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BACKGROUND AND AIM Portal vein tumor thrombus (PVTT) predicts a poor prognosis in hepatocellular carcinoma (HCC) patients. Platelets (PLTs) play an important role in HCC progression and metastasis. However, the relationship between PLTs and PVTT remains unclear. This study aimed to evaluate the value of PLT counts in the prognosis of HCC patients with PVTT after hepatectomy. METHODS From January 2002 to December 2012, 694 HCC patients with PVTT after hepatectomy were evaluated. The patients were divided into the thrombocytopenia group (PLT 300 × 109 /L) based on the preoperative PLT level. A propensity score matching (PSM) analysis was used. RESULTS Before the PSM, PVTT patients with thrombocytopenia exhibited longer recurrence-free survival (RFS) and overall survival (OS) compared with those with normal PLT counts (both P

Portal vein tumor thrombus (PVTT) is a significant poor prognostic factor for hepatocellular carcinoma (HCC). Patients with PVTT limited to a first-order branch of the main portal vein (MPV) or above could benefit from negative margin (R0) liver resection (LR). An Eastern Hepatobiliary Surgery Hospital (EHBH)/PVTT scoring system was established to predict the prognosis of HCC patients with PVTT after R0 LR and guide selection of subgroups of patients that could benefit from LR. HCC patients with PVTT limited to a first-order branch of the MPV or above who underwent R0 LR as an initial therapy were included. The EHBH-PVTT score was developed from a retrospective cohort in the training cohort using a Cox regression model and validated in a prospective internal validation cohort and three external validation cohorts. There were 432 patients in the training cohort, 285 in the prospective internal validation cohort, and 286, 189, and 135 in three external validation cohorts, respectively. The score was calculated using total bilirubin, α-fetoprotein (AFP), tumor diameter, and satellite lesions. The EHBH-PVTT score differentiated two groups of patients (≤/>3 points) with distinct long-term prognoses (median overall survival [OS], 17.0 vs. 7.9 months; P < 0.001). Predictive accuracy, as determined by the area under the time-dependent receiver operating characteristic curves (AUCs; 0.680-0.721), was greater than that of the other commonly used staging systems for HCC and PVTT. Conclusion: The EHBH-PVTT scoring system was more accurate in predicting the prognosis of HCC patients with PVTT than other staging systems after LR. It selected appropriate HCC patients with PVTT limited to a first-order branch of the MPV or above for LR. It can be used to supplement the other HCC staging systems.

Background: Survival benefit of surgical resection for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) has been approved recently. However, risk factors for in-hospital mortality in these patients remain unclear. We aimed to determine risk factors and reduce the mortality of these patients. Methods: We analyzed data for 521 of all 1531 HCC patients with PVTT underwent surgery. The primary outcome measure was in-hospital mortality after surgical resection. Univariate and Multivariate cox-regression were performed to identify independent predictors of in-hospital mortality. The methods of Kaplan-Meier, bootstrap and ten-fold-cross validation were applied to validate the risk factors. Results: 521 of 1531 patients in 2004-2012 occurred for the diagnosis of HCC associated with PVTT and underwent surgical resection as a training cohort. Other 325 patients in 2013-2016 were included as a validation cohort. Overall mortality of postoperative in-patients was 3.3% (17/521) and 2.8 % (9/325), respectively. Univariate analysis of mortality revealed that frequency of hospitalization, total albumin, different types of PVTT, bleeding volume, blood transfusion, resection volume, and tumor volume were related with mortality. Therefore, the bootstrap validation reflected that the risk factors of multivariate cox regression in model1(frequency of hospitalization, bleeding volume, and tumor volume) and model 2 (frequency of hospitalization, bleeding volume and total albumin) were stable with mortality in hospital. Ten-fold cross-validation of cox regression analysis showed that the mean C-statistic with 95%CI of model1 and model2 respectively were 0.887(0.779-0.976) and 0.867(0.789-0.966) for predicting in-hospital mortality. Consistency results of models were in the training cohort and validation cohort. Conclusion: Total albumin, tumor volume, intraoperative bleeding and frequency of hospitalization were independent predictive factors for in-hospital mortality in HCC patients with PVTT under surgery. Further study is warranted to utilize these factors to lower in-hospital mortality.

Portal vein tumor thrombus (PVTT) is a type of intrahepatic metastasis arising from hepatocellular carcinoma (HCC) and is highly correlated with a poor prognosis. Hypoxia is common in solider tumors, including HCC, where it alters the behavior of HCC cells. We asked whether and how hypoxia contributes to PVTT formation. We demonstrated that increased intratumoral hypoxia is strongly associated with PVTT formation in HCC. We also showed that 14-3-3ζ is induced by hypoxia in HCC cells and correlates with PVTT formation in clinical HCC samples. In addition, 14-3-3ζ up-regulates HIF-1α expression by recruiting HDAC4, which prevents HIF-1α acetylation, thereby stabilizing the protein. Under hypoxic conditions in vitro, 14-3-3ζ knockdown inhibits hypoxia-induced HCC invasion by the HIF-1α/EMT pathway. Blockade of 14-3-3ζ in HCC cells reduces PVTT formation and distant lung metastasis in vivo. Moreover, a combination of 14-3-3ζ and HIF-1α expression is more prognostic for HCC patients than either protein alone. These results suggest that the hypoxia/14-3-3ζ/HIF-1α pathway plays an important role in PVTT formation and HCC metastasis.

// Yanan Pang 1, * , Weixing Guo 2, * , Jiaqi Wang 1, * , Guixia Xu 1 , Kai Cheng 1 , Guangwen Cao 3 , Mengchao Wu 2 , Shuqun Cheng 2 , Shanrong Liu 1 1 Changhai Hospital, Second Military Medical University, Shanghai, China 2 Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China 3 Department of Epidemiology, Second Military Medical University, Shanghai, China * These authors have contributed equally to this work Correspondence to: Shanrong Liu, e-mail: liushanrong@hotmail.com Shuqun Cheng, e-mail: chengshuqun@aliyun.com Keywords: HBV-HCC, CGH, integration, biomarker Received: July 31, 2015 Accepted: January 01, 2016 Published: January 12, 2016 ABSTRACT Integration of hepatitis B virus (HBV) DNA into the human liver cell genome is believed to promote HBV-related carcinogenesis. This study aimed to quantify the integration of HBV DNA into the leukocyte genome in hepatocellular carcinoma (HCC) patients in order to identify potential biomarkers for HBV-related diseases. Whole-genome comparative genomic hybridization (CGH) chip array analyses were performed to screen gene copy number variations (CNV) in the leukocyte genome, and the results were confirmed by quantitative polymerase chain reaction (qPCR). The commonly detected regions included chromosome arms 19p, 5q, 1q and 15p, where 200 copy number gain events and 270 copy number loss events were noted. In particular, gains were observed in 5q35.3 (OR4F3) and 19p13.3 (OR4F17) in 90% of the samples. Successful homologous recombination of OR4F3 and the HBV P gene was demonstrated, and the amplification at 5q35.3 is potentially associated with the integration of HBV P gene into natural killer cells isolated from peripheral blood mononuclear cells (PBMCs). Receiver operating characteristic (ROC) curve analysis indicated that the combination of OR4F3 and OR4F17 a novel potential biomarker of HBV-related diseases.

