\r\n\tThis book chapter’s main theme will be focused on transmission dynamics, pathogenesis, mechanisms of host interaction and response, epigenetics and markers, molecular diagnosis, RNA interacting proteins, RNA binding proteins, advanced development of tools for diagnosis, possible development of concepts for vaccines and anti drugs for RNA viruses, immunological mechanisms, treatment, prevention and control. \r\n\t
",isbn:"978-1-80355-667-3",printIsbn:"978-1-80355-666-6",pdfIsbn:"978-1-80355-668-0",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"52f8a3a1486912beae40b34ac557fed3",bookSignature:"Ph.D. Yogendra Shah",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11369.jpg",keywords:"HIV, Dengue, Zika, West Nile Virus, Chikungunya, Rabies, SARS-CoV2, MERS-CoV, Hanta Virus, Influenza, Whole Genome Sequencing, DNA Sequencing",numberOfDownloads:217,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 4th 2021",dateEndSecondStepPublish:"November 1st 2021",dateEndThirdStepPublish:"December 31st 2021",dateEndFourthStepPublish:"March 21st 2022",dateEndFifthStepPublish:"May 20th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"9 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Dr. Shah obtained his Ph.D. degree in Veterinary Medicine from Hokkaido University, Japan. He was awarded the Young Science and Technology Award from the Nepal Academy of Science and Technology (NAST) in 2019. His research interests include infectious diseases, zoonotic infectious diseases, and vector-borne diseases.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"278914",title:"Ph.D.",name:"Yogendra",middleName:null,surname:"Shah",slug:"yogendra-shah",fullName:"Yogendra Shah",profilePictureURL:"https://mts.intechopen.com/storage/users/278914/images/system/278914.jpg",biography:"Dr. Yogendra Shah is a consultant microbiologist/virologist, senior research microbiologist, and lecturer at Seti Provincial Hospital, COVID-19 PCR laboratory, National Zoonoses and Food Hygiene Research Center, and Kathmandu College of Science and Technology, Nepal. He obtained a Ph.D. in Veterinary Medicine (Bacteriology) from the Graduate School of Veterinary Medicine, Hokkaido University, Japan, in 2017. His research focuses on better understanding the molecular epidemiological features/transmission dynamics of infectious diseases and zoonotic infectious diseases in Nepal by employing molecular techniques like ELISA, polymerase chain reaction (PCR), loop-mediated isothermal amplification (LAMP), and DNA sequencing. He was awarded the Young Science and Technology Award from the Nepal Academy of Science and Technology (NAST) in 2019. His research interests include infectious diseases, zoonotic infectious diseases, and vector-borne diseases. 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From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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\n\t\t\t
1. Introduction
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Evaluation of liver biopsy for tumour diagnostics is a highly practical task with major clinical influence. The liver is frequently affected by wide spectrum of neoplasms including benign tumours as well as primary malignancies [1-3]. In addition, due to the rich dual blood flow to liver, secondary malignant tumours also often develop here. In order to ensure the optimal management of the patient, a correct diagnosis is necessary. At present, biopsy is the gold standard in oncology [4-5].
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The scope of liver neoplasms can be following. The benign tumours include hepatic adenoma, bile duct adenoma, cavernous haemangioma and angiomyolipoma, among others. The primary liver malignancies embrace hepatocellular carcinoma [6,7], cholangiocarcinoma [3] and hepatoblastoma [8]. The diagnostics of hepatocellular carcinoma (HCC) is especially urgent topic due to high incidence in Asia and rising – in Europe and USA, possibly because of high prevalence of chronic hepatitis C [4,9]. Also, prognostic data should be reported including the features of early vs. progressed HCC, presence of stem cell immunophenotype, multicentric growth or metastatic spread [7]. Among mesenchymal malignant tumours, epithelioid haemangioendothelioma and angiosarcoma [10,11] are notable. Metastatic tumours represent the bulk of malignancies in Western countries [2]. Cystic liver tumours include biliary cystadenoma and biliary cystadenocarcinoma [12-14].
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Most of the above mentioned neoplastic processes can be diagnosed in core biopsy. The key aspects include the following. First, the biopsy must be representative regarding the biological process and radiologically detected changes [15]. Further, the obtained tissue must be subjected to adequate technological process. Innovations here allow shortening the turnover time significantly. Next, the evaluation of morphology must be done searching for the characteristic traits of the above noticed tumours. However, due to the limited tissue amount in the biopsy, the tumour architecture sometimes is difficult to identify embarrassing the distinction between nodular hyperplastic process, benign tumour or low-grade malignancy. In contrast, high-grade malignancies can show significant cytological atypia by few signs of differentiation embarrassing the detection of histogenesis [6] and the distinction between primary and metastatic tumour.
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Immunohistochemical markers as glypican-3 [1], Hep Par 1 [3,6], CD10 [3], alpha-fetoprotein [6] and TTF-1 [16] are useful in the HCC diagnostics. Alterations of CD31 and CD34-positive endothelial cell network reflect vascular remodelling during hepatic carcinogenesis [7]. Cytokeratin (CK) 19 and 7 are characteristic for cholangiocellular carcinoma [3]. In metastases, organospecific markers including CDX2, mammaglobin, nuclear expression of TTF-1 or presence of neuroendocrine markers can confirm extra-hepatic origin [17]. As colorectal, breast, lung and neuroendocrine cancers are frequent cause of metastatic liver damage [2] high diagnostic value of immunohistochemistry (IHC) can be expected. However, the exact detection of histogenesis can be difficult with metastatic pancreatic or gastric tumours and high-grade malignancies. IHC is mandatory for the diagnostics of haematological neoplasms and epithelioid haemangioendothelioma. Assessment of tumour biological potential can be done by IHC, evaluating Ki-67, Cyclin D1, FOXJ1, stem cell markers, matrix metalloproteinases and other markers [7-8,18-22]. Novel markers appear continuously as heat-shock protein 70 [23].
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Nowadays, pathology is not any more purely descriptive but it is becoming more functional and clinically relevant. The classic morphologic characteristics must be combined with integrated evaluation of neoplastic process in the liver, including histogenesis, grading, clonal changes, type and extent of vascularisation, immunophenotype, heterogeneity, prediction of treatment sensitivity and the clinical behaviour [7]. New technologies as proteomic profiling and genomic marker analysis should be applied in the evaluation of liver tumours [4]. MicroRNA studies can lead to new findings in cancer pathogenesis and prediction of treatment efficacy [24,25].
\n\t\t\t
The aim of the following chapter is to describe morphological and immunohistochemical characteristics of primary and secondary liver tumours in order to develop logistic basis for differential diagnosis of these processes in biopsy materials. Short discussion about the genesis and clinical course of each tumour will be included as well.
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\n\t\t
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2. Benign epithelial liver tumours
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Liver cell adenoma and bile duct adenoma will be discussed here. The regenerative processes with the emphasis on focal nodular hyperplasia are described considering the differential diagnosis.
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2.1. Liver cell adenoma and its differential diagnosis with focal nodular hyperplasia
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Liver cell adenoma or hepatic adenoma is defined as benign tumour arising from hepatocytes. The epidemiology is characterised by female predominance (90%) and strong association with oral contraceptive use [26-27] as 85% of affected persons have such history. Liver cell adenoma was rare before the era of oral contraceptives [27]. At present, the incidence has increased but is still low: 3-4 /100 000 per year in long-term users of oral contraception [27-29]. The patients mostly are 20-39 years old. The other risk factors of hepatic adenoma include androgen burden. The tumours can also arise spontaneously or occasionally can be related to glycogen storage diseases or diabetes mellitus. Clinically, the patients mostly are symptomatic. Abdominal fullness can be attributed to the presence of mass lesion; pain can be caused by necrosis [27]. Rupture and bleeding (40%) represent dangerous complications [27,29-31]; the risk of these events is increased in pregnant ladies affected by liver cell adenoma due to prior use of hormonal contraceptives. Risk of malignant transformation also is recognised [29,32]. By literature analysis, Farges and Dokmak concluded that 5% of resected hepatic adenomas bear HCC foci [32]. The risk of malignant transformation is higher in adenomas exceeding the size of 5 cm irrespectively of the number of adenomas as well as in males. Grossly, liver cell adenomas are mostly unifocal (80%) and subcapsular. The tumours can be quite large (5-20 cm). In most cases (75%) adenomas are encapsulated [27]. However, the capsule can be thin or absent [10]. In contrast to HCC, adenomas usually are not associated with cirrhosis [31]. Otherwise, radiological similarities exist between adenoma and HCC as both can be large, have rich vascularity and can undergo necrosis [31]. Microscopically, the tumour is composed by hepatocytes lacking anaplasia and arranged in thin (1-2 cells) trabeculae [27,29]. Cellular atypia and macrotrabeculae must be absent. Single arterioles, a pair of arteriole and venule or isolated biliary ducts are scattered throughout the lesion. However, well-formed triads enveloped in connective tissue are absent within the lesion. The tumour can be distinguished from normal liver by larger size of neoplastic cells, presence of capsule and lack of triad-containing portal tracts. Steatosis, hydropic degeneration or Mallory hyaline can be observed. Fibrous tissue, haemosiderin and calcifications can develop in the consequence of haemorrhage. The immunophenotype is characterised by expression of Hep Par 1 and other antigens that confirms the hepatic origin and by lower proliferation than in HCC. Molecular typing is emerging for liver cell adenoma as well. At present, up to 4 molecular types are identified:
hepatic adenoma not displaying any before described feature or unsuitable for analysis [29].
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The hepatic adenomas with TCF1 gene mutation comprise 35-40% of liver cell adenomas. The patients are female. The tumour loses the expression and functions of hepatocyte nuclear factor 1 (HNF1) encoded by TCF1 gene. Inactivation of the gene can be caused by mutation in both alleles or by combination of a mutation and 12q deletion leading to loss of heterozygosity in the corresponding region [33]. Germ-line mutation of HNF1 gene manifests as maturity-onset diabetes of the young (MODY), type 3, in association with liver adenomatosis [34]. However, the spectrum of HNF1A somatic mutations in liver cell adenoma differs from that in patients with MODY3 and suggests genotoxic damage [35]. By IHC, loss of liver fatty acid binding protein can be observed. Not surprisingly, the adenomas show steatosis [29].
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Inflammatory hepatic adenomas constitute 50% of liver cell adenomas and can be associated with obesity, smoking and alcohol use. Pathogenetically, inflammatory hepatic adenoma is characterised by IL-6 pathway activation centred on gp130 protein in IL-6 receptor. The receptor can be subjected to ligand-independent activation due to mutation in IL6ST gene, or the levels of gp130 can be elevated. The IL-6 receptor activation leads to recruitment of inflammatory cells through gp130-mediated production of chemokine CCL20. The mutation was found in 60% of inflammatory adenomas [36]. However, the IL-6 pathway activation is universal in the inflammatory hepatic adenoma. Microscopically, inflammatory infiltrates are observed in addition to the architecture and cytologic details of adenoma. Occasional bile ductules, dilated sinusoids and arterioles can be present. Haemorrhage is frequent. By IHC, expression of acute phase reactants serum amyloid A and C-reactive protein is marked [29].
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A group of hepatic adenomas is associated with beta-catenin mutation [37-38].The beta-catenin pathway is not affected in TCF1 inactivated group [29,38]. Beta-catenin activation can be assayed by immunohistochemical over-expression of glutamine synthetase or by aberrant nuclear localisation of beta-catenin. However, the tumours can show dysplastic changes more characteristic for HCC thus possibly this group will be reclassified into well-differentiated HCC [29,36].
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The last group of hepatic adenomas (5%) lacking TCF1 inactivation, inflammatory signature and beta-catenin mutation [29] could represent distinct group with peculiar pathway of molecular pathogenesis or result of technological shortcomings.
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The differential diagnosis of hepatic adenoma in biopsy includes low-grade HCC and hyperplastic lesions like focal nodular hyperplasia, nodular regenerative hyperplasia and partial nodular transformation [27].
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Focal nodular hyperplasia (FNH) is a comparatively frequent differential diagnosis of hepatic adenoma. The FNH incidence is estimated as 3% [29-30,39]. FNH is characterised by presence of hypervascular stellate scar in liver parenchymal nodule. The blood vessels are located in the middle of star-like fibrous tissue while the periphery is occupied by proliferating bile ductules. The morphologically remarkable abundant vascularity is in accordance with the hypothesis of the FNH origin due to microscopic arterial malformation [40-42]. The crucial difference between FNH and adenoma is pathogenetic as the former is thought to be hyperplastic lesion, while adenoma is a neoplasm. The presence of stellate scar and lack of peripheral capsule in FNH contrasts with presence of peripheral capsule and almost complete lack of connective tissue or portal triads within adenoma. If the architecture is incompletely represented in the biopsy, molecular characteristics should be able to discriminate between the two inherently different processes, the hyperplasia and tumour. The immunohistochemical markers of biliary differentiation have been employed in the differential diagnostics between FNH and hepatic adenoma. As described by Walther and Jain, CK19 and CD56 detect rich network of proliferating biliary ducts in the fibrous septa of FNH but reveal only few isolated ducts within the parenchyma of hepatic adenoma. Expression of CK7 is remarkable for the focal presence in parenchyma of liver cell adenoma in contrast to FNH while both lesions show expression of CK7 in biliary ducts. Thus, panel of CK19, CD56 and CK7 can be advised to solve the differential diagnosis in core biopsy [29]. Immunohistochemical expression pattern of glutamine synthetase differs between normal liver tissue, FNH and liver cell tumours as well. In healthy tissue, glutamine synthetase is present in perivenular hepatocytes. These positive areas are expanded in FNH [39]. In hepatic adenomas, glutamine synthetase expression is either diffuse of negative. In the last situation, the negativity in the tumour can be incomplete, with focally preserved expression in the tumour periphery [29] and thus difficult to interpret, especially in small biopsies where the preserved positive focus seems to be dominant.
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In nodular regenerative hyperplasia, the liver contains many small regenerative nodules. Partial nodular transformation affects hilar area and is characterised by group of regenerative nodules surrounded by fibrous tissue [27].
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Considering the differential diagnosis with HCC, thick trabecular cords, cytologic anaplasia and invasive growth reveal the malignant biological potential. The thickening of trabeculae is defined as presence of more than 2 cell layers in the trabeculae. The anaplasia is recognised by nuclear hyperchromasia, prominent nucleoli and increase in the nucleo: cytoplasmic ratio. Presence of mitoses practically excludes the diagnosis of hepatic adenoma. Atypical mitoses are absolute evidence of malignancy. The invasive growth can manifest as invasion through the capsule, infiltration into liver parenchyma and true invasion into blood vessels [27].
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2.2. Bile duct adenoma
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Bile duct adenoma is defined as a benign neoplasm of portal bile ducts. The epidemiologic data suggest rare occurrence. However, as the tumours mostly are small and asymptomatic [27], the true incidence and prevalence is unknown. Grossly, bile duct adenomas are mostly solitary (83%), subcapsular (95%) and small (below 1 cm). By light microscopy, the lesion is characterised by demarcated proliferation of bile ducts lacking atypia. The immunophenotype repeats the staining characteristics of biliary ducts exhibiting expression of cytokeratins 7 and 19 [27]. The differential diagnosis can include small foci of low-grade cholangiocarcinoma or metastatic low-grade adenocarcinoma, but the benign cytological appearance is helpful. Von Meyenburg hamartoma differs from bile duct adenoma, as the hamartomas would be multiple and show traits of cholestasis. However, the exact separation might not be of crucial importance due to benign course of biliary adenoma and pathogenetic suggestion that biliary adenoma represent a reactive process rather than true neoplasm.
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3. Malignant epithelial primary liver tumours
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Three primary liver tumours are of utmost importance. Hepatocellular carcinoma is the most frequent primary epithelial liver tumour with grave prognosis. Cholangiocarcinoma ranks second by the incidence except for endemic regions. Hepatoblastoma is notable for the occurrence in the infancy.
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3.1. Hepatocellular carcinoma
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Hepatocellular carcinoma is defined as malignant tumour developing from hepatocytes and/or showing hepatocellular differentiation. It is the most common primary malignant tumour of the liver constituting 80-85% of primary epithelial liver malignancies [29,43]. Considering the epidemiology, the worldwide burden of hepatocellular carcinoma can reach 1 million of new cases per year. The incidence shows major geographic differences. HCC is the 2nd most common cancer in Asia, and the 4th – in Africa [10]. The annual age-standardised incidence is the highest in East Asia, including China and Japan. Low-risk areas comprise Europe, esp. northern and western parts; North and South America, Australia and New Zealand [10].The age-adjusted incidence rates in Mozambique are as high as 112.9 and 30.8/100 000 in males and females, respectively. In China these values reach 34.4 and 11.6. In contrast, the age-adjusted incidence rates in British males and females are 1.6 and 0.8, respectively [31]. The HCC risk factors include liver cirrhosis independently of cause, chronic hepatitis B or C, ethanol consumption and non-alcoholic liver steatosis as well as mycotoxins. The aflatoxin B1 or other mycotoxins produced by Aspergillus fungi could be responsible for part of HCC in areas where grains, rice and peanuts are stored in hot and humid conditions [31]. Most of HCC cases develop from dysplastic cirrhotic nodule [29], thus the differential diagnostics between dysplastic nodule and cancer represent evaluation of one point in a complex road of pathogenesis. Clinically, most of the patients approach doctor due to symptoms attributable to mass lesion in the liver (abdominal pain, sensation of fullness), tumour-related intoxication (weight loss, weakness, lack of appetite) and loss of liver functions (jaundice). Alternatively, the symptoms can be related to pre-existing cirrhosis and the tumour could be identified during routine control of cirrhotic patient or during workup for unspecific or unrelated symptoms [31]. Radiologically, the number and size of tumour masses can be evaluated. Ultrasonography can be used for screening. Typical findings regarding vascularity include hypervascularity and thrombosis of portal vein, frequently due to invasion. If it is necessary to confirm invasion into portal vein, biopsy can be obtained from it [31].
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By microscopy, the typical patterns include trabecular, acinar and ductular structure. The neoplastic cells in low-grade cases resemble liver cells by possessing wide eosinophilic cytoplasm and distinct cell borders. Nuclear atypia is present and nucleo: cytoplasmic ratio is increased, although to different degree. Mitoses can be present; atypical mitoses can be observed (Figure 1). The architecture shows unequivocal deviations from normal structure such as thick trabeculae with more than 2 cell layers (in contrast to adenoma), solid areas, duct-like or gland-like structures. However, careful evaluation of the architecture under high power magnification must be carried out. There are many secondary phenomena raising the similarity between HCC and liver tissue: presence of macrovesicular or microvesicular fat, Mallory hyaline and bile. The capillaries can be dilated [27]. Among the histochemical staining methods, absent reticulin staining [44] is characteristic. PAS stain can reveal glycogen and intracytoplasmic globules; the latter structure remains positive after diastase digestion [27,44]. With some experience, morphology is helpful to distinguish finely granular glycogen or rounded globules in HCC from mucus droplets in metastatic adenocarcinoma or cholangiocarcinoma.
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Figure 1.
Hepatocellular carcinoma displaying marked cytologic atypia. Note the presence of atypical mitosis. Haematoxylin-eosin (HE), original magnification (OM) 100x.
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Fibrolamellar hepatocellular carcinoma (FLHC) has distinctive aetiology, epidemiology and course. The general HCC risk factors are not associated with this subtype [31]. FLHC is rare, constituting only 1-4% of HCC [27]. It is less common in high-risk areas than in North America and Europe. The patients are young adults or even children [10]. FLHC is diagnosed at the mean age of 25 years in contrast to mean age of 52 years in typical HCC patient group [27]. Controversial data are reported about the sex predilection: some but not all authors have noted that females are mostly affected [10,31]. Clinically, symptoms attributable to liver enlargement, parenchymal damage (elevated liver enzyme level) or tumour-related intoxication (weight loss or fever) can be present. Cirrhosis is absent. The tumour can be multifocal, and metastases can affect lungs and regional lymph nodes [31]. The histological structure is remarkable for the lamellar fibrosis. The stroma is composed of thick, parallel strands of hyalinised collagen [27]. The cells are large, polygonal, with wide eosinophilic cytoplasm. The vesicular nuclei possess large nucleoli. Cytoplasmic pale bodies are more frequent (up to 50% of cases) and more abundant than in other types [10,27]. The pale bodies are rounded and very lightly eosinophilic thus staining paler than the surrounding cytoplasm. These structures represent cystically dilated endoplasmic reticulum. Pale bodies can be positive for fibrinogen by IHC. The immunophenotype is remarkable for diffuse expression of CK7. The hepatocellular differentiation can be confirmed by Hep Par 1; alpha-fetoprotein is present in approximately 20% of cases. The FLHC prognosis is better than in the general group. The mean survival is 32 months in contrast to 5.9 months in trabecular HCC [27]. However, it is found that the beneficial prognosis of FLHC is different from cancer in cirrhotic liver but not from HCC in the absence of liver cirrhosis [10].
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IHC has an important role in the diagnostics of HCC. Frequently tested antigens include glypican-3, Hep Par 1, alpha-fetoprotein, CD10, carcinoembryonic antigen CEA, TTF-1, arginase-1, evaluation of cytokeratins and endothelial network as well as MOC-31 and markers of extra-hepatic tumours.
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Glypican-3 is a cell surface protein [1] that is involved in the control of cell proliferation and survival. Glypican-3-knockout mice exhibit alterations in Wnt signalling [45]. Glypican-3 also interacts with Hedgehog signalling pathway [46]. In the practical surgical pathology, the value of glypican-3 is associated with the cancer diagnostics as it is expressed in 70-75% of HCC but not in benign liver tissue [48-49] or cholangiocellular carcinoma [1]. Hepatoblastoma can be positive as well. However, glypican-3 can be expressed in metastatic melanoma [50], ovarian clear-cell carcinoma [51], choriocarcinoma, yolk sac tumour [52-53] as well as in blastomas including neuroblastoma and Wilms’ tumour [54]. In addition, 10% of gastric cancer cases are positive for glypican-3 [55]. In melanoma, 80% of tumours contain detectable level of glypican-3 protein and mRNA [1]. Regarding ovarian cancer, the rate of glypican expression could be as high as 18% of all ovarian cancer cases and 60% of clear cell carcinoma cases [51]. However, negative reports regarding clear cell carcinoma of ovary are published as well [53]. Glypican-3 is silenced in breast cancer, lung adenocarcinoma and mesothelioma [56-58]. Another problem has been highlighted by Abdul-Al et al., who have described frequent granular cytoplasmic expression of glypican-3 in chronic active hepatitis C [59]. Regenerative changes were suggested as the explanation. Authors emphasized that membranous staining was not observed in hepatitis [59]. Glypican-3 has prognostic significance in HCC as it is associated with poor prognosis [60] and shorter recurrence-free period after liver transplantation [49]. The applications of glypican-3 could extend beyond liver biopsy – and return to it. It could possible to use glypican-3 plasma levels for diagnostics and monitoring of HCC [61-63]. Immunotherapy could be guided towards glypican-3; the present research is exploring both antibody and cell-based immunological mechanisms [64-65]. Cancer vaccine could be generated against this molecule [1]. Glypican-3 is among genes that are distinctly expressed in liver cancer stem cells; it is suggested that glypican could be promising candidate for gene therapy without inducing damage to normal liver stem cells [66].
