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Purpose: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancers in adults, and microRNAs (miRNAs) differentially expressed in ccRCC tumors have been identified and proposed to predict prognosis. In the present study, we comprehensively analyzed the genome-wide miRNA expression profiles in ccRCC, with the aim to generate a tumor-specific miRNA signature of prognostic values. Methods: The miRNA profiles in tumor and the adjacent normal tissue were analyzed, and the association of the differentially expressed miRNAs with patient survival was examined with univariate Cox regression analysis. Finally, a tumor-specific miRNA signature was generated and examined with Kaplan-Meier survival, univariate, and multivariate Cox regression analyses. Results: A total of 147 miRNAs were found differentially expressed between tumor and matched non-tumor tissues from 58 ccRCC patients. The prognostic values of these differentially expressed miRNAs were subsequently analyzed in the 411 ccRCC patients, and 22 miRNAs were found significantly correlated with patient survival. Finally, a tumor-specific miRNA signature of 22 miRNAs was generated and validated as an independent prognostic parameter. Conclusions: A tumor-specific miRNA signature consisting of 22 miRNAs was identified and validated as an independent prognostic factor, which could serve as a novel biomarker for ccRCC prognostication and help in predicting treatment outcome. [ABSTRACT FROM AUTHOR]

Background: We aimed to develop a clinicopathological model that would predict the risk of bone metastasis (BM) in hepatocellular carcinoma (HCC). Methods: We first evaluated a training cohort of 201 HCC patients who had undergone hepatectomy and found that the following factors independently predicted BM development: vascular invasion, tumor-node-metastasis stage, CXCR4, connective tissue growth factor, and interleukin-11. These variables were used to construct a clinicopathological prediction model that may be scored from 0 to 19. The predictive value of the model was demonstrated in a validation cohort of 179 post-hepatectomy HCC patients. Results: During a median follow-up of 54.3 months for the training cohort and 52.5 months for the validation cohort, 23 patients (11.4%) in the former and 19 patients (10.6%) in the latter developed BM. A cutoff value of 9.4 best discriminated BM risk and was able to exclude future BM development with high accuracy in the validation cohort. The sensitivity and specificity of the method were 73.7 and 78.7%, respectively, the positive predictive value was 29.2%, and the negative predictive value 96.2%. The 1- and 2-year cumulative BM rates were (respectively) 10.8% and 27.4% in the high-risk group and 2.4 and 4.3% in the low-risk group. The hazard ratio for BM of the high- versus low-risk group was 9.240 (95% CI: 3.319-25.722). Conclusion: The simple prediction model constructed from clinicopathological parameters is accurate in predicting BM development in HCC patients. [ABSTRACT FROM AUTHOR]

Purpose: Metabolic syndrome and insulin resistance have been linked to increased risk of occurrence and mortality of hepatocellular carcinoma (HCC). Recently, retinol-binding protein 4 (RBP4) was clarified as a specific serological marker of insulin resistance. The aim of this study was to determine whether serum RBP4 could be used as a potential marker for predicting prognosis in patients with HCC after curative resection. Methods: Western immunoblotting and Enzyme-linked immunosorbent assay were used to measure the RBP4 expression in cell lines, supernatant, and serum. Serum RBP4 levels were compared with clinicopathological features and outcomes of patients with HCC. Furthermore, we investigated the impact of serum RBP4 level, serum C-peptide level, and HOMA-IR on overall survival (OS) and disease-free survival (DFS) of patients with HCC in the training cohort (156 patients with HCC), and then were validated in the validation cohort (105 patients with HCC). Results: RBP4 protein overexpressed in HCC cell lines compared with normal liver cell line ( P < 0.001) and correlated with metastatic potential. Serum RBP4 levels were associated with OS [hazard ratio (HR) = 2.208, P < 0.001] and DFS (HR = 1.878, P = 0.029) of patients with HCC. By multivariate analysis, the serum RBP4 level was identified as an independent factor for OS (HR = 2.170, P = 0.004) and DFS (HR = 1.769, P = 0.037) of patients with HCC. The prognostic value of serum RBP4 level was confirmed in the validation cohort. Conclusions: The serum RBP4 level is potential to be a useful prognostic factor for HCC after curative resection. [ABSTRACT FROM AUTHOR]