Microvascular invasion (MiVI) is a major risk factor of survival outcomes after curative resection for patients with hepatocellular carcinoma (HCC). This study aimed to investigate the impact of postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) on HCC patients with MiVI.From January 2004 to June 2013, HCC patients with histologically confirmed MiVI and well-tolerated liver function who underwent PA-TACE after R0 hepatectomy (RH) or RH alone were studied retrospectively. In the PA-TACE group, PA-TACE was given 4 weeks after RH. Uni- and multivariate analyses were used to identify the prognostic significance of PA-TACE.Of the 322 HCC patients with MiVI included in the analysis, 185 entered into the RH group and 137 entered into the PA-TACE group. The baseline characteristics of the two groups were similar except for alanine aminotransferase (ALT) level (p = 0.037). The 1-, 2-, 3-, and 5-year recurrence-free survival (RFS) rates were respectively 69.3, 55.5, 46.7, and 35.0 % for the PA-TACE group and 47.0, 36.2, 34.1, and 30.3 % for the RH group (log-rank, χ(2) = 6.309; p = 0.012). The 1-, 2-, 3-, and 5-year overall survival (OS) rates were respectively 94.2, 78.8, 71.5, and 54.0 % for the PA-TACE group and 78.9, 62.2, 54.1, and 43.2 % for the RH group (log-rank, χ(2) = 7.537; p = 0.006). Multivariate Cox proportional hazards regression analysis showed PA-TACE to be an independent risk factor of postoperative RFS and OS.This study showed that PA-TACE may be beneficial for HCC patients with MiVI.

Background. Though there is considerable evidence that sphingosine kinase 1(SPHK1) plays a key role in hepatocellular carcinoma(HCC) progression, the prognostic value of SPHK1 expression in HCC with portal vein tumor thrombus (PVTT) remains unclear. Aims. The purpose of this study was to investigate the relationship of SPHK1 expression with PVTT and HCC recurrence after hepatectomy. Methods. After screening of gene expression profiling of tumor cell lines, real-time PCR and immunohistochemistry were used to investigate the SPHK1 expression in PVTT and HCC samples. The clinical data of 199 HCC patients with nonmain PVTT who underwent liver resection with curative intention were studied. Results. We identified SPHK1 as the most over-expressed gene in PVTT via gene expression profiling of one human PVTT cell line (CSQT-2). SPHK1 expression was an independent factor affecting survival (hazard ratio [HR] 1.799, 95% confidence interval [CI] 1.337–2.368, P < 0.001) and tumor recurrence (HR 1.451, 95% CI 1.087-1.935, P = 0.011). Patients with SPHK1 over-expression had a poorer prognosis than those with SPHK1 under-expression (P < 0.001 and P = 0.011 for survival and tumor recurrence). Conclusions. SPHK1 might represent a novel and useful prognostic marker of HCC progression in patients with PVTT.

Background Lymph node metastasis (LNM)has widely been recognized as a poor prognostic indicator for hepatocellular carcinoma (HCC) patients. Preoperative prediction of LNM is important for clinicians to decide on treatment. This study was designed to develop a simple and convenient system to predict LNM. Methods Consecutive HCC patients who were suspected to have LNM were divided into a training, an internal validation and an external validation cohort. The receiver operating characteristic (ROC) analysis was used to determine the threshold value of the preoperative serological variables. A nomogram visualization system model was then established. Result Of the 287 patients, there were 31 patients who had LNM (10.8%), and 21 of 203 patients (10.3%) were in the training cohort and 10 of 84 patients (11.9%) in the internal validation cohort. Sixteen of 176 patients (9.1%) in the external validation cohort had LNM. The serological indices including neutrophil/lymphocyte rate, age, platelet, prothrombin time, and total protein, were included in the nomogram. The areas of the ROC curve were 0.846, 0.679 and 0.738 in predicting LNM in the training cohort, the internal validation cohort and the external validation cohort, respectively. Conclusion The scoring system constructed using the preoperative serological variables predicted LNM in HCC patients.

Background/Aims: Although it has been widely accepted that protein arginine methyltransferase 1 (PRMT1) is a cancer-promoting gene in various cancers, the mechanism of PRMT1 in hepatocellular carcinoma (HCC) requires more exploration. This study aimed to investigate the role of PRMT1 in HCC growth and metastasis. Methods: We compared PRMT1 expression and clinicopathological characteristics using paired HCC and adjacent noncancerous liver tissues from 210 patients and immunohistochemistry analyses. Cell proliferation, colony formation and migration were determined in HCC cell lines with PRMT1 overexpression or downregulation through MTT, crystal violet and Boyden chamber assays. Tumour growth was monitored in a xenograft model, and intrahepatic metastasis models were established. Results: PRMT1 expression was greatly increased in clinical HCC samples and strongly associated with poor prognosis and recurrence; PRMT1 expression was also positively correlated with microvascular invasion (P = 0.024), tumour differentiation (P = 0.014), tumour size (P = 0.002), and portal vein tumour thrombus (PVTT) (P = 0.028). Cell proliferation, colony formation and migration in vitro were enhanced by PRMT1 upregulation and decreased by PRMT1 downregulation in HCC cell lines. Moreover, low PRMT1 expression resulted in slow tumour growth and decreased tumour weight in vivo, as well as tumour metastasis. These phenotypes were associated with STAT3 signalling pathway activation. Cryptotanshinone, a STAT3 inhibitor, inhibited STAT3 phosphorylation and reversed the HCC phenotype of PRMT1 expression. Conclusions: We revealed a significant role for PRMT1 in HCC progression and metastasis in vitro and in vivo via STAT3 signalling pathway activation. PRMT1 may be a potential novel prognostic biomarker and new therapeutic target for HCC.

Background Chemerin, a known chemoattractant, participates in multiple biological events. However, its role in cancer remains largely unknown. Methods Chemerin expression was evaluated by real-time PCR, western blot and immunohistochemistry. Forced expression, RNAi, immunoprecipitation, etc. were used in function and mechanism study. Mouse models of extrahepatic and intrahepatic metastasis were employed to evaluate the therapeutic potential of chemerin. Results Chemerin expression was significantly downregulated in hepatocellular carcinoma, and associated with poor prognosis of HCC patients. Forced expression of chemerin inhibited in vitro migration, invasion and in vivo metastasis of HCC cells. Administration of chemerin effectively suppressed extrahepatic and intrahepatic metastases of HCC cells, resulting in prolonged survival of tumour-bearing nude mice. Chemerin upregulated expression and phosphatase activity of PTEN by interfering with PTEN–CMKLR1 interaction, leading to weakened ubiquitination of PTEN and decreased p-Akt (Ser473) level, which was responsible for suppressed migration, invasion and metastasis of HCC cells. Positive correlation between chemerin and PTEN, and reverse correlation between chemerin and p-Akt (Ser473) were also observed in HCC clinical samples and intrahepatic mouse model in vivo. Conclusions Our study has revealed the suppressive role and therapeutic potential of chemerin in HCC metastasis, providing both a prognostic marker and drug candidate for HCC.

