Factor For Hepatocellular Carcinoma Patients Research Articles

Skeletal muscle depletion predicts the prognosis of patients with hepatocellular carcinoma treated with sorafenib.

The aim of this study was to determine whether skeletal muscle depletion predicts the prognosis of patients with hepatocellular carcinoma (HCC) that is being treated with sorafenib. We evaluated 40 consecutive HCC patients who received sorafenib treatment. The skeletal muscle cross-sectional area was measured by computed tomography at the third lumbar vertebra (L3), from which the L3 skeletal muscle index (L3 SMI) was obtained. The factors contributing to overall survival, sorafenib dose reduction, and discontinuation of sorafenib were analyzed using the Cox proportional hazards model. L3 SMI (p = 0.020) and log (α-fetoprotein (AFP)) (p = 0.010) were identified as independent prognostic factors in HCC patients treated with sorafenib. The initial dose of sorafenib (p = 0.008) was an independent risk factor for sorafenib dose reduction, and log (AFP) (p = 0.008) was the only significant risk factor for the discontinuation of this drug. L3 SMI was not a risk factor for either dose reduction (p = 0.423) or the discontinuation (p = 0.132) of sorafenib. A multiple linear regression analysis determined the following relationship between skeletal muscle mass (assessed as L3 SMI) and the explanatory factors: L3 SMI = −0.1896 × (Age) − 10.3441 × (Child-Pugh score) − 9.3922 × (log (AFP)) + 1.6139 × (log (AFP)) × (Child-Pugh score) + 112.9166. Skeletal muscle depletion is inversely associated with age, Child-Pugh score, and log (AFP). Moreover, it is an independent prognostic factor for HCC patients treated with sorafenib.

Serum ferritin as a new prognostic factor in hepatocellular carcinoma patients treated with radiofrequency ablation

Hepatic iron accumulation is considered to be a cofactor that influences liver injury and hepatocarcinogenesis. Aim of this study is to determine whether serum ferritin (SF) levels relate to overall survival (OS) and time to recurrence (TTR) in hepatocellular carcinoma (HCC) patients treated with percutaneous radiofrequency ablation (RFA). We measured SF levels in 103 HCC patients (median age 70, M/F = 82.5%/17.5%) who underwent RFA between 2005 and 2010. Correlation between SF and other prognostic factors at baseline was analyzed. SF levels were entered into a Cox model and their influence on OS and TTR was evaluated in univariate and multivariate analyses. SF did not correlate with α-fetoprotein (rho: -0.12, P = 0.22), neutrophil/lymphocyte ratio (rho: -0.1020, P = 0.30), Model for End-Stage Liver Disease (rho: 0.18, P = 0.06), Child-Pugh score (P = 0.5), or Barcelona Cancer of the Liver Clinic stage (P = 0.16). A log-rank test found the value of 244 ng/mL as the optimal prognostic cut-off point for SF. Median OS was 62 months (54-78) and survival rate was 97%, 65%, and 52% at 1, 4, and 5 years, respectively. Performance status and SF were the only predictors of OS at multivariate analysis. Median TTR was 38 months (34-49) with a recurrence-free survival rate of 82.5%, 26.2%, and 23.3% at 1, 4, and 5 years, respectively, while SF and age were the only predictors of TTR. SF level, possibly reflecting the degree of hepatic inflammation and fibrosis, is a negative risk factor for survival and recurrence after percutaneous RFA in HCC patients.

The study of AGO1 regulates p53 expression and the prognosis of patients with hepatocellular carcinoma after curative resection

Objective To investigate AGO1 expression,functions and prognostic value in Hepatocellular carcinoma patients underwent radical resection.Methods AGO1 expression was measured in HCCLM3,MHCC97L,and HepG2 cell lines.Using small interfering RNA,AGO1 functions and its effects on p53 were investigated in HCCLM3 and HepG2 cell lines.Immunohistochemistry in tissue microarrays consisting of 200 tumor tissue from hepatocellular carcinoma (HCC) patients underwent radical resection was used to analyze the AGO1 expression with prognosis.Results AGO1 mRNA expression in HCC cell lines HCCLM3,MHCC97L and HepG2 is 0.400 ± 0.025,0.188 ± 0.022 and 0.154 ± 0.019,increased in parallel with the metastatic potential of the HCC cell lines (P ＜ 0.05).Cell proliferation,invasion,and p53 expression significantly decreased after AGO1 depletion in the HCC cell lines.Intratumoral AGO1 was correlated with younger age (P ＜ 0.05),higher α-fetoprotein (P ＜ 0.01),HBeAg-positive status (P ＜0.05),liver cirrhosis (P ＜ 0.05),intrahepatic and extrahepatic recurrence (P ＜ 0.01),and was an independent risk factor for overall survival (P ＜ 0.01) and recurrence-free survival (P ＜ 0.01).Conclusion These findings indicate that AGO1 may promote HCC proliferation and metastasis through the P53 pathways,and AGO1 may be a reliable prognostic factor in HCC patients after resection. Key words: AGO1 ; Hepatocellular carcinoma; Prognosis; p53

