Association Between EphA1 and Tumor Microenvironment in Gastric Carcinoma and its Clinical Significance.

BACKGROUND With the growing global burden of gastric carcinoma (GC) and the urgent need for biomolecular targeted therapies, this study aimed to elucidate the relationship between EphA1 and the tumor microenvironment (focusing primarily on the key inflammatory cytokines IL-6 and tumor angiogenic cytokine VEGF) to identify a new potential therapeutic target. MATERIAL AND METHODS IHC and qRT-PCR were performed to quantify the protein and gene expression levels of EphA1, IL-6, and VEGF in normal mucosal tissues, carcinoma tissues, and paracarcinomatous tissues from 57 GC patients. Spearman's rank correlation test was performed to determine the relationship between EphA1, IL-6, and VEGF expression levels. The relationships of EphA1 with clinicopathologic parameter and survival in GC patients were also evaluated. RESULTS The protein and gene expression levels of EphA1 were all attenuated gradually from carcinoma tissues to paracarcinomatous tissues and then to normal mucosal tissues in GC patients. Additionally, significant correlations between the overexpression of EphA1 with aggressive clinicopathological features and shorter survival time of GC patients were verified. In particular, we found a significant positive correlation between the expression of EphA1 and tumor microenvironment hallmark proteins IL-6 and VEGF in carcinoma tissues and paracarcinomatous tissues. CONCLUSIONS EphA1 can promote the occurrence and development of GC by its selective high expression in cancer tissues and its relationship with malignant clinical features and prognosis of GC patients. The underlying potential mechanism appears to involve enhancement of the tumor microenvironment, which via drives the expression of tumor microenvironment hallmark proteins IL-6 and VEGF.

Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial.

OBJECTIVE: There is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We conducted a multicentre, randomised, controlled, phase IV trial evaluating the benefit of an aqueous extract of Trametes robinophila Murr (Huaier granule) to address this unmet need. DESIGN AND RESULTS: A total of 1044 patients were randomised in 2:1 ratio to receive either Huaier or no further treatment (controls) for a maximum of 96 weeks. The primary endpoint was RFS. Secondary endpoints included OS and tumour extrahepatic recurrence rate (ERR). The Huaier (n=686) and control groups (n=316) had a mean RFS of 75.5 weeks and 68.5 weeks, respectively (HR 0.67; 95% CI 0.55 to 0.81). The difference in the RFS rate between Huaier and control groups was 62.39% and 49.05% (95% CI 6.74 to 19.94; p=0.0001); this led to an OS rate in the Huaier and control groups of 95.19% and 91.46%, respectively (95% CI 0.26 to 7.21; p=0.0207). The tumour ERR between Huaier and control groups was 8.60% and 13.61% (95% CI -12.59 to -2.50; p=0.0018), respectively. CONCLUSIONS: This is the first nationwide multicentre study, involving 39 centres and 1044 patients, to prove the effectiveness of Huaier granule as adjuvant therapy for HCC after curative liver resection. It demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group. TRIAL REGISTRATION: NCT01770431; Post-results.

Overexpression of Acyl-CoA Ligase 4 (ACSL4) in Patients with Hepatocellular Carcinoma and its Prognosis.

BACKGROUND Recently, accumulating studies have found that ACSL4 dysregulation is related to a great number of malignant tumors. The purpose of the present study was to explore the relationship between ACSL4 expression level and clinical prognosis of hepatocellular carcinoma (HCC) patients. MATERIAL AND METHODS The Oncomine and TCGA databases were used to predict the expression of ACSL4 mRNA in HCC and its association with HCC prognosis. Further, immunohistochemistry was performed to verify the ACSL4 protein expression in 116 paired HCC and adjacent normal tissues. Kaplan-Meier and cox analysis were performed to validate the correlation between ACSL4 expression and HCC prognosis. RESULTS We first used the Oncomine database to find that ACSL4 mRNA expression level was significantly higher in HCC tissues than that in normal tissues (p all <0.001). The results were consistent with those in the TCGA database. Then, immunohistochemical results demonstrated that the ACSL4 positive expression rate was 70.7% in HCC tissues. ACSL4 differential expression level was significantly related to Edmondson grade (p=0.010), AFP (p=0.001) and TNM stage (p=0.012). Survival analysis revealed that both overall survival (OS) and disease-free survival (DFS) time were remarkably reduced in HCC patients with ACSL4 high expression (p=0.001 and 0.000, respectively). Moreover, Cox multivariate analysis demonstrated that ACSL4 expression was the only independent prognostic factor for both OS and DFS (both p values=0.001). CONCLUSIONS Taken together, our study demonstrated that ACSL4 was overexpressed in HCC, and it will be a new potential therapeutic target for HCC as an independent adverse prognostic parameter.

