Treatment Of HCC Patients Research Articles

Radiofrequency and Microwave Ablation in the Treatment of Hepatocelular Carcinoma

Background: Radiofrequency ablation (RFA) and microwave ablation (MWA) are the most common thermal ablation methods. Studies evaluating the effectiveness of these techniques have been carried out in recent years. Objectives: Evaluation of local therapeutic effectiveness of imaging guided percutaneous thermal ablation methods, short-middle term radiologic and clinical outcomes and to compare the effectiveness of treatment between two MWA and RFA methods. Patients and Methods: We retrospectively browsed clinical-radiologic-pathologic-demographic parameters of patients who had undergone RF or MW treatment due to HCC between January 2012 and January 2015. Twelve females (30%) and 28 males (70%) who had at least 6 months follow-up were included. We evaluated the risk factors which we considered to affect the prognosis by means of Log-Rank (Mantel-Cox) analysis. Complications rates, ablative effectiveness, local progression free and disease free survival rates for 6 months and 1 year periods were calculated by Kaplan Meier test for each group separately. The results of two groups were compared by chi-square test. Results: 6-month, 1-year and 2-year survival rates for thermal ablation were 84.6%, 78.7% and 65% for general; 76.3%, 55.2%, 33% for disease free and 78.9%, 76.2%, 37.3% for local progression free respectively. Size and number of lesions were the only parameters that effective for all type of survival rates. In addition, Child-Pugh classification, AFP (alpha-fetoprotein) level and gender were found to affect just; general, disease free and local progression free survival rates respectively. No statistically significant difference was found in complication, ablative effectiveness, 6 month and 1 year general, disease free and progression free survival rates between RF and MW separately. Conclusion: RF and MW ablation methods have similar complication rates, tumor ablation efficiency and survival rates for treatment in HCC patients.

Identification and interaction analysis of key genes and microRNAs in hepatocellular carcinoma by bioinformatics analysis

BackgroundHepatocellular carcinoma (HCC) is the most common liver malignancy worldwide. However, present studies of its multiple gene interaction and cellular pathways still could not explain the initiation and development of HCC perfectly. To find the key genes and miRNAs as well as their potential molecular mechanisms in HCC, microarray data GSE22058, GSE25097, and GSE57958 were analyzed.MethodsThe microarray datasets GSE22058, GSE25097, and GSE57958, including mRNA and miRNA profiles, were downloaded from the GEO database and were analyzed using GEO2R. Functional and pathway enrichment analyses were performed using the DAVID database, and the protein–protein interaction (PPI) network was constructed using the Cytoscape software. Finally, miRDB was applied to predict the targets of the differentially expressed miRNAs (DEMs).ResultsA total of 115 differentially expressed genes (DEGs) were found in HCC, including 52 up-regulated genes and 63 down-regulated genes. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses from DAVID showed that up-regulated genes were significantly enriched in chromosome segregation and cell division, while the down-regulated genes were mainly involved in complement activation, protein activation cascades, carboxylic acid metabolic processes, oxoacid metabolic processes, and the immune response. From the PPI network, the 18 nodes with the highest degree were screened as hub genes. Among them, ESR1 was found to have close interactions with FOXO1, CXCL12, and GNAO1. In addition, a total of 64 DEMs were identified, which included 58 up-regulated miRNAs and 6 down-regulated miRNAs. ESR1 was potentially targeted by five miRNAs, including hsa-mir-18a and hsa-mir-221.ConclusionsThe roles of DEMs like hsa-mir-221 in HCC through interactions with DEGs such as ESR1 and CXCL12 may provide new clues for the diagnosis and treatment of HCC patients.

Inhibition of E-selectin expression on the surface of endothelial cells inhibits hepatocellular carcinoma growth by preventing tumor angiogenesis.