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Hep Par 1 is positive in normal liver, liver adenomas and HCC. The antibody was developed in 1993 using an immunogen from failed liver allograft. The target antigen has been identified as carbamoyl phosphate synthetase. This enzyme catalyses the rate-limiting step in the urea cycle and is located in the mitochondria [67]. The specifity and sensitivity of this marker in HCC diagnostics exceeds 80% and has reached 90% in several studies [6,67]. Unfortunately, sensitivity is lower in high-grade HCC. The expression in non-hepatocellular tumours including colorectal, pancreatic, breast, urothelial, prostate cancer, neuroendocrine tumours, renal cell carcinoma, melanoma and angiomyolipoma is either negative or focal. However, few gastric, colorectal and lung adenocarcinomas can be positive [6,67]. In the biopsy material, heterogeneity in the HCC can cause diagnostic problems [6].
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Arginase-1 is an enzyme involved in the urea cycle as well. It is found in benign hepatocytes and hepatocellular neoplasms. The antibody has received high sensitivity estimates of 96% and favourable performance characteristics [68,69].
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Alpha-fetoprotein is an oncofetal protein produced by the liver and yolk sac endoderm. The antigen is remarkable for expression in malignant hepatocellular tumours (Figure 2) in contrast to benign liver tissue, and for the high specifity. However, sensitivity is low (30-50%) and heterogeneity adds further problems in biopsy evaluation [6]. Nevertheless, positive expression is valuable.
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Figure 2.
Heterogeneous intense cytoplasmic expression of alpha-fetoprotein in hepatocellular carcinoma. Immunoperoxidase (IP), anti-alpha-fetoprotein, OM 100x.
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Polyclonal antibodies against carcinoembryonic antigen (CEA) yield positive reaction more than in 70% of HCC cases, while monoclonal anti-CEA only rarely stains HCC. Reactivity with polyclonal CEA antibodies mostly is observed in canaliculi; this pattern can be observed in benign or malignant liver tissues and is attributable to cross-reaction with biliary glycoprotein on the canalicular surface [67]. The canalicular pattern is specific for HCC and can be used to exclude cholangiocarcinoma and metastatic adenocarcinoma. It is not useful in the differential diagnosis between HCC and benign hepatocellular mass lesions. Although good general sensitivity has been reported, it is higher in well or moderately differentiated HCC that present less problems regarding the differential diagnosis with cholangiocellular carcinoma or metastasis [67]. Cytoplasmic stain is not observed in healthy liver or benign neoplasms; it is characteristic of malignancy but seen mostly in cholangiocellular carcinoma and metastatic neoplasms. The rate of cytokeratin fraction expression is 15% for CK7, 20% for CK20 and 10% for CK19. Diffuse strong expression of endothelial markers CD31 and CD34 is not characteristic for normal liver tissue in contrast to HCC [27]. The visualisation of endothelial layer is valuable also in estimating the thickness of trabeculae. However, pattern of diffuse, strong endothelial marker expression has low sensitivity of 20-40%. The patchy expression is also difficult to evaluate in liver biopsies. The visualisation of endothelium thus is not recommended for the distinction between adenoma and carcinoma [6].
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The transcription factor TTF-1 is expressed as intense granular cytoplasmic staining in normal liver parenchyma [16] and hepatocellular tumours (Figure 3). The reaction is ensured by cross-reactivity with hepatocyte mitochondrial antigen and is seen with the clone 8G7G3/1 [69]. The reported sensitivity is 60-70%. However, it parallels the expression of Hep Par 1 decreasing the practical value [6]. Its expression can be retained even in metastatic HCC [16].
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Figure 3.
Granular cytoplasmic expression of TTF-1 in hepatocellular carcinoma. IP, Anti-TTF-1, OM 400x.
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MOC-31 is an epithelial cell surface glycoprotein of unknown function. Evaluating liver biopsies, it is valuable as non-hepatocellular marker. MOC-31 is negative in HCC but positive in most metastatic adenocarcinomas and cholangiocellular cancer [67]. However, mesothelioma is MOC-31 negative as well; calretinin should be used in the panel to exclude this possibility [17].
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Molecular subtyping is emerging for HCC. The subtypes are distinguished by high proliferation and chromosomal instability; by activation of Wnt signalling pathway and by interferon signalling due to tumour-infiltrating cells [70-77].
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The requests for clinically relevant classification have resulted in the separation of HCC into early and progressed entities. The early HCC is recognized as small (not exceeding the diameter of 2 cm), well differentiated and lacking vascular invasion. The invasion into portal tracts can be present and is highlighted by lack of proliferating ductules. Macrovesicular steatosis is present in 40% of early HCC but appears mostly in Eastern cohorts. It can be attributable to incomplete neoarterialisation – the process of portal tract replacement by unpaired arteries outside the portal tracts. In early HCC, there is still comparatively large venous flow. The tumours in general may be radiologically hypovascular. The early HCC is more likely to become the biopsy target due to equivocal findings at imaging. Progressed HCC includes HCC of higher grade (moderate or poor differentiation degree, G2 or G3), possessing vascular invasion, larger size or stem/progenitor cell immunophenotype and mixed hepatobiliary differentiation. The stem cell immunophenotype can be detected by IHC for CK19, EpCAM, CD133, and mixed hepatobiliary immunophenotype – by expression of CK7 and CK19 [7]. The 5-year survival is 89% in the early HCC group in contrast to 48% in the progressed group. The intrahepatic metastatic spread must be distinguished from multifocal carcinoma that is prognostically better disease. The multifocal disease is characterised by “nodule in nodule” structure or by presence of at least one G1 nodule [7].
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The differential diagnosis includes benign hepatic lesions, metastatic malignancies and cholangiocarcinoma. IHC is of major importance. Markers, that are expressed both in benign and malignant liver cells (CEA by polyclonal antibody, CD10, Hep Par 1, TTF-1 and (occasionally) cytokeratins [27]) identify the hepatocellular origin of tumour but cannot be used to prove the malignant biological potential of suspicious biopsied tissue. If these are found in high-grade tumour, diagnosis of HCC is preferable in contrast to metastasis. The expression of alpha-fetoprotein and glypican-3 is typical for malignant tumour of hepatocellular origin [27]. These findings are important in differential diagnosis with non-hepatocellular and/or metastatic tumour in line with other markers specific for particular histogenesis. Regarding the differential diagnosis of HCC and dysplastic cirrhotic nodule, a panel of immunohistochemical stains is recommended employing glypican-3, glutamine synthetase and heat-shock protein 70 [48,78-80]. In biopsy, the panel has lower sensitivity although good specifity: accuracy 60.8% for 3 markers and 78.4% for 2 markers with 100% specifity. The findings were acceptable even in the group of low-grade HCC: the accuracy still was 57% for 3 markers and 72.9% for 2 markers with 100% specifity [23].
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HCC (except fibrolamellar type) mostly is associated either with cirrhosis or chronic active hepatitis with fibrosis that has not reached the degree of cirrhosis. To facilitate the differential diagnosis between HCC and liver adenoma or FNH it is wise to take separate biopsiesfrom the lesion and from distant liver tissues if possible.
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The future pathways for molecular diagnostics of HCC include mRNA analysis of GPC3, survivin and LYVE1 genes [78]. Glypican-3, encoded by GPC3, and survivin is up-regulated in parenchymal HCC cells while LYVE1 protein is down regulated in endothelial cells in case of malignancy. MYC pathway studies could also bring new information [29].
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In addition, molecular studies can predict the HCC prognosis. Down-regulation of p57 accelerates the growth and invasion of HCC cells [18]. The reduced p57 expression correlates with larger tumour size, higher TNM stage, presence of extrahepatic metastases and decreased survival. In cell lines, the down-regulation of p57 increases the expression of cyclin D1 and CDK2, enhancing the cellular proliferation. The matrix metalloproteinase-1 (MMP-1) and protease activated receptor-1 (PAR-1) are expressed in HCC but not in normal liver. The up-regulation of MMP-1/PAR-1 axis has prognostic value [20] and potentially could be used in the identification of malignancy. Co-expression of stem cell transcription factors Oct4 and Nanog indicates aggressive tumour behaviour and predicts recurrence after HCC resection [22]. FOXJ1 is over-expressed in HCC. It is associated with histological grade, poor prognosis and with tumour cell proliferation [19]. Hedgehog signalling pathway mediates invasion and metastasis of HCC via ERK pathway. Up-regulation of cell proliferation is associated with down-regulation of p27 and p21 and up-regulation of cyclin D1 [81]. Osteopontin plays role in the proliferation of HCC through interaction with the cell surface receptor CD44 [82] and is considered the key mediator for vasculogenic mimicry [83]. Bax-interacting factor is over-expressed in HCC and correlates with shortened survival [84]. NY-ESO-1 protein is a potential marker for early recurrence after surgical treatment [85]. Hepatocyte nuclear factor 4 suppresses the HCC development [86]. Sulfatase 2 protects HCC cells against apoptosis [87]. Interleukins as IL-17 and IL-6 have tumour-promoting role [88]. Interaction with matrix metalloproteinases 2 and 9 is likely [89]. Up-regulation of sirtuins has been identified [90]. Typing of immune cells in biopsy is mostly done for research purposes [91]. If any of those parameters will show prognostic and predictive value, the relevant IHC analysis should be included in the protocol of liver biopsy evaluation. The technological future developments include virtual microscopy. Fractal analysis [92] and quantitative IHC can be applied [93].
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Methylation studies have been carried out in HCC [94]. The expression of microRNAs is undergoing active analysis in HCC [95-96]. MicroRNAs are non-coding, short RNA molecules that can bind to messenger RNA and to prevent their translation into protein, providing additional regulation of gene expression. MicroRNAs act as large-scale molecular switch due to ability simultaneously down-regulate many genes. MicroRNA-181 down-regulates the differentiation and maturation of hepatocytes [96]. Suppression of microRNA-181 expression leads to reduced motility and invasion of HCC stem cells [25]. MicroRNA-182 could promote metastasis [97]. MicroRNA-183 inhibits apoptosis [98]. MicroRNA expression can be subjected to regulation with IL-6 [25]. Reduced expression of microRNA-26 in HCC is associated with poor prognosis. However, better response of interferon alpha postoperative adjuvant therapy can be expected [95]. MicroRNA-21 induces resistance to the anti-tumour effect of interferon and fluorouracil combination therapy [99]. Circulating microRNAs are valuable in tumour diagnosis and monitoring the treatment [24].
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3.2. Hepatoblastoma
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Hepatoblastoma is defined as a primary malignant blastomatous liver tumour showing complex differentiation towards fetal and embryonal hepatocytes as well as mature tissues including osteoid, connective tissue and striated muscle. Epidemiologically, hepatoblastoma is a rare malignant liver tumour of childhood with the incidence of 1 case / 1 million [8,10]. In children, hepatoblastoma is the most common primary liver tumour. Characteristically, the tumour develops within first five years of life: 4% of hepatoblastomas are present at birth, 69% have developed by 2 years of age and 90% - by 5 years of age. Only 3% of patients are older than 15 years [100]. The risk of hepatoblastoma is increased in APC-mutation-carrying children from familial adenomatous polyposis (FAP) kindreds. Clinically, enlarging abdomen can be the first sign. The other possible manifestations include weight loss, anorexia, nausea, vomiting and abdominal pain. Jaundice is rarely observed [100]. Paraneoplastic syndromes can occur. Among those, anaemia and thrombocytosis are frequent. Precocious puberty due to production of chorionic gonadotropin is rare. Grossly, the tumours mostly occur as single lesions [10] measuring 5-22 cm [100]. Pseudocapsule can develop due to compression of surrounding liver tissue. Microscopically, hepatoblastoma can display any of different histological patterns, or combination of these patterns. The fetal epithelial differentiation is characterised by thin trabeculae of small cuboidal cells. The nuclei are small and round with fine chromatin and small nucleolus. The cytoplasm can be either clear or finely granular resulting in “light and dark” pattern under low magnification. Foci of extramedullary haemopoesis can be present. The combined fetal and embryonal pattern is characterised by presence of small tumour cells in solid or acinar groups. The small cells have scant cytoplasm, higher nucleo: cytoplasmic ratio and coarse chromatin. Hepatoblastoma is called macrotrabecular if the cells compose 6-12 cell layers in the trabeculae in most of the tumour. Larger cells are present in the macrotrabeculae in addition to fetal and embryonal type. In teenagers, macrotrabecular hepatoblastoma must be differentiated from hepatocellular carcinoma. Small cell undifferentiated hepatoblastoma morphologically resembles small cell cancer displaying solid small blue cell pattern with focal necrosis. Mixed epithelial and mesenchymal hepatoblastomas contain mesenchymal components including fibrous tissue, osteoid, cartilage, striated muscle, bone or melanin [100]. Mixed epithelial and mesenchymal hepatoblastoma with teratoid features is recognised by the presence of endodermal, neuroectodermal and complex mesenchymal tissues. The neuroectodermal component can comprise melanin, glial and neuronal cells [10].After treatment, connective tissue, necrosis and signs of haemorrhage develop in association with residual neoplastic tissue, and squamous islands become more common. Immunohistochemically, expression of alpha-fetoprotein, beta-catenin and cell cycle markers is associated with the histological pattern. The fetal subtype is characterised by low proliferation that parallels the scant mitotic activity; alpha-fetoprotein can be present and the expression of beta-catenin is retained in the membranous localisation. The combined fetal and embryonal subtype is characterised by shift of beta-catenin expression towards the nuclei in higher grade embryonal component. An interesting circular pattern can be observed. In the rounded cell groups, the middle is occupied by progenitor-type pale, small cells displaying low proliferative activity and nuclear expression of beta-catenin. The progenitor-type cells are surrounded by intensively proliferating embryonal type cells characterised by mixed nuclear and cytoplasmic expression of beta-catenin. The outermost layer of these concentric structures is composed by fetal type cells with low proliferative activity and retained membranous expression of beta-catenin. The small cell subtype lacks alpha-fetoprotein but has high proliferative activity, usually reaching 80%; cytokeratins are expressed as well. Even in the mixed epithelial and mesenchymal hepatoblastoma, cytokeratins and alpha-fetoprotein can be expressed even in the ostecyte-like and osteoblast-like cells embedded in or associated with the osteoid, correspondingly [10]. In the study of Purcell et al., cyclin D1 and Ki-67 were two markers (out of 5, including also beta-catenin, E-cadherin and alpha-fetoprotein) that were shown to have prognostic value regarding survival [8].
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3.3. Cholangiocarcinoma
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Cholangiocarcinoma (CC) is defined as malignant epithelial liver tumour with biliary histogenesis or biliary differentiation. Epidemiologically, CC is a rare tumour with male predilection. It composes 15% of primary liver cancer [100] but the relative incidence range of cholangiocarcinoma is wide, from 5% in males and 12% in females in Osaka, Japan, to 90% in males and 94% of primary liver cancer cases in females in Thailand. The age-standardized incidence per 100 000 males ranges from 84.6 in Thailand to 2.8 in Osaka, Japan; 1.0 in France or 0.9 in Italy. The known risk factors include association with ulcerative colitis and primary sclerosing cholangitis [27]. The rate of cholangiocarcinoma in primary sclerosing cholangitis patients is estimated as 10-20%. The presence of parasites, especially Clonorchis sinensis and Opisthorchis viverrini, also increases the risk of cholangiocarcinoma. The high-incidence area in Laos and North and Northeast Thailand corresponds to the endemic area of Opisthorchis viverrini. Korea has high rate of cholangiocellular cancer due to endemic spread of Clonorchis sinensis. Clinically, the patients can present with painless jaundice [31], general malaise, mild abdominal pain and weight loss [100]. Grossly, several types exist. Peripheral tumours arise from portal bile ducts. Hilar lesions arise in large ducts. The diffuse intraductal papillomatosis involves ducts as widespread carcinoma in situ lacking dominant mass but leading to severe obstruction of bile flow. Histologically, cholangiocarcinoma has adenocarcinomatous structure characterised by tubular complexes and moderate amount of desmoplastic stroma. The architectural variants include high-grade tumour lacking the characteristic architecture, signet-ring cell tumour with presence of signet-ring cells, mucinous type with extensive secretion of extracellular mucin, adenosquamous type with focal squamous differentiation and spindle cell type with pseudosarcomatoid structure, presence of malignant spindle cells and signs of epithelial differentiation. The tumour has no functional connection with bile excretory system although morphological connection in the form of invasion or cancer in situ can exist. CC arises from ductal epithelium and not from hepatocytes. Due to these two reasons, presence of bile in the lumina of malignant glands is not characteristic but eosinophilic or mucinous secretion can be present. Mucin stains as PAS or mucicarmine can be positive [44]. The immunophenotype is derived from the immunophenotype of bile duct epithelium, with expression of following cytokeratins: CK19 (100%), CK7 (80-100%), CK20 (20%). Diffuse cytoplasmic expression of CEA is found by polyclonal antibody in almost all cases and is frequent by monoclonal antibody as well [27]. However, it is suggested that morphology cannot reliably distinguish cholangiocarcinoma from metastatic pancreatic or colorectal cancer [31]. In case of pancreatic adenocarcinoma, the marked cellular atypia disproportionally to better preserved architecture can be a clue. Colorectal adenocarcinoma in typical cases is characterised by columnar morphology and diffuse intense expression of CK20, CDX2 and CEA and lack of CK7. Other authors have drawn attention to the impossibility to distinguish cholangiocarcinoma from metastatic gastric cancer and cancer of gall bladder; metastatic pancreatic cancer also remains a problem [6]. The morphological differential diagnosis includes benign proliferation of bile ducts, hepatocellular carcinoma and metastatic adenocarcinoma [27]. In order to discriminate between biliary adenoma and cholangiocarcinoma, invasion (including single invasive cells and perineural invasion) and cellular atypia should be sought for. Radiologic findings are helpful as bile duct adenoma usually is smaller than 1 cm, but cholangiocarcinomas are large. The differential diagnosis with hepatocellular carcinoma can rely both on morphology and immunophenotype. Immunohistochemically, markers of biliary differentiation CK7 and CK19 are positive in cholangiocellular carcinoma. Hep Par 1 can be used to exclude hepatocellular differentiation [6,29]. Proteomic analysis of differentially expressed proteins in peripheral cholangiocarcinoma is under research [101].
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4. Vascular tumours
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Cavernous haemangioma, epithelioid haemangiendothelioma and angiosarcoma are endothelial tumours representing the whole spectrum of biological potential. Haemangioma is entirely benign although can cause complications due to large size; epithelioid haemangioendothelioma is notable for the peculiar structure leading to marked difficulties in the biopsy diagnostics, and angiosarcoma is a frank malignancy with grave prognosis. In addition, angiomyolipoma will be discussed as well although it should be noted that this tumour has complex structure including rich vascularity as one component.
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4.1. Cavernous haemangioma
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Haemangioma is defined as benign endothelial tumour [102]. Due to bleeding risk, it is only rarely seen in liver biopsy; in addition, the possibilities of radiological diagnostics are good and the prognosis only rarely necessitates active treatment. However, epidemiologically the lesion is the most common benign tumour of the liver with incidence 0.4% [27]. Clinically, haemangioma usually are asymptomatic due to small size and slow expansive growth. Occasionally, a giant haemangioma (10-30 cm) can cause pain due to mass effect. Thrombosis and bleeding can be dangerous complications. In neonates, blood shunting can lead to heart failure. Grossly, haemangiomas are mostly solitary (90%), of small or moderate size (less than 5 cm) and subcapsular. Microscopic structure is similar to cavernous haemangioma elsewhere in the body. Cavernous, lake-like blood spaces can be seen, separated by hypocellular fibrous septa (Figure 4). Thrombosis can be present. The immunophenotype reflects the endothelial origin. In the rare situation, when biopsy is obtained from cavernous haemangioma, the differential diagnosis can include hepatic tumours with rich vascularity as adenoma and cholangiocellular carcinoma. These are diagnosed by the presence and cytological properties of liver cells. Other vascular tumours could be considered, including infantile haemangioendothelioma, angiomyolipoma, epithelioid haemangioendothelioma and angiosarcoma. The infantile haemangioendothelioma can be recognized by capillary structure and occurrence in infants [27]. Angiomyolipoma shows combination of fat, smooth muscle and blood vessels with radiating immature smooth muscle cells. The higher cellularity and presence of fat are features incompatible with cavernous haemangioma. Epithelioid haemangioendothelioma is discussed separately; the occurrence of vascular lakes usually is not observed. Angiosarcoma can have cavernous architecture but the hallmark of it is the cellular atypia.
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Figure 4.
Cavernous haemangioma in liver tissue. Note the large, cavernous spaces filled with red blood cells. HE, OM 50x.
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4.2. Angiomyolipoma
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Angiomyolipoma is defined as benign mesenchymal tumour with complex structure including immature smooth muscle, blood vessels and fat. Epithelioid cells and perivascular HMB-45-positive cells can be present. Research of the tumour histogenesis has resulted in the concept of PEComa, a tumour of perivascular epithelioid cells, showing myomatous, lipomatous and melaninogenic differentiation. Epidemiologically, liver angiomyolipoma is rare. It has been diagnosed in wide age range (10-86 years). In tuberous sclerosis, the incidence of angiomyolipoma is increased. These patients may develop multiple angiomyolipomas in liver as well as kidney angiomyolipoma. Awareness of this condition is necessary to escape over-diagnosis of metastatic malignant tumour. Clinically, the tumour can be asymptomatic. However, large tumours can cause pain; rupture and bleeding is also possible. By radiologic studies, the tumour is hypervascular again. Grossly, angiomyolipoma usually is solitary (except in tuberous sclerosis), measuring 0.8-36 cm. The microscopic picture (Figure 5) is straightforward if all three components are present in liver biopsy and have typical structure. The smooth muscle cells can have epithelioid appearance leading to morphological similarity to liver parenchymal cells; the rich vascularity could lead to diagnostic confusion with hepatocellular tumour already earlier. The epithelioid cells sometimes can cause suspicion for malignancy due to large nuclei and nucleoli. However, the nucleo: cytoplasmic ratio remains low due to increased cell size.
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Figure 5.
The microscopic structure of angiomyolipoma. Note the peculiar, thick-walled blood vessels, immature smooth muscle proliferation with high cellularity as well as the presence of fat. HE, OM 100x.