Prognostic value of polarized macrophages in patients with hepatocellular carcinoma after curative resection.

As the most predominant tumour-infiltrating immune cells, tumour-associated macrophages (TAMs) are significant for fostering tumour growth, progression and metastasis. CD68-positive TAMs display dissimilarly polarized programmes comprising CD11c-positive pro-inflammatory macrophages (M1) and CD206-positive immunosuppressive macrophages (M2). The aim of this study is to determine the prognostic significance of diametrically polarized TAMs in hepatocellular carcinoma (HCC) and their application to risk stratification of patients according to their specific prognostic values. This study included 80 consecutive patients with HCC, and we evaluated diametrically polarized functional status of macrophages by immunohistochemical staining of CD68, CD11c and CD206. Prognostic values and clinicopathologic features were assessed in these patients. High versus low CD11c-positive TAM density (P = 0.005) and low versus high CD206-positive TAM density (P = 0.002) were associated with better overall survival, whereas CD68-positive TAM density had no prognostic significance (low versus high, P = 0.065). Furthermore, the presence of these positive staining macrophages did not show any prognostic significance for recurrence-free survival (all P > 0.05). Multivariate Cox regression analysis identified CD11c-positive and CD206-positive TAMs as an independent prognostic factor (P < 0.001, P = 0.031, respectively). Intratumoural infiltration of diametrically polarized TAMs, a novel identified independent prognostic factor for survival in patients with HCC, could be combined with the TNM stage and the Barcelona Clinic Liver Cancer stage to improve a risk stratification system.

Expression of Kindlin-1 in human hepatocellular carcinoma and its prognostic significance.

Kindlin-1 is a member of the Kindlin family of focal adhesion proteins and is implicated in cell adhesion, proliferation, polarity, and motility. Although expression of Kindlin-1 has recently been reported in a variety of human cancers, studies on its expression in human hepatocellular carcinoma (HCC) are currently lacking. This study aimed to determine the clinicopathological parameters and prognostic value of Kindlin-1 in HCC patients after surgical resection. The messenger RNA (mRNA) and protein levels of Kindlin-1 in 22 matched HCC specimens were assessed by quantitative real-time PCR (qRT-PCR) and Western blotting assays. The clinical and prognostic significance of Kindlin-1 in 68 cases of HCC was determined by immunohistochemistry. Kindlin-1 expression was higher in HCC tumor tissues relative to that in adjacent normal tissue at the both mRNA and protein levels (p < 0.05). Immunohistochemical results revealed that overexpression of Kindlin-1 was detected in 37 of 68 (54.4 %) tumor tissues and in seven of 68 (10.3 %) adjacent non-tumor tissues (p < 0.05). Positive Kindlin-1 expression was significantly correlated with tumor size, tumor capsula, status of metastasis, and tumor-node-metastasis (TNM) stage. Additionally, Kaplan-Meier survival analysis showed that positive Kindlin-1 expression was associated with unfavorable overall survival (OS) and disease-free survival (DFS). Multivariate analysis identified Kindlin-1 as an independent prognostic predictor for OS and DFS in HCC patients (p = 0.041 and 0.027, respectively). Taken together, our data suggest that Kindlin-1 could play an important role in HCC and might serve as a promising prognostic marker and potential target for HCC therapy.