// Xiaolong Li 1, 2, * , Weixing Guo 1, * , Lei Guo 1, * , Wan Yee Lau 1, 3 , Naijian Ge 1 , Kang Wang 1 and Shuqun Cheng 1 1 Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China 2 Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China 3 Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR * These authors have contributed equally to this work Correspondence to: Shuqun Cheng, email: chengshuqun@aliyun.com Keywords: hepatocellular carcinoma; portal vein tumor thrombus; radiotherapy; transarterial chemoembolization Received: June 01, 2017 Accepted: April 06, 2018 Published: May 11, 2018 ABSTRACT Background and Objective: To compare the survival outcomes of patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) who received transarterial chemoembolization (TACE) before or after intensity-modulated radiotherapy (IMRT). Methods: During the study period, the survival outcomes of HCC patients with PVTT who underwent TACE before (TACE-RT) or after IMRT (RT-TACE) were compared. Using propensity score matching (PSM), matched pairs of patients were compared. Results: There were 76 patients in the TACE-RT group and 36 patients in the RT-TACE group. Using a 2:1 matching, 75 patients were included into this study after PSM: 50 patients in the TACE-RT group and 25 patients in the RT-TACE group. Before PSM, patients in the RT-TACE group showed significantly better survival when compared with the TACE-RT group (median survival, 13.2 months vs.7.4 months; P = 0.014) for patients with main trunk PVTT, and after PSM, the corresponding median survival was 13.2 months vs.7.4 months ( P = 0.020). When compared with TACE-RT, RT-TACE had a significantly lower rate of worsening in liver function (9.5% vs. 33.3%, P = 0.044) for patients with main trunk PVTT. Conclusions: For HCC patients with main trunk PVTT, IMRT followed by TACE yielded better survival outcomes and liver function when compared to TACE followed by IMRT.

OBJECTIVE: To investigate the effect of air pollution on respiratory health in school-aged children in the main urban area of Chongqing, China. METHODS: The main urban area of Chongqing was divided into polluted area and clean area according to the air pollution data shown on the Environmental Protection Agency Website of Chongqing between 2010 and 2015. A cluster sampling method was used to select 695 third-or fourth-grade children from 2 primary schools in the clean or polluted area as study subjects, with 313 children from the clean area and 382 children from the polluted area. Pulmonary function was examined for all children and a standard American epidemiological questionnaire (ATS-DLD-78-C) was used to investigate the prevalence of respiratory diseases and symptoms. RESULTS: Compared with the clean area, the polluted area had significantly higher concentrations of inhalable particles (PM(10)), fine particulate matter (PM(2.5)), and nitric oxide (NO(X)) (P < 0.05). The multivariate logistic regression analysis was performed after adjustment for confounding factors, and the results showed that compared with those in the clean area, the children in the polluted area had significantly higher risks of cough (OR=1.644), cough during cold (OR=1.596), expectoration during cold (OR=2.196), persistent expectoration (OR=1.802), and wheezing (OR=2.415). The boys and girls in the clean area had significantly higher forced vital capacity and forced expiratory volume in one second than those in the polluted area (P < 0.05). CONCLUSIONS: Air pollution in the main urban area of Chongqing is associated with the increased prevalence of respiratory symptoms in school-aged children and has certain effect on children's pulmonary function.

SummaryIn selective autophagy, receptors are central for cargo selection and delivery. However, it remains yet unclear whether and how multiple autophagy receptors might form complex and function concertedly to control autophagy. Optineurin (OPTN), implicated genetically in glaucoma and amyotrophic lateral sclerosis, was a recently identified autophagy receptor. Here we report that tumor-suppressor HACE1, a ubiquitin ligase, ubiquitylates OPTN and promotes its interaction with p62/SQSTM1 to form the autophagy receptor complex, thus accelerating autophagic flux. Interestingly, the Lys48-linked polyubiquitin chains that HACE1 conjugates onto OPTN might predominantly target OPTN for autophagic degradation. By demonstrating that the HACE1-OPTN axis synergistically suppresses growth and tumorigenicity of lung cancer cells, our findings may open an avenue for developing autophagy-targeted therapeutic intervention into cancer.

e14707 Background: There is an unmet need for the postoperative adjuvant therapy in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI), which is associated with early recurrence after curative resection. This study aimed to investigate the role of Sorafenib as a postoperative adjuvant therapy in HCC patients with MVI after R0 liver resection (LR). Methods: Consecutive HCC patients with pathologically confirmed MVI who underwent R0 LR between January 2009 and December 2016 at the Eastern Hepatobiliary Surgery Hospital were retrospectively reviewed. Patients in the LR+sorafenib group (n = 581) received oral sorafenib (400 mg/d) at 1 weeks after R0 LR, while patients in the LR group (n = 147) only underwent R0 LR. Propensity score matching (PSM) was performed to balance the baseline characteristics between the two groups. Overall survival (OS) and recurrence-free survival (RFS) were followed up, and multivariate Cox regression analysis was performed. Results: After PSM, there were 113 patients in each group. The LR+sorafenib group demonstrated improved OS (median, 43.3 vs. 34.9 months; 1-year, 85% vs. 65%; 3-year, 66% vs. 51%; 5-year, 57% vs. 37%; log-rank P = 0.007) and RFS (median, 32.0 vs. 15.0 months; 1-year, 72% vs. 55%; 3-year, 47% vs. 36%; 5-year, 39% vs. 19%; log-rank P = 0.001) compared with the LR group after PSM. Multivariate Cox regression analysis indicated that R0 LR with postoperative sorafenib therapy was associated with better OS and PFS ( P < 0.001). On subgroup analysis, similar survival benefits were observed for sorafenib in patients with Barcelona Clinic Liver Cancer (BCLC) 0-A, BCLC B and Child-Pugh A stages of disease. Conclusions: Sorafenib used as a postoperative adjuvant therapy in HCC patients with MVI after R0 LR was associated with significantly better survival outcomes than LR alone.

Background: Preoperative alpha-L-fucosidase (AFU) has been used as a diagnostic biomarker for hepatocellular carcinoma (HCC), but its role as a prognostic predictor after partial hepatectomy has not been well defined. The study aimed to investigate the prognostic significance of preoperative serum AFU for HCC patients after hepatic resection. Methods: A retrospective training data set and a prospective validation data set were used to evaluate the prognosis of HCC after partial hepatectomy. A total of 669 patients with histopathologically confirmed HCC were enrolled. Univariate and multivariate analyses were used to identify the prognostic significance of preoperative serum AFU. Results: The retrospective training data set showed a preoperative AFU>35 u l−1 should be used. The prospective validation data set showed preoperative AFU was an independent prognostic factor of overall survival (OS) (P=0.008; hazard ratio: 2.333; 95% confidence interval: 1.249–4.369). Patients with a preoperative AFU>35 u l−1 had a lower recurrence-free survival rate and an OS rate than those with AFU⩽35 u l−1, and they have a higher tendency to form macrovascular invasion. Furthermore, the prognostic significance of AFU>35 u l−1 could also be applied to patients with alpha-fetoprotein levels of ⩽400 ng ml−1. Conclusions: Preoperative serum AFU is a prognostic predictor of HCC.

The Hepatitis B virus (HBV) is an important etiological factor for hepatocarcinogenesis, because HBV DNA load and HBV reactivation are major risks that influence the long-term survival of hepatocellular carcinoma (HCC) patients who underwent hepatectomy and, thus, may cause postoperative liver function deterioration, tumor recurrence, and reduce patient's overall survival. However, anti-HBV therapy can suppress HBV replication, improve the remnant liver function, render patients better able to tolerate HCC treatments, and may even improve their prognosis. In this paper, an anti-HBV therapy that benefits the prognosis of HBV-related HCC following hepatectomy is reviewed.

