GSTT1 null genotype contributes to hepatocellular carcinoma risk: a meta-analysis.

Studies investigating the association between genetic polymorphism of glutathione S-transferase T1 (GSTT1) and hepatocellular carcinoma (HCC) risk have reported conflicting results. Therefore, we conducted this meta-analysis to provide more precise evidence. Databases including PubMed, Embase, SCOPUS, ISI Web of Science, and Wangfang were searched for relevant studies. Potential sources of heterogeneity were also assessed by subgroup analysis. Funnel plots and Egger's linear regression were used to test publication bias among the articles. Finally, a total of 28 studies involving 3,897 HCC patients and 6,117 controls were included in this meta-analysis. In a combined analysis, the summary odds ratio for HCC of the GSTT1 null genotype was 1.43 (95% confidence interval (CI) 1.22­1.68, P < 10(−5)). In the subgroup analysis by ethnicity, significantly increased risks were found in East Asians for GSTT1 null polymorphism, while no significant associations were found among Caucasian, South Asian, and African populations. When stratified by a source of controls, both population- and hospital-based studies get consistent positive results. By pooling data from 10 studies (1,639 cases and 2,224 controls) that considered combinations of GSTT1 and GSTM1 genotypes, a statistically significant increased risk for HCC (odd ratio = 1.85, 95% CI 1.37­2.49) was detected for individuals with combined deletion mutations in both genes compared with positive genotypes. No evidence of publication bias was observed. Our result suggests that the GSTT1 null genotype contributes to an increased risk of HCC in East Asians and that interaction between unfavorable GSTs genotypes may exist.

Survival benefit of surgical treatment for hepatocellular carcinoma with inferior vena cava/right atrium tumor thrombus: results of a retrospective cohort study.

BACKGROUND: The significance of surgery in the treatment of hepatocellular carcinoma (HCC) extending into the inferior vena cava (IVC)/right atrium (RA) is currently unclear. We sought to clarify whether surgical treatment can improve survival in such patients. METHODS: A retrospective review was undertaken of patients with HCC and IVC/RA tumor thrombus who were potential candidates for surgery but who were finally treated surgically and nonsurgically between September 2000 and October 2010. The patients were subdivided according to therapeutic modalities, and the results for each group were compared. RESULTS: A total of 56 patients were included in this study. They were divided into three groups. Twenty-five patients underwent hepatectomy plus thrombectomy (surgical group), with minor morbidity and no mortality; the patients in this group had 1-, 3-, and 5-year survival rates of 68.0, 22.5, and 13.5%, respectively, with a median survival of 19 months. Twenty patients were treated with transcatheter arterial chemoembolization, with 1- and 3-year survival rates of 15.0 and 5.0%, respectively (median survival 4.5 months). Eleven patients received symptomatic treatment only, and no one in this group survived longer than 1 year (median survival 5 months). The patients in surgical group survived significantly longer than the patients in the other two groups (p < 0.001). CONCLUSIONS: Although technically challenging, surgery for HCC with IVC/RA tumor thrombus can be safely performed and should be considered in patients with resectable primary tumor and sufficient hepatic reservoir because compared with transcatheter arterial chemoembolization or symptomatic treatment, it significantly improved patient survival.

Precise local resection for hepatocellular carcinoma based on tumor-surrounding vascular anatomy revealed by 3D analysis.

PURPOSES: Local resection for hepatocellular carcinoma (HCC) has been traditionally performed non-anatomically. The purpose of this study is to evaluate the feasibility of precise local resection of HCC according to the anatomy of tumor-surrounding vessels revealed by three-dimensional (3D) analysis technique. METHODS: The CT datasets of the livers of the patients with HCC were analyzed three-dimensionally. The tumor-bearing vessels were identified and virtually resected, and the depending parenchymal volume was calculated for definition of an optimal liver division plane. The actual local resections were then carried out according to the simulations. RESULTS: Precise local resection based on tumor-surrounding vascular anatomy was performed in 13 HCC patients. Both resection margin and volume were significantly correlated with those predicted by preoperative simulations. After precise local resection, neither ischemia nor congestion was observed in the remnant livers. All patients obtained adequate resection margins, without recurrences in the resection sites after a median follow-up time of 18 months. CONCLUSIONS: Local resection for HCC can be carried out precisely according to the anatomy of tumor-surrounding vessels when guided by a 3D analysis. This precise procedure will enhance both the accuracy and safety of traditional local resection.

Clinical parameters predicting survival duration after hepatectomy for intrahepatic cholangiocarcinoma.