To clarify clinicopathologic differences between patients with intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC), and identify potential factors influencing survival after hepatectomy for ICC. Comparison of clinicopathologic data was made between patients who underwent hepatectomy for ICC ( n = 272) and HCC ( n = 5,829) during the same period. Twenty-five clinicopathologic variables were selected for univariate and multivariate analyses to evaluate their influence on prognosis of ICC. Compared with patients with HCC, ICC patients were more common in females and more elderly, had a lower proportion of asymptomatic tumors, lower serum alpha-fetoprotein, higher serum carcinoembryonic antigen, carbohydrate antigen 19–9 and alkaline phosphatase levels; lower incidence of hepatitis history, associated cirrhosis and serum hepatitis B surface antigen; lower proportion of small tumors, well-encapsulated tumors and tumor emboli in the portal vein; higher proportion of single tumor, perihila lymph node involvement and poor differentiation; and less frequency of limited resection (all, P < 0.0001). Distant metastasis was less frequent in patients with ICC ( P = 0.027). A total of 5-years overall and disease-free survival (in brackets) after resection was 26.4% (13.1%) and 44.5% (33.1%) ( P < 0.0001, P < 0.0001) for patients with ICC and HCC, respectively. Factors influencing survival after resection of ICC can be divided mainly into two categories: early detection of asymptomatic ICC ( P < 0.0001) and curative resection ( P = 0.002). ICC Patients have distinct clinicopathologic features as compared with HCC patients. Surgery remains the only effective treatment for ICC. Early detection of asymptomatic ICC and curative resection were the key to achieve optimal survival. [ABSTRACT FROM AUTHOR]

We aimed to evaluate the prognostic value of preoperative plasma osteopontin (OPN) levels in 101 patients with hepatocellular carcinoma (HCC) who underwent liver resection. Plasma OPN levels were detected by ELISA. The association of plasma OPN levels of patients with clinicopathological characteristics, tumor recurrence, and survival was analyzed. The median plasma OPN level of patients was 176.90 ng/ml (range 13.73–780.00 ng/ml), which was significantly higher than that of 24 healthy volunteers (63.74 ng/ml, range 12.20–122.32 ng/ml). Plasma OPN levels were significantly different in patients with different numbers of tumor nodules (168.18 and 217.11 ng/ml for single and multiple nodules, respectively; P = 0.002), different Edmondson’s grades (201.24, 168.36, and 503.58 ng/ml for grades I, II, and III/IV, respectively; P = 0.015), and different TNM stages (168.16, 167.54, and 216.18 ng/ml for stages I, II, and III/IV, respectively; P = 0.016). Significantly higher plasma OPN levels were found in patients with a recurrence of HCC after resection, compared with those without recurrence (213.55 versus 153.70 ng/ml; P = 0.0013). A higher plasma OPN level was a leading independent prognostic factor for both overall survival (OS) and disease-free survival (DFS) in univariate and multivariate Cox models. This suggests that the preoperative plasma OPN level can be used as a predictive marker for HCC recurrence and may be helpful to assess the prognosis of patients with HCC after surgery. [ABSTRACT FROM AUTHOR]

Purpose: We demonstrated that chromosome 8p deletion is associated with metastasis of human hepatocellular carcinoma (HCC). This study assesses the value of circulating plasma DNA level and its allelic imbalance (AI) on chromosome 8p in the prediction of HCC prognosis. Methods: Blood samples were collected from 79 patients with HCC before operation, 20 patients with liver cirrhosis, and 20 healthy volunteers. The HCC and adjacent non-tumor liver tissues were obtained from surgical specimens. Plasma DNA was extracted and quantified. Two microsatellite markers on chromosome 8p, D8S258 and D8S264, were selected and used in the AI analysis. Results: The circulating plasma DNA level was found to closely associate with tumor size ( P=0.008) and TNM stage ( P=0.040), negatively associate with the 3-year disease-free survival (DFS) ( P=0.017) and overall survival (OS) ( P=0.001). AI at D8S258 in plasma DNA was significantly correlated with tumor differentiation ( P=0.050), TNM stage ( P=0.010), and vascular invasion ( P=0.023), negatively correlated with the 3-year DFS ( P=0.005) and OS ( P=0.036). However, AI at D8S264 was only closely associated with 3-year DFS ( P=0.014). Combined detection of AI at D8S258 and circulating plasma DNA level was independently associated with DFS ( P=0.018) and OS ( P=0.002) of patients with HCC. For patients with both AI at D8S258 and a higher level of plasma DNA, the 3-year DFS and 3-year OS rates were decreased remarkably ( P=0.014 and 0.044). Conclusion: Combination of circulating plasma DNA level and AI at D8S258 might be an independent predictor for prognosis of HCC patients. [ABSTRACT FROM AUTHOR]

