Wei

Clinical value of apoptosis and angiogenesis factors in estimating the prognosis of hepatocellular carcinoma.

PurposeWhereas some studies have indicated that the prognosis of hepatocellular carcinoma (HCC) was correlated to some apoptosis and angiogenesis factors: p53, survivin, matrix metalloproteinases (MMPs, including MMP-2 and MMP-9) and vascular endothelial growth factor (VEGF), other studies have failed to confirm this. The aim of the present study is to investigate the expression of p53, survivin, MMPs and VEGF in HCC and the relationship between these factors and the prognosis of HCC patients.MethodsThe expression of p53, survivin, MMP-2, MMP-9 and VEGF was measured by immunohistochemical assays in the liver resection specimens of 90 patients with HCC.ResultsThe positive rate of p53, survivin, MMP-2, MMP-9 and VEGF was 33.3, 51.1, 60.0, 37.8 and 76.7%, respectively. The expression of MMP-2, MMP-9 and VEGF was correlated to the recurrence of HCC patients, respectively (Pxa0<xa00.01). No correlation was found between the expression of apoptosis factors (p53 and survivin) and the recurrence of HCC patients, respectively (Pxa0>xa00.05). The positive correlations were found between MMP-2 and VEGF (rxa0=xa00.32, Pxa0<xa00.01), MMP-9 and VEGF (rxa0=xa00.24, Pxa0<xa00.05). Significant differences of disease-free survival rates occurred among subgroups according to the expression of MMP-2, MMP-9 and VEGF (Pxa0<xa00.01). Multivariate analysis revealed that macroscopically disseminated nodules, tumor micrometastasis, high serum alpha-fetoprotein level, positive expression of MMP-9 and VEGF were independent recurrence risk factors.ConclusionsOur investigation revealed that p53 and survivin could not estimate the prognosis of HCC patients. Angiogenesis factors (MMPs and VEGF) positively correlated to the prognosis of HCC patients. The expression of MMPs and VEGF in HCC tissues could be regarded as a valuable indicator in estimating the prognosis of HCC patients.

A randomized controlled trial of hepatectomy with adjuvant transcatheter arterial chemoembolization versus hepatectomy alone for Stage III A hepatocellular carcinoma

PurposeHepatectomy is considered as the potentially curative treatment for hepatocellular carcinoma (HCC) and used in some selected Stage IIIA HCC, which include multiple tumors more than 5xa0cm or tumor involving a major branch of the portal or hepatic vein(s) (UICC TNM staging system, sixth edition). Transcatheter arterial chemoembolization (TACE) was used in retrospective studies to improve the survival outcome of resected HCC. However, its beneficial effect on the survival outcomes of the Stage IIIA patients has not been evaluated. The present study is to evaluate if hepatectomy combining with adjuvant TACE for Stage IIIA HCC result in better long-term survival outcome when compared with hepatectomy alone.MethodsFrom January 2001 to March 2004, we conducted a prospective randomized trial in patients with Stage IIIA HCC (NCT00652587), recruiting 115 Stage IIIA HCC patients to undergo hepatectomy with adjuvant TACE (HT arm) or to undergo hepatectomy alone (HA arm) in our cancer center. Survival outcomes of the two arms were analyzed.ResultsThe demographic data were well matched between the two arms. There were no significant differences in the morbidity and in-hospital mortality between the two arms of patients. The most significant toxicities associated with adjuvant TACE were nausea/vomiting (54.4%) and transient hepatic toxicity (elevation of aminotransferase, 52.6%). Although there was no significant difference in the rate of recurrence between the two arms (50/57 vs. 56/58, Pxa0=xa00.094), HT arm seemed to have more proportion of single lesion of recurrent HCC (χ2xa0=xa03.719, Pxa0=xa00.054) and more proportion of potential curative therapy for recurrence (χ2xa0=xa04.456, Pxa0=xa00.035). Until the time of censor, 92 patients had died. The 1-, 3-, and 5-year overall survival rates and median overall survival for HT arm were 80.7, 33.3, 22.8% and 23.0xa0months, respectively. The corresponding overall survival rates and median overall survival for HA arm were 56.5, 19.4, 17.5% and 14.0xa0months, respectively. The difference was significant (stratified log-rank test, Pxa0=xa00.048). The 1-, 3-, and 5-year disease-free survival rates and median disease-free survival for HT arm were 29.7, 9.3, 9.3% and 6.0xa0months, respectively; correspondingly, for HA arm were 14.0, 3.5, 1.7% and 4.0xa0months, respectively (stratified log-rank test, Pxa0=xa00.004).ConclusionsFor Stage IIIA HCC, hepatectomy with adjuvant TACE efficaciously and safely improved survival outcomes when compared with hepatectomy alone.