Prognostic Values of Vascular Endothelial Growth Factor and Matrix Metalloproteinase-2 in Hepatocellular Carcinoma after Radiotherapy

Objectives: Hepatocellular carcinoma (HCC) is a highly vascularized tumor. In this study, we investigated the prognostic and predictive values of proangiogenic factors in HCC patients receiving radiotherapy. Methods: Between September 2008 and December 2009, a total of 50 patients treated with radiotherapy were prospectively enrolled in this study. Serum and urine samples were collected <1 week before and after radiotherapy. Results: After completion of radiotherapy, serum vascular endothelial growth factor (VEGF)/platelet (Plt) levels were significantly increased (p < 0.01). Patients who experienced hepatic tumor recurrence outside the radiation field showed higher VEGF-A/Plt levels before and after radiotherapy than patients who did not (p = 0.04), whereas patients who had hepatic tumor recurrence inside the radiation field showed significantly higher matrix metalloproteinase (MMP)-2 levels after radiotherapy (p = 0.04). On multivariate analyses, a high level of either VEGF/Plt or MMP-2 (≥median) before radiotherapy was a significant independent prognostic factor for a worse progression-free survival (p = 0.04). Conclusions: In HCC patients receiving radiotherapy, levels of VEGF/Plt and MMP-2 before radiotherapy can be useful to predict treatment outcome. This study also suggests the necessity of anti-angiogenic therapy, such as sorafenib, since radiotherapy increases VEGF/Plt levels, and higher levels of VEGF/Plt are associated with a poor outcome.

Hypomethylation of long interspersed nuclear element-1 (LINE-1) is associated with poor prognosis via activation of c-MET in hepatocellular carcinoma.

Long interspersed nuclear element-1 (LINE-1) methylation status, representing global DNA methylation levels, is associated with patient prognosis in several types of cancer. This study was designed to examine the prognostic significance of LINE-1 methylation in patients with hepatocellular carcinoma (HCC) and the possible mechanisms related to oncogene activation. Seventy-five HCC patients who underwent hepatectomy between 2006 and 2012 were enrolled in this study. Quantitative pyrosequencing was performed to quantify the methylation level of three CpG sites in the LINE-1 promoter. Clinicopathological variables and prognosis were compared between LINE-1 hypo- and hypermethylation groups. LINE-1-inserted c-MET (L1-MET) gene expression and its correlation with LINE-1 methylation levels also were analyzed. LINE-1 was significantly hypomethylated in tumor tissues compared with nontumor tissues (48.3 ± 12.2 % vs. 68.2 ± 2.0 %, respectively, p < 0.0001). LINE-1 hypomethylation was not associated with any clinicopathological factors in HCC patients, except sex (p < 0.05). However, patients with LINE-1 hypomethylation exhibited significantly poorer outcome, and multivariate analysis revealed that LINE-1 hypomethylation was an independent risk factor for overall survival (hazard ratio (HR) = 6.1, p = 0.031) and disease-free survival (HR = 2.34, p = 0.045). L1-MET expression was significantly higher in tumor tissues (p < 0.01). L1-MET expression levels were inversely correlated with LINE-1 methylation levels, and positively correlated with c-MET expression (p < 0.05). Furthermore, higher c-MET protein expression was observed in the LINE-1 hypomethylated tumor tissues compared with hypermethylated tumor tissues (p = 0.032). LINE-1 hypomethylation is significantly associated with poor prognosis in patients with HCC, possibly due to activation of c-MET expression.

