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      Peritumoral EpCAM Is an Independent Prognostic Marker after Curative Resection of HBV-Related Hepatocellular Carcinoma

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          Abstract

          Accumulating evidence suggests that the tumor microenvironment has a profound influence on tumor initiation and progression, opening a new avenue for studying tumor biology. Nonetheless, the prognostic values of the peritumoral expression of EpCAM and CD13 remain to be elucidated in hepatocellular carcinoma (HCC) patients. In this study, the expression of EpCAM and CD13 was assessed by immunohistochemistry in peritumoral liver hepatocytes from 106 hepatitis B virus- (HBV-) related HCC patients who had undergone curative hepatectomy. The peritumoral EpCAM-positive group had a significantly worse overall survival (OS) ( p = 0.003) and recurrence-free survival (RFS) ( p = 0.022) compared to the negative group. Peritumoral CD13-positive patients were also associated with poor OS ( p = 0.038), while not significantly associated with RFS. The adjusted multivariate COX proportional hazard regression analysis suggested that only the positive expression of peritumoral EpCAM precisely predicted poor OS. Being peritumoral EpCAM positive was also significantly associated with a larger tumor size, liver cirrhosis, and more frequent vascular invasion; however, no statistically significant association was observed between CD13 and any clinicopathological features. Taken together, peritumoral EpCAM and CD13 expression was associated with a poor prognosis, but EpCAM may be a better prognostic marker than CD13 in HBV-related HCC patients. In the future, peritumoral EpCAM could be a good target for adjuvant therapy after curative hepatectomy.

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          Most cited references23

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          Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers.

          For almost four decades, my work has focused on one challenge: improving the delivery and efficacy of anticancer therapeutics. Working on the hypothesis that the abnormal tumor microenvironment-characterized by hypoxia and high interstitial fluid pressure--fuels tumor progression and treatment resistance, we developed an array of sophisticated imaging technologies and animal models as well as mathematic models to unravel the complex biology of tumors. Using these tools, we demonstrated that the blood and lymphatic vasculature, fibroblasts, immune cells, and extracellular matrix associated with tumors are abnormal, which together create a hostile tumor microenvironment. We next hypothesized that agents that induce normalization of the microenvironment can improve treatment outcome. Indeed, we demonstrated that judicious use of antiangiogenic agents--originally designed to starve tumors--could transiently normalize tumor vasculature, alleviate hypoxia, increase delivery of drugs and antitumor immune cells, and improve the outcome of various therapies. Our trials of antiangiogenics in patients with newly diagnosed and recurrent glioblastoma supported this concept. They revealed that patients whose tumor blood perfusion increased in response to cediranib survived 6 to 9 months longer than those whose blood perfusion did not increase. The normalization hypothesis also opened doors to treating various nonmalignant diseases characterized by abnormal vasculature, such as neurofibromatosis type 2. More recently, we discovered that antifibrosis drugs capable of normalizing the tumor microenvironment can improve the delivery and efficacy of nano- and molecular medicines. Our current efforts are directed at identifying predictive biomarkers and more-effective strategies to normalize the tumor microenvironment for enhancing anticancer therapies.
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            Molecular targeted therapies in hepatocellular carcinoma.

            Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with several genomic alterations. There is evidence of aberrant activation of several signaling cascades such as epidermal growth factor receptor (EGFR), Ras/extracellular signal-regulated kinase, phosphoinositol 3-kinase/mammalian target of rapamycin (mTOR), hepatocyte growth factor/mesenchymal-epithelial transition factor, Wnt, Hedgehog, and apoptotic signaling. Recently a multikinase inhibitor, sorafenib, has shown survival benefits in patients with advanced HCC. This advancement represents a breakthrough in the treatment of this complex disease and proves that molecular therapies can be effective in HCC. It is becoming apparent, however, that to overcome the complexity of genomic aberrations in HCC, combination therapies will be critical. Phase II studies have tested drugs blocking EGFR, vascular endothelial growth factor/platelet-derived growth factor receptor, and mTOR signaling. No relevant data has been produced so far in combination therapies. Future research is expected to identify new compounds to block important undruggable pathways, such as Wnt signaling, and to identify new oncogenes as targets for therapies through novel high-throughput technologies. Recent guidelines have established a new frame for the design of clinical trials in HCC. Randomized phase II trials with a time-to-progression endpoint are proposed as pivotal for capturing benefits from novel drugs. Survival remains the main endpoint to measure effectiveness in phase III studies. Patients assigned to the control arm should receive standard-of-care therapy, that is, chemoembolization for patients with intermediate-stage disease and sorafenib for patients with advanced-stage disease. Biomarkers and molecular imaging should be part of the trials, in order to optimize the enrichment of study populations and identify drug responders. Ultimately, a molecular classification of HCC based on genome-wide investigations and identification of patient subclasses according to drug responsiveness will lead to a more personalized medicine.
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              High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma.

              To investigate prognostic values of the intratumoral and peritumoral expression of macrophage colony-stimulating factors (M-CSF) in hepatocellular carcinoma (HCC) patients after curative resection. Expression of M-CSF and density of macrophages (M Phi) were assessed by immunohistochemistry in tissue microarrays containing paired tumor and peritumoral liver tissue from 105 patients who had undergone hepatectomy for histologically proven HCC. Prognostic value of these and other clinicopathologic factors was evaluated. Neither intratumoral M-CSF nor M Phi density was associated with overall survival (OS) or disease-free survival (DFS). High peritumoral M-CSF and M Phi density, which correlated with large tumor size, presence of intrahepatic metastasis, and high TNM stage, were independent prognostic factors for both OS (P = .001 and P < .001, respectively) and DFS (P = .001 and P = .003, respectively) and affected incidence of early recurrence. In a small HCC subset, peritumoral M-CSF was also correlated with both OS and DFS (P = .038 and P = .001, respectively). The combination of peritumoral M-CSF and M Phi had a better power to predict the patients' death and disease recurrence (P < .001 for both). High peritumoral M-CSF and M Phi were associated with HCC progression, disease recurrence, and poor survival after hepatectomy, highlighting the importance of peritumoral tissue in the recurrence and metastasis of HCC. M-CSF and M Phi may be targets of postoperative adjuvant therapy.
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                Author and article information

                Journal
                Dis Markers
                Dis. Markers
                DM
                Disease Markers
                Hindawi
                0278-0240
                1875-8630
                2017
                10 May 2017
                : 2017
                : 8495326
                Affiliations
                1Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan, Hubei 430022, China
                2Department of Pediatrics, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, Hubei 430064, China
                3Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
                Author notes

                Academic Editor: Stamatios E. Theocharis

                Author information
                http://orcid.org/0000-0003-0673-1886
                http://orcid.org/0000-0002-2068-7618
                http://orcid.org/0000-0002-0290-7015
                Article
                10.1155/2017/8495326
                5442434
                28572700
                1ebbfb4a-bc02-47d2-94cf-0f788c88081c
                Copyright © 2017 Xiao-Meng Dai et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 November 2016
                : 12 February 2017
                : 5 March 2017
                Funding
                Funded by: Huazhong University of Science and Technology
                Award ID: WJ2016-YZ-10
                Award ID: 2016YXMS241
                Categories
                Research Article

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