الفهرس 
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Abstract
The incidence of hepatocellular carcinoma (HCC) is increasing,currently it is the second leading cause of cancer related death worldwide, accounting for approximately 800,000 deaths every year. (WHO, 2014)In Egypt, hepatocellular carcinoma (HCC) is the second mostcommon cancer in men and the6th most common cancers in women. (GLOBOCAN 2008 database (version 1.2)Almost 80 percent of cases are due to underlying chronic hepatitis Band C virus infection. The association between chronic HBV infection and HCC has been demonstrated in several studies. (Chen et al., 2010).It is now widely accepted that tumor angiogenesis plays a crucial role in tumor growth, tumor propagation and metastasis formation. Among angiogenic activators, the vascular endothelial growth factor (VEGF) and its receptors represent one of the major inducers of tumor angiogenesis. Thus, this system has become the focus of therapeutic interventions. (Gerald W. Prager et al., 2011)HCC is a highly vascular tumor, and angiogenesis is believed to playa considerable role in its development and progression. (Ahmed O. Kase et al., 2009) Furthermore, angiogenesis may be an important target for the secondary prevention of cancer, and biomarkers of angiogenesis may allow hepatocellular carcinoma to be diagnosed at a curable stage. (Ahmed O. Kaseb et al., 2009) Summary & Conclusion 82 Several studies have been made reviewing the role of circulating vascular endothelial growth factor in: 1) The utility of circulating VEGF for HCC screening in patients withcirrhosis. 2) The role of circulating VEGF as a predictor of the invasive potential of HCC . 3) Monitoring anti-HCC treatment effects by serial measurements of circulating VEGF. They found evidence to support a potential role for VEGF in screening and surveillance of HCC. They also found support for developing the use of VEGF in the monitoring of treatment outcomes. (Ahmed O. Kaseb et al., 2009) Results suggest that plasma IGF-1 may serve as a new tool for assessing liver reserve in patients with HCC and that baseline plasma assessment of both IGF-1 and VEGF significantly improves prediction of OS and prognostic stratification of patients with HCC according to BCLC staging. (Ahmed O. Kaseb et al., 2011) This simple noninvasive approach may prove beneficial in prognostic stratification of patients with HCC in clinical trials, guiding therapy decisions and ultimately improving HCC outcome. However, randomized biomarker trials are needed to determine whether this molecular staging strategy can improve HCC management compared with the conventional staging approach before wide acceptance by the scientific community. (Ping Zhan et al., 2013) Summary & Conclusion 83 Notebly, no validated biomarkers are currently available for routine clinical use to guide patient selection for anti-angiogenic treatment. (Gerger et al., 2011) The introduction of anti-angiogenic therapies have been demonstrated to prolong progression-free survival (PFS) and/or overall survival (OS), and improves objective tumor responses, in patients with advanced malignancies such as in renal cell cancer, non-small-cell lung cancer (NSCLC), ovary and colorectal cancer (Gerald W. Prager et al., 2011). Association of VEGF overexpression with poor outcomes provides a rationale for anti-angiogenics use in the treatment of cancer. VEGF has become a leading therapeutic target for the treatment of cancer. Potentially therapeutic strategies to inhibit VEGF pathway include monoclonal antibodies directed against VEGF and Tyrosine Kinase Inhibitors (TKIs). (Kowanetz and Ferrara, 2006 There appears to be a strong rationale targeting angiogenesis as a therapeutic strategy in HCC : First, HCCs are vascular tumors and increased levels of vascular endothelial growth factor (VEGF) and microvessel density (MVD) have been observed. Second, high VEGF expression has been associated with inferior survival. Third, inhibition of angiogenesis can modulate tumor growth in preclinical models. There are many anti-angiogenic agents in clinical Summary & Conclusion 84 trials in HCC and most of them are targeting VEGF and the VEGF receptor (VEGFR). They differ with respect to the target inhibition profiles and potency to selective targets. (Zhu AX et al 2011) Despite the improved OS with sorafenib in advanced HCC, the benefits are still modest. Therefore, developing more effective systemic therapies for advanced HCC remains a challenge. Future research should continue to unravel the mechanism of hepatocarcinogenesis, to refine the molecular classification of HCC, and to identify key relevant molecular targets for therapeutic intervention. (Zhu, 2012) For other anti-angiogenic therapies, while developing more selective or potent anti-VEGF agents, it is likely that progress will come from the use of agents targeting multiple pro-angiogenic factors (Zhu, 2012) Before proceeding to phase III studies with any of these agents, it is important to carefully assess their efficacy signals and safety profiles in early clinical trials, preferably from randomized phase II studies. Combination strategies with targeted agents or combining targeted agents with chemotherapy regimens deserve further exploration; however, the tolerability and safety profiles of the combined regimens may prove to be challenging. (Zhu, 2012) While developing other anti-angiogenic and targeted agents in HCC, it is imperative that continuing efforts to identify and validate surrogate and predictive biomarkers that would be helpful to predict clinical efficacy, toxicity, and resistance to these agents. Hopefully researcher can continue to witness meaningful progress for the development of molecularly targeted agents in HCC in the coming years. (Zhu, 2012) References 85 REFERENCES Abou-Alfa GK, Johnson P, Knox JJ, et al. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA. 2010 ;304:2154–60 Abu Dayyeh BK, Yang M, Fuchs BC, et al. A functional polymorphism in the epidermal growth factor gene is associated with risk for hepatocellular carcinoma. Gastroenterology, 2011 Jul;141(1):141-9. Ahmed O. Kaseb, Amr Hanbali, Matthew Cotant, et al. Philip, Cancer 2009; American Cancer Society Cancer 2009;115:4895–906. VC 2009 American Cancer Society. Ahmed O. Kaseb, Jeffrey S. Morris, Manal M. Hassan, Adnan M. Siddiqui et al. 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