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The optimum strategy, hepatic resection (HR) or liver transplantation (LT), for treatment of early hepatocellular carcinoma (HCC) associated with liver diseases of Child–Pugh A is far from established. The aim of this study was to compare and determine which strategy is optimal for HCC fulfilling the Milan criteria. Consecutive data were collected in 1,018 HCC patients treated with HR and 89 HCC patients listed for LT (1 drop out for HCC progression) between January of 2003 and December of 2007. The independent prognostic factors identified by multivariate analysis were tumor size-plus-number, microscopic venous invasion, and operation type (LT or HR). When tumor size-plus-number was ≤4 or microscopic venous invasion was absent, there was no significant difference in overall survival (OS) between the LT and HR group. When tumor size-plus-number was >4 or microscopic venous invasion was present, OS was higher in the LT group. Since the pathological microscopic venous invasion was not easily available before operation which is limitation for widespread clinical use, thus in practice, we concluded that, for early HCC associated with Child–Pugh A cirrhosis, when tumor size-plus-number is >4, LT provides the best cure; when it is ≤4, HR remains the initial treatment of choice. [ABSTRACT FROM AUTHOR]

To evaluate current selection criteria for patients undergoing liver transplantation (LT) in response to hepatocellular carcinoma (HCC), and to analyze the prognostic factors for successful transplantation. We evaluated the outcome of 1,078 consecutive patients with HCC from the Shanghai Multi-Center Collaborative LT Group who underwent LT over a 6-year period. Clinicopathologic data for these patients were evaluated. The prognostic significance was assessed using Kaplan–Meier survival estimates and log-rank tests. Multivariate study with Cox’s proportional hazard model was used to evaluate the prognosis-relative aspects. We determined that expansion of Milan criteria to include: a solitary lesion ≤9 cm in diameter, no more than three lesions with the largest ≤5 cm, a total tumor diameter ≤9 cm without macrovascular invasion, lymph node invasion and extrahepatic metastasis (referred to as the “Shanghai criteria”), resulted in overall survival (OS) and disease-free survival (DFS) rates that were similar to the Milan criteria. Multivariate analysis using the Cox proportional hazards regression model showed that the Child-Pugh-Turcotte classification ( P = 0.010, 0.000), tumor differentiation ( P = 0.001, 0.000), tumor size ( P = 0.000, 0.000) and number ( P = 0.014, 0.016), macrovascular invasion ( P = 0.022, 0.000) and alpha-fetoprotein (AFP) levels ( P = 0.031, 0.003) were independent predictors of OS and DFS, while post-LT chemotherapy (OS, P = 0.000) and tumor encapsulation (DFS, P = 0.038) were independent predictors of OS or DFS. Shanghai criteria expanded the current criteria while maintaining similar survival. [ABSTRACT FROM AUTHOR]

To clarify the clinicopathologic features of patients surviving ≥20 years after resection for hepatocellular carcinoma (HCC). Between 1961 and 1987, a total of 396 patients underwent hepatic resection for HCC; 53 (13.4%) patients survived ≥20 years, and 343 (86.6%) patients survived <20 years. A comparative study between the two groups was made. By March of 2007, 67.6% (36/53) patients are still alive, disease free; 5.7% (3/53) patients died of tumor recurrence or metastasis; 11.3% (6/53) patients died of liver failure; 5.7% (5/53) patients were lost during follow-up. The longest patient survived 43 years and 2 months. Five young patients got married after resection and have had babies. One patient with a tumor measuring 17 × 13 × 9 cm (largest tumor in this series) survived for 37 years after resection, still alive, free of disease. Reresection for recurrence was done in nine patients, mean survival being 26 years and 11 months. Reresection for solitary pulmonary metastasis was carried out in three patients, mean survival being 29 years and 2 months. In comparison with patients surviving <20 years, patients surviving ≥20 years were significantly younger ( P = 0.031), had a higher incidence of asymptomatic tumors (56.6 vs. 34.4%, P = 0.002); lower γ-glutamyl transpeptidase level (≤50 U/L, 64.2 vs. 25.9%, P < 0.000), lower proportion of liver cirrhosis (66.0 vs. 83.6%, P = 0.002); higher percentage of small tumors (≤5 cm, 62.3 vs. 29.9%, P < 0.000), single nodule tumors (90.6 vs. 62.9%, P < 0.000), and well-encapsulated tumors (86.8 vs. 43.6%, P < 0.000); lower proportion of tumor emboli in the portal vein (3.8 vs. 22.5%, P = 0.002), better differentiation of tumor cells (Edmondson grade I, 21.6 vs. 9.1%, P = 0.036), and higher curative resection rate (100 vs. 64.1%, P < 0.000). Early detection and curative resection are the principal factors improving long-term survival. Long-term follow-up after resection of HCC is very important, and should continue for the remainder of the patient’s life. Reresection for recurrence and metastasis is important approach to improve prognosis. [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]