Protective effect of S-adenosylmethionine on hepatic ischemia-reperfusion injury during hepatectomy in HCC patients with chronic HBV infection.

BACKGROUND: Although hepatectomy is often performed with the Pringle maneuver, the problem of hepatic ischemia-reperfusion injury (HIRI) can also be serious. Thus, the present study was designed to investigate the protective effect of S-adenosylmethionine (SAMe) on HIRI, especially for patients with hepatocellular carcinoma (HCC) associated with chronic hepatitis B virus (HBV) infection and cirrhosis. METHODS: Eighty-one HCC patients with chronic HBV infection, undergoing partial hepatectomy with inflow occlusion, were divided into three groups. In the pretreatment group (PR group, n = 26), patients were given SAMe two hours before surgery. In the post-treatment group (PO group, n = 25), patients were given SAMe six hours after surgery. And in the control group (control group, n = 30), patients received partial hepatectomy without any SAMe. All pre-, intra- and postoperative blood samples were collected to measure the plasma levels of transaminases, bilirubin and cytokines. The results were compared among the three groups. RESULTS: There were no statistically significant intergroup differences observed in age, gender, hepatic inflow occlusion time and the results of liver function tests. Preoperative administration of SAMe (PR group) significantly reduced the plasma levels of alanine transaminase (ALT), aspartate transferase (AST), total bilirubin (TBIL) and direct bilirubin (DBIL) as compared to the other two groups. In the PO group, TBIL and DBIL were significantly lower than in the control group. Significant differences were also seen in IL-6 and TNF-α between the PR group and the other groups. In all groups, postoperative liver reserve function in the PR group as revealed by ICGR15 (Post ICGR15) was at its best before abdominal closure. Compared to the control group, the risk of complications and the hospital stay after surgery were significantly meliorated in the PR group. Additionally, patients with cirrhosis had a more acute rate of change in ALT and AST than non-cirrhotic patients. CONCLUSIONS: Taken together, our preliminary findings suggest that preoperative administration of SAMe is useful and safe for reducing the HIRI in partial hepatectomy, especially for HCC patients whose disease is associated with chronic HBV infection and cirrhosis.

Anatomical right hemicolectomy: a novel surgical method and its clinical application.

BACKGROUND/AIMS: Presently, the notion of traditional right hemicolectomy has not met the rapidly developed requirements for precise gastrointestinal surgical procedures. In this study, we introduced a novel surgical method, namely "anatomical right hemicolectomy," and evaluated the safety and short-term effects of this method for the treatment of right hemicolon carcinoma. METHODOLOGY: The clinical data of 10 cases with progressive right hemicolon carcinoma underwent anatomical right hemicolectomy from January 2013 to February 2014 were collected and analyzed retrospectively. RESULTS: All the operations were successfully completed. The number of cleared lymph nodes was 18.0±6.7, the mean operative time was 162.7±25.3 mins, the mean blood loss was 95.2±32.5 ml, time to first flatus was 4.2±1.9 days, and the mean size of tumor was 4.96±3.2 cm. In these 10 patients, there was no case of respiratory infections, intestinal obstruction, anastomotic bleeding, anastomotic stricture, anastomotic leakage and other complications. All patients recovered, and subsequently discharged. CONCLUSIONS: In summary, anatomical right hemicolectomy was a safe and feasible method for the treatment of progressive right hemicolon carcinoma; it was worth popularizing widely.

STAT3 activation mediates epithelial-to-mesenchymal transition in human hepatocellular carcinoma cells.