Interactions between endothelial and tumor cells via E-selectin and sialyl Lewis x (sLex) have been suggested to play a significant role in the development of metastasis and tumor growth. In this work, we tested whether inhibition of E-selectin expression on the surface of endothelial cells might impair endothelial/tumor cells interactions and tumor growth of hepatocarcinoma cells in vitro and in vivo. We used HepG2 cells that highly express sLex antigens and HuH7 cells that do not express sLex. Inhibition of E-selectin expression on the surface of endothelial cells was obtained by using cimetidine and amiloride treatment. Cimetidine and amiloride inhibited, respectively, by 20 and 64% E-selectin expression by activated endothelial cells and significantly subsequent adhesion of HepG2 cells to activated endothelial cells. Subcutaneous injection of cimetidine or amiloride resulted in a significant inhibition of HepG2 cells tumor growth in nu/nu mice but not of HuH7 cells. Thus, cimetidine and amiloride administration led to an inhibition of 57 and 75% of HepG2 tumor growth in vivo, respectively. This effect was associated with an inhibition of vasculogenesis as demonstrated by anti-CD31 immunostaining. Inhibition of E-selectin expression allows an anti-tumoral effect on sLex-expressing HCC tumors in vivo. This suggests that interactions between HCC cells and endothelial cells through sLex antigens and E-selectin might be a target for treatment of HCC. Further studies might evaluate the clinical impact of cimetidine and amiloride in the treatment of HCC patients alone or in combination with other anti-tumoral agents.

Efficacy of perifosine alone and in combination with sorafenib in an HrasG12V plus shp53 transgenic mouse model of hepatocellular carcinoma.

Perifosine has shown antitumor activity via inhibition of Akt phosphorylation in many advanced solid tumors. This study investigated the efficacy of perifosine alone and in combination with sorafenib in a transgenic mouse model of HCC. The mouse model of HCC was generated by hydrodynamic injection of transposons encoding HrasG12V and short-hairpin RNA downregulating p53. The transgenic mice were treated with perifosine alone and in combination with sorafenib to evaluate efficacy of drugs on tumor growth and survival. Treatment with perifosine for 5 weeks, alone and in combination with sorafenib, strongly inhibited tumor growth and increased survival. Perifosine inhibited HCC cell proliferation, induced apoptosis, and decreased tumor angiogenesis. Furthermore, its combination with sorafenib enhanced these effects. In addition, Akt phosphorylation was decreased by perifosine and further decreased by combination treatment. Although perifosine alone did not appear to activate the caspase pathway, combination treatment increased the cleavage of caspase-3, caspase-9, and poly (ADP-ribose) polymerase. The preclinical effect that current study showed represents a strong rationale for clinical trials using perifosine alone and in combination with sorafenib in the treatment of HCC patients.

New Aspects of Therapy of Hepatocellular Carcinoma Egyptian Patients

Background: The purpose of this study was design to investigate the potential impact of chemo and hormonal therapy drugs either with natural oils or other with vitamin E on HCC Egyptian patients. Methods: A retrospective analysis of medical records was performed on 100 unresectable HCC Egyptian patients in stage A or B who were identified through the National Cancer Institute Cairo University and Menoufia University, from 2010 to 2013. All of patients had been received systemic chemo and hormonal and therapy (5-fluorouracil, Oxaloplatin and tamoxifen) either with five type of natural oils or other with vitamin E. Clinical picture , hematological test, metabolic parameters, telomerase activity, VEGF, MAD, GSH, zinc, ER ,PR, KRAS, BRAF and NRAS has been assessed. Survival curves were also analyzed at pre-and post-treatment. All patients were applied to do regular exercise, control their diet before receiving treatment. The survival rate was determined. Results: the present data indicate that oral NS.O and CUR.O showed greatly kept hematological finding, serum levels of telomerase activity, VEGF, GSH, MAD ALT, AST, GGT, bilirubin, albumin and zinc to the normal levels (p < 0.001), the toxicity has been reduced without affecting response to chemo and hormonal therapy and survival , the quality of life, clinical picture and survival seemed to be better.Fortunately the depletion in the serum levels of the VEGF and the telomerase activity correlates with good of clinical picture compared with other groups under investigation. Conclusion: Using Chemo and hormonal therapy, in combination with oral NS.O and CUR.O was identified as the most suitable treatment for HCC patients resulted in improving survival, maximizing clinical benefit, and minimizing risk of chemo and hormonal therapy toxicity. The telomerase activity and VEGF levels can be used as markers to predict survival and response to treatment in HCC patients in the future.