Risk Factors for Early and Late Intrahepatic Recurrence in Patients with Single Hepatocellular Carcinoma Without Macrovascular Invasion after Curative Resection

BACKGROUNDnPrognostic factors of postoperative early and late recurrence in patients with hepatocellular carcinoma (HCC) undergoing curative resection remain to be clarified. The aim of this study was to identify risk factors for postoperative early (≤ 2 year) and late (> 2 year) intrahepatic recurrences in patients with single HCCs without macrovascular invasion.nnnMETHODSnA total of 280 patients from December 2004 to December 2007 were retrospectively included in this study. Intrahepatic recurrence was classified into early (≤ 2 year) and late (> 2 year) and the Chi-Square test or Fishers exact test and multivariate logistic regression analysis were performed to determine significant risk factors.nnnRESULTSnDuring the follow-up, 124 patients had intrahepatic recurrence, early and late in 82 and 42 patients, respectively. Multivariate logistic regression analysis showed that microvascular invasion (p=0.006, HR: 2.397, 95% CI: 1.290-4.451) was the only independent risk factor for early recurrence, while being female (p = 0.031, HR: 0.326, 95% CI: 0.118-0.901), and having a high degree of cirrhosis (P=0.001, HR: 2.483, 95% CI: 1.417-4.349) were independent risk factors for late recurrence.nnnCONCLUSIONSnEarly and late recurrence of HCC is linked to different risk factors in patients with single HCC without macrovascular invasion. This results suggested different emphases of strategies for prevent of recurrence after curative resection, more active intervention including adjuvant therapy, anti-cirrhosis drugs and careful follow-up being necessary for patients with relevant risk factors.

Hepatic resection versus transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma with hepatic vein tumor thrombus

OBJECTIVEnTo compare the outcomes of hepatic resection and transcatheter arterial chemoembolization for resectable hepatocellular carcinoma with hepatic vein tumor thrombus.nnnMETHODSnFrom January 2006 to November 2013, 28 patients initially diagnosed with resectable hepatocellular carcinoma combined with hepatic vein tumor thrombus received hepatic resection. These patients were compared with 56 case-matched controls (1:2 ratio) selected from a pool of 91 patients who received transcatheter arterial chemoembolization as an initial treatment during the same period. Clinical characteristics, adverse events, overall survival and survival-related factors were analyzed.nnnRESULTSnThe 1-, 2- and 3-year overall survival rates were 66.5, 37.4 and 28.5% for the hepatic resection group and 32.3, 18.7 and 15.6% for the transcatheter arterial chemoembolization group (P = 0.015), respectively. No significant difference was found between the two groups in terms of complications and mortality. Multivariate analyses revealed combined portal vein tumor thrombosis (HR = 2.116; 95% CI: 1.26-3.57; P = 0.005) and treatment allocation (hepatic resection = 2.289; 95% CI, 1.30-4.02; P = 0.004) as risk factors for overall survival.nnnCONCLUSIONSnHepatic resection provides a good prognosis for hepatocellular carcinoma patients with hepatic vein tumor thrombus compared with patients undergoing transcatheter arterial chemoembolization, and the most important factor related to survival was co-existence with portal vein invasion.

Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis

BackgroundDovitinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptors and platelet-derived growth factor receptor β. Dovitinib is currently in clinical trials for the treatment of hepatocellular carcinoma (HCC).MethodIn this study, we used five HCC cell lines and five endothelial cell lines to validate molecular and cellular targets of dovitinib.ResultsTumor growth and pulmonary metastasis were significantly suppressed in an orthotopic HCC model. Immunoblotting revealed that among known dovitinib targets, only PDGFR-β was expressed in two HCC cell lines, while four of five endothelial lines expressed PDGFR-β, FGFR-1, and VEGFR-2. Dovitinib inhibited endothelial cell proliferation and motility at 0.04 μmol/L, a pharmacologically relevant concentration; it was unable to inhibit the proliferation or motility of HCC cells at the same concentration. Immunohistochemical analyses showed that dovitinib significantly decreased the microvessel density of xenograft tumors, inhibiting proliferation and inducing apoptosis in HCC cells.ConclusionOur findings indicate that dovitinib inhibits HCC growth and metastasis preferentially through an antiangiogenic mechanism, not through direct targeting of HCC cells.

Morphologic classification of microvessels in hepatocellular carcinoma is associated with the prognosis after resection.

Background and Aim:u2002 The relationship between neovasculature in hepatocellular carcinoma (HCC) and the prognosis of patients still remains controversial. The aim of the present study was to investigate the prognostic significance of morphologic features of the microvessels in patients with HCC after resection.

Serum and tissue vascular endothelial growth factor predicts prognosis in hepatocellular carcinoma patients after partial liver resection

BACKGROUND/AIMSnTo explore the effect of vascular endothelial growth factor (VEGF) expression on prognosis of hepatocellular carcinoma (HCC) after partial liver resection.nnnMETHODOLOGYnThe expression of VEGF in 64 preoperative serum and resection specimens of HCC, confirmed by pathology, was detected by enzymelinked immunosorbent assay (ELISA) and immunohistochemistry. Correlations of VEGF level to clinicopathological features were analyzed. Cox regression model was used to analyze the recurrence risk factors after hepatectomy.nnnRESULTSnSerum level of VEGF in HCC patients was 334.50±247.62pg/mL, significantly higher than healthy control group (p<0.01); it was also significantly higher in recurrent group than in non-recurrent group (p<0.05). VEGF was expressed in cytoplasm of HCC specimens. The positive rates of VEGF was significantly higher in recurrent group than in non-recurrent group (85.0% vs. 54.5%, p<0.05). The 1-, 2- and 3-year disease-free survival rates were significantly higher in VEGF(-) group than in VEGF(+) group (81.3% vs. 52.2%, 68.8% vs. 33.3%, and 62.5% vs. 29.1%, p<0.01). The overall survival rates of VEGF(-) subgroup was borderline significant higher than that of VEGF(+) subgroup (p=0.068). Multivariate analysis revealed that preoperative macroscopically disseminated nodules, tumor micrometastasis, serum and tissue VEGF level were independent recurrence risk factors.nnnCONCLUSIONSnSerum and tissue VEGF level of HCC patients ascends distinctly, correlates to the recurrence of HCC after partial liver resection which can be used to estimate the risk of postoperative recurrence of HCC.

Efficacy and safety of preoperative chemoembolization for resectable hepatocellular carcinoma with portal vein invasion: a prospective comparative study