Purpose Postoperative prognosis of hepatitis B virus (HBV) –related hepatocellular carcinoma (HCC) is poor. The effect of nucleotide/nucleoside analog (NA) treatment on the prognosis has not been fully clarified. Patients and Methods We carried out a two-stage longitudinal study that included a randomized clinical trial (RCT) to evaluate the effect of NA treatment on postoperative prognosis of HBV-HCC. Seven hundred eighty patients (163 in the RCT) were enrolled onto this study following radical hepatectomy. Lamivudine, adefovir dipivoxil, or entecavir were postoperatively administered to antiviral groups. Surgical specimens were examined immunohistochemically for carboxylic acid–terminal truncated HBV X protein (Ct-HBx). Results In the nonrandomized cohort, high viral load (≥ 104 copies/mL) significantly predicted unfavorable overall survival and recurrence-free survival (RFS), whereas antiviral treatment significantly improved both types of survival. In the RCT, antiviral treatment significantly decreased HCC recurrence and HCC-related death, with hazard ratios (HRs) of 0.48 (95% CI, 0.32 to 0.70) and 0.26 (95% CI, 0.14 to 0.50), respectively, in multivariate Cox analyses. Patients who received antiviral treatment had significantly decreased early recurrence (HR, 0.41; 95% CI, 0.27 to 0.62) and improved liver function 6 months after surgery compared with the controls (P < .001). Those with recovered liver function had a higher 2-year RFS rate than those without (P = .003). Ct-HBx expression in adjacent hepatic tissues significantly predicted an unfavorable RFS in the antiviral group (P < .001). Conclusion Although it might not affect the HCC-promoting potential of Ct-HBx, NA treatment is effective in normalizing liver function, decreasing HBV-HCC recurrence, and improving postoperative survival. This effect should be validated in a multicenter phase III RCT.

// Juxian Sun 1, * , Jie Shi 1, * , Bin Huang 2, * , Fantian Cheng 1, 3 , Weixing Guo 1 , Wan Yee Lau 1, 4 and Shuqun Cheng 1 1 Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China 2 Department of Imaging, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China 3 Department of Hepatopancreatobiliary Surgery I, The Central Hospital of Wuhan, Tongji Medical University of Science and Technology, Wuhan, China 4 Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China * These authors contributed equally to this work Correspondence to: Shuqun Cheng, email: chengshuqun@aliyun.com Keywords: blood supply, portal vein tumor thrombus, hepatocellular carcinoma, TACE Received: February 08, 2017 Accepted: June 29, 2017 Published: August 01, 2017 ABSTRACT Purpose: To investigate the degree of arterial blood supply of portal vein tumor thrombus (PVTT) in patients with hepatocellular carcinoma (HCC), and to evaluate its impact on overall survival after transarterial chemoembolization using lipiodol +/– gelatin sponge particles (TACE). Results: Of the 10 patients who underwent surgery, the number of patients with good/mild/poor staining of PVTT by methylene blue were 3, 4, and 3, respectively. The degrees of methylene blue staining in these patients correlated well with the degrees of accumulation of lipiodol in PVTT in these patients, i.e. good/mild/poor in 3, 4, and 3 patients, respectively. For the 77 patients who underwent TACE as treatment, they were divided into 2 groups: good accumulation of lipiodol ( n = 27) and mild/poor accumulation of lipiodol ( n = 50) on CT. The overall median survival between the 2 groups was 10.0 months vs 2.7 months, ( p < 0.001). Multi-variable analysis showed degree accumulation of Lipiodol (OR, 2.057; 95% CI,1.414–2.993; p < 0.001) to be an independent prognostic factor. Patients and Methods: Patients with HCC with PVTT who underwent surgical resection received preoperative TACE. At operation, arterial injection of methylene blue into the common hepatic artery was carried out. During the study period, other patients with unresectable HCC with PVTT were treated with TACE. Conclusion: In about 1/3 of patients with HCC with PVTT, the arterial blood supply from the hepatic artery to the PVTT was good. These patients responded better to TACE than those patients with mild/poor arterial supply.

The effect of portal vein tumor thrombus (PVTT) on the prognosis of patients with hepatocellular carcinoma has become clear over the past several decades. However, identifying the mechanisms and performing the diagnosis and treatment of PVTT remain challenging. Therefore, this study aimed to summarize the progress in these areas. A computerized literature search in Medline and EMBASE was performed with the following combinations of search terms: “hepatocellular carcinoma” AND “portal vein tumor thrombus.” Although several signal transduction or molecular pathways related to PVTT have been identified, the exact mechanisms of PVTT are still largely unknown. Many biomarkers have been reported to detect microvascular invasion, but none have proved to be clinically useful because of their low accuracy rates. Sorafenib is the only recommended therapeutic strategy in Western countries. However, more treatment options are recommended in Eastern countries, including surgery, radiotherapy (RT), transhepatic arterial chemoembolization (TACE), transarterial radioembolization (TARE), and sorafenib. Therefore, we established a staging system based on the extent of portal vein invasion. Our staging system effectively predicts the long-term survival of PVTT patients. Currently, several clinical trials had shown that surgery is effective and safe in some PVTT patients. RT, TARE, and TACE can also be performed safely in patients with good liver function. However, only a few comparative clinical trials had compared the effectiveness of these treatments. Therefore, more randomized controlled trials examining the extent of PVTT should be conducted in the future.

Background/Purpose: Patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) have an extremely poor prognosis and relatively few treatment options. Method: During a consensus meeting, experts met to examine the published data for HCC treatment strategies in patients with PVTT. Results: Many treatment guidelines consider the presence of PVTT a contraindication to partial hepatectomy or liver transplantation. Transarterial chemoembolization (TACE) is associated with an increased risk of ischemic necrosis of liver and of treatment-related death in patients with PVTT, and is, therefore, limited to a select group of patients with good hepatic function and adequate collateral circulation around the occluded portal vein. Systemic sorafenib results in survival benefit in patients regardless of the presence of PVTT. However, side effects are common, and there are no effects on time-to-symptom progression or quality of life. Transarterial radioembolization (TARE) with yttrium-90 microspheres is emerging as a valuable strategy. A wider range of patients with PVTT are suitable for this procedure compared to TACE. TARE is as effective as TACE in HCC and has quality-of-life advantages. Conclusion: In patients with HCC with PVTT, medical evidence suggests that TARE is a good choice of treatment.

Circulating tumor cells (CTCs) originate from tumor tissues and are associated with cancer prognosis. However, existing technologies for CTC detection are limited owing to a lack of specific or accurate biomarkers. Here, we developed a new method for CTC detection based on the karyoplasmic ratio, without biomarkers. Consecutive patients with liver cancer or non-cancer liver diseases were recruited. CTCs in blood samples were analyzed by imaging flow cytometry based on the karyoplasmic ratio as well as EpCAM and CD45. Microvascular invasion (MVI), tumor recurrence, and survival were recorded for all patients. A total of 56.2 ± 23.8/100,000 cells with high karyoplasmic ratios (HKR cells) were detected in cancer patients, which was higher than the number of HKR cells in the non-cancer group (7.6 ± 2.2/100,000). There was also a difference in HKR cells between liver cancer patients with and without MVI. Based on a receiver operating characteristic curve analysis, the threshold was 21.8 HKR cells per 100,000 peripheral blood mononuclear cells, and the area under the curve was higher than those of traditional methods (e.g., CD45 and EpCAM staining). These results indicate that the new CTC detection method was more sensitive and reliable than existing methods. Accordingly, it may improve clinical CTC detection.