BACKGROUND: Currently, the most effective treatment for intrahepatic cholangiocarcinoma (ICC) is complete hepatic tumour excision. OBJECTIVE: To identify the clinical parameters associated with survival duration for ICC patients following hepatectomy, and to construct a mathematical model for predicting survival duration. METHODS: Demographic data and clinical variables for 102 patients diagnosed with ICC, who underwent exploratory laparotomy at a single centre from July 1998 to December 2000 and were followed for an average of 24 months, were collected in 2011. Patients were randomly assigned into training (n=76) and validation (n=26) groups. Univariate and multivariate analyses were performed to identify factors associated with posthepatectomy survival duration. RESULTS: Univariate analysis revealed that more than three lymph node metastases, a serum carbohydrate antigen 19-9 level greater than 37 U/mL, stage IVa tumours, and intra- or perihepatic metastases were significantly associated with decreased survival duration. Curative resection was significantly associated with increased survival duration. A mathematical model incorporating parameters of age, sex, metastatic lymph node number, curative surgery, carbohydrate antigen 19-9 concentration, alpha-fetoprotein concentration, hepatitis B, TNM stage and tumour differentiation was constructed for predicting survival duration. For a survival duration of less than one year, the model exhibited 93.8% sensitivity, 92.3% total accuracy and a positive predictive value of 93.8%; for a survival duration of one to three years, the corresponding values were 80.0%, 69.2% and 57.1%, respectively. CONCLUSIONS: The mathematical model presented in the current report should prove to be useful in the clinical setting for predicting the extent to which curative resection affects the survival of ICC patients, and for selecting optimal postoperative treatment strategies.

[Extended hepatic pedicle occlusion in major hepatectomy for primary liver cancer].

OBJECTIVE: To evaluate the influence of extended hepatic pedicle occlusion (HPO) on hepatic ischemic/reperfusion (I/R) injury and intraoperative blood loss in major hepatectomy for primary liver cancer (PLC). METHODS: Between June 2001 and December 2005, a total number of 843 patients with PLC had been operated on. Those whose hepatic pedicle were occluded continuously for or longer than 30 min during hepatectomy were retrospectively reviewed (continuous HPO group) and compared to the patients whose hepatic pedicle were occluded for the same length of time but intermittently (intermittent HPO group). The amount of intraoperative blood loss, the percentage of the patients who needed blood transfusion and postoperative liver biochemical tests were compared between the two groups. RESULTS: There were 35 cases in continuous HPO group and 38 cases in intermittent HPO group with occlusion time between 30 min and 45 min. The two groups were matched for underlying liver disease ,preoperative liver function, tumor size and location, major intrahepatic vessel involvements and the types and extensions of the hepatectomies. The mean intraoperative blood loss in continuous HPO group was significantly less than that in intermittent HPO group (660 ml vs. 1054 ml, P < 0.05); accordingly, the percentage of patients who need blood transfusion in continuous HPO group was significantly lower than that in intermittent HPO group (48.6% vs. 78.9%, P < 0.01). Patients in both of the groups were recovered smoothly after operation, with no occurrence of liver failure. CONCLUSIONS: The hepatic pedicle can be continuously occluded for 3045 min in cirrhotic patients with well compensated liver function, and when compared to routine intermittent HPO, continuous HPO significantly decreases the intraoperative blood loss and reduces the need for transfusion. Meanwhile it does not increase the hepatic I/R injury.

[Surgical resection of hepatic tumor in segment IXb by anterior transhepatic approach].

OBJECTIVE: To evaluate the feasibility and the effect of surgical resection of hepatic tumor originated from segment IXb. METHODS: The cases with hepatic tumors in segment IXb who had been operated on between March 2003 and January 2007 were retrospectively reviewed. RESULTS: A total of 15 tumors in segment IXb, including 13 primary liver cancers and 2 benign tumors with a mean diameter of (4.3 +/- 1.6) cm, were successfully resected by anterior transhepatic approach under sequential occlusions of portal tride and total hepatic vascularity or portal tride clamping only. There was no operative mortality,with a mean operative time of (190.3 +/- 37.6) min and a mean operative blood lose of (376.7 +/- 252.7) ml. All the patients had uneventful postoperative course except one who suffered from ascites and edema of the low body, which was successfully managed medically. The mean postoperative hospital stay was (13.3 +/- 6.0) d. During the follow-up of 1-47 months, two patients with benign tumor enjoyed a normal life. Among the 13 patients with primary live cancers, 1 patient died of recurrence, 2 patients remained alive with intrahepatic recurrence and 10 patients survived without any sign of relapse, with a median tumor-free survival time of 23.5 months. CONCLUSIONS: Surgical resection of hepatic tumor in segment IXb, despite their sophisticated anatomic position, is feasible in technique with high safety. The local resection can provide the patients with potential to cure.

