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Tissue Biomarkers in Hepatocellular Tumors: Which, When, and How

An excellent oveview of hepatocellular carcinoma histopathology from Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
Front Med (Lausanne). 2017; 4: 10.
Published online 2017 Feb 23. doi:  10.3389/fmed.2017.00010
Luca Di Tommaso and Massimo Roncalli


Few tissue markers are currently available to pathologists in the study of hepatocellular tumors. These markers should be used carefully taking into consideration not only morphology but also, and sometimes even more important, the clinical setting where the lesion to be diagnosed had developed. Glypican-3, heat shock protein 70, and glutamine synthetase (GS) are markers currently used...

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GPC3 in odontogenic tumors

Glypican-3 distinguishes aggressive from non-aggressive odontogenic tumors: a preliminary study.

Mendes RB, Dias RB, et al., Dos Santos JN


Glypican-3 is a cell surface proteoglycan that is found in embrionary tissues, and there are no studies investigating this protein in odontogenic tumor. Thus, the aim of this study was to investigate glypican-3 in a series of aggressive and non-aggressive odontogenic tumors.


Fifty-nine cases of tumors were divided into aggressive odontogenic tumors (20 solid ameloblastomas, four unicystic ameloblastoma, 28 KOTs including five associated with Gorlin-Goltz syndrome) and non-aggressive odontogenic tumors....

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Expression of PAX8 Target Genes... Papillary Thyroid Carcinoma.

PLoS One. 2016 Jun 1;11(6):e0156658. doi: 10.1371/journal.pone.0156658. eCollection 2016.
Rosignolo F, Sponziello M, Durante C, Puppin C, Mio C, Baldan F, Di Loreto C, Russo D, Filetti S, Damante G.
Link to PuMed

PAX8 is a thyroid-specific transcription factor whose expression is dysregulated in thyroid cancer. A recent study using a conditional knock-out mouse model identified 58 putative PAX8 target genes. In the present study, we evaluated the expression of 11 of these genes in normal and tumoral thyroid tissues from patients with papillary thyroid cancer (PTC).

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Modeling of Hepatocytes Proliferation...

...Isolated from Proximal and Distal Zones from Human Hepatocellular Carcinoma Lesion.
Montalbano M, Curcurù G, Shirafkan A, Vento R, Rastellini C, Cicalese L.


Isolation of hepatocytes from cirrhotic human livers and subsequent primary culture are important new tools for laboratory research and cell-based therapeutics in the study of hepatocellular carcinoma (HCC). Using such techniques, we have previously identified different subpopulations of human hepatocytes and among them one is showing a progressive transformation of hepatocytes in HCC-like cells. We have hypothesized that increasing the distance from the neoplastic lesion might affect hepatocyte function and transformation capacity.

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Randomized Phase II placebo controlled study...

...of codrituzumab in previously treated patients with advanced hepatocellular carcinoma.
Abou-Alfa GK, Puig O, Daniele B, Kudo M, Merle P, Park JW, et al.
LInk to PubMed

Codrituzumab, a humanized monoclonal antibody against Glypican-3 (GPC3) that is expressed in HCC, interacts with CD16/ FcγRIIIa and triggers antibody-dependent cytotoxicity. Codrituzumab was studied versus placebo in a randomized phase II trial in advanced HCC patients who had failed prior systemic therapy.

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CK19 and Glypican 3 Expression...

...Profiling in the Prognostic Indication for Patients with HCC after Surgical Resection.

PLoS One. 2016 Mar 15;11(3):e0151501. doi: 10.1371/journal.pone.0151501. eCollection 2016.           images pone 120x30
Feng J, Zhu R, Chang C, Yu L, Cao F, Zhu G, Chen F, Xia H, Lv F, Zhang S, Sun L.

This retrospective study was designed to investigate the correlation between a novel immunosubtyping method for hepatocellular carcinoma (HCC) and biological behavior of tumor cells. A series of 346 patients, who received hepatectomy at two surgical centers from January 2007 to October 2010, were enrolled in this study. The expressions of cytokeratin 19 (CK19), glypican 3 (GPC3), and CD34 were detected by immunohistochemical staining. The clinical stage was assessed using the sixth edition tumor-node-metastasis (TNM) system (UICC/AJCC, 2010).