To explore the effect of exposure to vehicle exhaust in pregnant mice on the reproductive function and DNA methylation in male offspring mice.Twenty pregnant mice were randomized into control group and vehicle exhaust exposure group (n=10) and exposed to routine laboratory condition and to vehicle exhaust for 10 consecutive days (8 h per day) in a tunnel with a heavy traffic, where the concentrations of TSP, PM10, PM2.5, SO2 and NOX and the decibel of noise were measured. The offspring mice were raised till reaching maturity, and the epididymides of the male mice were collected to test the weight coefficients, DNA methylation level, and mRNA levels of Aldh7a1 and Rpe.The body weight and the weight coefficients of the epididymides and testes differed significantly between the exposure group and the control group (P0.05). The concentrations of TSP, PM2.5, PM10 and NOx and the decibel of noise were significantly higher in the traffic environment and the control environment (P0.05). Reduced representation bisulphite sequencing (RRBS) and Gene ontology (GO) showed that 58 genes had significantly different methylation levels between the two groups, mostly relating to the process of spermatogenesis (P0.05). Compared with the control group, Aldh7a1 and Rpe mRNA expressions in the testes were down-regulated significantly in the exposure group (P0.05).Exposure of pregnant mice to vehicle exhaust causes damages of the reproductive function in the male offspring mice.

Development of portal vein tumor thrombus deteriorates the prognosis of hepatocellular carcinoma, while surgical treatment can offer a promising prognosis for selected patients. However, the possibility of residual lesions in portal vein after conventional thrombectomy is a main risk factor leading to postoperative recurrence. Therefore, ensuring the complete removal of tumor thrombus during operation is critical to improve prognosis. For the first time, we report here one case of hepatocellular carcinoma with portal vein tumor thrombus in which cystoscope was successfully applied as a substitute of intravascular endoscope to visualize the cavity of the portal vein. The patient was a 61-year-old man with a 7-cm tumor in the right lobe of the liver, with tumor thrombus invading the right branch and adjacent to the conjunction of the portal vein. After removal of the tumor, the Olympus CYF-VA2 cystoscope was used to check the portal vein from the opening stump of the right branch of the portal vein. In this case, residual thrombus tissue was found near the opening stump and the conjunction of the portal vein. The residual lesion was carefully retrieved from the stump after retraction of the cystoscope. The procedure was repeated until no residual lesion was found. The whole duration time of thrombectomy was 22.5 (15 + 7.5) min. The patient was free from recurrence at 8 months after the procedure. Our work indicated that the cystoscope is a suitable substitute, with a proper size and function to check the portal vein system and ensure the curability of thrombectomy. Although well-designed clinic trails are still needed, this procedure may further improve the postoperative prognosis of hepatocellular carcinoma with portal vein tumor thrombus.

Background & Aims Portal vein tumor thrombus (PVTT) has previously been demonstrated to correlate with poor prognosis of hepatocellular carcinoma. Approximately 50–80% of HCC is accompanied by portal or hepatic vein invasion. The underlying mechanisms of PVTT development remain unclear. This study aimed to elucidate the role of miR-135a in PVTT tumorigenesis. Methods In the present study, we investigated the expression of microRNAs and mRNAs in PVTT tissues using advanced microRNA and cDNA microarray techniques. MicroRNA (miR)-135a was noted to be highly over-expressed in PVTT and the cell line CSQT-2 and was selected for further study. We characterized the function of miR-135a in vitro and in vivo . We also analyzed the clinical relevance of miR-135a in relation to the prognosis and survival of HCC patients with PVTT. Results Our analyses found that the miRNA and mRNA expression profiles of PVTT were distinct from the parenchyma tumor. Overexpression of miR-135a favors invasive and metastatic behavior in vitro . Furthermore, in a CSQT-2 orthotopic transplantation nude mouse model, blockade of miR-135a significantly reduced PVTT incidence. We also found that miR-135a was transcribed by forkhead box M1 (FOXM1), and metastasis suppressor 1 (MTSS1) was identified as the direct and functional target of miR-135a. Additionally, the cohort analysis revealed the relevance of miR-135a with respect to the prognosis and survival of HCC patients with PVTT. Conclusions Our data suggest an important role for miR-135a in promoting PVTT tumorigenesis and indicate the potential application of miR-135a in PVTT therapy.

Liver damage in hepatic surgery from warm ischemia and reperfusion (I/R), especially in patients with underlying chronic liver disease, is still challenging. We propose a new method of perfusion of the liver by catheterizing the umbilical vein in the period of hepatic inflow occlusion, and evaluate the influence of transfusion of normal saline (NS) on liver injury in a modified I/R rat model.Twenty-eight rats were randomized into four groups (n=7): group I (sham-operated group): no I/R or transfusion; group II (I/R group): I/R + no transfusion; group III (37°C NS group): I/R + transfusion of 37°C NS ; group IV(24°C NS group): I/R + transfusion of 24°C NS. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), as well as lactate dehydrogenase (LDH) were measured in rat serum. Light and electron microscopic examinations were performed on the liver tissues.Perfusion of 24°C NS in the period of inflow occlusion resulted in significant reductions of liver enzymes levels compared to the I/R alone group and 37°C NS group (P0.001 and P0.001, respectively). Histologic evaluation revealed the injury grade to be relatively lower in group IV compared to group II and III (P0.001 and P0.001, respectively).This new hypothermic perfusion technique may be very useful in preserving the hepatocytes in hepatic surgery; it is an inexpensive and easy method, which makes it possible to increase its application.

Portal vein tumor thrombus (PVTT) is not commonly used in the treatment of intrahepatic cholangiocarcinoma (ICC), and its impact on the prognosis of ICC is unclear. We aimed to assess the outcomes of ICC with or without PVTT after hepatic resection.From January 2000 to December 2005, the data from all consecutive patients with ICC who underwent hepatic resection at our hospital were retrospectively analyzed. According to the Cheng's PVTT Classification (types I-IV), we compared the survival outcomes of ICC patients (with or without PVTT) and prognosis of patients with ICC with different types of PVTT.Three hundred and three patients with ICC were enrolled in this study (59 with PVTT). The incidence of PVTT was 19.4% (59/303). The median survival times were 12.68 and 28.91 months for ICC patients with and without PVTT, respectively (P 0.001). The multivariate analysis demonstrated that PVTT (hazard ratio [HR] 1.783; confidence interval 95% [1.279; 2.487]) was an independent risk factor for overall survival. Patients with type I PVTT exhibited significantly better survival than those with types II and III PVTT.The ICC patients with PVTT exhibit a poorer prognosis compared with ICC patients without PVTT after hepatic resection.

Hepatocellular carcinoma (HCC) with main portal vein tumor thrombus (mPVTT) has a poor prognosis even after surgical resection. Whether neoadjuvant radiotherapy improves surgical outcomes is currently unknown. The aim of this study was to compare the survival of patients with resectable HCC and mPVTT who underwent neoadjuvant therapy to those who underwent surgery alone.A non-randomized comparative study was performed. For patients in the neoadjuvant radiotherapy group, three-dimensional conformal radiotherapy was administrated with a daily fraction of 300 cGy in 6 consecutive days. Hepatectomy was carried out 4 weeks after completion of irradiation.95 patients were enrolled into this study. In the neoadjuvant radiotherapy group (n = 45), 12 patients showed gross radiological reduction in extent of PVTT. In 6 patients, the extent of PVTT was reduced to be within the ipsilateral side of the portal vein. When compared with patients who underwent surgery alone (n = 50), neoadjuvant radiotherapy significantly decreased the rates of HCC recurrence and HCC-related death, with hazard ratios of 0.36 (95% CI, 0.19-0.70) and 0.32 (95% CI, 0.18-0.57), respectively.For patients with HCC with mPVTT, neoadjuvant radiotherapy before partial hepatectomy provided better postoperative survival outcomes than partial hepatectomy alone.