Complex IV subunit 1 defect predicts postoperative survival in hepatocellular carcinoma

Mitochondrial oxidative phosphorylation (OXPHOS) is responsible for adenosine triphosphate synthesis and OXPHOS deficiency plays a significant role in tumorigenesis. The defects of mitochondrial-encoded OXPHOS subunits have been found in normal and cirrhotic liver, however their contributions in hepatocellular carcinoma (HCC) are not clear. The present study aimed to examine these defects in resected HCC tissues. In total, 102 human HCC tissues were collected from patients undergoing curative resection, and immunohistochemical staining was performed to assess tissue expression of complex I subunit 6, complex III subunit 3, complex IV subunit 1 (CIV-1) and complex V subunit 6. Cox proportional hazard model analysis was performed, including all clinicopathological factors, to postoperatively estimate the overall survival rate. The results showed that the majority of HCC tissues contained various degrees of expression defects for OXPHOS subunits. Among these, the major CIV-1 defect (expression defect area of >25% of the examined area) (P<0.001) and early distant metastasis (P<0.001) were independently associated with the overall survival rate. Kaplan-Meier analysis also demonstrated that the major CIV-1 defect was significantly associated with a poor overall survival rate (log-rank, P=0.002). The findings in the present study clearly indicate that the major CIV-1 expression defect may serve as an independent negative prognostic factor in HCC patients following curative resection.

Expression of CD133 and CD105 on cells in peripheral blood of patients with primary hepatocellular carcinoma

Objective To investigate the relationship of CD133+and CD105+cells in the peripheral blood with the clinical prognosis of patients with primary hepatocellular carcinoma(HCC).Methods The proportions of CD45-CD133+CD105+cells were determined in 80 primary HCC patients and 20 healthy subjects by flow cytometry,and the correlation of the proportion with age,gender,clinical stage,histological differentiation,lymph node metastasis,and surgical outcomes were analyzed.The survival rate was analyzed by Kaplan-Meier curves,and multivariate analysis was performed using Cox proportional hazards model.Results The proportion of CD45-CD133+CD105+cells in the peripheral blood of primary HCC patients was significantly higher compared with those in the postoperative patients and healthy controls(P=0.003,P=0.000).The proportion of preoperative CD45-CD133+CD105+cells in the postoperative recurrent group was significantly higher than those in the non-recurrent group(P=0.015).The proportion of CD45-CD133+CD105+cells in the peripheral blood of primary HCC patients was significantly associated with the clinical stage,degrees of differentiation,and presence/absence of lymph node metastasis(P0.05),and not associated with age or gender.CD133 expression was positively correlated with CD105expression(r=0.846,P0.05).Postoperative survival rate was significantly lower in patients with CD45-CD133+CD105+proportion 0.5% compared with≤ 0.5%(P0.05).The postoperative survival rate of patients with CD45-CD133+cell proportion1.1% was significantly lower than that with CD45-CD133+cell proportion ≤1.1%(P0.05).The postoperative survival rate of patients with CD45-CD105+proportion 36% was significantly lower than those with CD45-CD105+proportion ≤ 36%(P0.05).Peripheral blood CD45-CD133+CD105+cell proportion,degree of differentiation,and presence/absence of lymph nodemetastasis were the independent factors influencing HCC prognosis.Conclusion Proportion of CD45-CD133+CD105+cells in the peripheral blood is greatly increased in HCC patients,which is closely associated with the degree of malignancy of HCC.Decreased CD45-CD133+CD105+cell proportion in the peripheral blood is an independent favorable prognostic factor for HCC patients,and targeted lowering of CD45-CD133+CD105+cell proportion in the peripheral blood of primary HCC patients may represent a new treatment.

Assessment of Blood Flow in Hepatocellular Carcinoma: Correlations of Computed Tomography Perfusion Imaging and Circulating Angiogenic Factors

