 2002 to 2008 was studied. According to preoperative viral load (using 10,000 copies/mL of hepatitis B virus DNA level as cut-off value), two groups were compared. Prognostic factors for overall survival and recurrence-free survival were evaluated. Additionally, subgroup analysis was conducted in patients with high viral load to investigate prediction of postoperative antiviral therapy on the long-term prognosis. RESULTS With a median follow-up of 49.1 months, patients with high viral load had lower median overall survival (78.3 months vs. 111.4 months, P<0.001) and RFS (44.6 months vs. 94.8 months, P<0.001) compared with those with low viral load. Multivariate analysis revealed that preoperative high viral load was an independent risk factor affecting both overall survival and recurrence-free survival (both P<0.001). The subgroup analysis revealed that postoperative antiviral therapy independently improved recurrence-free survival for patients with high viral load (P=0.001). CONCLUSIONS Hepatitis B virus-related HCC patients with preoperative high viral load led to poorer overall and recurrence-free survival than those with low viral load after curative resection. To prevent postoperative recurrence, antiviral therapy should be initiated in those patients with hepatitis B virus DNA ≥ 10,000 copies/ml.

Krüppel-Like Factor 8 Is a New Wnt/Beta-Catenin Signaling Target Gene and Regulator in Hepatocellular Carcinoma

Krüppel-like factor 8 (KLF8) plays important role in cell cycle and oncogenic transformation. Here we report the mechanisms by which KLF8 crosstalks with Wnt/β-catenin signaling pathway and regulates hepatocellular carcinoma (HCC) cells proliferation. We show that overexpression of KLF8 and nucleus accumulation of β-catenin in the human HCC samples are positively correlated. More importantly, KLF8 protein levels plus nucleus accumulation of β-catenin levels were significantly elevated in high-grade HCC compared to low-grade HCC. Using HCC HepG2 cells we find that, on the one hand both protein and mRNA of KLF8 are up-regulated under Wnt3a stimulation, on the other hand overexpression of KLF8 increases the cytoplasm and nucleus accumulation of β-catenin, recruits p300 to β-catenin/T-cell factor 4 (TCF4) transcription complex, enhances TOP flash report gene transcription, and induces Wnt/β-catenin signaling target genes c-Myc, cyclin D1 and Axin1 expression. Knockdown of KLF8 using shRNA inhibits Wnt3a induced transcription of TOP flash report gene and expression of c-Myc, cyclin D1 and Axin1. Knockdown of β-catenin by shRNA rescues the enhanced HepG2 and Hep3B cells proliferation ability induced by overexpression of KLF8.

Partial hepatectomy for ruptured hepatocellular carcinoma.

Improvements in surgical technique and perioperative care have made partial hepatectomy a safe and effective treatment for hepatocellular carcinoma (HCC), even in the event of spontaneous HCC rupture.

Perioperative blood transfusion does not influence recurrence-free and overall survivals after curative resection for hepatocellular carcinoma: A Propensity Score Matching Analysis.

BACKGROUND & AIMS Whether perioperative blood transfusions (PBTs) negatively impact oncologic outcomes after curative resection for HCC remains controversial. We aimed to identify the independent predictive factors of PBT for curative resection of hepatocellular carcinoma (HCC), and to investigate the impact of PBT on long-term recurrence and survivals after resection. METHODS Of 1103 patients who underwent curative liver resection for HCC between 1999 and 2010, 285 (25.8%) patients received PBT. Univariable and multivariable regression analyses were used to identify independent predictive factors of PBT. Propensity scores and Cox regression analyses were used to compare the overall survival (OS) and recurrence-free survival (RFS) between patients who did and did not receive PBT. RESULTS Multivariable regression analysis revealed that performance status, preoperative hemoglobin, cirrhosis, portal hypertension, tumor rupture, tumor size, macroscopic vascular invasion, and intraoperative blood loss were independent predictive factors of PBT for HCC resection. Propensity score matching analysis created 234 pairs of patients. Before propensity matching, PBT was significantly associated with increased risks of OS (HR: 2.455, 95% CI: 2.077-2.901, p<0.001) and RFS (HR: 2.018, 95% CI: 1.718-2.370, p<0.001) in the entire cohort. After propensity matching, PBT was not significantly associated with increased risks of OS (HR: 1.229, 95% CI: 0.988-1.527, p=0.063) and RFS (HR: 1.188, 95% CI: 0.960-1.469, p=0.113). After adjustment for other prognostic variables in the propensity matched cohort, PBT was still found not to be associated with OS and RFS after HCC resection. CONCLUSIONS The present study identified that PBT did not influence RFS and OS after curative resection of HCC.

TGF-β Regulates Hepatocellular Carcinoma Progression by Inducing Treg Cell Polarization

Background/Aims: TGF-β plays a key role in the progression of various tumors. The main objective of our study was to investigate whether TGF-β is able to regulate N-nitrosodiethylamine (DEN)-induced hepatocellular carcinoma (HCC) progression in a mouse model by inducing Treg cell polarization. Methods: HCC progression, TGF-β and Foxp3 expression levels, serum TGF-β, IL10 and GP73 levels as well as percentage of Treg cells were analyzed in healthy, HCC and HCC+SM-16 mouse groups. The effect of TGF-β on Treg cell polarization in vitro was measured by flow cytometric analysis. The expression of TGF-β and IL10 was identified by IHC in HCC patients and the correlation between TGF-β and IL10 was also assessed. Results: TGF-β expression is up-regulated in a DEN-induced HCC mouse model. TGF-β can promote the differentiation of Foxp3+CD4+ T cells (Treg cells) in vitro. However, blocking the TGF-β pathway with a specific TGF-β receptor inhibitor, SM-16, reduced HCC progression and the percentage of Treg cells in liver tissue. The correlation between TGF-β and Treg cells was also confirmed in HCC patients and the expression of both TGF-β and IL-10 was shown to be associated with HCC progression. Conclusion: TGF-β is necessary for HCC progression, acting by inducing Treg cell polarization.