[Surgical management of small intrahepatic lesions adjacent to the major vasculature].

OBJECTIVE: To assess the feasibility and the significance of surgical resection of small intrahepatic lesions adjacent to the major vasculature. METHODS: The results of treatment were retrospectively reviewed in 40 patients who received operation for intrahepatic lesions less than 3 cm in diameter between Jan. 2003 and Dec. 2005. The lesions were all adjacent to the major vasculature in the liver. RESULTS: In the 40 patients, a total of 44 small intrahepatic lesions were successfully resected with minimal morbidity and blood loss (mean 163 ml). A second lesion was found in 4 patients (10%) during intraoperative exploration. Histologically the lesion was malignant in 29 cases (including 4 cases with two lesions) and benign in 11 cases, with correct preoperative diagnosis in 62.5% of all cases. For 26 patients with hepatocellular carcinoma, the 1-, 2-, and 3-year postoperative survival rates were 90.1%, 83.2% and 64.7%, respectively, while the patients with benign lesions were cured with the operation. CONCLUSIONS: Surgical resection of small intrahepatic lesions adjacent to the major vasculature is demanding but feasible and with satisfying effect. The significance of surgical management of these small lesions is not only excising the lesions but also making definite diagnosis and finding new lesions in some patients.

Intermittent portal triad clamping in resection of liver tumors involving the hepatocaval confluence.

OBJECTIVE: To review our experience in and the results of resecting liver tumors involving the hepatocaval confluence under intermittent portal triad clamping (PTC). METHODS: Sixty-eight consecutive patients with liver tumors involving the hepatocaval confluence underwent hepatectomies with liver parenchymal transections under intermittent PTC. RESULTS: All the tumors were successfully resected under PTC, except for one in which the infrahepatic inferior vena cava was concomitantly occluded in addition to PTC. There was neither operative death nor uncontrollable massive bleeding or air embolism occurred in our patients. The bleedings from the main and short hepatic veins and right adrenal veins were properly managed during the operation, with a mean intraoperative blood loss of 1400 ml. Of the 68 tumors resected, 65 were hepatocellular carcinomas (HCC). Their 1-, 2-, 3- and 4-year survival rates were 64.11%, 52.82%, 44.90% and 36.98%, respectively, and the patients with HCC with capsules survived significantly longer than those with HCC without capsules. CONCLUSIONS: The liver tumors involving the hepatocaval confluence could be safely resected simply under PTC, without routine use of total hepatic vascular exclusion. As for HCCs in this area, the tumor with capsule is a better indicator for surgical resection than that without capsule.

[Curative effect of percutaneous microwave coagulation therapy for hepatocellular carcinoma].

OBJECTIVE: To observe the curative effect of percutaneous microwave coagulation therapy (PMCT) with 2450 MHz microwave antenna for hepatocellular carcinoma. METHODS: Under local or epidural anesthesia, a thin percutaneous microwave antenna was introduced with ultrasound guidance into the tumor in the liver for thermo-coagulation. RESULTS: Among the 97 hepatic cancer lesions in 52 patients, 61(62.9%) with phi < 3 cm were coagulated once. In follow-up of 6-12 months of these lesions, 57(93.4%) showed no recurrence by CT or MRI. Thirty-six (37.1%) with 3 cm < phi < 5 cm coagulated twice showed that 27 (75.0%) gave CR and 9 (25.0%) gave PR by CT or MRI in follow up of 6 months. There were no serious clinical side effects or complications in the PMCT patients. CONCLUSION: Percutaneous microwave coagulation therapy gives good curative effect on liver tumor with phi < 3 cm. It is partly effective on lesions 3 cm < phi < 5 cm.

[Surgical treatment for the giant hepatic carcinomas occupying the central part of the liver].