Hepatocellular carcinoma (HCC) is a highly vascular tumor through the process of angiogenesis. To evaluate more non-invasive techniques for assessment of blood flow (BF) in HCC, this study examined the relationships between BF of HCC measured by computer tomography (CT) perfusion imaging and four circulating angiogenic factors in HCC patients. Interleukin 6 (IL-6), interleukin 8 (IL-8), vascular endothelial growth factor (VEGF), and platelet derived growth factor (PDGF) in plasma were measured using Bio-Plex multiplex immunoassay in 21 HCC patients and eight healthy controls. Circulating IL-6, IL-8 and VEGF showed higher concentrations in HCC patients than in controls (p < 0.05), and predicted HCC occurrence better than chance (p < 0.01). Twenty-one patients with HCC received 21-phase liver imaging using a 64-slice CT. Total BF, arterial BF, portal BF, arterial fraction (arterial BF/total BF) of the HCC and surrounding liver parenchyma, and HCC-parenchyma ratio were measured using a dual-vessel model. After analyzing the correlations between BF in HCC and four circulating angiogenic factors, we found that the HCC-parenchyma ratio of arterial BF showed a significantly positive correlation with the level of circulating IL-8 (p < 0.05). This circulating biomarker, IL-8, provides a non-invasive tool for assessment of BF in HCC.

Overall response of both intrahepatic tumor and portal vein tumor thrombosis is a good prognostic factor for hepatocellular carcinoma patients receiving concurrent chemoradiotherapy

This study investigated the prognostic significance of portal vein tumor thrombosis (PVTT) response in hepatocellular carcinoma (HCC) patients treated with localized concurrent chemoradiotherapy (CCRT). We retrospectively analyzed 100 patients treated with CCRT for UICC Stage T2–4N0M0 HCC with PVTT between 2002 and 2011. The radiotherapy (RT) volume included both primary tumor and PVTT, and the median radiation dose was 45 Gy. Treatment response was evaluated for up to 6 months after RT. With respect to PVTT response to treatment, complete response (CR) and partial response (PR) were achieved in 14% and 48% of patients, respectively, yielding an objective response (OR) rate of 62%. PVTT size (≤3cm diameter) was associated with a higher rate of a CR (P = 0.001). The median overall survival (OS) was 11.6 months. Independent prognostic factors for OS were OR of the tumor to RT and a CR of the PVTT. Achieving an OR in both the tumor and the PVTT demonstrated a significant correlation with improved survival (P = 0.002). Progression of intrahepatic metastasis was affected not by CCRT but by the clinical features of the PVTT, particularly the initial PVTT site. PVTT response following CCRT seems prognostically significant. CR of the PVTT was associated with improved survival. Achieving an OR in both the tumor and PVTT was also associated with improved survival.

Increase in CD14+HLA-DR -/low myeloid-derived suppressor cells in hepatocellular carcinoma patients and its impact on prognosis.

Myeloid-derived suppressor cells (MDSCs) are known as key immune regulators in various human malignancies, and it is reported that CD14(+)HLA-DR(-/low) MDSCs are increased in hepatocellular carcinoma (HCC) patients. However, the host factors that regulate the frequency and the effect on the prognosis of HCC patients are still unclear. We investigated these issues and clarified the relationships between a feature of MDSCs and host factors in HCC patients. We examined the frequency of MDSCs in 123 HCC patients, 30 chronic liver disease patients without HCC, and 13 healthy controls by flow cytometric analysis. The relationships between the clinical features and the frequency of MDSCs were analyzed. In 33 patients who received curative radiofrequency ablation (RFA) therapy, we examined the impact of MDSCs on HCC recurrence. The frequency of MDSCs in HCC patients was significantly increased. It was correlated with tumor progression, but not with the degree of liver fibrosis and inflammation. In terms of serum cytokines, the concentrations of IL-10, IL-13, and vascular endothelial growth factor were significantly correlated with the frequency of MDSCs. In HCC patients who received curative RFA therapy, the frequency of MDSCs after treatment showed various changes and was inversely correlated with recurrence-free survival time. The frequency of MDSCs is correlated with tumor progression, and this frequency after RFA is inversely correlated with the prognosis of HCC patients. Patients with a high frequency of MDSCs after RFA should be closely followed and the inhibition of MDSCs may improve the prognosis of patients.

Clinical features and prognostic factors of hepatocellular carcinoma patients; single center experience

Fourth (18.8%) chronic alcoholic, 142 (66.7%) hepatitis B, and 26 (12.2%) patients were hepatitis C. Median overall survival was 5.5 months (95% CI: 3.5-7.5). We detected statically significant effect of ECOG performance status, Child-Pugh score, portal venous thrombosis, levels of albumin, bilirubin, AST and AFP, presence of cirrhosis and the choice of treatment modality on overall survival. Assessment of response to first-line chemotherapy, 65 (91.5%) patients had progressive disease, two (2.8%) patients had stable disease, four (5.6%) patients had a partial response.