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In difficult cases, IHC is helpful. The smooth muscle cells express actin (Figure 6) and fat cells – S-100 protein. HMB-45 expression can be observed in perivascular epithelioid cells (Figure 7). The differential diagnosis can include hepatocellular neoplasms or spindle cell sarcomas. Actin expression and complex histological structure helps to exclude hepatocellular origin of the tumour. Complex structure, combined immunophenotype and low proliferation help to exclude sarcoma [27].
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Figure 6.
Actin-positive smooth muscle component in angiomyolipoma. IP, anti-actin, OM 100x.
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Figure 7.
Expression of melanosome protein HMB-45 in angiomyolipoma. IP, anti-HMB-45, OM 400x.
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4.3. Epithelioid haemangioendothelioma
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Epithelioid haemangioendothelioma (EHE) is defined as intermediate-grade malignancy derived from endothelial cells. The mean age of patients is 47 years, ranging 12-86 years. The clinical picture can include symptoms related to enlarging mass in liver (abdominal pain, hepatomegaly) and tumour-related intoxication (fatigue, malaise, anorexia). Radiologically, the tumour can be found by computed tomography. EHE can be radiologically avascular [10,27,103]. This finding is probably related to fibrosis and scarcity of functioning blood vessels despite the endothelial origin of the tumour. Grossly, multiple tumours can involve liver or liver and lungs. In the lungs, epithelioid haemangioendothelioma is known also as intravascular bronchioloalveolar tumour. Despite the multifocality (Figure 8), slow progress is possible in our experience.
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Biopsy material is usually sufficient to diagnose the tumour. However, in our experience, immunohistochemical investigation is crucial in order to find out the presence of tumour cells on the background of stromal fibrosis and reactive inflammation, to detect the endothelial origin and to evaluate the low biological potential as reflected by low to moderate proliferation activity by Ki-67 (Figures 9-11).
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Figure 8.
Multiple foci of epithelioid haemangioendothelioma in liver biopsy. The tumour is highlighted by immunohistochemical visualisation of vimentin regarding its mesenchymal nature. IP, anti-vimentin, OM 50x.
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Figure 9.
Epithelioid haemangioendothelioma presenting as a fibrotic focus in liver biopsy. HE, OM 100x.
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Figure 10.
Loss of liver parenchyma due to infiltration of epithelioid haemangioendothelioma. IP, anti-cytokeratins AE1/AE3, OM 200x.
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Figure 11.
Expression of CD34 in epithelioid haemangioendothelioma. Note also the positive reaction in the lining of a venule. IP,anti-CD34, OM 400x.
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The tumour is growing within sinusoids and venules compressing the adjacent parenchyma. As was mentioned, the expression of endothelial markers is typical. Focal expression of cytokeratin and/or actin is possible [103] and should not cause confusion if panel of immunostains is performed. Stromal fibrosis follows than and can become marked so that neoplastic cells are obscured (Figure 9). Two cell types are described: epithelioid and dendritic. The morphological differential diagnosis includes non-neoplastic fibrosis and/or inflammation and granulation tissue, angiosarcoma and metastatic cancers with marked stromal fibrosis. The non-neoplastic conditions can be ruled out by tumour architecture as revealed by immunohistochemistry. Epithelial tumours can be excluded by the predominance of endothelial markers by IHC. Among the vascular malignancies, the diagnosis of epithelioid haemangioendothelioma is preferred for lesions with low grade atypia, absence of frankly malignant spindle cells, low proliferation, limited destruction of surrounding liver tissue and absence of necrosis.
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4.4. Angiosarcoma
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Angiosarcoma is defined as malignant tumour of endothelial cells. Epidemiologically, it is characterised by rare occurrence in the liver constituting 2% of primary hepatic malignancies [11]. Elderly (50-60-year-old) males represent the largest group of affected patients [27]. The described risk factors include history of thorotrast use for arteriography, exposure to vinyl chloride in the plastics industry where it has been used for polymerisation, arsenic compounds (used as insecticides, possibly present in wine and used in the treatment of psoriasis), copper compounds, pesticides and other chemical carcinogens. In all cases, long latent period (6-35 years) embarrass the data collection. The clinical picture can show signs and symptoms of liver damage (hepatomegaly, local pain, jaundice), disorders of blood cell function (anaemia, thrombocytopenia, disseminated intravascular coagulation), and tumour-related intoxication manifesting as weight loss. Ascites, bleeding into abdominal cavity and liver failure is possible [27]. Grossly, multiple masses with signs of haemorrhage are present. Morphologically, the cellular atypia as well as vascular differentiation can be observed in variable extent. High-grade tumours exhibit solid growth with few vascular spaces. Immunohistochemically, endothelial markers CD31 and CD34 are expressed. However, the immunophenotype can be not straightforward. In our experience, it is important to use several endothelial markers. At first, the reactivity can be uneven [27]. Even more, CD34 is technologically beneficial antibody characterised with high affinity. However, during the evaluation it is necessary to consider CD34 expression in non-endothelial tumours including gastrointestinal stromal tumour and solitary fibrous tumour, among others.
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5. Metastatic liver tumours
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In Western countries, metastatic tumours represent the most common malignant liver lesion with the rate 94-98% among all malignant liver tumours [27]. Almost all malignant tumours, including carcinomas, sarcomas, melanomas and haematological malignancies, can secondary involve the liver by haematogenous, lymphogeneous or transperitoneal spread. Theoretically, metastatic tumour retains the morphological characteristics of the primary site. However, the balance between anaplasia and differentiation can shift towards anaplasia in such degree that signs of differentiation towards specific tissue or cell type are hardly recognisable. Some tumours like squamous cell cancer and melanoma lack specifity regarding the organ of origin. Even adenocarcinomas retain few specific features. Therefore the differential diagnostics between primary and secondary liver tumours represents a complicated practical task. Clinical data can be absent if metastatic liver lesion presents as cancer of unknown origin. The diagnosis can be reached by logical analysis of morphology, IHC and molecular data. If the establishment of exact histogenesis is unsuccessful, the biopsy investigation should be directed towards the analysis of treatment possibilities. Pathologist should comment in detail morphological and immunophenotype data that could either prove or disregard any particular type of treatment.
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In case of liver metastasis, the primary tumour most frequently is located in colon, pancreas, stomach, breast, oesophagus, genitourinary organs [100, 103]. Lung cancer can metastasize to liver as well [6]. Neuroendocrine tumours, even small, can give rise to hepatic metastases. The clinical course in this case can be prolonged and occasionally characterised by carcinoid syndrome including flushing, diarrhoea and palpitations.
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The spectrum of metastatic tumours in liver biopsies depend on the frequency of different tumours, the biological properties of different neoplasms predicting the possibility of metastatic spread to liver as well as by the medical paradigm considering the indications for liver biopsies. In the files of single university hospital, metastatic tumours constituted 45% of tumours or tumour-like liver lesions. Adenocarcinoma was the most frequent histological type of metastases (65.5%) comprising metastases of colorectal (48.2%), pancreatic (13.5%), breast (13%), gastric (6.2%), lung (4.5%) and oesophageal cancer (3.7%). Neuroendocrine carcinomas were seen frequently (16%). Lymphoma constituted 0.4% of all tumours [2]. Metastases in cirrhotic liver were rare [2]. In another study, including 130 cases of metastatic liver disease, gastrointestinal tract was found to be the most common primary location (45.3%) of cancer metastasizing to liver followed by neuroendocrine tumours (10.7%) [104]. In children, neuroblastoma, nephroblastoma and rhabdomyosarcoma are the most frequent source of metastases [103].
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The spread to liver occurs in 5-10% of patients with Hodgkin’s lymphoma and 15-40% of non-Hodgkin’s lymphoma cases at the time of diagnosis. Leukemias can involve the liver as well. Grossly, large cell lymphoma can form masses similarly to carcinoma. In case of Hodgkin’s disease, the size of nodules is variable. Leukemic infiltrate can be present without visible mass lesion. Myeloid leukemias preferentially infiltrate sinusoids, lymphoid – portal tracts, but hairy cell leukemia can involve both portal tracts and sinusoids forming small blood containing cavities, surrounded by neoplastic cells [103].
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Malignant melanoma (Figures 12-14) is one of the greatest challenges in diagnostic surgical pathology [105] due to amelanotic, clear cell, sarcomatoid, small cell, haemangiopericytoid, signet-ring cell, myxoid, metaplastic and rhabdoid forms. The diagnosis largely depends on IHC. Evaluating the intermediate filaments, melanoma expresses vimentin. Despite the reported concerns of cytokeratin expression in melanoma, this is rare event (3%) in formalin-fixed tissues. Similarly, the expression of glial fibrillar acidic protein and actin is observed in 1% of melanomas [105]. Interspersed normal cells should be excluded from evaluation of cytokeratin and actin reactivity. Melanoma is characterised by nuclear and cytoplasmic expression of S-100 protein in 97.4-98%. S-100 protein can be observed in carcinomas, histiocytic neoplasms and malignant peripheral nerve sheath tumour, therefore melanoma-specific antibodies, e.g., HMB-45 and MART-1/Melan-A must be included in the panel. Melanoma can express bcl-2, CD10, CD68, CD56, CD57, CD99, CD117 antigens leading to diagnostic confusion with lymphoma, renal cell cancer, hepatocellular cancer, GIST, seminoma and other neoplasms. Expression of Melan-A is found also in metastatic adrenocortical carcinoma (50-60%) that can be recognised by inhibin expression in around 70% of cases [6]. S-100, HMB-45, Melan-A and inhibin are absent from HCC [6].
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Figure 12.
Diffuse sinusoidal spread of undifferentiated malignant tumour. By immunohistochemistry, metastatic melanoma was revealed (see also Figure 13). HE, OM 400 x.
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Figure 13.
Intense perinuclear expression of melanosome protein HMB-45 in metastatic melanoma. IP, anti-HMB-45, OM 400x.
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Figure 14.
Lack of cytokeratins AE1/AE3 in metastatic melanoma. Note the unusual sinusoidal spread. IP, anti-AE1/AE3, OM 400x.
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Metastatic breast cancer expresses CK7 but not CK20. However, this immunophenotype is shared by many adenocarcinomas. To identify the tumour as metastasis from breast primary tumour, gross cystic disease fluid protein fraction-15 (GCDFP-15) and/or mammaglobin can be detected. The specifity of GCDFP-15 is estimated as 99%, and the sensitivity ranges from 50 to 74%. Breast cancers of luminal molecular type express oestrogen (ER) and progesterone receptors (PR). Naturally, the expression of female steroid hormone receptors is shared by ovarian and endometrial cancer. Nowadays the detection of ER and PR is routine in breast cancer diagnostics but less experience is obtained with expression of hormone receptors in extra-genital carcinomas. The scientific studies report expression of ER in carcinoma of lung, stomach and thyroid [105]. The cross-reactivity can be associated by certain antibody clones. Also, HER-2 positive and triple negative molecular types of breast cancer are more prone to develop visceral metastases. Thus, negative ER/PR expression cannot exclude metastatic breast cancer, and positive findings should be interpreted with caution recognising the possibility of metastatic ovarian or endometrial cancer and cross-reactivity or true expression of hormone receptors in extra-genital tumour. ER/PR expression in lung or thyroid tumour can be controlled by TTF-1 protein expression and/or evaluation for neuroendocrine markers and calcitonin.
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\n\t\t\t
Figure 15.
Surfactant A in pulmonary adenocarcinoma. IP, anti-surfactant apoprotein A, OM 400x.
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Adenocarcinoma, squamous cell cancer, small cell cancer and carcinoid are the most frequent lung neoplasms. Lung adenocarcinoma is characterised by expression of CK7 (100%) and TTF-1 (60-75%). Expression of CK20 is rare. Cytokeratins 5/6 and 34betaE12 can be present but are not dominant in comparison with CK7. Vimentin can be found in lung adenocarcinomas. Nuclear expression of TTF-1 and/or cytoplasmic expression of surfactant apoprotein A (Figure 15) is an evidence of pulmonary origin. Small cell cancer expresses neuroendocrine markers and pan-cytokeratin. The expression of chromogranin A and CK AE1/AE3 can be limited to perinuclear dot reactivity. Simultaneous detection of leukocyte common antigen can be suggested to perform differential diagnosis with haematological neoplasm. Nuclear expression of TTF-1 protein is frequently present (Figures 16-18). The high proliferation fraction by Ki-67 is characteristic albeit unspecific. The immunophenotype of squamous cell cancer is unspecific and characterised by cytoplasmic expression of CK5/6 and CK 34betaE12 in association with strong nuclear reactivity with p63 protein. CK7 can be present but is not dominant. TTF-1 protein is absent. Carcinoid is characterised by neuroendocrine differentiation and low proliferative activity. The TTF-1 expression is not frequent [17,105-107].
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\n
\n
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Figure 16.
Small cell cancer. Note the “salt-and-pepper” chromatin and high mitotic activity. HE, OM 400x.
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Figure 17.
Granular cytoplasmic and perinuclear expression of chromogranin A in small cell cancer. IP, anti-chromogranin A, OM 400x.
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Figure 18.
Nuclear TTF-1 expression in small cell cancer. IP, anti-chromogranin A, OM 400x.
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Mesothelioma is characterised by expression of CK7, CK5/6, vimentin and calretinin (Figure 19). HBME-1 can be expressed as well but lacks specifity.
\n\t\t\t
Figure 19.
Nuclear and cytoplasmic expression of calretinin in epithelioid mesothelioma.IP, anti-calretinin, OM 400x.
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Metastatic colorectal carcinoma can be recognised by diffuse intensive cytoplasmic expression of CK20 and nuclear expression of CDX2 [108]. Carcinoid of the midgut and hindgut also are positive for CDX2 [109].
\n\t\t\t
Neuroendocrine tumours are characterised by strong cytoplasmic expression of chromogranin A and synaptophysin and negativity for Hep Par 1 [6]. CD56 is considered to be the most sensitive neuroendocrine marker. In our experience, it shows reliable performance in small or compressed biopsies making it especially valuable tool for the evaluation of scant tissue material. Occasional CD56 expression in HCC is described [6].
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Renal cell carcinoma is characterised by negativity for Hep Par 1 and CEA expression (by polyclonal anti-CEA antibody). Unfortunately, the rate of RCC expression decreases from 50-80% in primary clear cell renal carcinoma and 60-90% in papillary renal cell cancer to 20% in metastatic renal cell carcinoma. CD10 can be present both in HCC and renal cell carcinoma. Although the pattern of expression is different this can be difficult to evaluate, especially in core biopsy. PAX-2 is advised as marker of metastatic renal cell carcinoma with the expression rate 70-80%. Expression of vimentin is more characteristic in clear cell renal carcinoma (60-70%) than in hepatocellular carcinoma; chromophobe renal cell carcinoma also is negative [6].
\n\t\t\t
As tumour heterogeneity remains a source of problems [69] and the immunophenotype can be inherently complex and subjected to cross reactivity, we recommend wide IHC panels including several markers for HCC and cholangiocarcinoma as well as markers for metastatic tumour, including the organospecific antigens (see Tables 1-2).
\n\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Tumour
\n\t\t\t\t\t\t
Immunophenotype
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Malignant melanoma
\n\t\t\t\t\t\t
Vim + CK AE1 / AE3 – S-100 + HMB-45 + MART-1 / Melan A +
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Lung adenocarcinoma
\n\t\t\t\t\t\t
CK7+ CK20- CK34betaE12-/+ TTF-1+ Surfactant apoprotein A +
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Small cell cancer
\n\t\t\t\t\t\t
CK AE1/AE3 + ChrA+ CD56 +TTF-1 +
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Squamous cancer
\n\t\t\t\t\t\t
CK34betaE12+ CK7-/+ CK20 – p63+
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
NET
\n\t\t\t\t\t\t
CK AE1/AE3 + ChrA+ TTF-1 +/ - (lung) or CDX2 + (midgut, hindgut)
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Breast cancer
\n\t\t\t\t\t\t
CK 7 + CK20 – MG +/– ER +/– PR +/–
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Colorectal cancer
\n\t\t\t\t\t\t
CK20+ CK7- CDX2+ TTF-1-
\n\t\t\t\t\t
\n\t\t\t\t
Table 1.
The immunophenotype of selected malignant tumours. Abbreviations in the Table: Vim, vimentin; CK, cytokeratin; TTF-1, thyroid transcription factor 1; ChrA, chromogranin A; NET, neuroendocrine tumour; MG, mammaglobin; ER, oestrogen receptor; PR, progesterone receptor
\n\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Antigen
\n\t\t\t\t\t\t
Valuable positive expression
\n\t\t\t\t\t\t
Notes
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Glypican-3
\n\t\t\t\t\t\t
Hepatocellular carcinoma
\n\t\t\t\t\t\t
Occasional positivity in non-hepatocellular tumour
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Arginase-1
\n\t\t\t\t\t\t
Hepatocellular carcinoma
\n\t\t\t\t\t\t
Sensitivity for hepatocellular carcinoma 96% Normal liver tissue positive Metastatic tumours rarely positive [69]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Hep Par 1
\n\t\t\t\t\t\t
Hepatocellular carcinoma
\n\t\t\t\t\t\t
Sensitivity for hepatocellular carcinoma around 50% [69] Gastric carcinoma can be positive
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
AFP
\n\t\t\t\t\t\t
Hepatocellular carcinoma
\n\t\t\t\t\t\t
Sensitivity for hepatocellular carcinoma around 15% [69]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
CD10
\n\t\t\t\t\t\t
Renal cell carcinoma Hepatocellular carcinoma
\n\t\t\t\t\t\t
Negative in adrenal carcinoma
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
CK7
\n\t\t\t\t\t\t
Cholangiocellular carcinoma Metastatic cancers
\n\t\t\t\t\t\t
Positivity does not exclude hepatocellular carcinoma Valuable for primary evaluation of malignant tumour within liver
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
CK17
\n\t\t\t\t\t\t
Cholangiocellular carcinoma Metastatic cancers
\n\t\t\t\t\t\t
Positive tumours as pancreatic cancer (58%), squamous carcinoma (75%), urothelial carcinoma (75%) and cholangiocellular carcinoma (35%) can be distinguished from negative ones (gastric, colorectal, prostate, breast cancer, hepatocellular carcinoma)
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
CK19
\n\t\t\t\t\t\t
Cholangiocellular carcinoma Metastatic cancers
\n\t\t\t\t\t\t
Positivity does not exclude hepatocellular carcinoma
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
CK20
\n\t\t\t\t\t\t
Metastatic colorectal cancer
\n\t\t\t\t\t\t
Useful in conjuction with CK7 for initial grouping of cancers showing adenocarcinomatous structure
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
CDX2
\n\t\t\t\t\t\t
Metastatic colorectal cancer and NETs
\n\t\t\t\t\t\t
Heterogeneous focal expression in gastric and pancreatic carcinomas Mucinous ovarian cancers can be positive Morules in endometrioid carcinoma are positive
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Calretinin
\n\t\t\t\t\t\t
Mesothelioma Adrenal cortical carcinoma Sex cord-stromal tumours of the genital tract
\n\t\t\t\t\t\t
Squamous carcinoma frequently positive
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Surfactant apoprotein A
\n\t\t\t\t\t\t
Lung adenocarcinoma. In our experience possess high affinity and is useful, if positive
\n\t\t\t\t\t\t
Reactivity in thyroid cancer (43% in small group) has been reported Heterogeneous expression has been observed [69]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
TTF-1, nuclear expression
\n\t\t\t\t\t\t
Metastatic pulmonary adenocarcinoma (75% of non-mucinous type and 10% of mucinous type), small cell cancer (pulmonary, 50-90%; non-pulmonary, 44-80%) or thyroid cancer including papillary, follicular and medullary but not anaplastic carcinoma [69]
\n\t\t\t\t\t\t
Regarding pulmonary adenocarcinoma, less subjected to heterogeneity-related evaluation problems than surfactant apoprotein A Endometrial (17%) or breast (2.4%) cancer occasionally positive [69]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
TTF-1, cytoplasmic expression:
\n\t\t\t\t\t\t
Hepatocellular carcinoma
\n\t\t\t\t\t\t
Expression in benign liver parenchyma is present Gastric or prostatic cancer can show cytoplasmic positivity
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Chromogranin A and synaptophysin
\n\t\t\t\t\t\t
NET
\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
CD56
\n\t\t\t\t\t\t
NET, cholangiocarcinoma
\n\t\t\t\t\t\t
Other tumours can be positive
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Oestrogen and progesterone receptors
\n\t\t\t\t\t\t
Breast, ovarian or endometrial cancer, endometrial stromal sarcoma
\n\t\t\t\t\t\t
Non-gynaecologic cancers can be occasionally positive, including lung cancer (4-15-67%)
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
CD117
\n\t\t\t\t\t\t
GIST Seminoma
\n\t\t\t\t\t\t
CD34 is co-expressed in GISTs PLAP is co-expressed in germ cell tumours
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Mammaglobin
\n\t\t\t\t\t\t
Breast cancer
\n\t\t\t\t\t\t
High heterogeneity Sensitivity for breast cancer 40-85% Ovarian (17%), endometrial (40-70%) and endocervical (30%) carcinoma can also be positive [69]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
GCDFP-15
\n\t\t\t\t\t\t
Breast cancer
\n\t\t\t\t\t\t
Sensitivity for breast cancer 50-60% High heterogeneity Not associated with mammaglobin thus simultaneous evaluation can be recommended [69]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
PSA
\n\t\t\t\t\t\t
Prostatic cancer \n\t\t\t\t\t\t
\n\t\t\t\t\t\t
Negative in 5% high-grade prostate cancers. Reactivity in few breast carcinomas and rectal NETs have been observed [69]
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
Pax8
\n\t\t\t\t\t\t
Thyroid cancer Female genital tract carcinomas Renal cell cancer
\n\t\t\t\t\t\t
Sensitivity for thyroid cancer 79-100% and for renal cancer 71-98% Breast cancer is negative. Positivity is useful to discriminate breast cancer from ovarian or endometrial cancer NETs can be positive
\n\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t\t\t
P63
\n\t\t\t\t\t\t
Squamous cell cancer Urothelial carcinoma
\n\t\t\t\t\t\t
\n\t\t\t\t\t
\n\t\t\t\t
Table 2.