BACKGROUND/AIMS: Epithelial-to-mesenchymal transition (EMT) is critical for the development of the invasion and metastasis in human cancers. Recently, signal transducer and activator of transcription 3 (STAT3) activation has been linked to EMT program in breast cancer. However, the actual association of STAT3 activation with EMT, and its mediated tumor invasion and metastasis remains elusive in hepatocellular carcinoma (HCC). The aim of this study was to investigate the correlation between STAT3 activation and EMT, as well as the underlying mechanism involved in HCC progression. METHODOLOGY: We treated SMMC-7721 cells with a known STAT3 activator, epithelial growth factor (EGF); in the absence or presence of JSI-124, a selective STAT3 inhibitor. The EMT-associated morphologic and molecular changes of cells were analyzed. The EMT-mediated HCC cell invasion, migration and adhesion were evaluated. RESULTS: In this study, we found that STAT3 activation induced by EGF was associated significantly with morphologic changes, cytoskeleton rearrangement and molecular changes consistent with EMT in SMMC-7721 cells; STAT3 activation-mediated EMT may be transcriptionally induced by Twist. STAT3 activation-mediated EMT also promoted HCC cell invasion, migration and adhesion significantly. CONCLUSIONS: In summary, our study show for the first time that STAT3 activation may induce invasion and metastasis through the mediation of EMT in HCC cells. Activated STAT3 and EMT markers can serve as molecular targets for HCC treatment.

The Research of No-Touch Isolation Technique on the Prevention of Postoperative Recurrence and Metastasis of Hepatocellular Carcinoma after Hepatectomy.

BACKGROUND/AIMS: To evaluate the efficacy of a surgical no-touch isolation technique in primary hepatocellular carcinoma patients compared with traditional hepatectomy. METHODOLOGY: Eighty hepatocellular carcinoma patients were randomly divided into traditional hepatectomy (n = 40) and no-touch isolation technique groups (n = 40). We compared peripheral blood variations in alpha-fetoprotein mRNA, miRNA-221, miRNA-224, and miRNA-122 expression levels in both groups pre- and postoperatively using real-time fluorescent quantitative polymerase chain reaction. RESULTS: The patients in the no-touch isolation technique group had better clinical curative effect. In the traditional hepatectomy group, variations in alpha-fetoprotein mRNA copy number pre- and postoperatively indirectly indicated a significant increase in the number of exfoliated carcinoma cells induced by manipulating the liver, increasing the risk of postoperative recurrence and metastasis (P < 0.05). Traditional hepatectomy patients showed higher increases in miRNA-221 and miRNA-224 expression than those in the no-touch isolation technique group (P < 0.05). Tumor resection resulted in preoperative expression and high postoperative expression of miRNA-122. No-touch isolation technique patients showed a slight and significant increase (P < 0.01) in miRNA-122, which was positively correlated with postoperative liver function index. Conclusion: The no-touch isolation technique is more effective than traditional hepa- tectomy in tumor resection for primary hepatocellular carcinoma.

Aberrant estrogen receptor alpha expression correlates with hepatocellular carcinoma metastasis and its mechanisms.

BACKGROUND/AIMS: Metastasis one of the obstacles before poor prognosis of hepatocellular carcinoma (HCC) is improved. Estrogen receptor alpha (ERalpha) plays an important role in the development and progression of HCC. However, the molecular mechanism of ERalpha in mediating HCC metastasis is still unclear. The aim of the present study was to detect aberrant ERalpha expression in HCC and elucidate its possible mechanisms in HCC metastasis. METHODOLOGY: We detected expression of ERalpha, phospho-estrogen receptor alpha (p-ERalpha), nuclear factor kappa B (NF-kappaB) p65 and Matrix metalloproteinase-9 (MMP-9) between HCC tissues with portal vein tumor thrombus (PVTT) and those without PVTT by immunohistochemical method. Moreover, the expression of above parameters was also determined in HCC cells of different metastatic potential by using immunocytochemical and reverse transcriptase-polymerase chain reaction (RT-PCR) methods. RESULTS: The expression of ERalpha and p-ERalpha was lower in HCC with PVTT than those without PVTT. Meanwhile, the expression pattern of above parameters was also similar in HCC cells of different metastatic potential, whereas, the expression of NF-kappaB p65 and MMP-9 was higher in HCC with PVTT than those without PVTT. The expression of NF-kappaB p65 and MMP-9 in HCC cells was also analogous to the tissues. CONCLUSIONS: These results demonstrated that expression of ERalpha, p-ERalpha, NF-kappaB p65 and MMP-9 correlated with invasion and metastasis in HCC. The mechanism of HCC metastasis may mediate through cross-talk between the NF-KB and ER signaling pathways. Meanwhile, ERa regulated MMP-9 through NF-kappaB indirectly.