The ratio of serum gamma-glutamyl transferase (GGT) to alanine aminotransferase (ALT) is a parameter for assessing responses to antiviral therapies. The relationship between the prognosis of hepatitis B-associated hepatocellular carcinoma (HCC) and preoperative GGT/ALT is studied in hepatectomized Child-Pugh A patients. Two hundred and nineteen patients with hepatitis B virus-related HCC were included. Serum ALT and GGT levels were examined preoperatively and the GGT/ALT ratios were calculated. Their prognostic capabilities were evaluated by Cox-regression model. As dichotomized variables, GGT and ALT were distributed unequally ( P < 0.001). Most patients had high levels of GGT ( n = 110) but low levels of ALT ( n = 185). ALT displayed no relation to recurrence or survival, while GGT was independently associated with survival ( P = 0.002). The GGT/ALT ratio could predict survival precisely either in a continuous or dichotomized fashion ( P < 0.001 and 0.001, respectively), and also related to recurrence when dichotomized ( P = 0.002). Additionally, high GGT/ALT ratio was associated with high early recurrence rates, more recurrence-related deaths and various aggressive tumor characteristics such as larger tumor size, vascular invasion, poor encapsulation and advanced BCLC stage. In further stratified analyses, this ratio could discriminate the outcomes of patients with high- or low-α-fetoprotein level. The elevated GGT/ALT ratio was a promising predictor for poor prognosis of Child-Pugh A HCC patients after operation mainly through its tight relevance to the primary tumor burden. [ABSTRACT FROM AUTHOR]

Immunosuppressive therapy after liver transplantation for hepatocellular carcinoma (HCC) is one of the major contributory factors for HCC recurrence and metastasis. Sirolimus, a potent immunosuppressant, has been reported to be an effective inhibitor in a variety of tumors. The present study is designed to explore whether sirolimus could block the growth and metastatic progression of HCC. MHCC97H cells were used as targets to explore the effect of sirolimus on cell cycle progression, apoptosis, proliferation, and its antiangiogenic mechanism. LCI-D20, a highly metastatic model of human HCC in nude mice, was also used as the model tumor to explore the effect of sirolimus on tumor growth and metastatic progression. In vitro, sirolimus induced cell cycle arrest at the G1 checkpoint and blocked proliferation of MHCC97H cells but did not induce apoptosis. In vivo, sirolimus prevented tumor growth and metastatic progression in LCI-D20. Intratumoral microvessel density and circulating levels of VEGF in tumor-bearing mice were also significantly reduced in sirolimus treatment group. Quantitative RT-PCR showed that sirolimus down-regulated the mRNA expression of VEGF and HIF-1a, but not of bFGF, and TGF-b in MHCC97H cells. Furthermore, western blot analysis confirmed that sirolimus also decreased expression of HIF-1a at protein level, in parallel with the down-regulation of the levels of VEGF protein excretion in a time-dependent manner as compared to untreated control cells following anoxia. The immunosuppressive macrolide sirolimus prevents the growth and metastatic progression of HCC, and suppresses VEGF synthesis and secretion by downregulating HIF-1a expression. Sirolimus may be useful for clinical application in patients who received a liver transplant for HCC. [ABSTRACT FROM AUTHOR]

