Chemotherapy remains the main treatment for many cancer patients. However, P-glycoprotein (P-gp) mediated multidrug resistance poses severe challenges to current chemotherapies. As ideal vectors to overcome drug resistance, nanovehicles are extensively explored for cancer treatment by diverting P-gp mediated drug efflux mechanisms. Surface engineering of nanocarriers has attracted great attention for targeted therapeutic delivery. The folate receptors, one of the most researched targets in cancer therapeutics, are over-expressed in several carcinomas. And folate has become one of the most investigated ligands in cancer therapeutic direction due to its small size, easy conjugation to nanocarriers, nontoxic, nonimmunogenic nature, and well stability in storage or in circulation. This review discussed the current status of folate functionalized nanoparticles in diverting P-gp mediated drug efflux mechanisms.

Sorafenib is a novel oral multikinase inhibitor that inhibits Raf kinase because of its anti-proliferative property. Sorafenib also inhibits receptor tyrosine kinases of multiple proangiogenic factors, such as VEGFR-1/2/3 and PDGFR-β. The combina-tion of both its anti-proliferative and anti-angiogenic properties makes sorafenib an attractive agent in cancer treatment. To date, sorafenib is the only approved systemic treatment for patients with hepatocellular carcinoma. The most common adverse events of this inhibitor included hand-foot skin reactions, nausea, diarrhea, weight loss, and hypertension. These adverse events can severely affect patient compliance, which may negate the effect of therapy. Correct understanding and treatment of these adverse events can improve clinical outcome. This paper discusses the clinical aspect of sorafenib-induced adverse events and the molecular basis behind their toxic-ity. Recommendations for the management of the adverse effects are also provided.

Objective To study severe or rare complications following radiofrequency ablation (RFA) for liver cancer. Methods Clinical records of severe or rare complications following RFA in 272 cases of liver cancer from January 2002 to December 2004 were retrospectively studied. Results A total of 301 RFA procedures were performed in the 272 cases. The incidence of severe or rare complications was 3.32% (10/301), and the death rate was 0.66% (2/301). Complications included 1 case of intraperitoneal hemorrhage, 2 cases of infection (1 case of peritonitis with sepsis and 1 case of liver Abscess superimposed upon bilioma), 3 cases of upper gastrointestinal bleeding (including 1 case of hemobilia), 1 case of hepatic arteriovenous fistula, 1 case of hemo-pneumothorax, 1 case of esophagopleural fistula and 1 case of needle-tract implantation of tumor. Conclusions In order of frequency,severe complications following RFA are upper gastrointestinal bleeding,infection and intraperitoneal hemorrhage.

Objective To assess clinicopathological features and prognosis of patients with combined hepatocellular and cholangiocarcinoma (cHCC-CC). Methods Clinicopathological and follow-up data of 115 cHCC-CC patients confirmed pathologically in Liver Cancer Institute of Fudan University from 1995 to 2007 were analyzed. Kaplan-Meier method was used to calculate 1-,3- and 5-year survival rates and tumor-free survival rates. Survival curves were analyzed using the log-rank test. The factors that impacted the prognosis of cHCC-CC were estimated. Results In 115 cases, one was Allen's type A, one was Allen's type B, and the other 113 were Allen's type C. Being with male in predominance, most of the cHCC-CC patients had liver cirrhosis background. They presented with elevated AFP or CA19-9, vascular invasion, resembling hepatocellular carcinoma(HCC)as well as lymph nodes metastasis. One-, 3-, 5-year survival rates of 115 patients were 68. 1%, 38. 1% and 33.6%, respectively, with median survival time of 13.0 months. Whereas the 1-, 3-, 5-year survival rates in radical resected patients were 78.4 % ,44.4 % and 44.4 % ,respectively, with median survival time of 16.0 months. Tumor free survival time at 1-, 3- and 5-year was 57.8 %, 12.6 % and 0.0 %,respectively,with median recurrent time of 10.0 months. One-, 3-, 5-year survival rates of 10 nonsurgical patients were 10/10,10/10 and 0/10,respectively, with median survival time of 5.3 months.TNM stage was independent factor for prognosis of the patients after resection. Whereas the lymph nodes involvement was independent factor for the tumor free survival time of radical resected patients.Conclusions Although clinicopathological characteristics of cHCC-CC are more similar to those of HCC, the prognosis of cHCC-CC is more unfavorable than that of HCC. TNM stage is an independent determinant of long time outcome for patients after resection.