Abstract 5038: Non-cording microRNA hsa-miR-199a expression in hepatocellular carcinoma correlates with patient survival

Abstract [Aim] MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at a post-transcriptional level. Previous study from our group identified forty nine miRNAs that are expressed differentially by comparing 26 pair samples of hepatocellular carcinoma (HCC) tumor tissue and non-tumor liver tissue using next-generation sequencer system. In this study, the expression of hsa-miR-199a and hsa-miR-199b, one of the extracted targets from our study, were investigated by real-time PCR using validation set HCC samples, and were examined the correlation between the miRNA expression and clinical data. [Patients and Methods] Forty-eight patients diagnosed as HCC had undergone surgical removal from 1991 to 1997 at the Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Japan. The formalin-fixed paraffin embedded samples were prepared using the standard protocol. The paraffin blocks were cut into 10μm sections, and the tumor samples were collected using Laser-captured microdissection and total RNA including miRNA fraction were isolated. After synthesized cDNA using miRNA specific primer, real-time PCR was performed using miRNA specific primer/probe. [Results] The expression level of hsa-miR-199a and hsa-miR-199b were down-regulated in tumor compared to non-tumor (P&amp;lt;0.0001, P=0.0002, respectively). The patients were divided into two groups, higher/lower expression of each miRNA, the group of the higher hsa-miR-199a expression was significantly longer overall survival time compared to the lower expression group (P=0.0303). However, hsa-miR-199b was not significant difference (P=0.3801). [Conclusion] The hsa-miR-199a may be potential prognostic factor for HCC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5038. doi:1538-7445.AM2012-5038

Hepatocellular carcinoma treated with sorafenib

We read with great interest the study by Pinter et al.,1 providing strong evidence for treatment using sorafenid of Child-Pugh class B patients with hepatocellular carcinoma (HCC). However, we consider that it is improper to exclude clinical cirrhosis stage from the multivariate analysis. The patients who belong to Child-Pugh class B are not all compensated, because gastrointestinal bleeding is not included in the definition of the Child-Pugh score,2 and we often find that the patients who belong to Child-Pugh class B are decompensated in our clinical practice.3 It is especially essential to assess prognostic variables separately for the different cirrhosis stages, because of the significant survival differences between patients with compensated cirrhosis and those with decompensated cirrhosis.4 Accordingly, Child-Pugh class is not always consistent with hepatic compensation. Moreover, multikinase inhibitors, including sorafenib, can cause bleeding because anti-VEGF agents are associated with an increased risk of bleeding.5, 6 In the published studies, gastrointestinal bleeding, as one of the reasons that prevent the treatment of sorafenib for HCC, was observed in patients with poor liver function (Table 1). Thus, it is necessary to include the cirrhosis stage into multivariate analysis to analyse the prognostic factors in HCC patients treated with sorafenib more exactly. Furthermore, this study failed to include the tumour-related factors in the prognostic analysis. However, a systematic review has shown that the five most common independent predictors of death in HCC are portal vein thrombosis, tumour size, α-fetoprotein Child-Pugh class and bilirubin in the prognostic studies, and it is suggested that tumour-related factors would be more important in the compensated patients whereas both liver- and tumour-related factors would be important in the decompensated patients.7 In addition, Baek et al. found that the presence of ascites, portal venous thrombosis, tumour size and number, performance status and baseline levels of α-fetoprotein, albumin and bilirubin were significantly related to the overall survival in advanced HCC patients treated with sorafenib.8 Therefore, the tumour-related factors should also be included in the prognostic analysis. Declaration of personal and funding interests: None.

Tools for monitoring patients with hepatocellular carcinoma on the waiting list and after liver transplantation

Norman Kneteman, Tito Livraghi, David Madoff, Eduardo de Santibanez, and Michael Kew Division of Transplantation, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada; Department of Interventional Radiology, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; Division of Interventional Radiology, New York-Presbyterian/Weill Cornell Medical Center, New York, NY; General Surgery and Liver Transplant Unit, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; and Department of Medicine, Groote Schuur Hospital, Cape Town, South Africa

PLOD2 induced under hypoxia is a novel prognostic factor for hepatocellular carcinoma after curative resection