Panel of antibodies for liver biopsy evaluation. Abbreviations in the Table: AFP, alpha-fetoprotein; CK, cytokeratin; NET, neuroendocrine tumour; TTF-1, thyroid transcription factor 1; GIST, gastrointestinal stromal tumour; PLAP, placental alkaline phosphatase; GCDFP-15, gross cystic disease fluid protein-15; PSA, prostate specific antigen
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\n\t\t\t
6. Cystic biliary tumours
\n\t\t\t
The cystic biliary tumours are defined by cystic structure and development of / differentiation towards intrahepatic bile duct epithelium. The group includes malignant biliary cystadenocarcinoma and benign biliary cystadenoma. Epidemiologically, cystic biliary tumours represent rare entities, with incidence of biliary cystadenocarcinoma approximately 1/10 million (corresponding to 0.01/100 000) and of biliary cystadenoma 1/100 000 - 5/100 000 [110]. Biliary cystadenocarcinoma is diagnosed mostly at the age 50-60 years [100]. Biliary cystadenoma is diagnosed in younger patients: mean age 40.6 (range 30-51) vs. 51.3 (range 41-63) years in biliary cystadenocarcinoma group [14]. In other studies even larger age difference (17 years) is found between patients affected by benign and malignant cystic biliary tumours, respectively [111-112]. Cystic biliary tumours are more common in women: 80-100% of biliary adenoma and 63-71.4% of biliary cystadenocarcinoma are described in female [14]. The clinical picture reflects the presence of mass lesion and is dominated by abdominal pain [113]. The other manifestations and complications include jaundice, cholangitis, tumour rupture [114], haemorrhage [115], compression of the portal or caval veins with possible subsequent ascites [113], hemobilia [12] and mucobilia [116]. Notably, the tumour can progress slowly [117] with the clinical history of biliary cystadenocarcinoma as long as 10-15 years [112,118]. The long course is is in accordance with the low grade of malignancy and gradual development of tumour through stages of increased epithelial proliferation, dysplasia, in situ cancer and, finally, invasive cancer. Thus, long anamnesis of cystic hepatic mass does not exclude the possibility of malignant tumour and the need for careful follow-up if the cyst is not removed by operation. Although biopsy can be considered in cases with unclear differential diagnosis, it is not the first choice because of the following considerations. First, simple liver cyst is the main differential diagnosis of cystic biliary tumours. Although biliary cystadenocarcinoma is rare, liver cysts have high prevalence being present in 2.5% of the population [119] and cannot be distinguished from cystic biliary tumours on the basis of CA19-9 and CEA levels [14,114]. However, core biopsy is unlikely to yield sufficient tissue in case of simple cyst or cystadenoma; it also is not suitable for the diagnostics of focal malignancy and rarely can lead to peritoneal carcinomatosis [13]. Therefore radiological diagnostics, especially computed tomography, is essential [117]. Grossly, biliary cystadenocarcinoma is multicystic. Internal mural nodules are irregularly distributed in the walls. The tumour most frequently is located within the liver (83%). Extra-hepatic bile ducts (13%) or the gall bladder (0.02%) has been affected by this tumour as well [14]. The size of cystic biliary tumours (1.5-30 cm) is not helpful in the differential diagnostics between simple hepatic cyst and cystic biliary tumours; it also has no correlation with malignant biological potential [120]. The metastatic spread of biliary cystadenocarcinoma can affect the liver, regional lymph nodes in the hepatoduodenal ligament, lungs, pleura or peritoneum [100]. Histologically, biliary cystadenocarcinoma is characterised by clear-cut signs of malignancy: cellular atypia, particularly nuclear polymorphism, mitotic activity and invasion into surrounding stroma. The tumour architecture is cystic and papillary. The benign counterpart of biliary cystadenocarcinoma, the biliary cystadenoma lacks the malignant features [100] and is composed by either mucinous or serous benign epithelium. Most of cystic biliary tumours possess characteristic mesenchymal, ovarian–type stroma. Hypothetically, these tumours arise from bile ducts proximal to the hilum of the liver and share the cystic structure and presence of peculiar ovarian-type mesenchymal stroma with mucinous cystic tumours of the pancreas and retroperitoneum, leading to the hypothesis that ectopic ovarian stroma during embryogenesis can become incorporated along the biliary tree, in the pancreas and retroperitoneal space and cause the proliferation of the adjacent epithelium by production of the hormones and growth factors [121]. Origin from intrahepatic peribiliary glands [122] or from ectopic rests of primitive foregut sequestered in the liver [114] has been hypothesised. Development from pluripotential stem cells is suggested on the basis of the presence of albumin messenger RNA and biliary type cytokeratins in the tumour cells [123]. Biliary cystadenocarcinoma without mesenchymal stroma more frequently arises in males and carries poorer prognosis in comparison with the tumour possessing mesenchymal stroma [122]. By immunohistochemistry, increasing proliferative activity by Ki-67 expression as well as increasing p53 protein expression from adenoma to carcinoma was shown in biliary cystadenocarcinoma without ovarian-type stroma [124]. Expression of cytokeratin (CK) 7 and absence of CK20, CEA, alpha-fetoprotein, calretinin, CD31 and chromogranin is described [125]. However, presence of CK20, although typical for colorectal cancer, is described in cholangiocarcinoma, especially non-peripheral [126]. It might be expected in biliary cystadenocarcinoma with growing awareness about this entity.
\n\t\t\t
There is evidence showing that at least some cases of biliary cystadenocarcinoma originate from pre-existing biliary cystadenoma. These data include the age difference between biliary cystadenocarcinoma and biliary adenoma patients [14] as well as morphologic findings of malignant transformation in a lesion with focally innocuous structure [127].
\n\t\t\t
Radiologically, presence of internal septations allows excluding a simple cyst. Vascularity of septa is characteristic for cystic biliary tumours [14] and is considered by some specialists to be more reliable in distinguishing biliary cystadenoma from cyst than the simple presence of septations [117]. Biliary cystadenoma is characterised by smooth and thin internal septa, but presence of enhanced mural nodules in the outer wall or septa is the most important sign of malignancy. Calcification is not frequent but has been found specific for malignancy by some [14] but not all [119] authors as far as cystic biliary tumours are concerned. Size, number of septations or location of the neoplasm does not help to differentiate between benign or malignant cystic biliary tumours [14]. Some authors have postulated that preoperative differentiation between biliary adenoma and cystadenocarcinoma by radiologic imaging is not possible therefore liver resection should be performed for all cystic biliary tumours [120]. This assumption is based on the experience that internal papillae with arterial enhancement may be present in both tumours so that computed tomography and magnetic resonance imaging yield overlapping data.
\n\t\t\t
The clinical differential diagnosis of cystic liver lesions, entering the differential diagnosis of biliary cystadenocarcinoma, include developmental, neoplastic, inflammatory and traumatic lesions as simple bile duct cyst, polycystic liver disease, biliary hamartoma, cystically degenerated cases of other primary or metastatic liver tumours, abscesses, hydatid cyst, extrapancreatic pseudocyst, hematoma and biloma [119,128].
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7. Conclusions
\n\t\t\t
In conclusion, wide variety of neoplastic processes can affect the liver. Most of non-cystic tumours can be reliably diagnosed in liver biopsy. Several demographic and clinical data should be submitted along with the liver biopsy. Patient’s age and presence or absence of clinical symptoms must be known. If there is history of contraceptive use it should be reported. Radiological data have high relevance: the size, localisation in respect to liver capsule and number of focal liver lesions should be known to the pathologist. The vascularity should be described. Knowing these data, pathologist should evaluate the haematoxylin-eosin stained specimen. Wide panel of immunohistochemical stains can be recommended than.
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\n\t\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/40425.pdf",chapterXML:"https://mts.intechopen.com/source/xml/40425.xml",downloadPdfUrl:"/chapter/pdf-download/40425",previewPdfUrl:"/chapter/pdf-preview/40425",totalDownloads:4588,totalViews:530,totalCrossrefCites:2,totalDimensionsCites:3,totalAltmetricsMentions:0,introChapter:null,impactScore:2,impactScorePercentile:82,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"April 27th 2012",dateReviewed:"August 29th 2012",datePrePublished:null,datePublished:"November 21st 2012",dateFinished:"October 23rd 2012",readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/40425",risUrl:"/chapter/ris/40425",book:{id:"3329",slug:"liver-biopsy-indications-procedures-results"},signatures:"Ilze Strumfa, Janis Vilmanis, Andrejs Vanags, Ervins Vasko, Dzeina Sulte, Zane Simtniece, Arnis Abolins and Janis Gardovskis",authors:[{id:"54021",title:"Prof.",name:"Ilze",middleName:null,surname:"Strumfa",fullName:"Ilze Strumfa",slug:"ilze-strumfa",email:"ilze.strumfa@rsu.lv",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/54021/images/system/54021.jpg",institution:{name:"Riga Stradiņš University",institutionURL:null,country:{name:"Latvia"}}},{id:"159993",title:"Dr.",name:"Janis",middleName:null,surname:"Vilmanis",fullName:"Janis Vilmanis",slug:"janis-vilmanis",email:"Janis.Vilmanis@rsu.lv",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Riga Stradiņš University",institutionURL:null,country:{name:"Latvia"}}},{id:"159994",title:"Dr.",name:"Andrejs",middleName:null,surname:"Vanags",fullName:"Andrejs Vanags",slug:"andrejs-vanags",email:"vanags314@inbox.lv",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"159996",title:"Dr.",name:"Zane",middleName:null,surname:"Simtniece",fullName:"Zane Simtniece",slug:"zane-simtniece",email:"Zane.Simtniece@rsu.lv",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Riga Stradiņš University",institutionURL:null,country:{name:"Latvia"}}},{id:"159997",title:"Dr.",name:"Dzeina",middleName:null,surname:"Sulte",fullName:"Dzeina Sulte",slug:"dzeina-sulte",email:"ilzestrumfa@yahoo.co.uk",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"159998",title:"Dr.",name:"Arnis",middleName:null,surname:"Abolins",fullName:"Arnis Abolins",slug:"arnis-abolins",email:"Arnis.Abolins@rsu.lv",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Riga Stradiņš University",institutionURL:null,country:{name:"Latvia"}}},{id:"160000",title:"Prof.",name:"Janis",middleName:null,surname:"Gardovskis",fullName:"Janis Gardovskis",slug:"janis-gardovskis",email:"janis.gardovskis@rsu.lv",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/160000/images/7691_n.png",institution:{name:"Riga Stradiņš University",institutionURL:null,country:{name:"Latvia"}}},{id:"165981",title:"Dr.",name:"Ervins",middleName:null,surname:"Vasko",fullName:"Ervins Vasko",slug:"ervins-vasko",email:"ervinsvasko@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Benign epithelial liver tumours",level:"1"},{id:"sec_2_2",title:"2.1. Liver cell adenoma and its differential diagnosis with focal nodular hyperplasia",level:"2"},{id:"sec_3_2",title:"2.2. Bile duct adenoma",level:"2"},{id:"sec_5",title:"3. Malignant epithelial primary liver tumours",level:"1"},{id:"sec_5_2",title:"3.1. Hepatocellular carcinoma",level:"2"},{id:"sec_6_2",title:"3.2. Hepatoblastoma",level:"2"},{id:"sec_7_2",title:"3.3. Cholangiocarcinoma",level:"2"},{id:"sec_9",title:"4. Vascular tumours",level:"1"},{id:"sec_9_2",title:"4.1. Cavernous haemangioma",level:"2"},{id:"sec_10_2",title:"4.2. Angiomyolipoma",level:"2"},{id:"sec_11_2",title:"4.3. Epithelioid haemangioendothelioma",level:"2"},{id:"sec_12_2",title:"4.4. Angiosarcoma",level:"2"},{id:"sec_14",title:"5. Metastatic liver tumours",level:"1"},{id:"sec_15",title:"6. Cystic biliary tumours",level:"1"},{id:"sec_16",title:"7. 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B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKnoflach\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBale\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tAccuracy and diagnostic yield of CT-guided stereotactic liver biopsy of primary and secondary liver tumours.\n\t\t\t\t\tComput Aided Surg\n\t\t\t\t\t16\n\t\t\t\t\t4\n\t\t\t\t\t181\n\t\t\t\t\t187\n\t\t\t\t\tdoi: 10.3109/10929088.2011.578367\n\t\t\t\t\n\t\t\t'},{id:"B16",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMishra\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorgan\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHamati\n\t\t\t\t\t\t\tA. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAl-Abbadi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tCarcinoma of unknown primary: check the liver... thanks to TTF-1.\n\t\t\t\t\tTenn Med\n\t\t\t\t\t105\n\t\t\t\t\t1\n\t\t\t\t\t35\n\t\t\t\t\t36\n\t\t\t\t\n\t\t\t'},{id:"B17",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBahrami\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTruong\n\t\t\t\t\t\t\tL. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRo\n\t\t\t\t\t\t\tJ. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tUndifferentiated tumour: true identity by immunohistochemistry.\n\t\t\t\t\tArch Pathol Lab Med\n\t\t\t\t\t132\n\t\t\t\t\t3\n\t\t\t\t\t326\n\t\t\t\t\t348\n\t\t\t\t\n\t\t\t'},{id:"B18",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuo\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLv\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTian\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHu\n\t\t\t\t\t\t\tT. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tW. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSui\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJiang\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRuan\n\t\t\t\t\t\t\tZ. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNan\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tDownregulation of p57 accelerates the growth and invasion of hepatocellular carcinoma.\n\t\t\t\t\tCarcinogenesis\n\t\t\t\t\t32\n\t\t\t\t\t12\n\t\t\t\t\t1897\n\t\t\t\t\t1904\n\t\t\t\t\n\t\t\t'},{id:"B19",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tH. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHuang\n\t\t\t\t\t\t\tX. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tH. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHe\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNi\n\t\t\t\t\t\t\tR. Z.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tC. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPeng\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tY. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhao\n\t\t\t\t\t\t\tY. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tY. X.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShen\n\t\t\t\t\t\t\tA. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tExpression of FOXJ1 in hepatocellular carcinoma: correlation with patients’ prognosis and tumor cell proliferation.\n\t\t\t\t\tMol CarcinogEpub ahead of print,doi: 10.1002/mc.21904\n\t\t\t\t\thttp://onlinelibrary.wiley.com/doi/10.1002/mc.21904/pdf(accessed 4 July)\n\t\t\t'},{id:"B20",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiao\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTong\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhao\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFeng\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHu\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPan\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tPrognostic value of matrix metalloproteinase-1/proteinase-activated receptor-1 signaling axis in hepatocellular carcinoma.\n\t\t\t\t\tPathol Oncol Res\n\t\t\t\t\t18\n\t\t\t\t\t2\n\t\t\t\t\t397\n\t\t\t\t\t403\n\t\t\t\t\n\t\t\t'},{id:"B21",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLu\n\t\t\t\t\t\t\tJ. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhao\n\t\t\t\t\t\t\tW. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHe\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWei\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tHedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway.\n\t\t\t\t\tActa Pharmacol Sin33\n\t\t\t\t\t5\n\t\t\t\t\t691\n\t\t\t\t\t700\n\t\t\t\t\n\t\t\t'},{id:"B22",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYin\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tY. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tB. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRen\n\t\t\t\t\t\t\tZ. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQiu\n\t\t\t\t\t\t\tS. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYi\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFan\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tCoexpression of stemness factors Oct4 and Nanog predict liver resection. \n\t\t\t\t\tAnn Surg OncolEpub Mar 30 ahead of print.doi: 10.1245/s10434-012-2314-6\n\t\t\t\t\thttp://www.springerlink.com/content/h31v0112827836r2/fulltext.pdf(accessed 04 August).\n\t\t\t'},{id:"B23",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDi Tommaso\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDestro\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSeok\n\t\t\t\t\t\t\tJ. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBalladore\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTerracciano\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSangiovanni\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIavarone\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tColombo\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJang\n\t\t\t\t\t\t\tJ. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYu\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJin\n\t\t\t\t\t\t\tS. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorenghi\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPark\n\t\t\t\t\t\t\tY. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoncalli\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tThe application of markers (HSP70 GPC3 and GS) in liver biopsies is useful for detection of hepatocellular carcinoma.\n\t\t\t\t\t J Hepatol\n\t\t\t\t\t50\n\t\t\t\t\t4\n\t\t\t\t\t746\n\t\t\t\t\t754\n\t\t\t\t\n\t\t\t'},{id:"B24",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlbulescu\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNeagu\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlbulescu\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTanase\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tTissular and soluble miRNAs for diagnostic and therapy improvement in digestive tract cancers\n\t\t\t\t\tExpert Rev Mol Diagn\n\t\t\t\t\t11\n\t\t\t\t\t1\n\t\t\t\t\t101\n\t\t\t\t\t120\n\t\t\t\t\n\t\t\t'},{id:"B25",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMeng\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGlaser\n\t\t\t\t\t\t\tS. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrancis\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDe Morrow\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHan\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJD\n\t\t\t\t\t\t\tPassarini\n\t\t\t\t\t\t\tStokes. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCleary\n\t\t\t\t\t\t\tJ. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVenter\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKumar\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPriester\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHubble\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStaloch\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSharma\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tC. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlpini\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tFunctional analysis of microRNAs in human hepatocellular cancer stem cells.\n\t\t\t\t\tJ Cell Mol Med\n\t\t\t\t\t16\n\t\t\t\t\t1\n\t\t\t\t\t160\n\t\t\t\t\t173\n\t\t\t\t\n\t\t\t'},{id:"B26",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBarthelmes\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTait\n\t\t\t\t\t\t\tI. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tLiver cell adenoma and liver cell adenomatosis\n\t\t\t\t\tHPB (Oxford)\n\t\t\t\t\t7\n\t\t\t\t\t3\n\t\t\t\t\t186\n\t\t\t\t\t196\n\t\t\t\t\n\t\t\t'},{id:"B27",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKanel\n\t\t\t\t\t\t\tG. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKorula\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tAtlas of liver pathology\n\t\t\t\t\t3rd edition. Philadelphia: Elsevier Saunders\n\t\t\t\t\n\t\t\t'},{id:"B28",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBioulac-Sage\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBalabaud\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZucman-Rossi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tSubtype classification of hepatocellular adenoma\n\t\t\t\t\tDig Surg\n\t\t\t\t\t27\n\t\t\t\t\t1\n\t\t\t\t\t39\n\t\t\t\t\t45\n\t\t\t\t\n\t\t\t'},{id:"B29",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWalther\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJain\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tMolecular pathology of hepatic neoplasms: classification and clinical significance.\n\t\t\t\t\tPathology Research Int\n\t\t\t\t\t2011\n\t\t\t\t\t403929\n\t\t\t\t\t10.4061/2011/403929\n\t\t\t\t\thttp://www.hindawi.com/journals/pri/2011/403929/\n\t\t\t\t\t(accessed 08 July 2012).\n\t\t\t\t\n\t\t\t'},{id:"B30",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBuell\n\t\t\t\t\t\t\tJ. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTranchart\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCannon\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDagher\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tManagement of benign hepatic tumours.\n\t\t\t\t\tSurg Clin North Am\n\t\t\t\t\t90\n\t\t\t\t\t4\n\t\t\t\t\t719\n\t\t\t\t\t735\n\t\t\t\t\n\t\t\t'},{id:"B31",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLongo\n\t\t\t\t\t\t\tD. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFauci\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKasper\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHauser\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJameson\n\t\t\t\t\t\t\tJ. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLoscalzo\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tHarrison’s principles of internal medicine.\n\t\t\t\t\tMcGraw-Hill\n\t\t\t\t\n\t\t\t'},{id:"B32",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFarges\n\t\t\t\t\t\t\tO.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDokmak\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tMalignant transformation of liver adenoma: an analysis of the literature\n\t\t\t\t\tDig Surg\n\t\t\t\t\t27\n\t\t\t\t\t1\n\t\t\t\t\t32\n\t\t\t\t\t38\n\t\t\t\t\n\t\t\t'},{id:"B33",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBluteau\n\t\t\t\t\t\t\tO.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJeannot\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBioulac-Sage\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMarques\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBlanc\n\t\t\t\t\t\t\tJ. 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C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFranco\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBalabaud\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLaurent-Puig\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZucman-Rossi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tBi-allelic inactivation of TCF1 in hepatic adenomas.\n\t\t\t\t\tNat Genet\n\t\t\t\t\t32\n\t\t\t\t\t2\n\t\t\t\t\t312\n\t\t\t\t\t315\n\t\t\t\t\n\t\t\t'},{id:"B34",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tReznik\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDao\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCoutant\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChiche\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJeannot\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tClauin\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRousselot\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFabre\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOberti\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFatome\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZucman-Rossi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBellanne-Chantelot\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tHepatocyte nuclear factor-1 alpha gene inactivation: cosegregation between liver adenomatosis and diabetes phenotypes in two maturity-onset diabetes of the young (MODY) 3 families.\n\t\t\t\t\tJ Clin Endocrinol Metab\n\t\t\t\t\t89\n\t\t\t\t\t3\n\t\t\t\t\t1476\n\t\t\t\t\t1480\n\t\t\t\t\n\t\t\t'},{id:"B35",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJeannot\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMellottee\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBioulac-Sage\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBalabaud\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tScoazec\n\t\t\t\t\t\t\tJ. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTran Van\n\t\t\t\t\t\t\tNhieu. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBacq\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMichalak\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBuob\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\tGroupe d’etude Genetique des Tumeurs Hepatiques (INSERM Network)\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLaurent-Puig\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRusyn\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZucman-Rossi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tSpectrum of HNF1A somatic mutations in hepatocellular adenoma differs from that in patients with MODY3 and suggests genotoxic damage.\n\t\t\t\t\tDiabetes\n\t\t\t\t\t59\n\t\t\t\t\t7\n\t\t\t\t\t1836\n\t\t\t\t\t1844\n\t\t\t\t\n\t\t\t'},{id:"B36",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRebouissou\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAmessou\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCouchy\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPoussin\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tImbeaud\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPilati\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIzard\n\t\t\t\t\t\t\tT. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlabaud\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBioulac-Sage\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZucman-Rossi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tFrequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours.\n\t\t\t\t\tNature\n\t\t\t\t\t457\n\t\t\t\t\t7226\n\t\t\t\t\t200\n\t\t\t\t\t204\n\t\t\t\t\n\t\t\t'},{id:"B37",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tY. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJeng\n\t\t\t\t\t\t\tY. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYeh\n\t\t\t\t\t\t\tS. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tP. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tP53 gene and Wnt signaling in benign neoplasms: beta-catenin mutations in hepatic adenoma but not in focal nodular hyperplasia.\n\t\t\t\t\tHepatology\n\t\t\t\t\t36\n\t\t\t\t\t4 Pt 1\n\t\t\t\t\t927\n\t\t\t\t\t935\n\t\t\t\t\n\t\t\t'},{id:"B38",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZucman-Rossi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJeannot\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNhieu\n\t\t\t\t\t\t\tJ. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tScoazec\n\t\t\t\t\t\t\tJ. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuettier\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRebouissou\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBacq\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLeteurtre\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tParadis\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMichalak\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWendum\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChiche\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFabre\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMellottee\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLaurent\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPartensky\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCastaing\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZafrani\n\t\t\t\t\t\t\tE. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLaurent-Puig\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBalabaud\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBioulac-Sage\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tGenotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC.\n\t\t\t\t\tHepatology\n\t\t\t\t\t43\n\t\t\t\t\t3\n\t\t\t\t\t515\n\t\t\t\t\t524\n\t\t\t\t\n\t\t\t'},{id:"B39",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBioulac-Sage\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLaumonier\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRullier\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCubel\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLaurent\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZucman-Rossi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBalabaud\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tOver-expression of glutamine synthetase in focal nodular hyperplasia: a novel easy diagnostic tool in surgical pathology\n\t\t\t\t\tLiver Int\n\t\t\t\t\t29\n\t\t\t\t\t3\n\t\t\t\t\t459\n\t\t\t\t\t465\n\t\t\t\t\n\t\t\t'},{id:"B40",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWanless\n\t\t\t\t\t\t\tI. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMawdsley\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAdams\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1985\n\t\t\t\t\tOn the pathogenesis of focal nodular hyperplasia of the liver.\n\t\t\t\t\tHepatology\n\t\t\t\t\t5\n\t\t\t\t\t6\n\t\t\t\t\t1194\n\t\t\t\t\t1200\n\t\t\t\t\n\t\t\t'},{id:"B41",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBioulac-Sage\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLaumonier\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCubel\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSaric\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBalabaud\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tOver-expression of glytamine synthase in focal nodular hyperplasia (part 1): early stages in the formation support the hypothesis of a focal hyper-arterialisation with venous (portal and hepatic) and biliary damage.\n\t\t\t\t\tComp Hepatol\n\t\t\t\t\t7\n\t\t\t\t\t2\n\t\t\t\t\n\t\t\t'},{id:"B42",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRebouissou\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBioulac-Sage\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZucman-Rossi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tMolecular pathogenesis of focal nodular hyperplasia and hepatocellular adenoma.\n\t\t\t\t\tJ Hepatol\n\t\t\t\t\t48\n\t\t\t\t\t1\n\t\t\t\t\t163\n\t\t\t\t\t170\n\t\t\t\t\n\t\t\t'},{id:"B43",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAltekruse\n\t\t\t\t\t\t\tS. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Glynn\n\t\t\t\t\t\t\tK. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tReichman\n\t\t\t\t\t\t\tM. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tHepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005.\n\t\t\t\t\tJ Clin Oncol\n\t\t\t\t\t27\n\t\t\t\t\t9\n\t\t\t\t\t1485\n\t\t\t\t\t1491\n\t\t\t\t\n\t\t\t'},{id:"B44",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBancroft\n\t\t\t\t\t\t\tJ. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGamble\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tTheory and practice of histological techniques, 5th ed.\n\t\t\t\t\tEdinburgh: Churchill Livingstone\n\t\t\t\t\n\t\t\t'},{id:"B45",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCapurro\n\t\t\t\t\t\t\tM. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXiang\n\t\t\t\t\t\t\tY. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLobe\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFilmus\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tGlypican-3 promotes the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling.\n\t\t\t\t\tCancer Res\n\t\t\t\t\t65\n\t\t\t\t\t14\n\t\t\t\t\t6245\n\t\t\t\t\t6254\n\t\t\t\t\n\t\t\t'},{id:"B46",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCapurro\n\t\t\t\t\t\t\tM. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXu\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShi\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJia\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFilmus\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tGlypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding\n\t\t\t\t\tDev Cell\n\t\t\t\t\t14\n\t\t\t\t\t5\n\t\t\t\t\t700\n\t\t\t\t\t711\n\t\t\t\t\n\t\t\t'},{id:"B47",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakatsura\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYoshitake\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSenju\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMonji\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKomori\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMotomura\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHosaka\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBeppu\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIshiko\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKamohara\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAshikara\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKatagiri\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFurukawa\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFujiyama\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOgawa\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakamura\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNishimura\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003\n\t\t\t\t\tGlypican-3, overexpressed specifically in human hepatocellular carcinoma, is a novel tumor marker.\n\t\t\t\t\tBiochem Biophys Res Commun\n\t\t\t\t\t306\n\t\t\t\t\t1\n\t\t\t\t\t16\n\t\t\t\t\t25\n\t\t\t\t\n\t\t\t'},{id:"B48",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamauchi\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWatanabe\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHishinuma\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOhashi\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMidorikawa\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorishita\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNiki\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShibahara\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMori\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMakuuchi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHippo\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKodama\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIwanari\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAburatani\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFukayama\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tThe glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma.\n\t\t\t\t\tMod Pathol\n\t\t\t\t\t18\n\t\t\t\t\t12\n\t\t\t\t\t1591\n\t\t\t\t\t1598\n\t\t\t\t\n\t\t\t'},{id:"B49",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tY. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhu\n\t\t\t\t\t\t\tZ. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTeng\n\t\t\t\t\t\t\tD. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYao\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGao\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShen\n\t\t\t\t\t\t\tZ. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tGlypican-3 expression and its relationship with recurrence of HCC after liver transplantation.\n\t\t\t\t\tWorld J Gastroenterol\n\t\t\t\t\t18\n\t\t\t\t\t19\n\t\t\t\t\t2408\n\t\t\t\t\t2414\n\t\t\t\t\n\t\t\t'},{id:"B50",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakatsura\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKageshita\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWakamatsu\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMonji\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIkuta\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSenju\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOno\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNishimura\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tIdentification of glypican-3 as a novel tumor marker for melanoma.\n\t\t\t\t\tClin Cancer Res\n\t\t\t\t\t10\n\t\t\t\t\t19\n\t\t\t\t\t6612\n\t\t\t\t\t6621\n\t\t\t\t\n\t\t\t'},{id:"B51",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStadlmann\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGueth\n\t\t\t\t\t\t\tU.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBaumhoer\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoch\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTerracciano\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSinger\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tGlypican-3 expression in primary and recurrent ovarian carcinomas.\n\t\t\t\t\tInt J Gynecol Pathol\n\t\t\t\t\t26\n\t\t\t\t\t3\n\t\t\t\t\t341\n\t\t\t\t\t344\n\t\t\t\t\n\t\t\t'},{id:"B52",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZynger\n\t\t\t\t\t\t\tD. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDimov\n\t\t\t\t\t\t\tN. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLuan\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTeh\n\t\t\t\t\t\t\tB. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tX. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tGlypican 3: a novel marker in testicular germ cell tumors.\n\t\t\t\t\tAm J Surg Pathol30\n\t\t\t\t\t12\n\t\t\t\t\t1570\n\t\t\t\t\t1575\n\t\t\t\t\n\t\t\t'},{id:"B53",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEsheba\n\t\t\t\t\t\t\tG. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPate\n\t\t\t\t\t\t\tL. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLongacre\n\t\t\t\t\t\t\tT. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tOncofetal protein glypican-3 distinguishes yolk sac tumor from clear cell carcinoma of the ovary.\n\t\t\t\t\tAm J Surg Pathol\n\t\t\t\t\t32\n\t\t\t\t\t4\n\t\t\t\t\t600\n\t\t\t\t\t607\n\t\t\t\t\n\t\t\t'},{id:"B54",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBaumhoer\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTornillo\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStadlmann\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoncalli\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDiamantis\n\t\t\t\t\t\t\tE. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTerracciano\n\t\t\t\t\t\t\tL. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tGlypican 3 expression in human nonneoplastic, preneoplastic, and neoplastic tissues: a tissue microarray analysis of 4,387 tissue samples\n\t\t\t\t\tAm J Clin Pathol\n\t\t\t\t\t129\n\t\t\t\t\t6\n\t\t\t\t\t899\n\t\t\t\t\t906\n\t\t\t\t\n\t\t\t'},{id:"B55",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tUshiku\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tUozaki\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShinozaki\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOta\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMatsuzaka\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNomura\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKaminishi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAburatani\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKodama\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFukuyama\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tGlypican 3-expressing gastric carcinoma: distinct subgroup unifying hepatoid, clear-cell and alpha-fetoprotein-producing gastric carcinomas.\n\t\t\t\t\tCancer Sci\n\t\t\t\t\t100\n\t\t\t\t\t4\n\t\t\t\t\t626\n\t\t\t\t\t632\n\t\t\t\t\n\t\t\t'},{id:"B56",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMurthy\n\t\t\t\t\t\t\tS. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShen\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDe Rienzo\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLee\n\t\t\t\t\t\t\tW. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFerriola\n\t\t\t\t\t\t\tP. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJhanwar\n\t\t\t\t\t\t\tS. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMossman\n\t\t\t\t\t\t\tB. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFilmus\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTesta\n\t\t\t\t\t\t\tJ. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000\n\t\t\t\t\tExpression of GPC3, an X-linked recessive overgrowth gene, is silenced in malignant mesothelioma.\n\t\t\t\t\tOncogene\n\t\t\t\t\t19\n\t\t\t\t\t3\n\t\t\t\t\t410\n\t\t\t\t\t416\n\t\t\t\t\n\t\t\t'},{id:"B57",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXiang\n\t\t\t\t\t\t\tY. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLadeda\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFilmus\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tGlypican-3 expression is silenced in human breast cancer.\n\t\t\t\t\tOncogene\n\t\t\t\t\t20\n\t\t\t\t\t50\n\t\t\t\t\t7408\n\t\t\t\t\t7412\n\t\t\t\t\n\t\t\t'},{id:"B58",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKim\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXu\n\t\t\t\t\t\t\tG. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBorczuk\n\t\t\t\t\t\t\tA. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBusch\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFilmus\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCapurro\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrody\n\t\t\t\t\t\t\tJ. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLange\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tD’Armiento\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRothman\n\t\t\t\t\t\t\tP. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPowell\n\t\t\t\t\t\t\tCA\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003\n\t\t\t\t\tThe heparan sulphate proteoglycan GPC3 is a potential lung tumor suppressor.\n\t\t\t\t\t Am J Respir Cell Mol Biol\n\t\t\t\t\t29\n\t\t\t\t\t6\n\t\t\t\t\t694\n\t\t\t\t\t701\n\t\t\t\t\n\t\t\t'},{id:"B59",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAbdul-Al\n\t\t\t\t\t\t\tH. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMakhlouf\n\t\t\t\t\t\t\tH. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGoodman\n\t\t\t\t\t\t\tZ. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tGlypican-3 expression in benign liver tissue with active hepatitis C: implications for the diagnosis of hepatocellular carcinoma\n\t\t\t\t\tHum Pathol\n\t\t\t\t\t39\n\t\t\t\t\t2\n\t\t\t\t\t209\n\t\t\t\t\t212\n\t\t\t\t\n\t\t\t'},{id:"B60",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShirakawa\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSuzuki\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShimomura\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKojima\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGotohda\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakahashi\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakagohri\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKonishi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKobayashi\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKinoshita\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakatsura\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tGlypican-3 expression is correlated with poor prognosis in hepatocellular carcinoma.\n\t\t\t\t\t Cancer Sci\n\t\t\t\t\t100\n\t\t\t\t\t8\n\t\t\t\t\t1403\n\t\t\t\t\t1407\n\t\t\t\t\n\t\t\t'},{id:"B61",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHippo\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWatanabe\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWatanabe\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMidorikawa\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamamoto\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIhara\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTokita\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIwanari\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIto\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakano\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNezu\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTsunoda\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYoshino\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOhizumi\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTsuchiya\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOhnishi\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMakuuchi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHamakubo\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKodama\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAburatani\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tIdentification of soluble NH2-terminal fragment of glypican-3 as a serological marker for early-stage hepatocellular carcinoma.\n\t\t\t\t\tCancer Res\n\t\t\t\t\t64\n\t\t\t\t\t7\n\t\t\t\t\t418\n\t\t\t\t\t423\n\t\t\t\t\n\t\t\t'},{id:"B62",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYan\n\t\t\t\t\t\t\tB. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGong\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSong\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKrausz\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTretiakova\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHyjek\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAl-Ahmadie\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlves\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXiao\n\t\t\t\t\t\t\tS. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAnders\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHart\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tArginase-1: a new immunohistochemical marker of hepatocytes and hepatocellular neoplasms.Am J Surg Pathol34\n\t\t\t\t\t8\n\t\t\t\t\t1147\n\t\t\t\t\t1154\n\t\t\t\t\n\t\t\t'},{id:"B63",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYao\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYao\n\t\t\t\t\t\t\tD. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBian\n\t\t\t\t\t\t\tY. Z.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tC. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQiu\n\t\t\t\t\t\t\tL. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSai\n\t\t\t\t\t\t\tW. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tJ. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tH. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tOncofetal antigen glypican-3 as a promising early diagnostic marker for hepatocellular carcinoma.\n\t\t\t\t\tHepatobiliary Pancreat Dis Int\n\t\t\t\t\t10\n\t\t\t\t\t3\n\t\t\t\t\t289\n\t\t\t\t\t294\n\t\t\t\t\n\t\t\t'},{id:"B64",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIshiguro\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSugimoto\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKinoshita\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiyazaki\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakano\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTsunoda\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSugo\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOhizumi\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAburatani\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHamakubo\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKodama\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTsuchiya\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamada-Okabe\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tAnti-glypican 3 antibody as a potential antitumor agent for human liver cancer.\n\t\t\t\t\tCancer Res\n\t\t\t\t\t68\n\t\t\t\t\t23\n\t\t\t\t\t9832\n\t\t\t\t\t9838\n\t\t\t\t\n\t\t\t'},{id:"B65",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakatsura\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKomori\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKubo\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYoshitake\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSenju\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKatagiri\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFurukawa\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOgawa\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakamura\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNishimura\n\t\t\t\t\t\t\tYl.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tMouse homologue of a novel human oncofetal antigen, glypican-3, evokes T-cell mediated tumor rejection without autoimmune reactions in mice.\n\t\t\t\t\tClin Cancer Res\n\t\t\t\t\t10\n\t\t\t\t\t24\n\t\t\t\t\t8630\n\t\t\t\t\t8640\n\t\t\t\t\n\t\t\t'},{id:"B66",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHo\n\t\t\t\t\t\t\tD. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tZ. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYi\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLam\n\t\t\t\t\t\t\tC. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNg\n\t\t\t\t\t\t\tM. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYu\n\t\t\t\t\t\t\tW. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLau\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWan\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYan\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFan\n\t\t\t\t\t\t\tS. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tGene expression profiling of liver cancer stem cells by RNA-sequencing.\n\t\t\t\t\tPLoS One\n\t\t\t\t\t7\n\t\t\t\t\t5\n\t\t\t\t\te37159\n\t\t\t\t\t10.1371/journal.pone.0037159\n\t\t\t\t\n\t\t\t'},{id:"B67",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChan\n\t\t\t\t\t\t\tE. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYeh\n\t\t\t\t\t\t\tM. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tThe use of immunohistochemistry in liver tumours.\n\t\t\t\t\tClin Liver Dis\n\t\t\t\t\t14\n\t\t\t\t\t4\n\t\t\t\t\t687\n\t\t\t\t\t703\n\t\t\t\t\n\t\t\t'},{id:"B68",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYan\n\t\t\t\t\t\t\tB. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGong\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSong\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKrausz\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTretiakova\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHyjek\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAl-Ahmadie\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlves\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXiao\n\t\t\t\t\t\t\tS. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAnders\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHart\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tArginase-1: a new immunohistochemical marker of hepatocytes and hepatocellular neoplasms\n\t\t\t\t\tAm J Surg Pathol\n\t\t\t\t\t34\n\t\t\t\t\t8\n\t\t\t\t\t1147\n\t\t\t\t\t1154\n\t\t\t\t\n\t\t\t'},{id:"B69",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiller\n\t\t\t\t\t\t\tR. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tImmunohistochemistry in the diagnosis of metastatic carcinoma of unknown primary origin. \n\t\t\t\t\tProceedings of the American Academy of Oral and Maxillofacial Pathology Annual Meeting30.04.2011San Juan, Puerto Rico. \n\t\t\t\t\tProceedings of the American Academy of Oral and Maxillofacial Pathology Annual Meeting, 30.04.2011, San Juan, Puerto Rico.\n\t\t\t\t\thttp://www.aaomp.org/annual-meeting/docs/2011_CE5_Miller--Met%20ca%20Final%20Handout.pdf(accessed 04 August)\n\t\t\t'},{id:"B70",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChiang\n\t\t\t\t\t\t\tD. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVillanueva\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHoshida\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPeix\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNewell\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMinguez\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLe Blanc\n\t\t\t\t\t\t\tA. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDonovan\n\t\t\t\t\t\t\tD. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThung\n\t\t\t\t\t\t\tS. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSole\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTovar\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlsinet\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRamos\n\t\t\t\t\t\t\tA. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBarretina\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoayaie\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchwartz\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWaxman\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBruix\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMazzaferro\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLigon\n\t\t\t\t\t\t\tA. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNajfeld\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFriedman\n\t\t\t\t\t\t\tS. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSellers\n\t\t\t\t\t\t\tW. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMeyerson\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLlovet\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tFocal gains of VEGFA and molecular classification of hepatocellular carcinoma.\n\t\t\t\t\tCancer Res\n\t\t\t\t\t\n\t\t\t\t\t68\n\t\t\t\t\t16\n\t\t\t\t\t6779\n\t\t\t\t\t6788\n\n\t\t\t\t\n\t\t\t'},{id:"B71",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHoshida\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNijman\n\t\t\t\t\t\t\tS. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKobayashi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChan\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrunet\n\t\t\t\t\t\t\tJ. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChiang\n\t\t\t\t\t\t\tD. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVillanueva\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNewell\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIkeda\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHashimoto\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWatanabe\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGabriel\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFriedman\n\t\t\t\t\t\t\tS. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKumada\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLlovet\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGolub\n\t\t\t\t\t\t\tT. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tIntegrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma.\n\t\t\t\t\tCancer Res\n\t\t\t\t\t69\n\t\t\t\t\t18\n\t\t\t\t\t7385\n\t\t\t\t\t7392\n\t\t\t\t\n\t\t\t'},{id:"B72",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLee\n\t\t\t\t\t\t\tJ. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChu\n\t\t\t\t\t\t\tI. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHeo\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCalvisi\n\t\t\t\t\t\t\tD. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSun\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoskams\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDurnez\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDemetris\n\t\t\t\t\t\t\tA. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThorgeirsson\n\t\t\t\t\t\t\tS. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tClassification and prediction of survival in hepatocellular carcinoma by gene expression profiling.\n\t\t\t\t\tHepatology\n\t\t\t\t\t40\n\t\t\t\t\t3\n\t\t\t\t\t667\n\t\t\t\t\t676\n\t\t\t\t\n\t\t\t'},{id:"B73",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLee\n\t\t\t\t\t\t\tJ. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHeo\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLibbrecht\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChu\n\t\t\t\t\t\t\tI. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKaposi-Novak\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCalvisi\n\t\t\t\t\t\t\tD. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMikaelyan\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoberts\n\t\t\t\t\t\t\tL. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDemetris\n\t\t\t\t\t\t\tA. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSun\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNevens\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoskams\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThorgeirsson\n\t\t\t\t\t\t\tS. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tA novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells.\n\t\t\t\t\tNat Med\n\t\t\t\t\t12\n\t\t\t\t\t4\n\t\t\t\t\t410\n\t\t\t\t\t416\n\t\t\t\t\n\t\t\t'},{id:"B74",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBoyault\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRickman\n\t\t\t\t\t\t\tD. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tde Reynies\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBalabaud\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRebouissou\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJeannot\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHerault\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSaric\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBelghiti\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFranco\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBioulac-Sage\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLaurent-Puig\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZucman-Rossi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tTranscriptome classification of HCC is related to gene alterations and to new therapeutic targets.\n\t\t\t\t\tHepatology\n\t\t\t\t\t45\n\t\t\t\t\t1\n\t\t\t\t\t42\n\t\t\t\t\t52\n\t\t\t\t\n\t\t\t'},{id:"B75",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBreuhahn\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVreden\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHaddad\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBeckebaum\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStippel\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFlemming\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNussbaum\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCaselmann\n\t\t\t\t\t\t\tW. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHaab\n\t\t\t\t\t\t\tB. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchirmacher\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tMolecular profiling of human hepatocellular carcinoma defines mutually exclusive interferon regulation and insulin-like growth factor II overexpression.\n\t\t\t\t\tCancer Res\n\t\t\t\t\t64\n\t\t\t\t\t17\n\t\t\t\t\t6058\n\t\t\t\t\t6064\n\t\t\t\t\n\t\t\t'},{id:"B76",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamashita\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tForgues\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKim\n\t\t\t\t\t\t\tJ. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYe\n\t\t\t\t\t\t\tQ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJia\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBudhu\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZanetti\n\t\t\t\t\t\t\tK. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQin\n\t\t\t\t\t\t\tL. X.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTang\n\t\t\t\t\t\t\tZ. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tX. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tEpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma.\n\t\t\t\t\tCancer Res\n\t\t\t\t\t68\n\t\t\t\t\t5\n\t\t\t\t\t1451\n\t\t\t\t\t1461\n\t\t\t\t\n\t\t\t'},{id:"B77",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVillanueva\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHoshida\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tToffanin\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLachenmayer\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlsinet\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSavic\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCornella\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLlovet\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tNew strategies in hepatocellular carcinoma: genomic prognostic markers.\n\t\t\t\t\tClin Cancer Res\n\t\t\t\t\t16\n\t\t\t\t\t19\n\t\t\t\t\t4688\n\t\t\t\t\t4694\n\t\t\t\t\n\t\t\t'},{id:"B78",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLlovet\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWurmbach\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoayaie\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFiel\n\t\t\t\t\t\t\tM. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchwartz\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThung\n\t\t\t\t\t\t\tS. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKhitrov\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVillanueva\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBattiston\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMazzaferro\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBruix\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWaxman\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFriedman\n\t\t\t\t\t\t\tS. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tA molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis.\n\t\t\t\t\tGastroenterology\n\t\t\t\t\t131\n\t\t\t\t\t6\n\t\t\t\t\t1758\n\t\t\t\t\t1767\n\t\t\t\t\n\t\t\t'},{id:"B79",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDi Tommaso\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFranchi\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPark\n\t\t\t\t\t\t\tY. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFiamengo\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDestro\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMorenghi\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMontorsi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTorzilli\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTommasini\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTerracciano\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTornillo\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVecchione\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoncalli\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tDiagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis.\n\t\t\t\t\tHepatology\n\t\t\t\t\t45\n\t\t\t\t\t3\n\t\t\t\t\t725\n\t\t\t\t\t734\n\t\t\t\t\n\t\t\t'},{id:"B80",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoskams\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKojiro\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tPathology of early hepatocellular carcinoma: conventional and molecular diagnosis\n\t\t\t\t\tSemin Liver Dis\n\t\t\t\t\t30\n\t\t\t\t\t1\n\t\t\t\t\t17\n\t\t\t\t\t25\n\t\t\t\t\n\t\t\t'},{id:"B81",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXie\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSong\n\t\t\t\t\t\t\tL. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tJ. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYun\n\t\t\t\t\t\t\tJ. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLai\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXie\n\t\t\t\t\t\t\tD. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLin\n\t\t\t\t\t\t\tB. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYuan\n\t\t\t\t\t\t\tY. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGao\n\t\t\t\t\t\t\tZ. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tUpregulator of cell proliferation predicts poor prognosis in hepatocellular carcinoma and contributes to hepatocarcinogenesis by downregulating FOXO3a\n\t\t\t\t\tPLoS One\n\t\t\t\t\t7\n\t\t\t\t\t7\n\t\t\t\t\te40607\n\t\t\t\t\t10.1371/journal.pone.0040607\n\t\t\t\t\thttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0040607(accessed 09 August 2012)\n\t\t\t'},{id:"B82",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPhillips\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHelbig\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tvan der Hoek\n\t\t\t\t\t\t\tK. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSeth\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBeard\n\t\t\t\t\t\t\tM. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tOsteopontin increases hepatocellular carcinoma cell growth in a CD44 dependant manner\n\t\t\t\t\tWorld J Gastroenterol\n\t\t\t\t\t18\n\t\t\t\t\t26\n\t\t\t\t\t3389\n\t\t\t\t\t3399\n\t\t\t\t\n\t\t\t'},{id:"B83",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXu\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJia\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMa\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHao\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tOsteopontin as a key mediator for vasculogenic mimicry in hepatocellular carcinoma.\n\t\t\t\t\tTohoku J Exp Med\n\t\t\t\t\t224\n\t\t\t\t\t1\n\t\t\t\t\t29\n\t\t\t\t\t39\n\t\t\t\t\n\t\t\t'},{id:"B84",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFan\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiao\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShan\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQian\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSong\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZha\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tBif-1 is overexpressed in hepatocellular carcinoma and correlates with shortened patient survival.