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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]

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 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]

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]

Purpose: To investigate the effects on sensitivity to fluoropyrimidine and endothelial cell (EC) migration by transfection with thymidine phosphorylase (TP) cDNA to a hepatocellular carcinoma (HCC) cell line SMMC-7721. Methods: SMMC-7721 was transfected with pcDNA3.1/zeo (+) with human TP cDNA. TP mRNA expression was determined by RT–PCR. Sensitivity to fluoropyrimidine was determined by 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide (MTT) assay. Induction of EC migration was detected by Boyden chamber assay. Results: The construction of pcDNA3.1/zeo(+)-TP was verified by digestion with restriction endonuclease Apa1. When comparison was made between SMMC-7721 cell clone transfected with pcDNA3.1/zeo(+)-TP (S-TP) and control clone transfected with pcDNA3.1/zeo(+) (S-vector), we found that TP mRNA expression level was much higher in S-TP, being 2.09±0.16 vs 0.48±0.06 in S-vector ( P<0.01), sensitivity to 5′-deoxy-5-fluorouridine (5′-dFUrd, a prodrug of 5-fluorouracil) in S-TP was significantly enhanced compared with that in S-vector (IC50; 56.81±9.85 μmol/l vs 162.25±11.03 μmol/l, P<0.01), and the culture medium of S-TP possessed more potential to induce EC migration than that of S-vector (the number of ECs appearing on the outer surfaces of the membrane was 275±29 vs 122±35 per field, P<0.01). Conclusion: Sensitivity to 5′-dFUrd could be enhanced by transfection with TP cDNA for SMMC-7721 cells. However, EC migration was also promoted at the same time. Therefore, transfection with TP alone might have no potential to enhance anti-tumoral effects of fluoropyrimidine in HCC. [ABSTRACT FROM AUTHOR]

Purpose. To investigate the antitumor effect of interferon-alpha 2a (IFN-α2a) combined with capecitabine on hepatocellular carcinoma (HCC) in nude mice in relation to thymidine phosphorylase (TP) expression. Methods. Thirty nude mice bearing orthotopic xenografts of a human HCC tumor (LCI-D20) were divided into control, capecitabine, IFN-α2a, and combination (capecitabine plus IFN-α2a) groups. Tumor growth was determined by measuring the tumor volume. An enzyme-linked immunosorbent assay (ELISA) was used to study the TP expression in the cancer tissues of the liver. Results. IFN-α2a enhanced the sensitivity of the LCI-D20 tumor response to capecitabine treatment. The tumor volume was significantly reduced in the capecitabine (455±236 mm3), IFN-α2a (248±114 mm3) or combination (46±29 mm3) treatment groups as compared to the control (1,033±146 mm3) (P<0.01). A significant difference was also found between the single treatment (capecitabine or interferon) and combination treatment group (P<0.01 and P<0.05, respectively). IFN-α2a up-regulated TP expression in LCI-D20 tumor. An approximate 1.5-fold increase in TP expression was observed in the mice which received IFN-α2a treatment compared to the control mice. Conclusion. IFN-α2a enhanced the antitumor effect of capecitabine on HCC in nude mice, which might be ascribed to the up-regulation of TP expression in liver cancer tissues by IFN-α2a. [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]

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]