OBJECTIVE: To evaluate the techniques and the effects of surgical resection of giant hepatic carcinomas which occupied the central part of the liver. METHODS: A retrospective study was carried out of hepatectomies performed for central giant hepatic carcinomas. The hepatic tumors included in this study were hepatocellular carcinomas, cholangiocarcinomas and hepatic metastases which situated in the central part of the liver (segment IV, V, VIII, I) with a diameter of larger than 10 cm and involved hepatocaval confluence, retrohepatic inferior vena cava (IVC) as well as hepatic portal. RESULTS: A total of 40 central giant hepatic carcinomas were successfully resected, with a mean diameter of 13.6 cm (range 10.5-19.0 cm). The types of the hepatectomies conducted were as follows: extended mid-hepatectomy in 9 cases, atypical mid-hepatectomy in 13 cases, extended left hepatectomy in 13 cases, total caudatectomy plus extended left hepatectomy in 3 cases and extended right hepatectomy in 2 cases. The mean operation time was 197 min (range 90 - 380 min) and the mean intraoperative blood lose 1,596 ml (range 300-11,000 ml), with operative mortality and morbidity being 0 and 20%, respectively. The postoperative 1, 3 and 5 year survival rates for the patients were 88%, 56% and 28%, respectively. CONCLUSIONS: The hepatic carcinomas of central type, when larger than 10 cm in diameter, frequently involves all the hepatic portal, hepatocaval confluence and retrohepatic IVC. Surgical resection of this kind of tumor, though sophisticated in technique, is safe and effective and, therefore, the first choice of the treatments.

[Resection of right or total hepatic caudate lobe including paracaval portion].

OBJECTIVES: To evaluate the surgical techniques and feasibility for resecting the hepatic caudate lobe including the paracaval portion. METHODS: Right posterior approach for right caudate lobectomy and left lateral approach for total caudate lobectomy were taken with or without some kinds of preparatory segmentectomies. RESULTS: Seven right and 6 total caudate lobectomies, all including paracaval portion, ware accomplished without operative death. The mean intraoperative blood loss was 896.15 (250 - 2 000) ml and the mean portal triad clamping time was 25.4 (10 - 83) min. The postoperative course was uneventful for all the cases, and the mean hospital stay was 12 (9 - 22) days. CONCLUSIONS: Although being complicated anatomically, resection of the hepatic caudate lobe including the paracaval portion is feasible with a high safety.

[Surgical treatment of hepatocellular carcinoma with tumor thrombus in the inferior vena cava].

OBJECTIVE: To clarify the proper surgical procedure of treating hepatocellular carcinoma (HCC) with a tumor thrombus in the inferior vena cava (IVC). METHODS: Four patients with HCC with a tumor thrombus in the IVC underwent hepatectomy and thrombectomy. Following hepatectomy, tumor thrombus was removed by incising the wall of the IVC in 3 patients and from the hepatic vein in one patient. The 3 patients underwent thrombectomy under either hepatic vascular exclusion (HVE) or Satinsky's vascular clamping. RESULTS: All the operations were successful without operative death and major complications. The postoperative course was uneventful in 3 patients and pleural effusion occurred in one patient who needed thoracentesis. Follow-up showed 3 patients died after 30, 10 and 14 months, respectively, and one patient is alive for 7 months. CONCLUSIONS: HCC with tumor thrombus in the IVC is operable and the proper procedure is hepatectomy plus thrombectomy.

A long-term follow-up and comprehensive observation of risk and prognosis factors of recurrence and survival after resection of hepatocellular carcinoma.

Although HBV, liver function and tumor characteristics were proven as hepatocellular carcinoma (HCC) prognosis-related, no large-scale and long-term follow-up studies have ever given robust evidence about prognosis predictive effect and contribution to different stage of postoperation. In this study, we evaluated the influence of above index on overall survival (OS) and disease-free survival (DFS) and other clinical data in a rather large population and long-term follow-up. Our study consisted of 1,326 HCC patients who underwent radical resection from 1996 to 2010. Epidemiology, clinical and prognosis data were analyzed. Risk factors of OS and DFS were explored. Cumulative survival comparison between groups was performed with log-rank. Multivariate analysis for independent prognostic factors was determined by Cox proportional hazards model. HBsAg status was a universal factor of HCC recurrence, while preoperational albumin (ALB) and portal vein tumor thrombus (PVTT) affected survival during the whole lifetime. Early stage recurrence was associated with capsule intact [OR (95 %) = 1.54,1.12-2.12, p = 0.009], preoperational alpha-fetoprotein (AFP), TNM and BCLC stages were the most important prognosis factors of recurrence in the early 5 years and PVTT affected the rest time. Survival was mainly associated with tumor characteristic and ALB. Short-time survival was affected with age and AFP, while BCLC was related with the long-time survival. We confirmed that during different periods after resection, factors affecting prognosis did not remain unchanged. Liver function and tumor characteristic affected DFS and OS the whole time, especially the early recurrence. However, HBV infection situation was associated with later recurrence. PVTT showed an opposite effect between early and later recurrence.

Survival outcomes and prognostic factors of surgical therapy for all potentially resectable intrahepatic cholangiocarcinoma: a large single-center cohort study.