Aim: To elucidate the relationship between local immunocompetent cells and prognosis of human hepatocellular carcinoma (HCC) after resection. Methods: HE staining and immunohistochemical study were carried out on specimens from patients underwent surgical resection. Local immunocompetent cells, such as dendritic cells (DCs), memory T cells, CD3+ T lymphocytes and CD8+ T lymphocytes, were counted and their relationships with tumor-free survival rate were analyzed by grouping DCs with the T lymphocytes retrospectively. Results: The number grade of infiltrating immunocompetent cells in HCC nodules and pericancerous tissues under HE staining had no significant correlation with tumor-free survival time ( P=0.054, 0.071, respectively). DCs were mainly among tumor cells, encircling tumor cells with their pseudopodia and were in contact with T lymphocytes. A certain number of DCs in HCC nodules (≥25/10HPF) statistically correlated to tumor-free survival time ( P=0.005), while a certain number of DCs in pericancerous tissues (≥28/10HPF) had no correlation with tumor-free survival time ( P=0.329). The number of memory T cells, CD3+ T lymphocytes and CD8+ T lymphocytes in HCC nodules strongly correlated to tumor-free survival time ( P=0.003, 0.005, 0.037, respectively). The tumor-free survival rate curves revealed that the more DCs or together with memory T cells/CD3+ T lymphocytes or that the more CD8+ T lymphocytes were detected in HCC nodules, the better the prognosis would be. Conclusions: Marked infiltration of DCs in HCC nodules was closely related to the prognosis of HCC after surgical resection and can be served as a predictive index for recurrence and metastasis of HCC. [ABSTRACT FROM AUTHOR]

Purpose: Second resection has been proved to be a safe and effective treatment for patients with intrahepatic recurrent HCC after primary resection; however, preoperative prognostic factors for outcome following second resection in patients with a hepatitis B virus (HBV) infection background remains to be clarified. Methods: Fifty-seven patients with intrahepatic recurrent an HCC and HBV infection background received second resection from 1997 to 2003 in our institute. All of them were negative for anti-hepatitis C virus (HCV) and positive regarding HBV profile. Patient and tumor factors were analyzed. Results: At the time of preparing this paper, 31 had re-recurrence and 21 patients had died. No postoperative mortality was noted. The 1-, 3-, and 5-year overall survival after second resection were 69.9%, 61.2%, and 30.6%, respectively. Univariate and multivariate analysis showed that vascular invasion and time to recurrence were the independent prognostic factors for overall survival following second resection. The 3- and 4-year overall survival after second resection were 57.7% and 46.6% in patients with the presence of any of two risk factors (n=46), and 100% and 100% in those with absence of both risk factors (n = 11, P = 0.008). Conclusions: Vascular invasion and time to recurrence were the prognostic factors for overall survival following second resection of intrahepatic recurrent HCC. [ABSTRACT FROM AUTHOR]