Objective To investigate the effects of hypoxia on malignant phenotype of a hepatocellular carcinoma(HCC)cell line and its molecular basis.Methods Human HCC cell line with highly metastatic potential(MHCC97H)was grown under hypoxia(induced by 100 μmol/L CoCl_2)and normoxic conditions respectively.To observe the effects of hypoxia on MHCC97H cells was observed,the tumorigenicity was carried out by soft agar cloning method in vitro and inoculation in nude mice in vivo;Invasive and metastatic potential were measured.Experiments with and/or without Matrigel in vitro and a metastatic human HCC orthotopic nude mice model by HAL in vivo.To clarify the molecular background,the proliferation of cells were analyzed by MTT assay and the cell cycle was detected by flow cytometry;The expression of embryonic stem cell(ES)-like genes(Oct4,Nanog and Sox2)were detected by real-time RT-PCR;CD90~+ and CD133~+ subpopulation from MHCC97H cells were isolated by flow cytometry and the expressions of CD90 and CD133 of MHCC97H cells were analyzed by immunofluorescence.Results Hypoxia increased tumor migration(t=2.792,P=0.023),invasiveness(t=7.624,P＜0.0001)and clone forming ability(t=3.292,P=0.011)of MHCC97H cells in vitro,and promoted tumorigenesis(x~2=8.571,P=0.015)and pulmonary metastasis(x~2=5.507,P=0.031)in vivo.The proliferation of MHCC97H cells arrest under hypoxic conditions accompanied with increased proportion of cells in G1 phase,the expressions of Oct4,Nanog,Sox2 significantly increased in response to hypoxia,but the fluorescence intensity and number of CD90~+ and CD133~+ MHCC97H cells decreased or unchanged.Conclusion Hypoxia increases aggressiveness of MHCC97H cells,which was correlated with the acquisition of embryonic stem cell-like characteristics.

Objective To investigate the selective oncolytic role and antitumor action of a novel recombinant adenovirus containing E1A and IL-24 on hepatocellular carcinoma cell(HCC). Methods The recombinant adenovirus expressing IL-24 (Ad. HS4. AFP. E1A/IL-24) was constructed by using modified human alpha-fetoprotein (HS4-AFP) promoter to drive adenovirus E1A gene and II-24 gene.Cell Counting Kit-8 were performed to test the selective cytotoxicity of the virus in hepatocellular carcinoma cell lines SMMC-7721, Hep3B, MHCC97-H and hepatocyte cell line L02 . The mRNA and protein expression of IL-24 gene were detected by RT-PCR and western blot. Cell growth curves and Annexin V/PI assay were used to study cell proliferation and apoptosis of MHCC97-H. The anti-metastatic effects of the recombinant adenovirus were evaluated in cell adhesion, migration, and cell motion. Matrix metalloproteinase-2 (MMP-2) expression was examined by RT-PCR and zymography.Results Selective replications of Ad. HS4. AFP. E1A/IL-24 adenovirus were observed in over expression AFP cell line MHCC97-H, a highly metastatic potential HCC cell line but not in hepatocyte cell line L02. The mRNA and protein of IL-24 were also over expressed in MHCC97-H. This recombinant adenovirus also showed the significant oncolytic action on MHCC97-H but not on L02 (P＜0. 05). Besides, the recombinant adenovirus significantly inhibited MHCC97-H metastatic potential such as cell adhesion, migration and invasion as well(P＜0.01). Conclusion The selective oncolytic adenovirus expressing E1A and II-24 has a selective antitumor effect and play an inhibitory role in metastasis of HCC.

Objective To investigate the effects of Pseudomonas aeruginosa vaccine (PA) on proliferation and invasiveness of the hepatocellular carcinoma cell line MHCC97L with metastatic potential. Methods Proliferation, growth curve, plate efficiency, flow cytometry, transwell invasion assay, cell motility assay, scarification test, vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP2) protein activity were evaluated after cells were treated with PA at various concentrations. Results PA can inhibit the proliferation and plate efficiency of MHCC97L cell markedly in a dose-dependent manner. The IC50 of cells treated with PA for 48 h and 72 h was 3.1 ×108/ml and 1.9 × 108/ml, respectively. The doubling time increased and plate efficiency decreased gradually when cells treated with 0.5 × 108/ml, 1 × 108/ml and 2 × 108/ml PA (P＜0.01). PA could induce cell cycle arrest at the G1 phase in a dose-dependent manner by flow cytometric analysis. The average amount of invading cell per field in cell invasion assay and motility assay were 4. 8 ± 1.3 and 8. 8±2.2 when cells treated with 1× 108/ml PA, which was significantly lower than that of control group (8. 6±2. 1 and 15. 6±1.2 ) (P＜0.01) Scarification test showed that the metastatic ability of cells treated with 1 × 108/ml PA significantly lower than that in the control group. Comparison between cells treated with 1 × 108/ml PA and control group, no remarkable difference was found regarding expression of VEGF and MMP2 in supernatant of cell culture. Conclusion PA can inhibit proliferation and plate efficiency of HCC cell line MHCC97L, which is in part mediated by the cell cycle arrest at the G1 phase. PA could inhibit invasiveness of HCC cell line MHCC97L, which is unrelated to the VEGF and MMP2 protein activity.