Overexpression of HOXA13 as a potential marker for diagnosis and poor prognosis of hepatocellular carcinoma.

HOXA13 is a member of homeobox genes that encode transcription factors regulating embryonic development and cell fate. Abnormal HOXA13 expression was reported in hepatocellular carcinoma (HCC), but its correlation with tumor angiogenesis and prognosis still remain unclear. This study was aimed to uncover the expression, diagnostic and prognostic significance of HOXA13 in HCC. Immunohistochemistry was performed to detect HOXA13 expression in HCC and corresponding paracarcinomatous tissues from 90 patients. Enzyme-linked immunosorbent assay was used to detect serum HOXA13 in 90 HCC patients and 20 healthy volunteers. Receiver operating characteristics was analyzed to calculate diagnostic accuracy of serum HOXA13, alpha-fetoprotein (AFP) and their combination. Immunoreactivity of HOXA13 was detected in 72.2% of HCC, and 12.2% of adjacent non-cancerous samples. HOXA13 expression was significantly associated with tumor size, microvascular invasion, pathological grade, tumor capsula status, AFP level, tumor-node-metastasis stage and positively correlated with VEGF (p < 0.001) and microvessel density (p < 0.001). The combination of serum HOXA13 and AFP had a markedly higher area under the curve than HOXA13 alone. HOXA13 expression was associated with unfavorable overall survival (OS) (p < 0.001) and disease-free survival (DFS) (p < 0.001). Multivariate analysis indicated that patients with HOXA13-expressing tumors had a significantly shorter OS (p = 0.030) and DFS (p = 0.005) than those with HOXA13-negative tumors. Thus, HOXA13 expression possibly plays an important role in tumor angiogenesis, progression and prognosis of HCC. Moreover, we demonstrate that serum HOXA13 may serve as a biomarker for early HCC diagnosing and predicting outcome.

Beneficial effects of S-adenosyl-L-methionine on post-hepatectomy residual liver function: a prospective, randomized, controlled clinical trial.

BACKGROUND/AIMS: Hepatectomy is associated with high rates of postoperative liver dysfunction in patients with cirrhosis. Since S-adenosyl-L-methionine (SAMe) can be used to treat liver disease, we performed a prospective clinical trial to investigate whether it could be used after hepatectomy to benefit residual liver function. METHODOLOGY: We studied 79 hepatitis-related chronic patients who underwent resection of hepatocellular carcinoma; 39 patients were randomly assigned to receive postoperative intravenous SAMe treatment, and 40 were randomly assigned to a control group. The postoperative SAMe treatment consisted of SAMe 1,000mg given intravenously for seven days. The other treatment was standardized. RESULTS: At inclusion into the trial no significant differences were observed between the two groups with respect to gender, age, Child classification, preoperative liver function tests, blood loss, total time of hepatic pedicle occlusion and the extent of liver resection. The overall frequency of postoperative liver insufficiency decreased from 42% in the control group to 31% in the SAMe group, although not statistically significant (p=0.121). When the patients who underwent hepatic pedicle occlusion by Pringle's maneuver over 15min were analyzed, the frequency of postoperative liver insufficiency (p=0.028), serum total bilirubin levels on days 5 (p=0.025) and 7 (p=0.032) preoperatively, and the maximum value of postoperative serum total bilirubin (p=0.040) were significantly greater in the control than in the SAMe group. CONCLUSIONS: The results indicate that the postoperative SAMe therapy can benefit residual liver function of the patients with cirrhosis, especially in those suffering greater ischemia reperfusion injury.

Prognostic significance of osteopontin in hepatocellular carcinoma: a meta-analysis.