\n\t\t\t\t\tOncol Lett\n\t\t\t\t\t3\n\t\t\t\t\t4\n\t\t\t\t\t851\n\t\t\t\t\t854\n\t\t\t\t\n\t\t\t'},{id:"B85",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXu\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGu\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tZ. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZheng\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXiong\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tS. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLu\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tNY-ESO-1 expression in hepatocellular carcinoma: a potential new marker for early recurrence after surgery\n\t\t\t\t\tOncol Lett\n\t\t\t\t\t3\n\t\t\t\t\t1\n\t\t\t\t\t39\n\t\t\t\t\t44\n\t\t\t\t\n\t\t\t'},{id:"B86",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNing\n\t\t\t\t\t\t\tB. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDing\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYin\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhong\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZeng\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tY. X.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tJ. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXie\n\t\t\t\t\t\t\tW. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tHepatocyte nuclear factor 4 alpha suppresses the development of hepatocellular carcinoma.\n\t\t\t\t\tCancer Res\n\t\t\t\t\t70\n\t\t\t\t\t19\n\t\t\t\t\t7640\n\t\t\t\t\t7651\n\t\t\t\t\n\t\t\t'},{id:"B87",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLai\n\t\t\t\t\t\t\tJ. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSandhu\n\t\t\t\t\t\t\tD. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYu\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoser\n\t\t\t\t\t\t\tC. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHu\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShire\n\t\t\t\t\t\t\tA. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAderca\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMurphy\n\t\t\t\t\t\t\tL. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAdjei\n\t\t\t\t\t\t\tA. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSanderson\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoberts\n\t\t\t\t\t\t\tL. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tSulfatase 2 protects hepatocellular carcinoma cells against apoptosis induced by the PI3K inhibitor LY294002 and ERK and JNK kinase inhibitors.\n\t\t\t\t\tLiver Int\n\t\t\t\t\t30\n\t\t\t\t\t10\n\t\t\t\t\t1522\n\t\t\t\t\t1528\n\t\t\t\t\n\t\t\t'},{id:"B88",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGu\n\t\t\t\t\t\t\tF. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tQ. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGao\n\t\t\t\t\t\t\tQ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJiang\n\t\t\t\t\t\t\tJ. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhu\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHuang\n\t\t\t\t\t\t\tX. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPan\n\t\t\t\t\t\t\tJ. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYan\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHu\n\t\t\t\t\t\t\tJ. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDai\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFan\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhaou\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tIL-17 induces AKT-dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma.\n\t\t\t\t\tMol Cancer\n\t\t\t\t\t10\n\t\t\t\t\t150\n\t\t\t\t\thttp://www.molecular-cancer.com/content/pdf/1476-4598-10-150.pdf(accessed 09 August 2012)\n\t\t\t'},{id:"B89",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLau\n\t\t\t\t\t\t\tG. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDong\n\t\t\t\t\t\t\tS. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLan\n\t\t\t\t\t\t\tH. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHuang\n\t\t\t\t\t\t\tX. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLuk\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYuan\n\t\t\t\t\t\t\tY. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuan\n\t\t\t\t\t\t\tX. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tInterleukin 17A promotes hepatocellular carcinoma metastasis via NF-kB induced matrix metalloproteinases 2 and 9 expression.\n\t\t\t\t\tPLoS One6\n\t\t\t\t\t7\n\t\t\t\t\te21816\n\t\t\t\t\thttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0021816(accessed 04 August 2012).\n\t\t\t'},{id:"B90",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWong\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLo\n\t\t\t\t\t\t\tA. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTo\n\t\t\t\t\t\t\tK. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChan\n\t\t\t\t\t\t\tA. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNg\n\t\t\t\t\t\t\tM. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHo\n\t\t\t\t\t\t\tC. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCheng\n\t\t\t\t\t\t\tS. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLai\n\t\t\t\t\t\t\tP. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYu\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNg\n\t\t\t\t\t\t\tH. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLing\n\t\t\t\t\t\t\tM. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHuang\n\t\t\t\t\t\t\tA. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCai\n\t\t\t\t\t\t\tX. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKo\n\t\t\t\t\t\t\tB. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tSirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth.\n\t\t\t\t\tCancer Res\n\t\t\t\t\t71\n\t\t\t\t\t12\n\t\t\t\t\t4138\n\t\t\t\t\t4149\n\t\t\t\t\n\t\t\t'},{id:"B91",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCariani\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPilli\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZerbini\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRota\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOlivani\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPelosi\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchianchi\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSoliani\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCampanini\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSilini\n\t\t\t\t\t\t\tE. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTrenti\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFerrari\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMissale\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tImmunological and molecular correlates of disease recurrence after liver resection for hepatocellular carcinoma.\n\t\t\t\t\tPLoS One\n\t\t\t\t\t7\n\t\t\t\t\t3\n\t\t\t\t\te32493\n\t\t\t\t\t10.1371/journal.pone.0032493\n\t\t\t\t\n\t\t\t'},{id:"B92",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStreba\n\t\t\t\t\t\t\tC. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPirici\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVere\n\t\t\t\t\t\t\tC. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMogoanta\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tComanescu\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRogoveanu\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tFractal analysis differentiation of nuclear and vascular patterns in hepatocellular carcinomas and hepatic metastasis\n\t\t\t\t\tRom J Morphol Embryol\n\t\t\t\t\t52\n\t\t\t\t\t3\n\t\t\t\t\t845\n\t\t\t\t\t854\n\t\t\t\t\n\t\t\t'},{id:"B93",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSzutowicz\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDziadziuszko\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tQuantitative immunohistochemistry in lung cancer: clinical perspective\n\t\t\t\t\tFolia Histochem Cytobiol\n\t\t\t\t\t48\n\t\t\t\t\t1\n\t\t\t\t\t7\n\t\t\t\t\t11\n\t\t\t\t\n\t\t\t'},{id:"B94",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDu\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBai\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGao\n\t\t\t\t\t\t\tY. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tY. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLou\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tF. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBai\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tAberrant methylation of SPARC in human hepatocellular carcinoma and its clinical implication.\n\t\t\t\t\tWorld J Gastroenterol\n\t\t\t\t\t18\n\t\t\t\t\t17\n\t\t\t\t\t2043\n\t\t\t\t\t2052\n\t\t\t\t\n\t\t\t'},{id:"B95",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBudhu\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYu\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tForgues\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRoessler\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAmbs\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMeltzer\n\t\t\t\t\t\t\tP. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCroce\n\t\t\t\t\t\t\tC. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQin\n\t\t\t\t\t\t\tL. X.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMan\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLo\n\t\t\t\t\t\t\tC. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLee\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNg\n\t\t\t\t\t\t\tI. O.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFan\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTang\n\t\t\t\t\t\t\tZ. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSun\n\t\t\t\t\t\t\tH. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tX. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tMicroRNA expression, survival, and response to interferon in liver cancer\n\t\t\t\t\tN Engl J Med\n\t\t\t\t\t361\n\t\t\t\t\t15\n\t\t\t\t\t1437\n\t\t\t\t\t1447\n\t\t\t\t\n\t\t\t'},{id:"B96",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamashita\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBudhu\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tForgues\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJia\n\t\t\t\t\t\t\tH. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDeng\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWauthier\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tReid\n\t\t\t\t\t\t\tL. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYe\n\t\t\t\t\t\t\tQ. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQin\n\t\t\t\t\t\t\tL. X.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTang\n\t\t\t\t\t\t\tZ. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCroce\n\t\t\t\t\t\t\tC. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tX. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tIdentification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells\n\t\t\t\t\t Hepatology\n\t\t\t\t\t50\n\t\t\t\t\t2\n\t\t\t\t\t472\n\t\t\t\t\t480\n\t\t\t\t\n\t\t\t'},{id:"B97",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShen\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2012\n\t\t\t\t\tMicroRNA-182 downregulates metastasis suppressor 1 and contributes to metastasis of hepatocellular carcinoma.\n\t\t\t\t\tBMC Cancer\n\t\t\t\t\t12\n\t\t\t\t\t1\n\t\t\t\t\t227\n\t\t\t\t\t10.1186/1471-2407-12-227\n\t\t\t\t\thttp://www.biomedcentral.com/1471-2407/12/227/abstract(accessed 01 August 2012)\n\t\t\t'},{id:"B98",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFu\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXu\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTie\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXing\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhu\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQin\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSun\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZheng\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tmiR-183 inhibits TGF-beta1-induced apoptosis by downregulation of PDCD4 expression in human hepatocellular carcinoma cells.\n\t\t\t\t\tBMC Cancer\n\t\t\t\t\t10\n\t\t\t\t\t354\n\t\t\t\t\t10.1186/1471-2407-10-354\n\t\t\t\t\thttp://www.biomedcentral.com/1471-2407/10/354accessed(04 August 2012)\n\t\t\t'},{id:"B99",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTomimaru\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEguchi\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNagano\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWada\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTomokuni\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKobayashi\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMarubashi\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakeda\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTanemura\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tUmeshita\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDoki\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMori\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tMicroRNA-21 induces resistance to the anti-tumour effect of interferon-alpha/5-fluoruracil in hepatocellular carcinoma cells.\n\t\t\t\t\tBr J Cancer\n\t\t\t\t\t103\n\t\t\t\t\t10\n\t\t\t\t\t1617\n\t\t\t\t\t1626\n\t\t\t\t\n\t\t\t'},{id:"B100",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHamilton\n\t\t\t\t\t\t\tS. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAaltonen\n\t\t\t\t\t\t\tL. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000\n\t\t\t\t\tPathology and genetics.\n\t\t\t\t\tTumours of the digestive system. Lyon: IARC Press\n\t\t\t\t\n\t\t\t'},{id:"B101",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDarby\n\t\t\t\t\t\t\tI. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVuillier-Devillers\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPinault\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSarrazy\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLepreux\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBalabaud\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBioulac-Sage\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDesmouliere\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tProteomic analysis of differentially expressed proteins in peripheral cholangiocarcinoma.\n\t\t\t\t\t Cancer Microenviron\n\t\t\t\t\t4\n\t\t\t\t\t1\n\t\t\t\t\t73\n\t\t\t\t\t91\n\t\t\t\t\n\t\t\t'},{id:"B102",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBioulac-Sage\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLaumonier\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLaurent\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBlanc\n\t\t\t\t\t\t\tJ. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBalabaud\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tBenign and malignant vascular tumors of the liver in adults\n\t\t\t\t\tSemin Liver Dis\n\t\t\t\t\t28\n\t\t\t\t\t3\n\t\t\t\t\t302\n\t\t\t\t\t314\n\t\t\t\t\n\t\t\t'},{id:"B103",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMills\n\t\t\t\t\t\t\tS. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCarter\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGreenson\n\t\t\t\t\t\t\tJ. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tReuter\n\t\t\t\t\t\t\tV. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStoler\n\t\t\t\t\t\t\tM. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tSternberg’s diagnostic surgical pathology, 5th ed.\n\t\t\t\t\tWolter Kluver Health / Lippincott Williams and Wilkins\n\t\t\t\t\n\t\t\t'},{id:"B104",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKhadim\n\t\t\t\t\t\t\tM. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJamal\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAli\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAkhtar\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAtique\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSarfraz\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAyaz\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tDiagnostic challenges and role of immunohistochemistry in metastatic liver disease\n\t\t\t\t\tAsian Pac J Cancer Prev\n\t\t\t\t\t12\n\t\t\t\t\t2\n\t\t\t\t\t373\n\t\t\t\t\t376\n\t\t\t\t\n\t\t\t'},{id:"B105",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDabbs\n\t\t\t\t\t\t\tD. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tDiagnostic immunohistochemistry\n\t\t\t\t\tNew York: Churchill Livingstone\n\t\t\t\t\n\t\t\t'},{id:"B106",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBoggaram\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tThyroid transcription factor-I(TTF-I/Nkx2.1/TITFI) gene regulation in the lung.\n\t\t\t\t\tClin Sci (Lond)\n\t\t\t\t\t116\n\t\t\t\t\t1\n\t\t\t\t\t27\n\t\t\t\t\t35\n\t\t\t\t\n\t\t\t'},{id:"B107",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCapelozzi\n\t\t\t\t\t\t\tVL.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tRole of immunohistochemistry in the diagnosis of lung cancer.\n\t\t\t\t\tJ Bras Pneumol\n\t\t\t\t\t35\n\t\t\t\t\t4\n\t\t\t\t\t375\n\t\t\t\t\t382\n\t\t\t\t\n\t\t\t'},{id:"B108",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKaimaktchiev\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTerracciano\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTornillo\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSpichtin\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStoios\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBundi\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKorcheva\n\t\t\t\t\t\t\tV.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMirlacher\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLoda\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSauter\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCorless\n\t\t\t\t\t\t\tC. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tThe homeobox intestinal differentiation factor CDX2 is selectively expressed in gastrointestinal adenocarcinomas.\n\t\t\t\t\tMod Pathol\n\t\t\t\t\t17\n\t\t\t\t\t11\n\t\t\t\t\t1392\n\t\t\t\t\t1399\n\t\t\t\t\n\t\t\t'},{id:"B109",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoskaluk\n\t\t\t\t\t\t\tC. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPowell\n\t\t\t\t\t\t\tS. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCerilli\n\t\t\t\t\t\t\tL. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHampton\n\t\t\t\t\t\t\tG. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrierson\n\t\t\t\t\t\t\tH. F. Jr\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003\n\t\t\t\t\tCdx2 protein expression in normal and malignant human tissues: an immunohistochemical survey using tissue microarrays.\n\t\t\t\t\tMod Pathol\n\t\t\t\t\t16\n\t\t\t\t\t9\n\t\t\t\t\t913\n\t\t\t\t\t919\n\t\t\t\t\n\t\t\t'},{id:"B110",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKoffron\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRao\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFerrario\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAbecassis\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tIntrahepatic biliary cystadenoma: role of cyst fluid analysis and surgical management in the laparoscopic era.\n\t\t\t\t\tSurgery\n\t\t\t\t\t136\n\t\t\t\t\t4\n\t\t\t\t\t926\n\t\t\t\t\t936\n\t\t\t\t\n\t\t\t'},{id:"B111",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWheeler\n\t\t\t\t\t\t\tD. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEdmondson\n\t\t\t\t\t\t\tH. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1985\n\t\t\t\t\tCystadenoma with mesenchymal stroma (CMS) in the liver and bile ducts. A clinicopathologic study of 17 cases, 4 with malignant change.\n\t\t\t\t\tCancer\n\t\t\t\t\t56\n\t\t\t\t\t6\n\t\t\t\t\t1434\n\t\t\t\t\t1435\n\t\t\t\t\n\t\t\t'},{id:"B112",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDavies\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChow\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNagorney\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1995\n\t\t\t\t\tExtrahepatic biliary cystadenomas and cystadenocarcinoma. Report of seven cases and review of the literature.\n\t\t\t\t\tAnn Surg\n\t\t\t\t\t222\n\t\t\t\t\t5\n\t\t\t\t\t619\n\t\t\t\t\t625\n\t\t\t\t\n\t\t\t'},{id:"B113",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYu\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYan\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZheng\n\t\t\t\t\t\t\tS. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tCystadenocarcinoma of the liver: a case report.\n\t\t\t\t\tHepatobiliary Pancreat Dis Int\n\t\t\t\t\t4\n\t\t\t\t\t3\n\t\t\t\t\t464\n\t\t\t\t\t467\n\t\t\t\t\n\t\t\t'},{id:"B114",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhou\n\t\t\t\t\t\t\tJ. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDong\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKong\n\t\t\t\t\t\t\tF. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGuo\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTian\n\t\t\t\t\t\t\tY. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tGiant mucinous biliary cystadenoma: a case report.\n\t\t\t\t\tHepatobiliary Pancreat Dis Int\n\t\t\t\t\t6\n\t\t\t\t\t1\n\t\t\t\t\t101\n\t\t\t\t\t103\n\t\t\t\t\n\t\t\t'},{id:"B115",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKitajima\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOkayama\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHirai\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHayashi\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tImai\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOkamoto\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAoki\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAkita\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGotoh\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOhara\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNomura\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJoh\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYokoyama\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tItoh\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003\n\t\t\t\t\tIntracystic hemorhage of a simple liver cyst mimicking a biliary cystadenocarcinoma.\n\t\t\t\t\tJ Gastroenterol\n\t\t\t\t\t38\n\t\t\t\t\t2\n\t\t\t\t\t190\n\t\t\t\t\t193\n\t\t\t\t\n\t\t\t'},{id:"B116",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJan\n\t\t\t\t\t\t\tY. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tM. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tT. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1994\n\t\t\t\t\tCholangiocarcinoma with mucobilia.\n\t\t\t\t\tJ Formos Med Assoc\n\t\t\t\t\t93\n\t\t\t\t\t3\n\t\t\t\t\tS149\n\t\t\t\t\t155\n\t\t\t\t\n\t\t\t'},{id:"B117",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThomas\n\t\t\t\t\t\t\tK. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWelch\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTrueblood\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSulur\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWise\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGorden\n\t\t\t\t\t\t\tD. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChari\n\t\t\t\t\t\t\tR. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWright\n\t\t\t\t\t\t\tJ. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJr Washington\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPinson\n\t\t\t\t\t\t\tC. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tEffective treatment of biliary cystadenoma.\n\t\t\t\t\tAnn Surg\n\t\t\t\t\t241\n\t\t\t\t\t5\n\t\t\t\t\t769\n\t\t\t\t\t775\n\t\t\t\t\n\t\t\t'},{id:"B118",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKubota\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKatsumi\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIida\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKishimoto\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBan\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakata\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakahashi\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKobayashi\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAndoh\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakamatsu\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJoh\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003\n\t\t\t\t\tBiliary cystadenocarcinoma, followed up as benign cystadenoma for 10 years\n\t\t\t\t\tJ Gastroenterol\n\t\t\t\t\t38\n\t\t\t\t\t3\n\t\t\t\t\t278\n\t\t\t\t\t282\n\t\t\t\t\n\t\t\t'},{id:"B119",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMortele\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRos\n\t\t\t\t\t\t\tP. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tCystic focal liver lesions in the adult: differential CT and MR imaging features.\n\t\t\t\t\tRadiographics\n\t\t\t\t\t21\n\t\t\t\t\t4\n\t\t\t\t\t895\n\t\t\t\t\t910\n\t\t\t\t\n\t\t\t'},{id:"B120",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPoggio\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBuonocore\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tCystic tumours of the liver: a practical approach.\n\t\t\t\t\tWorld J Gastroenterol\n\t\t\t\t\t14\n\t\t\t\t\t23\n\t\t\t\t\t3616\n\t\t\t\t\t3620\n\t\t\t\t\n\t\t\t'},{id:"B121",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZamboni\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tScarpa\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBogina\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIacono\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBassi\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTalamini\n\t\t\t\t\t\t\tSessa. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCapella\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSolcia\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRickaert\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMariuzzi\n\t\t\t\t\t\t\tG. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKlopel\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1999\n\t\t\t\t\tMucinous cystic tumors of the pancreas: clinicopathologic features, prognosis, and relationship to other mucinous cystic tumors.\n\t\t\t\t\tAm J Surg Pathol\n\t\t\t\t\t23\n\t\t\t\t\t4\n\t\t\t\t\t410\n\t\t\t\t\t422\n\t\t\t\t\n\t\t\t'},{id:"B122",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSudo\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHarada\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTsuneyama\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKatayanagi\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZen\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakanuma\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tOncocytic biliary cystadenocarcinoma is a form of intraductal oncocytic papillary neoplasm of the liver.\n\t\t\t\t\tMod Pathol\n\t\t\t\t\t14\n\t\t\t\t\t12\n\t\t\t\t\t1304\n\t\t\t\t\t1309\n\t\t\t\t\n\t\t\t'},{id:"B123",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tD’Errico\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDeleonardi\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFiorentino\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tScoazec\n\t\t\t\t\t\t\tJ. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGrigioni\n\t\t\t\t\t\t\tW. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1998\n\t\t\t\t\tDiagnostic implications of albumin messenger RNA detection and cytokeratin pattern in benign hepatic lesions and biliary cystadenocarcinoma.\n\t\t\t\t\tDiagn Mol Pathol\n\t\t\t\t\t7\n\t\t\t\t\t6\n\t\t\t\t\t289\n\t\t\t\t\t294\n\t\t\t\t\n\t\t\t'},{id:"B124",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIshibashi\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOjima\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHiraoka\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSano\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKosuge\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKanai\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tInvasive biliary cystic tumour without ovarian-like stroma.\n\t\t\t\t\t Pathol Int\n\t\t\t\t\t57\n\t\t\t\t\t12\n\t\t\t\t\t794\n\t\t\t\t\t798\n\t\t\t\t\n\t\t\t'},{id:"B125",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBardin\n\t\t\t\t\t\t\tR. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTrupiano\n\t\t\t\t\t\t\tJ. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHowerton\n\t\t\t\t\t\t\tR. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGeisinger\n\t\t\t\t\t\t\tK. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tOncocytic biliary cystadenocarcinoma: a case report and review of the literature.\n\t\t\t\t\tArch Pathol Lab Med\n\t\t\t\t\t128\n\t\t\t\t\t2\n\t\t\t\t\te25\n\t\t\t\t\t28\n\t\t\t\t\n\t\t\t'},{id:"B126",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRullier\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLe Bail\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFawaz\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBlanc\n\t\t\t\t\t\t\tJ. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSaric\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBioulac-Sage\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000\n\t\t\t\t\tCytokeratin 7 and 20 expression in cholangiocarcinomas varies along the biliary tree but still differs from that in colorectal carcinoma metastasis\n\t\t\t\t\tAm J Surg Pathol\n\t\t\t\t\t24\n\t\t\t\t\t6\n\t\t\t\t\t870\n\t\t\t\t\t876\n\t\t\t\t\n\t\t\t'},{id:"B127",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIshak\n\t\t\t\t\t\t\tK. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWillis\n\t\t\t\t\t\t\tG. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCummins\n\t\t\t\t\t\t\tS. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBullock\n\t\t\t\t\t\t\tA. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1977\n\t\t\t\t\tBiliary cystadenoma and cystadenocarcinoma: report of 14 cases and review of the literature.\n\t\t\t\t\tCancer\n\t\t\t\t\t39\n\t\t\t\t\t1\n\t\t\t\t\t322\n\t\t\t\t\t338\n\t\t\t\t\n\t\t\t'},{id:"B128",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKarahan\n\t\t\t\t\t\t\tO. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKahriman\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSoyuer\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOk\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tHepatic von Meyenburg complex simulating biliary cystadenocarcinoma\n\t\t\t\t\tClin Imaging\n\t\t\t\t\t31\n\t\t\t\t\t1\n\t\t\t\t\t50\n\t\t\t\t\t53\n\t\t\t\t\n\t\t\t'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Ilze Strumfa",address:"ilze.strumfa@rsu.lv",affiliation:'
Department of Pathology, Riga Stradins University, Riga, Latvia
Department of Surgery, Riga Stradins University, Riga, Latvia
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\n
1. Introduction
\n
Loops, barrel rolls and pitch maneuvers are impressive aerial stunts. But even during the most intense in-air aerobatics, most planes are still constrained by aerodynamics. The air flowing over their wings gives them the lift to stay aloft and they control their movement by altering the surfaces that air flows over. The quick the rate of movement for the control surface, a fast response from the aircraft to change attitude. Pilots can pull off moves with precise control in conditions that would leave other aircraft hopelessly plummeting towards the ground. For fighter aircraft, there are numerous maneuvers can be done by the pilot to increase the aircraft maneuverability. These maneuvers such as, Cobra, Mango flip, high pass alpha that can save pilot’s life during a dog fight (see \nFigure 1\n). Nowadays, unmanned aeriel vehicles autopilots can perform these maneuvers to an extent. Consequently, in order assure that UAVs could perform such maneuvers, one may need to relax the quasi-steady modeling to an unsteady nonlinear model to deal with these abrupt changes in attitude. Prediction of dynamic lift response of Harsh maneuvers for flying vehicles necessitate a compact aerodynamic modeling. For instance, pitching maneuvers for fighter aircrafts (ex. F35 - SU-57) with specified handling qualities stimulate the idea to impose new modeling techniques to be applied on UAVs. The unsteady lift response plays an important role to control the vehicle at such low speeds. Escaping from a flying threat, first performed by Soviet test pilot Viktor Pugachoyov in 1989, the maneuver that would go on to be called “Pugachev’s Cobra” is one of the building blocks that makes up many other more complicated supermaneuvers. During flight, the pilot pulls back to an absurd angle of attack, taking the nose of the aircraft completely vertical or even beyond. From here, one of two things can happen. In a plane without thrust vectoring but with a thrust-to-weight ratio higher than one, the drag towards the tail of the plane can be used to pitch the nose forward again. If the plane does have thrust vectoring, that can help the re-orientation even more. But either way, the engines are firing hard enough the entire time to maintain the jet’s altitude despite the loss of speed and lift.