ObjectivesTo evaluate the outcomes of preoperative transarterial chemoembolization (TACE) for resectable hepatocellular carcinoma (HCC) with portal vein invasion.MethodsFrom February 2006 to July 2011, 320 patients initially diagnosed with resectable HCC and portal vein invasion were prospectively non-randomized into two arms. In the immediate resection arm (Arm 1, nu2009=u2009205) patients received immediate surgical resection. 115 patients were included in the preoperative TACE arm (Arm 2), and eventually 85 patients underwent TACE followed by surgical resection.ResultsThe 1-, 3- and 5-year overall survival rates were 48.3xa0%, 18.7xa0% and 13.9xa0% for Arm 1 and 61.2xa0%, 31.7xa0% and 25.3xa0% for Arm 2 (Pu2009=u20090.001), respectively. In the subgroup analysis of types I and II portal vein tumour thrombus (PVTT), the preoperative TACE arm demonstrated significantly better survival rates than the immediate resection arm (PIu2009=u20090.001, PIIu2009=u20090.036). However, no significant difference was found for patients with type III PVTT (PIIIu2009=u20090.684). No significant difference was found between the two arms in terms of complications and mortality.ConclusionsPreoperative TACE seems to confer a survival benefit for resectable HCC with PVTT, especially for types I and II PVTT, and preoperative TACE should therefore be recommended as a routine procedure.Key Points• Preoperative TACE improves the clinical outcomes for patients with PVTT• Preoperative TACE could significantly improve the rate of en bloc thrombectomy• Preoperative TACE does not increase the related adverse events

Optimal surgical strategy for hepatocellular carcinoma with portal vein tumor thrombus: A propensity score analysis

Objectives The optimal surgical resection method for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) that maximizes both safety and long-term outcome has not yet been determined. The aim of this study was to compare the clinical outcomes following peeling off versus en bloc resection for PVTT. Methods From 2005 to 2012, 252 patients with HCC and type I/II PVTT who underwent hepatic resection were divided into two groups according to whether they received en bloc resection (n = 113) or peeling off resection (n = 139). The clinical outcomes were compared before and after propensity score matching. Results The propensity model matched 113 patients with en bloc resection for further analyses. After matching, overall survival (OS) and disease-free survival (DFS) rates were significantly increased in the en bloc group compared with the peeling off group (p = 0.011 and p = 0.015). A multivariate analysis indicated that en bloc resection independently improved both OS and DFS (HR = 1.471, 95% CI: 1.071-2.018, p = 0.017 and HR = 1.415, 95% CI: 1.068-1.874, P=0.016). The adverse events were not significantly different between the two groups. However, the peeling off group showed a significantly increased recurrence rate of vascular invasion compared with the en bloc group (23.9% vs. 9.7%, p = 0.005). Similar results were also demonstrated prior to the matched analysis. Conclusions An en bloc resection is safe and confers a survival advantage compared with a peeling off resection in HCC patients with PVTT; thus, en bloc resection should be recommended as a standard treatment for these patients when possible.

Elevated expression of Cripto-1 correlates with poor prognosis in hepatocellular carcinoma

Cripto-1 could promote tumorigenesis in a wide range of carcinomas, yet little is known in hepatocellular carcinoma (HCC). The expression of Cripto-1 and MMP-9 were assessed by immunohistochemistry in 205 HCC specimens. The correlation between Cripto-1 and MMP-9, clinicopathological/prognostic value in HCC was examined. Cripto-1 overexpression was correlated with larger tumor, TNM stage, BCLC stage and tumor recurrence. In multivariate analyses, Cripto-1 was an independent predictor for overall survival (OS) and time to recurrence (TTR). Cripto-1 expression was increased in TNM and BCLC stage-dependent manner. Cripto-1 overexpression was associated with poor prognosis in patients subgroups stratified by tumor size, tumor differentiation, TNM and BCLC stage. In addition, Cripto-1 was positively correlated with MMP-9 among 205 HCC samples. Patients with Cripto-1 upregulation had poor OS and shorter TTR in low and high aggressiveness groups. Furthermore, Cripto-1 had predictive validity for early and late recurrence in HCC patients. Combination of Cripto-1 and serum AFP was correlated with OS and TTR. In conclusion, Cripto-1 overexpression contributes to aggressiveness and poor prognosis of HCC. Cripto-1/AFP expression could be a potential prognostic biomarker for survival in HCC patients.