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A New Cell Block Method...

...for Multiple Immunohistochemical Analysis of Circulating Tumor Cells in Patients with Liver Cancer.

Cancer Res Treat. 2016 Mar 30. doi: 10.4143/crt.2015.500.
Nam SJ, Yeo HY, Chang HJ, Kim BH, Hong EK, Park JW.                                                     e image pubmed linkout banner

We developed a new method of detecting CTCs in liver cancer patients by constructing cell blocks from peripheral blood cells, including CTCs, followed by multiple immunohistochemical analysis.

Materials and Methods:

Cell blocks were constructed from the nucleated cell pellets of peripheral blood after removal of red blood cells. The blood cell blocks were obtained from 29 patients with liver cancer, and from healthy donor blood spiked with seven cell lines. The cell blocks and corresponding tumor tissues were immunostained with antibodies to seven markers: CK, EpCAM, EMA, CK18, AFP, Glypican 3 and HepPar1.

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Results from the BRISK-FL trial

fierce biotech

BRISK-FL Study with Investigational Compound Brivanib in Hepatocellular Carcinoma Does Not Meet Overall Survival Primary Endpoint

(NYSE: BMY) today reported the result of the phase III BRISK-FL clinical trial of the investigational agent brivanib versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma (HCC; liver cancer). The study did not meet its primary overall survival objective based upon a non-inferiority statistical design.

BRISK-FL is a randomized, double-blind, multi-center phase III study of the investigational agent brivanib versus sorafenib in patients with advanced HCC who have not received prior systemic treatment. Bristol-Myers Squibb and the lead investigators plan to present the findings of the study at an upcoming scientific meeting.

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Adoptive immunotherapy...

...using T lymphocytes redirected to glypican-3 for the treatment of lung squamous cell carcinoma.

Oncotarget. 2016 Jan 19;7(3):2496-507. doi: 10.18632/oncotarget.6595.

Li K, Pan X, Bi Y, Xu W, Chen C, Gao H, Shi B, Jiang H, Yang S, Jiang L, Li Z.

There are unmet medical needs for patients with lung squamous cell carcinoma (LSCC). Therefore, in this study, we explored the antitumor potential of third-generation glypican 3 (GPC3)-redirected chimeric antigen receptor (CAR)-engineered T lymphocytes (CARgpc3 T cells) in tumor models of LSCC. First, we demonstrated by immunohistochemistry (IHC) that GPC3 was expressed in 66.3% of LSCC samples and in 3.3% of lung adenocarcinoma (LAD) samples but not in normal lung tissues.

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Immunohistochemical expression of glypican 3... endometrial carcinoma and correlation with prognostic parameters.

Int J Clin Exp Pathol. 2015 Oct 1;8(10):13225-32. eCollection 2015.

Hakim SA, Raboh NM.


Carcinogenesis is associated with several critical regulatory molecules which are involved in different signaling pathways such as the WNT signaling pathways. Among which the β-catenin dependent pathway has been associated with human endometrial cancer. Genetic and biochemical studies have demonstrated that glypicans can regulate several signaling pathways including those triggered by Wnts. Glypican 3 is one of six mammalian members of the glypican family of proteoglycans.

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Glypican-3 is a prognostic factor...

...and an immunotherapeutic target in hepatocellular carcinoma.

World J Gastroenterol. 2016 Jan 7;22(1):275-83. doi: 10.3748/wjg.v22.i1.275.

Haruyama Y, Kataoka H.

Glypican-3 (GPC3) is a cell surface oncofetal proteoglycan that is anchored by glycosylphosphatidylinositol. Whereas GPC3 is abundant in fetal liver, its expression is hardly detectable in adult liver. Importantly, GPC3 is overexpressed in hepatocellular carcinoma (HCC), and several immunohistochemical studies reported that overexpression predicts a poorer prognosis for HCC patients. Therefore, GPC3 would serve as a useful molecular marker for HCC diagnosis and also as a target for therapeutic intervention in HCC.

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