\n
Figure 1.
High alpha Fighter’s aircraft maneuvers.
\n
After few years, a German test pilot Karl-Heinz Lang performed the Herbst Maneuver in 1993. The Herbst Maneuver is basically Pugachev’s Cobra with a bit of a twist. Instead of just pulling up and going forward again, the Herbst Maneuver has the pilot roll the plane (experimental X-31) a bit while its nose is pointed at the sky, so that when the nose comes back down, the plane is pointed in a different direction. On the other hand, such maneuvers are also possessed by birds and flapping insects. They can twist their wings at high angles of attack while flapping their wings without approaching stall. This is known as non-conventional lifting mechanisms invoked from biomemetics in order to perform such maneuver with a stabilized flight (i.e. vibrational stabilization). In preliminary design of UAVs, potential flow models are used as a start point to ensure acceptable estimates for aerodynamic forces and moments. A recent motivation is devoted towards designing flight control systems that can achieve harsh maneuvers such as perching and sudden landing for fixed wing MAV’s [1, 2]. Bird perching is considered one of the most fascinating landing and decelerating maneuvers. \nFigure 2(a)\n shows a tailed swallow feeding a chick by pitching its wing at high angle of attack. For specific missions, such maneuver is useful for both flapping-wing and fixed-wing MAVs.
\n
Figure 2.
Example of bird perching and successful experiments based on perching manoeuver. (a) A wire-tailed swallow feeding a re-cently edged chick [3] (a) A wire-tailed swallow feeding a re-cently edged chick [3]. (b) A basic glider, manually thrown and con-trolled by perching [4].
\n
For classical unsteady aerodynamic models, Theodorsen [5], Wagner [6] and others have been studied extensively the classical theories of unsteady aerodynamics to be employed in the aeroelasticity field. However, aerodynamic models of harsh maneuvers characterized by sharp pitch rates and amplitudes still present a challenge in modeling. While advances in computational fluid dynamics and experimental methods have opened the study of these maneuvers as such a low-fidelity analytical modeling for rigorous prediction is still forthcoming. Roderich et al. [4] performed experiments for touchdown to take-off for a very basic glider as shown in \nFigure 2(b)\n.
\n
In the last two decades, there have been several efforts exerted on unsteady aerodynamic modeling based on potential flow theories as well as modified thin airfoil theory to simulate the wing motion for an arbitrary input [7, 8]. The AIAA Fluid Dynamics Technical Committee’s (FDTC) Low Reynolds Number Discussion Group introduced some cases for the assessment of experimental efforts [9], on large amplitude pitching maneuvers. The proposed motions are used as a benchmark for obtaining analytical and phenomenological models, in which a ramp up, hold, and ramp-down motions are analyzed using theory and numerical computations [10, 11, 12, 13, 14] Theodorsen’s and Wagner’s Inviscid theories are purely proper only for small amplitude oscillations associated with planar wakes. However, a tremendous work has shown that these methods remain substantially accurate even at moderate amplitudes and high frequencies. The results obtained by Ramesh et al. [9] during the hold and downstroke show that the aerodynamic forces are dominated by a deep-stall as well as leading edge vortex (LEV). The shedding effects were seen from the vorticity and dye injection plots from his experimental results. These results proved that viscous state indicate that the inviscid assumptions are insufficient for modeling the hold and downstroke portions of the motion and adequate for capturing the lift time history during the ramp phase.
\n
A tremendous work was done based on nonlinear unsteady reduced order modeling to solve flow at high frequencies [8, 15, 16, 17, 18, 19]. The recent work done by Yuelong et al. [20] examined the unsteady forces and moment coefficients obtained by a thin airfoil in a pitch ramp high-amplitude motion. Wind tunnel experiments have been conducted at Reynolds number (\n\nRe\n=\n45\n\n x \n\n\n10\n4\n\n\n), using a rigid flat-plate model. Forces have been measured for reduced pitch rates ranging from 0.01 to 0.18 reduced frequency (\n\nk\n=\nωc\n/\n2\n\nU\n∞\n\n\n) along with four maximum pitch angles (\n\n30\n°\n\n; \n\n45\n°\n\n; \n\n60\n°\n\n; \n\n90\n°\n\n) at different pivot axis locations. The results show that the unsteady aerodynamics is limited to a delayed stall effect for reduced pitch rates lower than k = 0.03. At higher pitch rates, the unsteady aerodynamic response is associated with a formation of circulation, which in turn increases with the pitch rate and the distance between the pivot axis and the 3/4-chord location. An enhanced response was noted in the normal force and moment coefficients due to these circulatory effects. These overshot is slightly reduced for a flat plate with a finite aspect ratio near eight compared to two-dimensional configuration. The authors proposed a new time-dependent model for both lift and moment coefficients. The model based on the Wagner function and a time-varying input along with nonlinear variation of the quasi steady aerodynamics. A satisfactory results for \n\n0\n°\n\n to \n\n90\n°\n\n pitch ramp motions were compared with experiments for different pivot locations and various circulation intensity based on pitch rates.
\n
On the other hand, fluid structure interaction modeling became essential for solving flow around vibrating and rotating structure [8, 21, 22, 23]. Modeling such moving bodies requires aerodynamic unsteady nonlinear models to assure accuracy in modeling results rather than using quazi-steady models. Carlos et al. [24] work discuses modeling and analyzing procedures of the non-linearities induced by the flow-structure interaction of an energy harvester consisting of a laminated beam integrated with a piezoelectric sensor. The cantilevered beam and the piezoelectric lamina are modeled using a nonlinear finite element approach, while unsteady aerodynamic effects are described by a state-space model that allows for arbitrary nonlinear lift characteristics.
\n
The major contribution about the classical unsteady formulations discussed in the literature is the inefficacy to account for a non-conventional lift curve, such as LEV effects and dynamic stall contributions. Taha et al. [7] developed a state space model that captures the nonlinear contributions of the LEV in an unsteady fashion. However, their underpinning dynamics is linear: convolution with Wagner’s step response. Consequently, there is a considerable gap in the literature for consolidating low fidelity models for predicting accurate lift forces associated with these large-amplitude maneuvers. An analytical unsteady nonlinear aerodynamic model that can be used to characterize the local and global nonlinear dynamic characteristics of the airflow is a mandatory task for aerodynamicists. Developing such a model will be indispensable for multidisciplinary applications (e.g., dynamics, control and aeroelasticity).
\n
The chapter investigates and assesses relevant classical analytical models in solving lift response for pitching maneuovers. In doing so, Theodorsen, Wagner and Unsteady vortex lattice methods are used to predict the lift dynamics, then the results are compared with the experimental data presented by Ramesh et al. [9]. Also, the work proposed a simple time-dependent model in order to predict the lift response for a two dimensional wing performing rapid pitch motion. In addition, the results provide a comparison with numerical simulation using the unsteady vortex lattice method. The aerodynamic system receives the time histories of angle of attack, quasi-steady lift as inputs and produces the corresponding total unsteady lift as output. In the following sections, each presented model will be explained in detail. The chapter is organized as follows. The adopted motion kinematics are presented in Section 2. Aerodynamic classical models are reported in Section 3, along with the effect of reduced pitch rate and pivot axis location. In Section 4, the effect of pitch amplitudes on the unsteady lift coefficient is investigated by comparing the obtained results using two different pitch amplitudes with the experimental results [9].
\n
\n
\n
2. Motion kinematics
\n
In order to explore the non-periodic motions of wings rapid manouevers, the ramp-hold-return motions were proposed by the AIAA FDTC Low Reynolds Number Discussion Group [25]. The smoothed ramp motion proposed by Eldredge’s canonical formulation [12] is used in this work as a reference case for comparison. Here, the experimental work done by Ramesh et al. [13] is considered as a benchmark. Variations of this motion are considered by varying the pitch amplitude (\n\n25\n°\n\n and \n\n45\n°\n\n) at a Reynolds number of 10,000. \nFigures 2\n and \n3\n show a schematic of the pitch motion variables and the two studied maneuvers versus the non-dimensional time, respectively. \nFigure 4\n shows the ramped motion for a maximum amplitude of \n\n25\n°\n\n versus the corresponding effective angle of attack and the local angle of attack at the \n\n3\n/\n4\n\n chord location as suggested by Pistolesi theorem [26].
\n
Figure 3.
Pitching motion nomenclature and motion variables (a = 1 is the leading edge pivot, a = 0 is the mid chord pivot and a = −1 is trailing edge pivot).
\n
Figure 4.
The proposed ramp maneuver with a maximum amplitudes of \n\n\n25\no\n\n\n and \n\n\n45\no\n\n\n and pitch rates of 0.2 and 0.4, respectively.
\n
To avoid any numerical instabilities, (e.g., dirac-delta function spikes in the calculation of the added mass force) all motions are smoothed based on a smoothing parameter introduced by Elderedge [12]. For a ramp going from 0 degrees angle of attack to 25 or 45 degrees, the first 10% (2.5 or 4.5 degrees) can be replaced with a sinusoidal tangent to the baseline ramp, and similarly in approaching the “hold” portion at the maximum amplitude angle of attack, consequently again on the downstroke. This treatment avoids a piece-wise linear fit which has discontinuities in the angle derivatives. The smoothing function G(t) is defined as:
where \n\na\n\n is the smoothing parameter and is taken to be 11, \n\n\nt\n1\n\n\n through \n\n\nt\n4\n\n\n are the transition times and a pitch amplitude angle \n\nA\n\n. As such, the smoothed angle of attack can be written as:
In order to analytically describe the generated lift force due to pitching maneuvers, a well established models were introduced. In this section, a detailed description of these models is discussed and explained in a straight forward manner.
\n
\n
3.1 Theodorsen model
\n
The tremendous work done by Wagner [6], Prandtl [27], Theodorsen [28] and Garrick [29] described some fundamental physical concepts in understanding and modeling the unsteady aerodynamics. These concepts are usually incorporated with a potential flow approach and small disturbance theory to obtain analytical expressions of flow quantities. The unsteady lift on a harmonically oscillating airfoil in incompressible flow has been studied by Kussner and Schwarz [30], but the most well known solution is due to Theodorsen [5]. The lift on a thin rigid airfoil undergoing oscillatory motion can be written as:
where, \n\n\nh\n¨\n\n\n and \n\n\nα\n¨\n\n\n are plunging and pitching accelerations respectively. The first group of terms are the noncirculatory components which account for the inertia of fluid (added mass force). The second group of terms are the circulatory components, where C(k) accounts for the influence of the shed wake vorticity (lift deficiency factor). Since Theodorsen function necessitates a periodic motion for its input parameters (e.g. angle of attack or quasi steady lift), a Fourier transform should be applied to the pitch ramp maneuver under study. The effective angle of attack of the proposed ramp pitch motion can be written as:
where \n\n\nA\n\nc\n\nk\n\n\n\n\n is the absolute value (amplitude) and \n\nϕ\n\n is the phase angle. The circulatory lift given after applying Fourier series is given by:
It should be noted that practically, this Fourier transform approach will be implemented numerically using discrete fourier transform. However, discrete Fourier transform in contrast with the exact Fourier transform (Fourier integral) will necessarily ignore some frequency contents due to the integration limits between \n\n−\n∞\n\n to \n\n+\n∞\n\n.
\n
\n
\n
3.2 Wagner step response and Duhamel superposition principle
\n
Using Wagner’s linear step response, the Duhamel principle can be used to include the unsteady effects in an exact form such as a finite-state aerodynamic models suitable for aeroelastic problems and flight mechanics simulations. Wagner [6] obtained the time dependant-response of the lift on a flat plate due to a step input (indicial response problem). Garrick [29] showed that by using Fourier transformation, Wagner function, \n\nW\n\ns\n\n\n, and Theodorsen function, \n\nC\n\nk\n\n\n can be related together. Wagner [6] determined the circulatory lift due to a step change in the wing motion. The unsteady lift is then written in terms of the static lift as:
\n
\n\nℓ\n\ns\n\n=\n\nℓ\ns\n\nW\n\ns\n\n\nE11
\n
where the non-dimensional time \n\nS\n\n is defined as \n\nS\n=\n\n\n2\n\nU\n∞\n\nt\n\nc\n\n\n for constant free-stream velocity \n\n\nU\n∞\n\n\n.
\n
By knowing the indicial response for a linear dynamical system, the response due to arbitrary motion (input) can be described as an integral (superposition) using the indicial response and an input varies with time. The variation of the circulatory lift for an arbitrary change in the angle of attack is given by:
We note that \n\nW\n\ns\n\n\n can also be used as an indicial response to aerodynamic inputs other than the angle of attack. Van der Wall and Leishman [32] used it as an indicial response to the wing normal velocity, \n\nw\n=\nUα\n\n, in the case of time-varying free stream. For a relatively high angle of attack, the Duhamel superposition is performed using a more exact normal velocity \n\nw\n=\nU\nsin\nα\n\n. Eq. (11) is then re-written as
This equation is usually used in dynamic stall models where relatively high angles of attack are encountered, e.g., the Beddoes-Leishman dynamic stall model [33].
\n
\n
\n
3.3 State space finite model
\n
RT Jones proposed an approximate expression for Wagner function as follows:
where \n\n\nA\n1\n\n=\n0.165\n,\n\nA\n2\n\n=\n0.335\n,\n\nc\n1\n\n=\n0.0455\n,\n\nc\n2\n\n=\n0.3\n\n and s is the reduced time parameter and is given by \n\n\nU\n∞\n\nt\n/\nb\n\n. By taking the Laplace transform with an operator P:
where \n\nX\n\n is the internal states of the system, which is related to the input via these coefficients \n\n\na\no\n\n=\n\n\n\n\n\nC\n1\n\n+\n\nC\n2\n\n\n\n\nU\n∞\n\n\nb\n\n\n, \n\n\na\n1\n\n=\n\n\n\n\n\nC\n1\n\n\nC\n2\n\n\n\n\nU\n∞\n2\n\n\n\nb\n2\n\n\n\n, \n\n\nb\no\n\n=\n\n\n\n\n\nC\n1\n\n\nC\n2\n\n\n\n\nU\n∞\n2\n\n\n\nb\n2\n\n\n\n, \n\n\nb\n1\n\n=\n\n\n\n\n\nC\n1\n\n\nU\n∞\n\n\nb\n\n+\n\n\n\nC\n2\n\n\nU\n∞\n\n\nb\n\n−\n\n\n\nA\n1\n\n\nC\n2\n\n\nU\n∞\n\n\nb\n\n−\n\n\n\nA\n2\n\n\nC\n1\n\n\nU\n∞\n\n\nb\n\n\n\n\n, \n\n\nb\n2\n\n=\n1\n−\n\nA\n1\n\n−\n\nA\n2\n\n\n as follows:
The unsteady Vortex lattice methods (UVLMs) are well suited to the bio-inspired flight problems because they can account for the circulation distribution variations on wings, the velocity potential time-dependency, and the shedding of wake downstream. Although they are considered low fidelity models, they may be extended to capture unconventional lift mechanisms such as leading edge vortex [34, 35, 36]. These discrete vortex models are widely used in modeling aerodynamics of aircraft and rotorcraft analysis, compared to computational fluid dynamics (CFD) models which are more computationally expensive [37]. The use of UVLM method is now a powerfull tool in hand for aerodynamicists for its ease implementation even for complex shapes.
\n
Zakaria et al. [8] used UVLM to model the aerodynamic loading on different Samara leaves (Maple seeds) during their steady state flight. The results were verified with experiments. Parameters including the drop speed, angular velocity and coning angle for different sets of Maple Samaras were determined from experiments. The aerodynamic loads were calculated using UVLM against the forces required for maintaining a steady state flight as obtained from the experiment. Consequently, the UVLM approach yields adequate aerodynamic modeling features that can be used for more accurate flight stability analysis of the Samara flight or of decelerator devices inspired by such flight. Also, Simon et al. [38] showed that by imposing an arbitrary input as a control surface deflection to an unsteady VLM suitable for efficient aerodynamic loads analysis within aeroelastic modeling, analysis and optimization frameworks for preliminary aircraft design. By using a continuous time state space aerodynamic model is extended for accepting arbitrary motion, control surface deflection and gust velocities as inputs. Their results showed good agreement for a large range of reduced frequencies. Accepting arbitrary motion, control surface deflection and gust velocities as inputs.
\n
The (UVLM) divides the lifting surface into panels. A point vortex is then associated with each of these panels. The center of this ring is set at the 1/4 of the panel chord length. One collocation point is set in each panel at the 3/4 of the panel length, and the panel normal vector is calculated in this point as shown in \nFigure 5\n.
\n
Figure 5.
A schematic diagram showing the panels on the airfoil camber and the shedded vortices used in UVLM modeling.
\n
The UVLM model is based on the following assumptions:
No penetration boundary condition.
Kelvin Circulation Theorem (Conservation of Circulation).
Vortices is convected by local velocities. (Wake deformation)
\n\n
The velocity induced by all the vortex points, including the shed vorticies through the wake, is calculated at each control point and the no-penetration kinematic boundary condition is applied to calculate vortex intensity on each panel. At each time step, there are (m + 1) unknowns (m \n\n\nγ\nboundvortices\n\n\n‘s and \n\n\nγ\natrailingedgevortex\n\n\n), then (m + 1) equations are needed for closure. For the no-penetration boundary condition at m control points, we have:
where \n\n\na\n\n\nK\n1\n\n,\n\nK\n2\n\n\n\n\n are the influence coefficients from the point vortex \n\n\nK\n2\n\n\n at the control point \n\n\nK\n1\n\n\n and it is equal to the normal velocity that the point vortex induces at the control point \n\n\nΓ\n\nK\n2\n\n\n=\n1\n\n. Each element on the right hand side is \n\n\nRHS\nK\n\n=\n−\n\n\n\n\nv\n→\n\n+\n\n\nv\n→\n\nw\n\n\n\nK\n\n⋅\n\n\nn\n→\n\nK\n\n\n, where \n\n\nv\n→\n\n\n is the wind flow velocity relative to the surface and \n\n\n\nv\n→\n\nw\n\n\n is the velocity induced at the control point \n\nK\n\n by all the other vortex point in the wake created before the time \n\nt\n\n. In order to satisfy the unsteady Kutta condition, the wake is created at each instant of time at the trailing edge by shedding a new vortex that has an intensity equal to the bound vortex on the panel along the trailing edge. At each instant of time all the points in the wake generated in previous steps are convected downstream following the induced velocity generated by all the vortices on the surface and through the wake. The velocity induced by each vortex is computed by using the Biot Savart law. This induced velocity is inversely proportional to the distance between the vortex location and the control point where the velocity is calculated. Having solved the linear system [39] in the bound vorticity, the pressure difference through the bound vortex sheet is computed based on the unsteady Bernoulli’s equation. More details can be found in [40].