Accurate assessment of characteristics of tumor and portal vein tumor thrombus is crucial in the management of hepatocellular carcinoma.Comparison of the three-dimensional imaging with multiple-slice computed tomography in the diagnosis and treatment of hepatocellular carcinoma with portal vein tumor thrombus.Patients eligible for surgical resection were divided into the three-dimensional imaging group or the multiple-slice computed tomography group according to the type of preoperative assessment. The clinical data were collected and compared.74 patients were enrolled into this study. The weighted κ values for comparison between the thrombus type based on preoperative evaluation and intraoperative findings were 0.87 for the three-dimensional reconstruction group (n = 31) and 0.78 for the control group (n = 43). Three-dimensional reconstruction was significantly associated with a higher rate of en-bloc resection of tumor and thrombus (P = 0.025). Using three-dimensional reconstruction, significant correlation existed between the predicted and actual volumes of the resected specimens (r = 0.82, P 0.01), as well as the predicted and actual resection margins (r = 0.97, P 0.01). Preoperative three-dimensional reconstruction significantly decreased tumor recurrence and tumor-related death, with hazard ratios of 0.49 (95% confidential interval, 0.27-0.90) and 0.41 (95% confidential interval, 0.21-0.78), respectively.For hepatocellular carcinoma with portal vein tumor thrombus, three-dimensional imaging was efficient in facilitating surgical treatment and benefiting postoperative survivals.

Merlin, which is encoded by the tumour suppressor gene Nf2, plays a crucial role in tumorigenesis and metastasis. However, little is known about the functional importance of Merlin splicing forms. In this study, we show that Merlin is present at low levels in human hepatocellular carcinoma (HCC), particularly in metastatic tumours, where it is associated with a poor prognosis. Surprisingly, a splicing variant of Merlin that lacks exons 2, 3 and 4 (Δ2–4Merlin) is amplified in HCC and portal vein tumour thrombus (PVTT) specimens and in the CSQT2 cell line derived from PVTT. Our studies show that Δ2–4Merlin interferes with the capacity of wild-type Merlin to bind β-catenin and ERM, and it is expressed in the cytoplasm rather than at the cell surface. Furthermore, Δ2–4Merlin overexpression increases the expression levels of β-catenin and stemness-related genes, induces the epithelium–mesenchymal-transition phenotype promoting cell migration in vitro and the formation of lung metastasis in vivo. Our results indicate that the Δ2–4Merlin variant disrupts the normal function of Merlin and promotes tumour metastasis., Merlin plays a crucial role as a tumour suppressor in liver tumorigenesis. Here, the authors show that a splicing variant of Merlin that lacks exons 2,3 and 4 (Δ2–4Merlin) is highly expressed in hepatocarcinoma and promotes tumour metastasis by interfering with the binding of wild-type Merlin to ß-catenin.

BACKGROUND:Hepatocellular carcinoma (HCC) is a common malignancy that has a poor prognosis because there is lack of methods for early diagnosis. We aimed to utilize two serum long non-coding RNAs (lncRNAs), uc001ncr and AX800134, to diagnose hepatitis B virus (HBV)-positive HCC. METHODS:lncRNA microarrays were utilized to measure the differential expression of lncRNAs between tumor tissues and corresponding non-tumor tissues in HBV-positive hapatocellular carcinoma. uc001ncr and AX800134 were selected as candidate lncRNAs and detected in three independent cohorts containing a total of 684 participants (healthy individuals and chronic HBV patients and HBV-positive HCC patients) who were recruited between March 2011 and December 2012. A logistic regression model was constructed using a training cohort (n = 353) and validated using an independent cohort (n = 181). The area under the receiver operating characteristic curve (AUC) was utilized to evaluate the diagnostic accuracy. RESULTS:We determined that a panel based on the expression of uc001ncr and AX800134 accurately diagnosed HBV-positive HCC (AUC values of 0.9494 and 0.9491 for the training and validation cohorts, respectively). The diagnostic performance of the panel remained high in patients with AFP≤400 ng/ml (AUC values of 0.9371 and 0.9527 for the training and validation cohorts, respectively). The panel also diagnosed early HCC (AUC values of 0.9450 and 0.9564 for the training and validation cohorts, respectively). CONCLUSION:Our results indicated that the serum expression of uc001ncr and AX800134 has potential as novel potential biomarker for the diagnosis of HCC, especially in patients with AFP≤400 ng/ml or early-stage disease (BCLC 0+A).

Cidan is a traditional Chinese medicine formula that has been used for >10 years as an antitumor drug. In the present study, the antitumor effect of cidan on hepatocellular carcinoma (HCC) and the underlying molecular mechanisms were investigated. A total of 372 patients with primary HCC, as confirmed by pathological examination in the Eastern Hepatobiliary Surgery Hospital and Beijing Oncology Hospital of Weida TCM, were prospectively enrolled in the study. In total, 92 patients were treated with cidan capsules for three months postoperatively, while 280 patients served as controls. The efficacy of cidan was analyzed by monitoring associated symptoms and liver function tests, including measuring the levels of α-1-fetoprotein, α-L-fucosidase, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase and γ-glutamyl transferase. In addition, in vivo analysis was performed using mice Hepa1-6 xenograft models, while in vitro studies were performed with SMMC-7721 and CSQT-1 cells; this included cidan-dependent cell viability and migration assays, cell cycle analyses and the evaluation of cidan effects on cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) mRNA transcription rates using quantitative polymerase chain reaction. The postoperative two-year overall survival (77 and 58% for the cidan and control groups, respectively; P

Sorafenib is a specific adenosine triphosphate–competitive RAF inhibitor used as a first-line treatment of advanced hepatocellular carcinoma (HCC). However, the responses are variable, reflecting heterogeneity of the disease, while the resistance mechanism remains poorly understood. Here, we report that sorafenib treatment can exacerbate disease progression in both patient-derived xenografts and cell line–derived xenografts and that the therapeutic effect of the drug inversely covaries to the ratio of epithelial cell adhesion molecule–positive cells, which may be tumor initiating cells in HCC. The TSC2-AKT cascade mediates this sorafenib resistance. In response to sorafenib treatment, formation of the TSC1/2 complex is enhanced, causing increased phosphorylation of AKT, which contributes to up-regulation of “stemness”-related genes in epithelial cell adhesion molecule–positive cells and enhancement of tumorigenicity. The expression of TSC2 negatively correlated with prognosis in clinical sorafenib therapy. Furthermore, all-trans retinoic acid decreased AKT activity, reduced the epithelial cell adhesion molecule–positive cell population enriched by sorafenib, and potentiated the therapeutic effect of sorafenib in the patient-derived xenograft model. Conclusion: Our findings suggest that a subtype of HCC is not suitable for sorafenib therapy; this resistance to sorafenib can be predicted by the status of TSC2, and agents inducing differentiation of tumor initiating cells (e.g., all-trans retinoic acid) should improve the prognosis of this subtype of HCC.(Hepatology 2015;62:1791–1803)