Osteopontin (OPN) has been implicated in tumor development and progression for several years. However, the prognostic value of OPN overexpression in patients with hepatocellular carcinoma (HCC) remains controversial. We performed a meta-analysis to assess the relationship between OPN overexpression and clinical outcome of HCC. A meta-analysis of seven studies (1,158 patients) was carried out to evaluate the association between OPN and overall survival (OS) and disease-free survival (DFS) in HCC patients. The correlation between OPN and tumor vascular invasion or other invasion-related parameters was also assessed. Data were synthesized with random effect model of DerSimonian and Laird, hazard ratio (HR) or odds ratio (OR) with its 95% confidence interval (CI) was used as the effect size estimate. Our analysis results indicated that high OPN expression predicted poor OS (HR: 1.37, 95% CI: 1.21-1.55) and DFS (HR: 1.62, 95% CI: 1.24-2.11) of HCC. OPN overexpression tended to be associated with the presence of tumor vascular invasion (OR: 1.93, 95% CI: 0.97-3.84) and advanced tumor grade (OR: 1.74, 95% CI: 0.95-3.18). By this study, we conclude that OPN overexpression indicates a poor prognosis for patients with HCC, it may also have predictive potential for HCC invasion and metastasis.

Activation of STAT3 signal pathway correlates with twist and E-cadherin expression in hepatocellular carcinoma and their clinical significance.

BACKGROUND: To examine the expression of signal transducer and activator of transcription 3 (STAT3) and its activated form (p-STAT3), Twist, and E-cadherin in hepatocellular carcinoma (HCC), and explore their correlations with HCC progression and prognosis. MATERIALS AND METHODS: The expression profiles of STAT3, p-STAT3, Twist, and E-cadherin were assessed on 100 clinical HCC samples and 10 normal liver tissues by using an immunohistochemical staining method, and their correlations with clinicopathologic parameters and survival of HCC patients were statistically analyzed. RESULTS: The results demonstrated that the positive rate of STAT3, p-STAT3, and Twist in HCC was significantly higher than that in normal liver tissues; furthermore, 52% of HCC lesions showed reduced E-cadherin expression. Correlation analysis indicated that p-STAT3 was positively correlated with Twist expression, whereas Twist was negatively correlated with E-cadherin expression; p-STAT3, Twist, or E-cadherin expression was significantly associated with HCC invasion and metastasis. Survival analysis showed that HCC patients with p-STAT3, Twist positive expression, or reduced E-cadherin expression had a significantly shorter survival duration than those with p-STAT3, Twist negative expression, or those with normal E-cadherin expression. Multivariate analysis identified p-STAT3, Twist, or E-cadherin expression as an independent prognostic factor for overall survival of HCC patients after surgery. CONCLUSIONS: By this study, we suggest that activated STAT3 signal may associate with Twist and E-cadherin expression and mediate HCC invasiveness and metastasis; abnormal p-STAT3/Twist/E-cadherin signal axis may predict poor prognosis of HCC patients.

Efficacy and feasibility of radiofrequency ablation for hepatocellular carcinoma patients.

BACKGROUND/AIMS: Radiofrequency ablation (RFA) is a new treatment which is used to treat hepatocellular carcinoma (HCC). We performed this clinical trial to investigate whether it could reduce the damage of residual liver function. METHODOLOGY: We studied 40 hepatitis-related chronic patients who underwent RFA for hepatocellular carcinoma. Indocyanine green (ICG) test was performed pre and postoperatively. RESULTS: There were 32 males and 8 females with an average age of 53.98+12.59 years who underwent RFA for HCC. The mean preoperative ICGR15 value of 40 of the patients was (10.17+9.54) lower than the postoperative ICG retention rate at 15 min (ICGR15) value (14.95+12.71).Differences between the preoperative ICGR15 and the postoperative ICGR15 values were not significantly different (p=0.074). The 1-, 2- and 3-year survival rates were 98.7%, 88.8% and 76.4%, respectively. CONCLUSIONS: The results indicate that RFA is a minimally invasive treatment which provides a possible treatment modality for HCC patients with poor liver function and the efficacy is as well as the surgical treatment for HCC patients within the Milan criteria.