Purpose. Large primary liver cancer (PLC) more than 10 cm in diameter is not infrequently encountered in clinical practice. This study evaluated the clinicopathological features and long-term results after surgery for large PLC. Methods. Comparison of clinicopathological data between patients with PLC ≥10 cm (n=1,227) and PLC <10 cm (n=2,349) during the same period. Results. In comparison with patients with PLC <10 cm, patients with PLC ≥10 cm were significantly younger (P<0.01), had a lower incidence of asymptomatic tumors (9.1% vs 39.5%, P<0.001), higher α-fetoprotein levels ( >400 ng/ml, 78.3% vs 49.2%, P<0.001), higher γ-glutamyl transpeptidase levels ( >6U, 87.7% vs 70.5%, P<0.001), a lower incidence of a history of hepatitis (45.0% vs 61.4%, P<0.001) and associated macronodular cirrhosis (cirrhotic nodules ≥0.3 cm, 59.8% vs 66.6%, P<0.001), poor differentiation of tumor cells (Edmondson grade 3–4, 24.3% vs 19.7%, P<0.01), a lower percentage of single nodule tumors (59.9% vs 75.4%, P<0.001) and well-encapsulated tumors (28.5% vs 62.1%, P<0.001), a higher proportion of tumor emboli in the portal vein (20.5% vs 9.0%, P<0.001), a lower resection rate (50.6% vs 86.8%, P<0.001), a lower curative resection rate (54.8% vs 78.3%, P<0.001), a higher operative mortality rate (4.5% vs 2.3%, P<0.001), and less local resection (52.5% vs 80.2%, P<0.001). The 5- and 10-year survival rates after resection were 26.2% and 17.5%, respectively, for patients with PLC ≥10 cm (n=621), and 54.3% and 39.5%, respectively, for patients with PLC <10 cm (n=2039) (P<0.01). Conclusions. Large PLC had specific clinicopathological features. Surgery is the first choice of treatment. In selected patients, resection is safe and offers the chance of long-term survival. Large PLC does not exclude the possibility of cure. [ABSTRACT FROM AUTHOR]

Purpose: To elucidate the relationship between angiogenesis and prognosis after curative resection of hepatocellular carcinoma (HCC). Methods: An immunohistochemical study using anti-CD34 monoclonal antibody was carried out on surgical specimens from 78 HCC patients who had undergone curative resection; microvessel density (MVD) was counted and the overall survival and disease-free survival were analyzed retrospectively. Results: Blood vessels in the tumor were strongly stained by anti-CD34 antibody, but not those in the surrounding liver parenchyma. There were three types of tumor vessels: capillary-like ( n = 59), sinusoid-like ( n = 16) and mixed-type ( n = 3). The median MVD count was 100 per field. The HCC were designated as hypovascular ( n = 36) with an MVD count below 100, and hypervascular ( n = 42) with an MVD count of 100 or more per field. The 5-year survival and disease-free survival rates were 49.7% and 42.8% respectively, and statistical analysis showed that the MVD level was not correlated with tumor size, capsule status, Edmondson's grade, α-fetoprotein level, associated cirrhosis, γ-glutamyltransferase, and serum HBsAg status. The sinusoid-like tumor vessels appeared more frequently in the more differentiated tumors ( P < 0.05). No statistical difference in overall and disease-free survival between different MVD levels and microvessel types was found. Tumor size was the only predicting factor in the entire series. In patients with small HCC (≤ 5 cm, n = 40), 5-year survival and disease-free survival rates were 58.9% and 52.7% respectively, higher than the values in large HCC (39.8% and 32.0% respectively, P < 0.05). The MVD level was an independent predicting factor of disease-free survival, 5-year disease-free survival in the hypovascular group (74.6%) being better than that in the hypervascular group (34.7%, P < 0.05). Conclusions: The MVD level was not related to tumor size, capsule statuo, Edmondson's grade, α-fetoprotein level, associated cirrhosis, γ-glutamyltransferase and serum HBsAg status. In the entire series, tumor size was the only factor influencing survival after curative resection. However, in patients with small HCC, the MVD level was an independent factor of disease-free survival. The pathological and clinical implications of different types of tumor vessels in HCC remain to be studied. [ABSTRACT FROM AUTHOR]

During 1958-1993, 2030 patients with pathologically proven primary liver cancer (PLC) were retrospectively reviewed. Comparison between small PLC (<-5 cm, n=514) and large PLC (>5 cm, n=1516) revealed that small PLC had a higher resection rate (92.4% versus 49.1%), lower operative mortality (1.7% versus 5.2%), a higher percentage of single tumour nodules (78.0% versus 53.4%), a higher percentage of well encapsulated tumour (74.5% versus 35.8%) and higher survival rates after resection (5-year, 63.8% versus 36.6%; 10-year, 46.8% versus 28.5%). No significant difference was found between survival following limited resection ( n=440) and lobectomy ( n=34) in patients with small PLC. Re-resection of any subclinical recurrence or solitary pulmonary metastasis after small PLC resection was done in 70 cases. These results indicate that resection is still the modality of choice for treatment of small PLC; limited resection instead of lobectomy was the key to increasing resectability and decreasing operative mortality; re-resection of subclinical recurrence was important to prolong survival further. [ABSTRACT FROM AUTHOR]