Purpose: Portal vein tumor thrombus (PVTT) is a major complication of hepatocellular carcinoma (HCC) and is associated with poor survival. Long noncoding RNAs (lncRNA) contribute to HCC metastasis, but whether and how lncRNAs affect PVTT development remains unclear. In the present study, a novel highly expressed lncRNA (ICAM-1–related, ICR) was identified in ICAM-1+ cancer stem cells (CSC) in HCC. This lncRNA regulated CSC properties and contributed to PVTT development. Experimental Design: We used microarray and bioinformatics analyses to identify differentially expressed lncRNAs. Real-time PCR and Western blotting were used to assess gene expression in cell lines and tumors. Sphere formation assays were performed to investigate stem cell properties of tumor cells in vitro. Retrospective and prospective studies were used to investigate the relationship between ICR expression and clinical outcomes. Results: Compared with the corresponding primary tumors, PVTT expressed different lncRNAs and mRNAs, including the upregulated lncRNA ICR and ICAM-1. ICR regulated ICAM-1 expression by increasing the stability of its mRNA through RNA duplex formation, which modulated the CSC properties of ICAM-1+ HCC cells. ICR transcription in ICAM-1+ HCC cells was regulated by Nanog, and inhibition of ICR in situ significantly reduced ICAM-1 expression and ICAM-1+ HCC cells in tumors in vivo. Moreover, elevated ICR and ICAM-1 expression in tumors was correlated with PVTT development and poor clinical outcomes. Conclusions: Our study demonstrates that ICR specifically regulates CSC properties of ICAM-1+ HCC cells and that ICR contributes to PVTT development. Therefore, ICR may be a promising target for HCC therapy. Clin Cancer Res; 22(8); 2041–50. ©2015 AACR.

This study aimed to investigate the association between HBV mutations and intrahepatic HBV status and to determine the clinical features and the contribution of HBV mutations to postoperative prognosis for hepatocellular carcinoma (HCC) patients with HBsAg (+) in China. Using TaqMan fluorescent real-time PCR, HBV covalently closed circular DNA (cccDNA) and total DNA (tDNA) were both quantified in 106 pairs of tumor tissues (TT) and adjacent non-tumor tissues (ANTT) obtained from HCC patients who received no antiviral treatment before surgical treatment. The prevalence of 19 hot spot mutations was evaluated by Sanger sequencing. HBV cccDNA and tDNA were lower in TT than in ANTT. The loads of cccDNA and tDNA in ANTT were associated with serum HBV DNA and HBeAg. Three Pre-S mutants (A2962G and C2964A in Pre-S1 and C105T in Pre-S2) were associated with higher tumor cccDNA levels (P < 0.05), and A2962G/C2964A mutants were associated with higher AFP levels. This would assist to disclose the virological features, to implement a more clinically personalized therapy and to improve the prognosis of HBV-related HCC patients.

Hilar cholangiocarcinoma has been reputed as a slow growth tumor in the past. Skeletal muscle is one of the most unusual sites of metastasis from any malignancy. We report herein a case of hilar cholangiocarcinoma with synchronous metastases to skeletal muscle and breast, and review the literature. The patient was a 48-year-old woman who presented with jaundice and weight loss. An inoperable hilar cholangiocarcinoma was diagnosed. She was treated with a combination of endoscopic plastic stent biliary drainage and three-dimensional conformal radiotherapy (3DCRT). Good response was achieved. Ten months later, she exhibited with a painful metastatic mass in the muscle rectus femoris of left thigh and a painless mass in the left breast. She underwent operation to relieve the pain, but died from liver failure after 8 months. The literature only offers isolated cases of cholangiocarcinoma with distant metastases, of which the common sites were cervical lymph node, bone, and portal venous system. Most patients were presented with multiple metastases with extensive local disease.

The optimal treatment for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) remains controversial. We aimed to investigate the best treatment for patients with HCC with PVTT. From January 2002 to January 2014, the data from all consecutive patients with HCC with PVTT who underwent surgical treatment (ST),TACE,TACE combined with sorafenib (TACE-Sor), or TACE combined with radiotherapy (TACE-RT) in the 4 largest tertiary hospitals in China were analyzed retrospectively. The patients were divided into 3 subtypes according to the extent of PVTT in the portal vein (type I-III). The primary endpoint was overall survival (OS). A total of 1580 patients with HCC with PVTT were included in the study. The median survival times (MST) for ST (n = 745) for type I, II, and III patients (95% CI) were 15.9 (13.3-18.5), 12.5 (10.7-14.3), and 6.0 (4.3-7.7) months, respectively. The corresponding figures for patients after TACE (n = 604) were 9.3 (5.6-12.9), 4.9 (4.1-5.7), and 4.0 (3.1-4.9), respectively; for patients after TACE-Sor (n = 113) 12.0 (6.6-17.4), 8.9 (6.7-11.1), and 7.0 (3.0-10.9), respectively; and for patients after TACE-RT (n = 118) 12.2 (0-24.7), 10.6 (6.8-14.5), and 8.9 (5.2-12.6), respectively. Comparison among the different treatments for the 3 subtypes of PVTT patients after propensity score (PS) matching showed the effectiveness of ST to be the best for type I and type II PVTT patients, and TACE-RT was most beneficial for type III patients. Treatment was an independent risk factor of OS. ST was the best treatment for type I and II PVTT patients with Child-Pugh A and selected B liver function. TACE-RT should be given to type III PVTT patients.

It is not known whether percutaneous radiofrequency ablation (PRFA) could get the same treatment efficacy and fewer complications as partial hepatectomy (PH) in patients with small centrally located hepatocellular carcinoma (HCC). The present study was designed to evaluate the efficacy of PH and PRFA in the treatment of small centrally located HCC.From January 2002 until December 2007, 196 patients with small centrally located HCC (≤5 cm) were included. Of these 196 patients, 94 received PRFA and 102 patients were treated with PH. Treatment outcomes, including major complications and survival data, were studied.No treatment-related death occurred in either group. There were no significant differences in survival rates between the two groups. The 1-, 3-, and 5-year disease-free survival rates for the PRFA and PH groups were 57.9%, 36.4%, 34.0%, and 59.8%, 42.4%, 40.8%, respectively (P = 0.50). The 1-, 3-, and 5-year overall survival rates for the two groups were 94.3%, 74.7%, and 49.8%, and 89.2%, 74.1%, and 63.1%, respectively (P = 0.96). PRFA had a lower rate of major complications than PH (8.5 vs. 19.6%), and the hospital stay was also shorter in the PRFA group than in the PH subgroup (4 vs. 13 days).Based on the data obtained, we concluded that PRFA might be equal to PH for the treatment of small centrally located HCC. However, PRFA has the benefits of shorter hospital stay as well as a lower rate of complications.