To evaluate the prognostic value of tumor-associated macrophages (TAM), individually or synergistically with CD45RO + memory T cells (TM), in hepatocellular carcinoma (HCC) patients following resection. The infiltration of TAM and TM was assessed by immunohistochemistry in tissue microarray containing 302 HCC specimens. Correlations between TAM/TM infiltration and clinicopathologic features, disease-free survival (DFS) and overall survival (OS) were statistically analyzed. High TAM infiltration was associated with both improved DFS ( P = 0.0021) and OS ( P = 0.0481). Multivariate analysis identified TAM infiltration as independent prognostic factor for DFS ( P = 0.004) and OS ( P = 0.049). A second analysis clarified the synergistic effect of TAM&TM infiltration for DFS ( P = 0.004) and OS ( P = 0.040). Both TAM infiltration alone and concomitant infiltration of TAM&TM are associated with improved DFS/OS, suggesting that TAM could protect HCC patients from recurrence/metastasis and prolong survival by distinct mechanisms. [ABSTRACT FROM AUTHOR]

To identify the side population (SP) cells from four hepatocellular carcinoma (HCC) cell lines with stepwise metastatic potentials. SP cells were sorted from HCCLM3, MHCC97-H, MHCC97-L and Hep3B by flow cytometry, and then analyzed by differentiation study, clonogenic assay, chemoresistance study and tumorigenicity assay in vivo. The expression of ABCG2 in SP cells was detected by immunocytochemistry, western blotting and real-time quantitative PCR, respectively. There was significant difference in SP proportion among HCCLM3, MHCC97-H, MHCC97-L and Hep3B (28.7 ± 1.6%, 14.5 ± 0.6%, 4.2 ± 0.4%, 0.9 ± 0.1%, respectively, P < 0.01). All the SP cells showed similar characteristics of self-renewal, high clonogenicity, remarkable chemo-resistance and high expression of ABCG2. As low as 2,000 SP cells could initiate tumors in non-obese diabetic/severe combined immunodeficiency mice successfully. SP cells purified from HCC cell lines harbors cancer stem cell-like properties, and may be related to the metastatic potentials and therapeutic-resistance of HCC. [ABSTRACT FROM AUTHOR]

To investigate the most suitable housekeeping genes for quantifying a change in mRNA expression levels due to hepatitis virus B related hepatocellular carcinoma (HCC). Expression of mRNA encoding ACTB, GAPDH, B2M, HPRT and TBP was measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in matched malignant and non-malignant tissues obtained from 65 non-treated HCCs. The software programs geNorm and NormFinder were used to ascertain the most suitable reference gene combination. All candidate genes showed significantly different expression between malignant and non-malignant samples. GAPDH and ACTB, genes most frequently used for normalization, were heavily regulated during HCC carcinogenesis and progression. B2M expression levels varied with hepatitis infection status. The combination of HPRT and TBP expression levels were the most stable, regardless of differences in tumor stage and cirrhotic and malignancy status. It is necessary to select reference genes based on tissue and disease specific expression profile and to further identify novel reference genes with greater expression stability for use in HBV related HCC gene expression studies. [ABSTRACT FROM AUTHOR]

Proteomic study was used to clarify the mechanism of hepatocellular carcinoma (HCC) immune escape concerning Dendritic cells (DCs’) dysfunction and their association with HCC invasion. Human peripheral blood mononuclear cells (PBMCs) derived DCs from healthy donors were pulsed with soluble cell lysates prepared from different metastatic potential human HCC cell lines. The total protein of these DCs was analyzed by two-dimensional electrophoresis and Electro-Spray Mass Spectrometry. The allostimulatoy capacity and phenotype of these DCs were also evaluated. The clinical significance of β-centractin, one of the largest quantitative changed spot, down-regulation in DCs was further evaluated in autologous PBMCs derived DCs pulsed with auto-tumor lysates in 26 HCC patients. The expression of β-centractin was found to be considerably lower either in DCs pulsed with HCCLM6 (high metastatic potential HCC cell line) lysates, accompanied by down-regulation of CD86 molecule and impaired allostimulatory capacity, than those of DCs pulsed with lysates from HCC cell lines with low or without metastatic potential or in DCs pulsed with lysates from HCC with invasiveness than those without invasiveness. The down-regulation of β-centractin in DCs pulsed with high metastatic potential HCC lysates might associate with DCs dysfunction and HCC invasiveness. [ABSTRACT FROM AUTHOR]