[Prognosis after hepatectomy for primary liver cancer of segment 7 or 8].

OBJECTIVE: To investigate the results of surgical treatment for primary liver cancer of segment VII or VIII. METHODS: The clinical data of 149 patients with primary liver cancer who underwent hepatectomy between January 2005 and December 2010 was retrospectively analyzed. There were 120 male and 29 female patients, aging from 19 to 75 years with a mean of 53.1 years. Among 149 patients, tumors were located at segment VII, VIII or several segments containing VII or VIII (VII/VIII group) in 53 patients, located at other segments (non-VII/VIII group) in 96 patients. The results of surgical treatment for VII/VIII group and non-VII/VIII group were compared by using t test, χ(2) test, Kaplan-Meier survival analysis and Cox proportion hazard regression analysis. RESULTS: Right liver lobe was turned over completely in VII/VIII group, hepatic lobe which tumor was located at was not or partly turned over in non-VII/VIII group. Compared with non-VII/VIII group, VII/VIII group had longer operative time ((215 ± 68) min vs. (123 ± 36) min, t = 2.860, P = 0.01). No significant difference was found for tumor size, tumor number, tumor encapsulation, microvascular invasion, Edmondson grade, pTNM stage, intraoperative blood loss, blood transfusion rate, R0 resection rate and postoperative complication rate between two groups. The cumulative 1-, 3-, and 5-year overall survival rates were 74.6%, 42.3%, 15.4% respectively, in VII/VIII group, and 89.3%, 63.0%, 40.4% respectively, in non-VII/VIII group (χ(2) = 13.501, P = 0.000). Univariate and multivariate analysis of prognostic factors indicated that tumor location (tumor was located at segment VII or VIII) had unfavorable prognostic influence on overall survival (χ(2) = 10.329, P = 0.001; HR = 1.693, 95%CI: 1.232 - 2.694, P = 0.013). CONCLUSION: The results of surgical treatment for primary liver cancer located at segment VII or VIII are worse than that located at other segments.

Effects of interferon treatment on development and progression of hepatocellular carcinoma in patients with chronic virus infection: a meta-analysis of randomized controlled trials.

Available literature on the effects of interferon (IFN) treatment on development and progression of hepatocellular carcinoma (HCC) in patients with chronic virus infection reports controversial results. The primary objective of this meta-analysis was to evaluate the effect of IFN on HCC risk in patients with chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection; IFN's efficacy on local tumor progression and survival of advanced HCC patients was also assessed. All randomized controlled trials (RCTs) comparing IFN with no antiviral treatment were selected. Finally, we identified 11 RCTs including 1,772 patients, who met our inclusion criteria to perform this meta-analysis. Our analysis results showed that IFN significantly decreased the overall HCC incidence in HCV-infected patients [relative risk (RR)=0.39; 95% confidence interval (CI)=0.26-0.59; p=0.000], subgroup analysis indicated that IFN decreased HCC incidence in HCV-related cirrhotic patients evidently (RR=0.44; 95% CI=0.28-0.68; p=0.000); but HCC incidence in nonresponders to initial antiviral therapy did not reduce by maintenance IFN therapy (RR=0.96; 95% CI=0.59-1.56; p=0.864). Analysis results also demonstrated that IFN did not significantly affect the overall rate of HCC in HBV-infected patients although there was a trend favoring IFN therapy (RR=0.23; 95% CI=0.05-1.04; p=0.056). Besides, IFN did not improve one-year overall survival of advanced HCC patients significantly (RR=1.61; 95% CI=0.96-2.69; p=0.072); however, a quantitative analysis on local tumor progression could not be performed owing to lack of unified definitions among trials included in our study. By this meta-analysis, we conclude that IFN therapy is effective in reducing overall HCC risk in chronic HCV-infected patients; using it in this subpopulation seems promising, but its administration in other subpopulations still requires further exploration.