Genome-wide association studies (GWAS) have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC). To further identify novel susceptibility loci associated with HBV–related HCC and replicate the previously reported association, we performed a large three-stage GWAS in the Han Chinese population. 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers were genotyped for the discovery stage. Top candidate SNPs were genotyped in the initial validation samples of 2,112 HBV–positive HCC cases and 2,208 HBV carriers and then in the second validation samples of 1,021 cases and 1,491 HBV carriers. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 (OR = 1.30, P = 1.13×10−19) and rs455804 (GRIK1) on 21q21.3 (OR = 0.84, P = 1.86×10−8), which were further replicated in the fourth independent sample of 1,298 cases and 1,026 controls (rs9272105: OR = 1.25, P = 1.71×10−4; rs455804: OR = 0.84, P = 6.92×10−3). We also revealed the associations of HLA-DRB1*0405 and 0901*0602, which could partially account for the association at rs9272105. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV–related HCC, suggesting the involvement of glutamate signaling in the development of HBV–related HCC., Author Summary Previous studies strongly suggest the importance of genetic susceptibility for hepatocellular carcinoma (HCC). However, the studies about genetic etiology on HBV–related HCC were limited. Our genome-wide association study included 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers for the discovery analysis. 2,112 HBV–positive HCC cases and 2,208 HBV carriers (the initial validation), and 1,021 cases and 1,491 HBV carriers (the second validation), were then analyzed for validation. The fourth independent samples of 1,298 cases and 1,026 controls were analyzed as replication. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 and rs455804 (GRIK1) on 21q21.3. HLA-DRB1 molecules play an important role in chronic HBV infection and progression to HCC. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV–related HCC, suggesting the involvement of glutamate signaling in the development of HBV–related HCC.

Surgical resection is the first-line treatment for hepatocellular carcinoma (HCC) patients with well-preserved liver function. Nevertheless, the rate of postoperative recurrence at 5 years is as high as 70%, and this gravely jeopardizes the therapeutic outcome. Clearly, new approaches are needed for preventing the relapse of this deadly disease. Taking advantage of a luciferase-labeled orthotopic xenograft model of HCC, we examined the role of sorafenib, the first systemic drug approved for advanced HCC patients, in the prevention of HCC recurrence. We found that sorafenib suppressed the development of postsurgical intrahepatic recurrence and abdominal metastasis and consequently led to prolonged postoperative survival of mice in this model. Furthermore, hyperactivity of extracellular signal-regulated kinase signaling caused by elevated levels of growth factors associated with postoperative liver regeneration enhanced the sensitivity of HCC cells to sorafenib; this provides a plausible explanation for the observation that recurrent tumors are more responsive to growth inhibition by sorafenib. Conclusion: Our results strongly suggest that by effectively reducing postoperative recurrence, sorafenib has a potential application in early-stage HCC patients who have undergone hepatectomy with curative intention. (HEPATOLOGY 2011;53:483-492)

Background: This study was conducted to investigate the expression of CXCR4 in portal vein tumor thrombus (PVTT) tissue and its possible role in the invasiveness of tumor thrombus cells. Methods: We detected differential expression of CXCR4 between PVTT and hepatocellular carcinoma (HCC) by an immunohistochemical assay. Lentivirus-mediated RNA interference and a migration assay were performed on human primary cells derived from PVTT to study the impact of CXCR4 on the invasiveness of HCC. Results: The expression of CXCR4 in tumor thrombus tissue was higher than that in HCC tissue. The invasion ratio of PVTT cells was significantly decreased (P < 0.05) after being infected with a CXCR4-targeting siRNA lentivirus, indicating that downregulation of CXCR4 by lentivirus-mediated RNA interference significantly impaired the invasive potential of PVTT. Conclusions: These results indicate that CXCR4 is an effective curative target for hepatocellular carcinomas with PVTT. Background Hepatocellular carcinoma (HCC) is an extremely common malignant tumor. China is developing one of the highest incidences of liver cancer worldwide. About 45% of de novo HCC cases were discovered in mainland China, and about 110, 000 people died of hepatoma. In fact, in Asian countries such as China, India, the Republic of Korea, Singapore and Vietnam, more than 80% to 90% cases of HCC were associated with human hepatitis B virus (HBV) infections. More than 2 billion people have been infected with HBV worldwide, and more than 350 million of these people became infectors; 75% of all infectors live in Asia, and 33% live in mainland China [1,2]. In fact, chronic HBV infection greatly increases the risk of liver cirrhosis and HCC, resulting in the deaths of nearly one million HBV infectors from a

We aimed to correlate the survival of patients with hepatocellular carcinoma (HCC) with macroscopic portal vein tumor thrombus (PVTT) who underwent partial hepatectomy with or without portal thrombectomy with our PVTT classification. Currently, different staging systems for HCC are widely used in clinical practice. However, they lack the refinement in giving prognosis and guiding surgical treatment once macroscopic PVTT is present. A retrospective study was carried out, in a single tertiary center, from January 2001 to December 2004 on 441 patients who underwent partial hepatectomy with or without portal thrombectomy for HCC with macroscopic PVTT. Overall survival was examined to determine whether it was correlated with our PVTT classification, and with the TNM staging, Cancer of the Liver Italian Program (CLIP) scoring system, and the Japan Integrated Staging (JIS) scoring system. With our PVTT classification, the numbers (percentages) of patients with types I, II, III, and IV PVTT were 144 (32.7%), 189 (42.9%), 86 (19.5%), and 22 (5.0%), respectively. The corresponding 1-, 2-, and 3-year overall survival rates for types I to IV PVTT were 54.8, 33.9, and 26.7%; 36.4, 24.9, and 16.9%; 25.9, 12.9, and 3.7%; and 11.1, 0, and 0%, respectively (log-rank of the survival curves P

The aim of this study was to compare the results of percutaneous radiofrequency ablation (RFA) with those of partial hepatectomy (PH) in the treatment of multicentric small hepatocellular carcinomas (HCCs). With advances in RFA, it is not known whether the minimally invasive approach with percutaneous RFA could attain comparable survival outcomes but with a lower morbidity in patients with multicentric HCCs. From January 2002 and December 2007, 159 patients who had two or three HCCs, with the largest tumor no more than 5 cm in diameter, had no major vascular invasion or extrahepatic metastases, and were treated with either PH (n = 73) or RFA (n = 86) were included in the study. There was no procedure-related mortality in both groups of patients. Major complications happened significantly more often after PH than after RFA (19.2 vs. 8.1%). The hospital stay was significantly longer after PH than after RFA (median = 9 vs. 3 days). The 1-, 3-, and 5-year overall survival rates for the PH and RFA groups were 91.8, 68.7, 44.5% and 94.2, 64.4, 21.2%, respectively. The corresponding disease-free survival rates for the two groups were 62.1, 33.6, 3.6% and 29.4, 2.7, 0%, respectively. The PH group had significantly longer overall survival and disease-free survival than the RFA group. PH resulted in better survival outcomes than RFA for patients with multicentric small HCCs. However, RFA had the benefits of lower procedure-related morbidity and shorter hospital stay.

Portal vein tumor thrombosis (PVTT) in patients with hepatocellular carcinoma (HCC) is known as a major complication associated with poor survival. We clinically defined a type of distinct PVTT (dPVTT) in small HCC patients that is distant to liver parenchyma tumor (PT). The biological features of dPVTT are not clear. We utilized two-dimensional electrophoresis and tandem MS to compare and identify differentially expressed proteins between dPVTT and PT tissues. Of the 65 spots identified as differentially expressed (p < 0.05) between the two cancerous tissues, 19 (corresponding to 19 unique proteins) were identified. Further analysis of five proteins confirmed quantitative differences between the two tumor tissues. Upon comparison with PT tissues of HCC, c-kit was also significantly upregulated in dPVTTs in small HCC patients and the CSQT-2 cell line derived from dPVTT tissues, which validated the differences between the dPVTT and PT tissues. The protein expression profiles and proteins identified in this study demonstrate the presence of dPVTTs with more malignant phenotypes and will be useful in clarifying the mechanisms through which dPVTT develops. Specific treatments targeting dPVTT might be applied to HCC patients with dPVTT.