Background/Aims: Recurrence after resection of hepatocellular carcinoma (HCC) is a frequent event. This study evaluated the effect of postoperative interferon α (IFN α) treatment on recurrence and survival in patients with hepatitis B virus (HBV)-related HCC. Method: Two hundred and thirty six patients were randomized after resection into IFN α treatment (5 mu i.m. tiw for 18 months) and control groups. Treatment was terminated if recurrence was diagnosed, and recurrence was managed the same way in both groups. Statistical analysis was based on the method of intent-to-treat. Results: The two groups were comparable in all clinicopathological parameters. The median overall survival was 63.8 months in the treatment group and 38.8 months in the control group ( P=0.0003); the median disease-free survival period was 31.2 versus 17.7 months ( P=0.142). Fever, leucocytopenia, and thrombocytopenia were adverse effects in the treatment group, but were mostly manageable. Conclusions: IFN α treatment improved the overall survival of patients with HBV-related HCC after curative resection, probably by postponing recurrence. [ABSTRACT FROM AUTHOR]

Dendritic cells (DC) are specialized antigen-presenting cells with powerful immunostimulatory properties. Their use for induction of anti-tumor immunity has been limited by several factors, including identification of appropriate tumor-associated antigens, delivery of antigens to DC, and maintaining DC in a highly activated state. Here, DC propagated in vitro were transduced with an adenoviral (Ad) vector to express hepatitis B surface antigen (HBsAg), an antigen present in hepatocellular carcinoma (HCC). Many patients with HCC demonstrate evidence of prior HBV exposure, suggesting that the presence of the virus in a quiescent state may promote tumorigenesis. Ad-HBsAg-transduced DC stimulated strong cytotoxic T lymphocyte (CTL) responses to HBsAg-expressing tumor cells, and protected mice from lethal tumor challenge. Immunity was antigen-specific, as wild-type tumor (HBsAg -) grew normally. Furthermore, DC transduced with an irrelevant vector had no effect. Vaccination with HBsAg protein, a clinically utilized preparation that confers immunity to HBV infection, did not protect against tumor challenge even though it induced a strong antibody response. These studies describe for the first time the contributions of humoral and cellular immune responses to tumor immunity induced by Ad-transduced DC compared to protein vaccination. [ABSTRACT FROM AUTHOR]

Metastasis remains one of the major challenges before hepatocellular carcinoma (HCC) is finally conquered. This paper summarized a decade's studies on HCC metastasis at the Liver Cancer Institute of Fudan University. We have established a stepwise metastatic human HCC model system, which included a metastatic HCC model in nude mice (LCI-D20), a HCC cell line with high metastatic potential (MHCC97), a relatively low metastatic potential cell clone (MHCC97L) and several stepwise high metastatic potential cell clones (MHCC97H, HCCLM3, and HCCLM6) from their parent MHCC97 cell. Endeavors have been made for searching human HCC metastasis-related chromosomes/ proteins/genes. Monogene-based studies revealed that HCC invasion/metastasis was similar to that of other solid tumors, and the biological characteristics of small HCC were only slightly better than that of large HCC. Using comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), genotyping, cDNA microarray, and 2-dimensional gel electrophoresis, we obtained some interesting results. In particular, in collaboration with the National Institute of Health (NIH) in the United States, we generated a molecular signature that can classify metastatic HCC patients, identified osteopontin as a lead gene in the signature, and found that genes favoring metastasis progression were initiated in the primary tumors. We also found that chromosome 8p deletion, particularly in the region of 8p23, was associated with HCC metastasis. Cytokeratin 19 was identified as one of the proteins, which was found in MHCC97H, but not in MHCC97L cells. Experimental interventions using the high metastatic nude mice model have provided clues for the prevention of HCC metastasis. Translation from workbench to bedside demonstrated that serum VEGF, microvessel density, and p53 scoring may be of value for the prediction of postoperative metastatic recurrence. Interferon alpha proved effective for the prevention of recurrence both experimentally and clinically. In conclusion, HCC metastasis that probably initiated in the primary tumor is a multigene-involved, multistep, and changing process. The further elucidation of the mechanism underlying HCC metastasis will provide a more solid basis for the prediction and prevention of the metastatic recurrence of HCC. [ABSTRACT FROM AUTHOR]