STK33 promotes hepatocellular carcinoma through binding to c-Myc

Objective STK33 has been reported to play an important role in cancer cell proliferation. We investigated the role of STK33 in hepatocellular carcinoma (HCC) and its underlying mechanisms. Design 251 patients with HCC were analysed for association between STK33 expression and clinical stage and survival rate. Tamoxifen (TAM)-inducible, hepatocyte-specific STK33 transgenic and knockout mice models were used to study the role of STK33 in liver tumorigenesis. HCC cell lines were used to study the role of STK33 in cell proliferation in vitro and in vivo. Results STK33 expression was found to be frequently upregulated in patients with HCC. Significant associations were found between increased expression of STK33 and advanced HCC staging and shorter disease-free survival of patients. Overexpression of STK33 increased HCC cell proliferation both in vitro and in vivo, whereas suppression of STK33 inhibited this effect. Using a TAM-inducible, hepatocyte-specific STK33 transgenic mouse model, we found that overexpression of STK33 resulted in increased hepatocyte proliferation, leading to tumour cell burst. Using a TAM-inducible, hepatocyte-specific STK33 knockout mouse model, we found that, when subjected to the diethylnitrosamine (DEN) liver cancer bioassay, STK33KOflox/flox, Alb-ERT2-Cre mice exhibited a markedly lower incidence of tumour formation compared with control mice. The underlying mechanism may be that STK33 binds directly to c-Myc and increases its transcriptional activity. In particular, the C-terminus of STK33 blocks STK33/c-Myc association, downregulates HCC cell proliferation, and reduces DEN-induced liver tumour cell number and tumour size. Conclusions STK33 plays an essential role in hepatocellular proliferation and liver tumorigenesis. The C-terminus of STK33 could be a potential therapeutic target in the treatment of patients with STK33-overexpressed HCC.

Risk Factors of Surgical Site Infection after Hepatic Resection

A study of 7,388 consecutive patients after hepatic resection between 2011 and 2012 identified hepatolithiasis, cirrhosis, and intraoperative blood transfusion as the only independent risk factors of both incisional and organ/space surgical site infection (SSI). Patients with these conditions should be cared for with caution to lower SSI rates.

Concomitant lung metastasis in patients with advanced hepatocellular carcinoma

AIM To investigate the clinical features and prognostic factors of advanced hepatocellular carcinoma (HCC) patients presenting with lung metastasis at initial diagnosis. METHODS Between 2001 and 2010, we recruited 76 consecutive HCC patients initially presenting with lung metastasis, without co-existing metastasis from other sites. These patients were divided into three groups: untreated group (n = 22), single treatment group (n = 19), and combined treatment group (n = 35). RESULTS Metastasis of bilateral lung lobes was common and noted in 35 patients (46.1%), and most of patients (59/76, 77.6%) presented with multiple lung metastatic nodules. Nineteen patients (25.0%) received single-method treatment, including hepatectomy in 4, transcatheter arterial chemoembolization in 6, radiotherapy in 5, and oral sorafenib in 4. Thirty-five patients (46.1%) received combined treatment modalities. The overall median survival of the all patients was 8.7 ± 0.6 mo; 4.1 ± 0.3, 6.3 ± 2.5 and 18.6 ± 3.9 mo, respectively in the untreated group, single treatment group and combined treatment group, respectively, with a significant difference (log-rank test, P < 0.001). Multivariate analysis revealed that Child-Pugh score, the absence or presence of portal vein tumor thrombus, and treatment modality were three independent prognostic factors affecting survival of patients with advanced HCC and concomitant lung metastasis. CONCLUSION Combined treatment modalities tend to result in a better survival as compared with the conservative treatment or single treatment modality for HCC patients initially presenting with lung metastasis.

Krüppel‐like factor 8 promotes cancer stem cell‐like traits in hepatocellular carcinoma through Wnt/β‐catenin signaling

Krüppel‐like factor 8 (KLF8) is highly expressed in hepatocellular carcinoma (HCC) and contributes to tumor initiation and progression by promoting HCC cell proliferation and invasion. However, the role of KLF8 in liver cancer stem cells (LCSCs) is not known. In the current study, we investigated the role of KLF8 in LCSCs to determine if KLF8 is a novel marker of these cells. We found that KLF8 was highly expressed in primary HCC tumors, distant migrated tissues, and LCSCs. Patients with high KLF8 expression had a poor prognosis. KLF8 promoted stem cell‐like features through activation of the Wnt/β‐catenin signaling pathway. Cell apoptosis was significantly increased in HCC cells with knockdown of KLF8 compared with the control cells when treated with the same doses of sorafenib or cisplatin. Taken together, our study shows that KLF8 plays a potent oncogenic role in HCC tumorigenesis by maintaining stem cell‐like features through activation of the Wnt/β‐catenin signaling pathway and promoting chemoresistance. Thus, targeting KLF8 may provide an effective therapeutic approach to suppress tumorigenicity of HCC.