Under hypoxia, tumour cells undergo genetic and adaptive changes that allow their survival. Previously, we reported that high expression of hypoxia-inducible factor (HIF)-1 was a significant predictive factor for recurrence in hepatocellular carcinoma (HCC). Hypoxia also stimulates expression of procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) genes via the HIF-1 pathway. The aim was to evaluate the relationship between hypoxia stress and expression of PLOD genes in HCC in vitro and to identify a new prognostic marker in HCC patients. The PLOD2 expression was assessed under hypoxia in hepatoma cell lines and characterized in 139 HCC samples following hepatic resection using microarray experiments, quantitative RT-PCR and immunohistochemistry. Prognostic factors in HCC patients were assessed using univariate and multivariate analyses. The PLOD2 expression was induced under the hypoxia in vitro. Disease-free survival in the high PLOD2 expression group of HCC patients was significantly shorter when compared with the low-expression group (P=0.002). In a subset of HCCs, we found that the PLOD2 expression of microarray was correlated with data of quantitative RT-PCR and immunohistochemistry. Of clinicopathological factors, PLOD2 expression was significantly correlated with tumour size (P=0.022) and macroscopic intrahepatic metastasis (P=0.049). In univariate analysis, six prognostic factors (tumour multiplicity, macroscopic intrahepatic metastasis, histological grade, microscopic portal invasion, microscopic intrahepatic metastasis and PLOD2 expression) were significant for disease-free survival. PLOD2 expression was identified as a significant, independent factor of poor prognosis (P=0.013). PLOD2 is a potential novel prognostic factor for HCC patients following surgery.

Hepatocellular carcinoma presenting with lung metastasis: Clinical characteristics and prognostic factors

e15604 Background: The efficacy of systemic chemotherapy for hepatocellular carcinoma (HCC) has been limited, but sorafenib has changed the strategy treating for metastatic HCC. The lung is one of the most common metastatic sites for HCC. Therefore, we focused on clinical features and prognostic factors of HCC patients (pts) with lung metastasis in this study. Methods: Between January 2000 and April 2008, 1,117 HCC pts were admitted into our division. During this period, extrahepatic metastasis was detected in 286 pts, and the initial metastatic site was lung in 130 pts. The relationships between the characteristics of these pts at the time of lung metastasis detection and prognosis were examined. Results: There were 107 males and 23 females. Median age was 64 years. The Child-Pugh classification was A in 84 pts, B in 32 pts. HCV Ab was positive in 57 pts, HBs Ag was positive in 46 pts, and both were negative in 27 pts. The median survival time of all pts was 298 days. Univariate analysis revealed 12 of the 20 variables evaluated to be significantly associated with survival time: number of lung metastasis, presence of intrahepatic HCC, maximum size of intrahepatic HCC, presence of tumor thrombus, AFP, PIVKA II, albumin, prothrombin time, ALP, presence of ascites, Child-Pugh classification, and previous history of hepatic resection. Multivariate analysis using the Cox proportional hazards model demonstrated a lower number (≤5) of lung metastases (p&lt;0.0001), the absence of intrahepatic HCC (p=0.0002), and the absence of ascites (p=0.0339) to be independent favorable prognostic factors. Conclusions: These results may provide useful reference data for determining treatment strategies and planning further clinical trials involving HCC patients with lung metastasis. No significant financial relationships to disclose.

Prognostic Impact of Surgical Complications and Preoperative Serum Hepatocyte Growth Factor in Hepatocellular Carcinoma Patients After Initial Hepatectomy

IntroductionThe relationship between postoperative complications and survival after hepatectomy is not completely understood. The purpose of this study was to determine if surgical complications would have a prognostic impact and to identify any difference of the prognostic factors between a complication group and complication-free group for hepatocellular carcinoma (HCC) patients after initial hepatectomy. Patients and MethodsOne hundred consecutive HCC patients were analyzed in this study. Operative variables and liver functional markers were compared between the complication group and complication-free group. The diagnostic accuracy for predicting complications was evaluated by the receiver operating characteristic (ROC) curve. The Kaplan–Meier method with log-rank test was employed for survival analysis. Univariate and multivariate analyses were performed to identify the prognostic factors in each group. Results and discussionA total of 45 complications in 32 patients were observed according to the modified Clavien classification. The albumin, γ-glutamyl transferase, choline esterase, indocyanine green retention rate at 15 min (ICGR15), hyaluronic acid, prealbumin, hepatocyte growth factor (HGF), HH15, and LHL15 levels before hepatectomy, operative time, and blood loss were significantly different between the two groups. Multivariate analysis revealed that γ-glutamyl transferase, ICGR15, and HGF were independent risk factors for postoperative complications. The values of the areas under the ROC curve for predicting complications proved the significance of the predictions. Although the recurrence-free survival rates were not significantly different, the overall survival rates were significantly different between the two groups. Univariate and multivariate analyses for the overall survival rate showed that the stage of the HCC and HGF for the complication group and tumor size for the complication-free group were independent prognostic factors for overall survival. ConclusionPostoperative surgical complications could have a prognostic impact on overall survival in HCC patients after initial hepatectomy. Serum HGF could be a factor connected to complications and survival in this group.