Aurora A plays a key role in cellular mitosis. It is located in the centrosome and spindle, and is mainly involved in the processes of centrosome maturation and separation, bipolar spindle assembly, and the regulation of mitotic progression. Recent studies have suggested that Aurora A is involved in tumorigenesis and tumor development through multiple mechanisms. Overexpression of Aurora A could cause abnormal centrosome amplification, aneuploidy formation, and G2/M checkpoint defects, which result in chromosome instability and imbalance between cell division and apoptosis, and eventually leads to abnormal cell proliferation. Aurora A also participates in the regulation of the p53 and BRCA1 pathways, leading to suppressor gene dysfunction and changes in cell viability, and it induces telomerase activity by upregulating c-Myc, resulting in tumorigenesis. In addition, Aurora A also induces drug resistance in liver cancer cells. Thus, Aurora A has gradually become a new target for cancer therapy in recent years. This paper has summarized the recent studies on Aurora A, and reviewed its biological functions in cell mitosis and roles in liver tumorigenesis.

Objective To compare the Barcelona clinic liver cancer staging classification (BCLC), the Japan integrated staging score (JIS), the cancer of the liver Italian program score (CLIP) and Chinese staging system in terms of their ability to predict outcomes and to guide option of therapy in patients with hepatocellular carcinoma (HCC) in China.Methods Clinical data of 861 HCC patients from Zhongshan Hospital between 2001 and 2002 were retrospectively analyzed. Patients were classified acccording to different staging systems. Survival for patients in different stages and the effects of therapeutic methods on survival time were compared. Results BCLC, JIS and Chinese staging system showed the ability in predicting survival for patients in different staging. CLIP failed to show significant difference in survival rates for each subgroup. There was no significant difference in survival rate between surgery and transarterial chemoembolization (TACE)/transarterial embolization (TAE) for patients classified as BCLC stage C, CLIP scores more than 3 or Chinese stage Ⅲ a.The survival rate, however, was higher in patients received operation than those received TACE/TAE if they were classified as earlier stages. Conclusions The BCLC, JIS and Chinese staging systems show prospective ability for Chinese HCC patients in prediction outcomes, whereas the BCLC and the Chinese staging systems are better at both predicting outcomes and guiding the option of treatment.

OBJECTIVETo investigate the correlation between magnetic resonance imaging (MRI) characteristics and intrahepatic recurrence of small hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA).

METHODSA total of 34 patients with 39 small HCC who underwent RFA were included in our study.MRI characteristics were compared between the recurrence group and the non-recurrence group; and a subgroup comparison was also made between the solitary recurrence group and the multiple recurrence group.Kaplan-Meier test,t-test/Mann-Whitney U test,Fisher's exact test and F-test were used for statistical analyses.

RESULTSThe median follow-up period was 25 (4-45) months and recurrence was observed in 19 (55.9%) of the patients.The 12-and 24-month cumulative recurrence-free survival rates were 71.3% and 51.8%,respectively.The recurrence group had a higher prevalence of lack of tumour capsule before RFA (P =0.017),no or disrupted periablational enhancement within 24 hours after RFA (P =0.012),and a smaller ablative margin (P=0.037).Meanwhile,the average apparent diffusion coefficient value within 24 hours after RFA was higher in the multiple recurrence group (1.57 * 10-3mm2/s) than in the solitary recurrence group (1.34 * 10(-3) mm2/s) (P =0.04).

CONCLUSIONMRI can provide early noninvasive findings useful for advanced warning ofintrahepatic recurrence after RFA.

Carcinoma, Hepatocellular ; pathology ; Catheter Ablation ; Humans ; Kaplan-Meier Estimate ; Liver Neoplasms ; pathology ; Magnetic Resonance Imaging ; Recurrence ; Retrospective Studies ; Survival Rate ; Treatment Outcome