222 PROMOTION OF LIVER CARCINOGENESIS BY HEPATITIS C VIRUS THROUGH ENHANCED C-MYC EXPRESSION, LEADING TO DNA DAMAGE AND OXIDATIVE STRESS

in pathologic angiogenesis and its inhibition does not affect healthy organs. To see whether PLGF plays a role in the development of HCC, we measured PLGF-serum levels in HCC and cirrhotic patients. To assess if PlGF inhibition could influence HCC-progression, PlGF knock out mice (PLGF−/−) were treated with diethylnitrosamine (DEN) and compared to wild type (WT) mice at several time points. Methods: Serum was collected from HCC-patients (n = 15), cirrhotic patients (n = 17) and healthy patients (n = 10) and analysed using the R&D PlGF ELISA kit. HCC-patients and cirrhotic patients were matched according to gender, etiology and age. 5-week-old male mice (PlGF −/− and WT) received intraperitoneal injections once a week with DEN (35mg/kg bodyweight), which gives rise to HCC after 25W. Mice were sacrificied after 20W, 25W and 30W of DEN administration. Results: Serum levels of PlGF were significantly increased in patients with cirrhosis (P < 0.05) and HCC (P < 0.01) compared to healthy serum. In addition, HCC-patients had higher serum levels of PlGF compared to cirrhotic patients without HCC (P < 0.05). PlGF inhibition significantly improved survival in mice with HCC (p < 0.05) and PlGF−/− had a significant lower tumour burden than WTs at 25W (P < 0.001) and 30W (P < 0.05). These tumours were less vascularised (P < 0.05) and had a more uniform blood vessel distribution (P < 0.001). Furthermore, tumour environment was characterised by less activated HSC (P < 0.05) and less macrophages (P < 0.05). Discussion: The expression levels of PlGF in human patients confirm the importance of PlGF in the hepatocarcinogenesis. Furthermore, inhibition of PlGF in a knock out model has a positive effect on survival in mice with HCC, it decreases tumour burden, restrains angiogenesis and reduces hepatic inflammation. Thus, inhibition of PlGF might serve as a promising treatment in HCC patients.

Differential Effects of Vitamin K1 on AFP and DCP Levels in Patients with Unresectable HCC and in HCC Cell Lines

DCP is a useful HCC tumor marker, which reflects a defect in vitamin K metabolism. We tested the hypothesis that vitamin K treatment of HCC patients might suppress this marker and possibly AFP also. HCC patients who had both elevated AFP and DCP were included. A phase I cohort was treated with escalating vitamin K1 intravenous weekly doses and a 27-patient phase II cohort was then treated with a fixed oral daily dose. A maximum tolerated dose was not reached up to 100-fold the normal vitamin K1 dose. No toxicities were found up to 1,000 mg/infusion. In the phase II cohort, 93% of patients had tumor marker responses by decreased DCP levels, but only 22% had responses by decreased AFP levels. CT scans showed 11% of patients had PRs, 59% had stable tumors and 29.6% had tumor progression. Mechanism studies showed that vitamin K1 induced phosphorylation of JNK and c-Jun and caspase-mediated apoptosis. Vitamin K1 was non-toxic at high doses, strongly inhibited plasma DCP levels, but weakly suppressed AFP levels. The results provide evidence that the two tumor markers are not directly linked and that DCP levels may not reflect HCC cell growth, as DCP levels were decreased in patients without AFP change, and were suppressed in vitro at 1% of the vitamin K1 concentration needed to inhibit AFP.