The Up-Regulation of Y-Box Binding Proteins (DNA Binding Protein A and Y-Box Binding Protein-1) as Prognostic Markers of Hepatocellular Carcinoma

The development of hepatocellular carcinoma is associated with the chronic inflammation of the liver caused by various factors such as hepatitis B or C virus infection. Previously, we reported DNA binding protein A (dbpA) as a candidate molecule that can accelerate inflammation-induced hepatocarcinogenesis. DbpA belongs to the Y-box binding protein family, and Y-box binding protein-1 (YB-1), the prototype member of this family, is reported to be a prognostic marker of malignant diseases other than hepatocellular carcinoma. The purpose of this study is to examine the significance of the expression of dbpA or of the T-to-G transversion in the dbpA promoter region, which enhances the promoter activity in vitro, for the progression of hepatocellular carcinoma. We studied the expression of dbpA (as well as of YB-1) in 82 formalin-fixed hepatocellular carcinoma tissues by immunohistochemistry and determined the sequence of the dbpA promoter region in 42 frozen hepatocellular carcinoma tissues. We examined the relationship between these findings and the clinicopathologic factors of hepatocellular carcinoma patients. DbpA expression was associated with the advanced stages of hepatocellular carcinoma, and the cases with the nuclear dbpA expression had a poor prognosis. DbpA contributed more significantly to this association than YB-1. Furthermore, the T-to-G transversion in the dbpA promoter region was related to the nuclear localization of dbpA. DbpA was a more significant prognostic marker of hepatocellular carcinoma than YB-1. The T-to-G transversion in the dbpA promoter region was suggested to be a predisposing factor for the progression of hepatocellular carcinoma.

Hypercoagulable states in patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) patients have an increased risk for venous thromboembolism, mainly portal venous thrombosis (PVT). The aim of this study was to assess the role of acquired and hereditary thrombotic risk factors in HCC patients. Thirty-one patients with HCC, 30 patients with cirrhosis but without HCC or PVT, and 48 matched healthy controls were studied. Mean levels of plasma protein C, protein S, antithrombin, and serum lipoprotein (a) were significantly lower in patients with HCC and in the cirrhotic group compared to the healthy controls. Mean serum homocysteine levels were significantly higher in patients with HCC compared to cirrhotics and healthy controls. The prevalence of activated protein C resistance, factor V Leiden mutation, prothrombin gene mutation G20210GA, and C677T methylenetetrahydrofolate reductase polymorphism was not significantly different among the three groups. In conclusion, thrombophilic defects are common in HCC patients and they might contribute to the observed thrombotic complications in this malignancy.

Hypercoagulable states in patients with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) patients have an increased risk for venous thromboembolism, mainly portal venous thrombosis (PVT). The aim of this study was to assess the role of acquired and hereditary thrombotic risk factors in HCC patients. Thirty-one patients with HCC, 30 patients with cirrhosis but without HCC or PVT, and 48 matched healthy controls were studied. Mean levels of plasma protein C, protein S, antithrombin, and serum lipoprotein (a) were significantly lower in patients with HCC and in the cirrhotic group compared to the healthy controls. Mean serum homocysteine levels were significantly higher in patients with HCC compared to cirrhotics and healthy controls. The prevalence of activated protein C resistance, factor V Leiden mutation, prothrombin gene mutation G20210GA, and C677T methylenetetrahydrofolate reductase polymorphism was not significantly different among the three groups. In conclusion, thrombophilic defects are common in HCC patients and they might contribute to the observed thrombotic complications in this malignancy.