BACKGROUND: Surgical resection is currently indicated for all potentially resectable intrahepatic cholangiocarcinoma (ICC), but the survival outcomes and the prognostic factors have not been well-documented due to its rarity. This study aims to assess these in a large, consecutive series of patients with ICC treated surgically. METHODS: A retrospective study was conducted on 1,333 ICC patients undergoing surgery between January 2007 and December 2011. Surgical results and survival were evaluated and compared among different subgroups of patients. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: R0, R1, R2 resection and exploratory laparotomy were obtained in 34.8, 44.9, 16.4, and 3.9% of the patients, respectively. The overall 1-, 3-, and 5-year survival rates for the entire cohort were 58.2, 25.2, and 17.0%, respectively, with corresponding rates of 79.1, 42.6, and 28.7% for patients with R0 resection; 60.5, 20.1, and 13.9% for patients with R1 resection; 20.5, 7.4, and 0% for patients with R2 resection; and 3.8, 0, and 0% for patients with an exploratory laparotomy. Independent factors for poor survival included positive resection margin, lymph node metastasis, multiple tumors, vascular invasion, and elevated CA19-9 and/or CEA, whereas hepatitis B virus infection and cirrhosis were independently favorable prognosis indicators. CONCLUSIONS: R0 resection offers the best possibility of long-term survival, but the chance of a R0 resection is low when surgery is performed for potential resectable ICC. Further randomized trials are warranted to refine indications for surgery in the management of ICC.

Aberrant expression of Notch3 predicts poor survival for hepatocellular carcinomas.

Using a meta-analysis on gene expression data of hepatocellular carcinomas (HCC) from the Oncomine database, we identified that the Notch3 gene ranked as the highest up-regulated Notch pathway member in HCC tissues compared with normal liver tissues. We further detected the expression of Notch3 in 95 cases of HCC samples by immunohistochemistry, and evaluated its clinicopathological and prognostic significance. We confirmed that Notch3 is overexpressed in HCC tissues compared with normal liver tissues, and a high expression level of Notch3 was significantly associated with bigger tumor size (p = 0.014), multiple tumors (p = 0.026), late tumor-node-metastasis (TNM) stage (p < 0.01) and shorter overall survival (p = 0.002). Furthermore, high Notch3 expression emerged as a significant independent prognostic factor in multivariate analysis. In conclusion, we identified a positive association between Notch3 expression with more aggressive traits and shorter survival in HCC. Our findings suggest that Notch3 might be an important regulator in the development of HCC, and a potential therapeutic target for patients with HCC.

Flufenamic acid promotes angiogenesis through AMPK activation.

Angiogenesis plays critical roles in development, tumor growth and metastasis. Flufenamic acid (FFA) is an anti-inflammatory agent known to alter ion fluxes across the plasma membrane. Its role in angiogenesis has not been fully addressed to date. Here, we report that FFA treatment promotes angiogenesis both in vitro and in vivo. Applying FFA for 12 h promoted tube formation of human umbilical vein endothelial cells (HUVECs) without affecting cell proliferation. Three angiogenesis-related genes, VEGF, e-NOS and AAMP, were analyzed by RT-PCR. A significant difference was found between the FFA group and the control; the FFA group had significantly higher mRNA accumulation levels of all the three genes (p<0.05). Moreover, in the chick embryo chorioallantoic membrane (CAM) assay, FFA promoted the formation of macroscopic blood vessels. Finally, western blotting showed that the FFA-treated group had significantly higher phosphorylated AMPK levels, compared with the control (p<0.05). These results suggest that FFA promotes angiogenesis both in vitro and in vivo likely via promoting tube formation through AMPK activation.

Downregulating the expression of heparanase inhibits the invasion, angiogenesis and metastasis of human hepatocellular carcinoma.

Invasion and metastasis are key features of human hepatocellular carcinoma (HCC). Heparanase is an endoglycosidase that can degrade extracellular matrix by cleaving heparan sulfate chains of heparan sulfate proteoglycan, thus playing important roles in the invasion and metastasis of human cancers. Heparanase has been detected in various human cancers and regarded as a prospective target in human cancer treatments. However, the effects of inhibiting the expression of heparanase on human HCC have not been fully evaluated. In this article we show that downregulating the expression of heparanase either by antisense oligodeoxynucleotide or by RNA interferencing can significantly reduce the expression of heparanase in SMMC7721 human HCC cells, leading to inhibition of the invasiveness, metastasis, and angiogenesis of HCC cells both in vitro and in vivo. Our results suggest that genetic downregulation of the expression of heparanase may serve as an efficient cancer therapeutic for human HCC.