Periostin: a putative mediator involved in tumour resistance to anti-angiogenic therapy?

Despite advances in the development of anti-angiogenic agents for cancer treatment, the increase in the survival duration of cancer patients is still rather modest. One major obstacle in anti-angiogenic therapy is the emergence of drug resistance. Understanding the molecular mechanisms that enable a tumour to evade anti-angiogenic treatment is valuable to improve therapeutic efficacy. Targeting blood supply usually causes hypoxic responses of tumours that trigger a series of adaptive changes leading to a resistant phenotype. Periostin, a secreted ECM (extracellular matrix) protein, is mainly produced by CAFs (cancer-associated fibroblasts) on hypoxic stress. As CAFs have been casually linked to tumour resistance to angiogenesis blockade and periostin can influence many aspects of tumour biology, we hypothesized that periostin might be a crucial mediator involved anti-angiogenic resistance in cancer treatment. This hypothesis is indirectly supported by the following facts: (a) high levels of periostin promote tumour angiogenesis; (b) periostin improves cancer cell survival under hypoxic conditions; and (c) genetic modulation of periostin induces EMT (epithelial-mesenchymal transition) and enhances cancer cell invasion and metastasis, which represents an escape mechanism from anticancer treatment. Testing and confirmation of this hypothesis will give more insight into the resistance mechanisms and provide the rationale for improvement of therapeutic outcome of anti-angiogenic therapy.

Protective effects of physiological doses of estrogen during hepatocarcinogenesis induced by diethylnitrosamine and N-nitrosomorpholine.

BACKGROUND/AIMS: Concern that much controversy exists with respect to the role of estrogen in hepatocarcinogenesis prompted us to examine the effect of estrogen, at physiological concentrations, on our established HCC rat model induced by diethylnitrosamine and N-nitrosomorpholine. METHODOLOGY: Female Sprague-Dawley rats were randomly divided into four groups (Group 1: Control, Group 2: Sham-operated, Group 3: Ovariectomy, Group 4: ovariectomy+estrogen) with treatment of a single i.p. injection of diethylnitrosamine (100mg/ kg body weight) followed by N-nitrosomorpholine (100ppm) in drinking water for 20 weeks for the established rat HCC model. Physiological estrogen was administered by 17α-Ethynylestradiol at a dose of 30µg/ kg body weight while rats in the sham-operated group were treated with saline after initiation of liver carcinogenesis. RESULTS: Treatment of ovariectomized animals with 17α-Ethynylestradiol (30µg/kg body weight/ day) resulted in a significant decrease in the initiation, development and metastasis of HCC and an increase in the survival time of animals dead before the termination of experiment as compared with rats treated with ovariectomy only (p<0.05); whereas this difference disappeared when compared with the other three groups. CONCLUSIONS: These findings show for the first time that estrogen, at physiological concentrations may reveal a protective role in hepatocarcinogenesis.

Can hepatocellular carcinoma be treated by Yondelis through targeting both tumor cells and tumor-associated macrophages?

BACKGROUND/AIMS: The initiation, progression, invasion and metastasis of hepatocellular carcinoma are closely associated with chronic inflammation caused by hepatitis virus infection, while tumor-associated macrophages are a major component of inflammatory infiltrates in intratumoral or peritumoral tissue of hepatocellular carcinoma. METHODOLOGY: Search MEDLINE, PUBMED databases, identify related articles and analyze related data. RESULTS: Evidence indicated that tumor-associated macrophages play an important role in disease progression, recurrence and survival of hepatocellular carcinoma patients. However, recent study showed that Yondelis (ecteinascidin-743) can suppress tumor growth through attacking tumor cells, macrophages and tumor-associated macrophages. CONCLUSIONS: Owing to the importance of tumor cells and tumor-associated macrophages in inflammatory microenvironment of hepatocellular carcinoma, treating hepatocellular carcinoma by Yondelis seems to be a promising therapeutic strategy but requires further study.