\n
The unsteady aerodynamic loads can be calculated from the circulation \n\n\nΓ\nK\n\n\n of the \n\n\nK\nth\n\n\n panel and its time rate of change [40]. Using the unsteady Bernoulli equation,
where \n\np\n\n denotes the static pressure, \n\nV\n\n is the tangent velocity, \n\nϕ\n\n is the velocity potential, and the subscripts \n\nu\n\n and \n\nl\n\n are used to represent the upper and lower surfaces, respectively.
In order to summarize the merit of the proposed classical potential models for solving high pitch maneuvers, \nTable 1\n is shown. \nTable 1\n represents the key parameters for each model in the sense of input motion, nonlinearity, wake deformation and camber variation for flying vehicles. The merit of each model is how one can apply simple analytical equation to solve such maneuver.
\n
\n
\n
\n
\n
\n
\n\n
\n
Models
\n
Input motion
\n
Nonlinearity
\n
wake deformation
\n
Camber variation
\n
\n\n\n
\n
Theodorsen
\n
Harmonic
\n
Geometric
\n
Flat
\n
\n\n\n×\n\n\n
\n
\n
\n
Wagner
\n
Step input
\n
Geometric
\n
\n\n\n×\n\n\n
\n
\n\n\n×\n\n\n
\n
\n
\n
State space
\n
Arbitrary
\n
\n\n\n×\n\n\n
\n
\n\n\n×\n\n\n
\n
\n\n\n×\n\n\n
\n
\n
\n
UVLM
\n
Arbitrary
\n
\n\n\n√\n\n\n
\n
\n\n\n√\n\n\n
\n
\n\n\n√\n\n\n
\n
\n\n
Table 1.
Classical aerodynamics proposed models for solving pitching maneuvers.
\n
\n
\n
\n
4. Maneuver case studies results
\n
\n
4.1 Case 1: Pitch ramp \n\n\nα\no\n\n=\n\n25\no\n\n\n\n
\n
\n
4.1.1 Leading edge pivot
\n
\n\nFigures 6\n–\n11\n show a comparison between the proposed models discussed above for different ramp amplitudes and hinge locations. A physical interpretation for the jump and attenuated lift peaks show four flow events as reported by Ramesh et al. [9] as follows: (i) onset of flow separation at the ramp start (\n\nτ\n=\n1\n\n), (ii) the formation of a leading edge vortex (\n\nτ\n=\n1\n−\n3\n\n), (iii) ramp hold (\n\nτ\n=\n3\n−\n4\n\n) and (iv) detachment of the leading-edge vortex (\n\nτ\n=\n4\n−\n6\n\n).
\n
Figure 6.
Comparison for the proposed models and experimental work done by Ramesh et al. with ramp rate of 0.2 and amplitude \n\n25\n°\n\n at the leading edge hinge location.
\n
Figure 7.
Comparison for the proposed models and experimental work done by Ramesh et al. with ramp rate of 0.2 and amplitude \n\n25\n°\n\n at the half chord hinge location.
\n
Figure 8.
Comparison for the proposed models and experimental work done by Ramesh et al. with ramp rate of 0.2 and amplitude \n\n25\n°\n\n at the leading edge hinge location.
\n
Figure 9.
Comparison for the proposed models and experimental work done by Ramesh et al. with ramp rate of 0.4 and amplitude \n\n\n45\n∘\n\n\n at leading pivot location.
\n
Figure 10.
Comparison for the proposed models and experimental work done by Ramesh et al. with ramp rate of 0.4 and amplitude \n\n45\n°\n\n at half chord pivot location.
\n
Figure 11.
Comparison for the proposed models and experimental work done by Ramesh et al. with ramp rate of 0.4 and amplitude \n\n45\n°\n\n at trailing pivot location.
\n
\n\nFigure 6\n shows the ramp pitch motion with an amplitude of \n\n\n25\no\n\n\n about a leading edge hinge. Almost all the theoretical models have the same jump during the transition of each event start and end positions during the whole ramp manoeuver compared to the experimental results. During upstroke, \n\nτ\n=\n1\n−\n3\n\n, a very good match is found between the experimental results and the UVLM results. The prediction of the quasi-steady model is higher compared to the experimental results which is expected as it lacks the dynamics of the flow and is based only the static behavior of the generated lift. On the other hand, all other presented models show an attenuated lift response during the ramp-up phase. During the ramp hold period, \n\nτ\n=\n3\n−\n4\n\n, a very good agreement between all the models and the experiments except the quasi-steady and Theodorsen FFT based model. During the ramp-down phase, the UVLM model matches very well with the experimental results preserving the lift dynamics. On the other hand, all models over predict the lift coefficient except the quazi-steady model shows a lower lift coefficient. As reported by Yu et al. [14], the reason for this discrepancy could be attributed to the sensitivity of these models to capture the LEV de-attachment and the lift decrease during this phase. Based on the observations of Ramesh et al. [9], this behavior points to an important aspect, where the lift dynamics results in a considerable delay; i.e. the lift response does not depend on the past history (memory effects).
\n
\n
\n
4.1.2 Half chord pivot
\n
\n\nFigure 7\n shows the ramp with amplitude of \n\n\n25\no\n\n\n at the mid chord hinge location. The results show a good agreement with the experimental results by having the same lift response slope except for Thoedorsen model based on FFT model (attenuated response) and the quasi-steady model (over predicted). Of particular interest, Duhamel and state space models coincide on top of each other having the same lift magnitude. This is excepted as the two models have the same mathematical base. At the ramp hold phase, the value of the saturated lift coefficient is approximately 2 for all models except the quasi-steady and Theodorsen based on FFT. Here, the impact of shifting the pivot location towards the trailing edge conducive in reducing the rotational effects which in turn decreases the lift coefficient by 15% at the ramp-up event compared to the quarter chord location. This conclusion was reported also by Yu et al. [14] in their recent work for examining the effect of pivot locations on force and moment coefficients.
\n
\n
\n
4.1.3 Trailing edge pivot
\n
In a similar manner, \nFigure 8\n shows a comparison between experimental and theoretical predictions for \n\n\n25\no\n\n\n ramp case pitched about the trailing edge pivot. Lift coefficient comparison shows a qualitatively good agreement between the experiment and all the presented models (lift coefficient pattern). Of particular interest, taking the lift transition peaks during different ramp regimes. UVLM model results match very well for the ramp-up and ramp-hold regimes then decrease slightly at the ramp-down regime to give an damped lift coefficient values. Theodorsen model based on Fast Fourier Transform records an attenuated lift coefficient compared to experiments. On the other hand, all other presented models show an over predicted lift coefficient compared to the experimental results while preserving the same lift response pattern for all ramp regimes.
\n
The common result in all pivot location cases (leading, half and trailing chord location), show that Theodorsen FFT model has a damped lift response compared to all the proposed models and experiments. This is because for a given AOA (\n\nα\n\n), one could be interested in the transient response, however, the analytical expressions cannot be obtained and the discrete Fourier Transform (FFT) has to be used instead. Discrete Fourier Transform compared to the exact Fourier Transform ignores some frequency content mathematically. In addition to the aside notion of flow dynamics, the leading edge location experiences rich dynamics when compared to the half and trailing pivot chord locations reported by Ford and Babinsky [41]. This is due to the inclusion of rotational effects which increase by increasing the spacing between the hinge point and the three-quarter chord location. It is clear that all models capture the lift peaks during transition between pitch ramps except the quasi-steady model. This lift peak has been reported by previous studies due to a delay in stall and/or a delay in LEV formation [39, 42].
\n
\n
\n
\n
4.2 Case 1: Pitch ramp \n\n\nα\no\n\n=\n\n45\no\n\n\n\n
\n
\n
4.2.1 Leading edge pivot
\n
\n\nFigures 9\n–\n11\n show the lift coefficient response for a ramp maneuver with an amplitude of \n\n\n45\no\n\n\n at three different pivot locations. At the leading edge pivot location; shown in \nFigure 8\n, at the beginning of the ramp (\n\nτ\n=\n0\n−\n1\n\n), Theodorsen model based on Fourier series model shows higher lift coefficient than all the other models as well as the experimental results. For the ramp upstroke, all the models showed a decrease in the lift coefficient compared to the experiment results preserving the same slope until the start of the second event then a continuous increase in lift response which appears as over predicted values compared to the experimental results presented by Ramesh et al. [9]. The UVLM model pertained the same lift pattern and all proposed models show a large discrepancy compared to experimental results. In addition, the UVLM model results show a good agreement with experiments at the ramp-up then starts to deviate with an increase in lift coefficient by 48% at hold-on and ramp down regimes. Furthermore, the quasi steady model shows a high lift coefficient at the end of the ramp-upstroke compared to the experiments, followed by a sharp decrease at the ramp-down stroke.
\n
\n
\n
4.2.2 Half chord pivot
\n
\n\nFigure 10\n shows the lift coefficient for a ramp amplitude of \n\n\n45\no\n\n\n at half chord pivot location. The proposed models show a good match at the ramp-up regime then an over predicted lift coefficient occurs after the ramp-hold and ramp-down regimes compared to the experimental results except for Theodorsen FFT based model and the quasi-steady model. Again, Theodorsen FFT based model gives an attenuated response, and the quasi-steady model shows a magnified response (qualitatively similar to the results presented in \nFigure 7\n of a pitch ramp amplitude of \n\n25\n°\n\n). During the ramp-hold phase, the UVLM model matches well with small discrepancy compared to all other models. At the final phase (ramp-down), all models show an over prediction for the lift coefficient. The results show a smooth transition without any sharp peaks in lift coefficient between different events.
\n
\n
\n
4.2.3 Trailing edge pivot
\n
\n\nFigure 11\n presents the lift coefficient for a ramp amplitude of \n\n\n45\no\n\n\n at trailing edge pivot location. By comparing \nFigure 11\n along with \nFigure 8\n, the two models (Thoedorsen FFT based and UVLM) show a very good prediction with the experimental results for the two phases (ramp-up and ramp hold), then show an increase in the lift coefficient at ramp down. On the contrary, all other models record an over predicted lift coefficient compared to the experimental results for all events preserving the lift response pattern. The quasi steady models for the two ramp cases (\n\n0\n°\n\n-\n\n25\n°\n\n-\n\n0\n°\n\n and \n\n0\n°\n\n-\n\n45\n°\n\n-\n\n0\n°\n\n) at the same pivot location (trailing edge). \nFigure 8\n and \nFigure 11\n, do not show any sharp peak for lift coefficient for the ramp transition regimes. This is expected due to the lack of inclusion of wing stall and rotational effects.
\n
It is clear that a very good matching found between the UVLM model and experiments which can be attributed to the favor of leading edge suction inclusion as well as the nonlinear behavior (\n\nsin\n\nα\n\n\n) that is induced by the no-penetration boundary condition in the UVLM model. Consequently, at this range of AoA (\n\n25\n°\n\n) (attached flow), the dominant effect for the LES and nonlinearity associated with the ramp maneuver appears to be matched well with the results of Ramesh et al. [9]. At high angle of attack maneuver (\n\n45\n°\n\n), this effect no longer exists as the flow separates and became more pronounced [43]. Recall that rotational lift is proportional to the distance between the pivot and three quarter chord point (Giacomelli and Pistolesi theorem [44]), which attains and preserves its largest value for a leading edge pivot. The UVLM results match the experimental results with small nuances even for large amplitude (\n\n45\n°\n\n) at the ramp-up regime and partially at the ramp-hold only. At ramp-down regime, the UVLM results deviate from the experimental results and appeared to be over predicted.
\n
\n\nFigures 12\n and \n13\n show the Shedding of trailing vortices and wake convection shape downstream for \n\n25\n°\n\n and \n\n45\n°\n\n amplitudes ramp maneuvers. All the figures show the same convection pattern for the three pivot locations with an increase in the y axis vortex location with increasing the ramp amplitude.
\n
Figure 12.
Shedding of trailing vortices and wake convection downstream for \n\n25\n°\n\n amplitude ramp maneuver. (a) Leading edge pivot. (b) Half chord pivot. (c) Trailing edge pivot.
\n
Figure 13.
Shedding of trailing vortices and wake convection downstream for \n\n45\n°\n\n amplitude ramp maneuver. (a) Leading edge pivot. (b) Half chord pivot. (c) Trailing edge pivot.
\n
\n
\n
\n
\n
5. Conclusion
\n
In this chapter, different classical analytical models were presented in a simple mathematical form based on potential flow to solve unsteady problems constrained by an input motion. A canonical pitch ramp motion is chosen to present the input motion for two different ramp amplitudes (\n\n25\n°\n\n and \n\n45\n°\n\n) and three pivot location on the airfoil chord (\n\nc\n/\n4\n,\nc\n/\n2\n,\n3\nc\n/\n4\n\n). The analytical results were compared to the experimental data and the comparison revealed an acceptable agreement at the pitch ramp amplitude of \n\n\n25\no\n\n\n compared to the results presented by the \n\n\n45\no\n\n\n ramp amplitude case. Thus, those models can be considered as promising aerodynamic models for predicting lift coefficient for such manoeuver at a ramp amplitude up to \n\n\n25\no\n\n\n only. Along the four analytical models, the UVLM showed very good results for the two ramp amplitude cases. It should be noted that, the UVLM captures all geometric nonlinearities, wake deformation, rolling wake, leading edge suction and post stall without the inclusion of leading edge vortex effects. Duhamel and the state space models appear to have the same behavior which asserts that the state space model shares the same physical base and obtained the same results compared to Theodorsen’s model.
\n
\n\nTable 2\n discuses and concludes the output of each proposed model with the perspective of output response, pitch amplitudes, computational cost and the obtained loads.
\n
\n
\n
\n
\n
\n
\n\n
\n
Models
\n
Response type
\n
Large amplitude
\n
Computational cost
\n
Loads
\n
\n\n\n
\n
Theodorsen
\n
Steady state harmonic
\n
\n\n\n×\n\n\n
\n
\n\n\n×\n\n\n
\n
force
\n
\n
\n
Wagner
\n
Transient
\n
\n\n\n×\n\n\n
\n
\n\n\n×\n\n\n
\n
Force
\n
\n
\n
State space
\n
Full response
\n
\n\n\n×\n\n\n
\n
\n\n\n×\n\n\n
\n
Force
\n
\n
\n
UVLM
\n
Full response
\n
\n\n\n√\n\n\n
\n
\n\n\n√\n\n\n
\n
Pressure
\n
\n\n
Table 2.
Proposed models output parameters for solving pitching maneuvers.
\n
The benefits of the UVLM compared to other methods is that is enabling aerodynamic modeling for arbitrary motion. An extension is easy to implement to include a formulation of the boundary conditions for arbitrary three-dimensional motion and control surface rotation. Furthermore the calculation of unsteady induced drag by a nonlinear extension of the force computation can be done. Furthermore the proposed UVLM method shows advantages in predicting unsteady aerodynamic forces of high frequency motion compared to other analytical models. In general, it can be said that the unsteady vortex lattice method is a powerful tool for modeling of incompressible and inviscid unsteady aerodynamics. A continuous time formulation in particular can be used to decrease the computational costs for aeroelastic simulations. The possibility of calculating unsteady loads without the need of approximations for time-domain simulation makes the method especially useful within aeroservoelastic optimization algorithms. Other models formulated in time domain (for example sensor and actuator models or control laws) can be easily integrated. Furthermore, the nonlinear aerodynamic state space formulation is suitable for the integration of further nonlinear aerodynamic correction models (e.g. stall models). This provides confidence towards the development of semi-empirical models based on potential flow theories and experiments that can predict unsteady forces of ramp maneuvers.
\n',keywords:"canonical maneuvers, pitching maneuvers, unsteady aerodynamics, unsteady lift response",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/74820.pdf",chapterXML:"https://mts.intechopen.com/source/xml/74820.xml",downloadPdfUrl:"/chapter/pdf-download/74820",previewPdfUrl:"/chapter/pdf-preview/74820",totalDownloads:371,totalViews:0,totalCrossrefCites:0,dateSubmitted:"June 27th 2020",dateReviewed:"September 28th 2020",datePrePublished:"January 15th 2021",datePublished:"June 9th 2021",dateFinished:"January 15th 2021",readingETA:"0",abstract:"In this chapter, a set of analytical aerodynamic models, based on potential flow, that can be used to predict the unsteady lift response during pitching maneuvers are presented and assessed. The result examines the unsteady lift coefficients experienced by a flat plate in high-amplitude pitch ramp motion. The pitch ramps are chosen based on two ramp pitch maneuvers of a maximum amplitudes of 25 and 45 degrees starting from zero degree. The aim is investigate the use of such classical models in predicting the lift dynamics compared to a full physical-based model. Among all classical methods used, the unsteady vortex lattice method (without considering the leading edge vortex) is found to be a very good predictor of the motion lift dynamic response for the \n\n25\n°\n\n ramp angle case. However, at high pitch maneuvers (i.e.,the \n\n45\n°\n\n ramp angle case), could preserve the response pattern with attenuated amplitudes without high computational burden. These mathematical analytical models presented in this chapter can be used to obtain a fast estimate for aircraft unsteady lift during pitch maneuvers instead of high fidelity models, especially in the early design phases.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/74820",risUrl:"/chapter/ris/74820",signatures:"Mohamed Yehia Zakaria",book:{id:"10372",type:"book",title:"Biomimetics",subtitle:null,fullTitle:"Biomimetics",slug:"biomimetics",publishedDate:"June 9th 2021",bookSignature:"Maki K. Habib and César Martín-Gómez",coverURL:"https://cdn.intechopen.com/books/images_new/10372.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83962-171-0",printIsbn:"978-1-83962-170-3",pdfIsbn:"978-1-83962-211-3",isAvailableForWebshopOrdering:!0,editors:[{id:"80821",title:"Dr.",name:"Maki K.",middleName:null,surname:"Habib",slug:"maki-k.-habib",fullName:"Maki K. Habib"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"213655",title:"Dr.",name:"Mohamed Y.",middleName:null,surname:"Zakaria",fullName:"Mohamed Y. Zakaria",slug:"mohamed-y.-zakaria",email:"zakaria@vt.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Virginia Tech",institutionURL:null,country:{name:"United States of America"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Motion kinematics",level:"1"},{id:"sec_3",title:"3. Classical models",level:"1"},{id:"sec_3_2",title:"3.1 Theodorsen model",level:"2"},{id:"sec_4_2",title:"3.2 Wagner step response and Duhamel superposition principle",level:"2"},{id:"sec_5_2",title:"3.3 State space finite model",level:"2"},{id:"sec_6_2",title:"3.4 Unsteady vortex lattice method (UVLM)",level:"2"},{id:"sec_7_2",title:"3.5 Models comparison",level:"2"},{id:"sec_9",title:"4. Maneuver case studies results",level:"1"},{id:"sec_9_2",title:"4.1 Case 1: Pitch ramp \n\n\nα\no\n\n=\n\n25\no\n\n\n\n",level:"2"},{id:"sec_9_3",title:"4.1.1 Leading edge pivot",level:"3"},{id:"sec_10_3",title:"4.1.2 Half chord pivot",level:"3"},{id:"sec_11_3",title:"4.1.3 Trailing edge pivot",level:"3"},{id:"sec_13_2",title:"4.2 Case 1: Pitch ramp \n\n\nα\no\n\n=\n\n45\no\n\n\n\n",level:"2"},{id:"sec_13_3",title:"4.2.1 Leading edge pivot",level:"3"},{id:"sec_14_3",title:"4.2.2 Half chord pivot",level:"3"},{id:"sec_15_3",title:"4.2.3 Trailing edge pivot",level:"3"},{id:"sec_18",title:"5. Conclusion",level:"1"},{id:"sec_21",title:"Nomenclature",level:"1"},{id:"sec_21",title:"Greek variables",level:"1"},{id:"sec_21",title:"Abbreviations",level:"1"}],chapterReferences:[{id:"B1",body:'\nCory, R. and Tedrake, R. (2008). “Experiments in fixed-wing uav perching." 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Journal of Fluids and Structures, 69(February 2017), Pages–187\n'},{id:"B35",body:'\nTaha, H. E., Hajj, M. R., and Beran, P. S. (2014). “State-space representation of the unsteady aerodynamics of flapping flight." Aerospace Science and Technology, 34, 1–11\n'},{id:"B36",body:'\nKussner, H. and Schwartz, I. (1941). “The oscillating wing with aerodynamically balanced elevator\n'},{id:"B37",body:'\nKatz, J. and Plotkin, A. (2001). Low Speed Aerodynamics. Cambridge University Press, 2 edition\n'},{id:"B38",body:'\nBinder, S., Wildschek, A., and De Breuker, R. “Extension of the continuous time unsteady vortex lattice method for arbitrary motion, control surface deection and induced drag calculation\n'},{id:"B39",body:'\nSodja, J., Drazumeric, R., Kosel, T., and Marzocca, P. (2014). “Design of flexible propellers with optimized load-distribution characteristics." Journal of Aircraft, 51(1), 117–128\n'},{id:"B40",body:'\nKonstadinopoulos, P., Thrasher, D., Mook, D., Nayfeh, A., and Watson, L. (1985). “A vortex-lattice method for general, unsteady aerodynamics." Journal of aircraft, 22(1), 43–49\n'},{id:"B41",body:'\nRamesh, K., Gopalarathnam, A., Edwards, J. R., Ol, M. V., and Granlund, K. (2011). “Theoretical, computational and experimental studies of a at plate undergoing high-amplitude pitching motion." AIAA Paper, 217\n'},{id:"B42",body:'\nGranlund, K. O., Ol, M. V., and Bernal, L. P. (2013). “Unsteady pitching at plates." Journal of Fluid Mechanics, 733\n'},{id:"B43",body:'\nYu, H.-T., Bernal, L. P., and Morrison, C. (2012). “Experimental investigation of pitch ramp-hold-return motion of at plates at low reynolds number." AIAA Paper, 51\n'},{id:"B44",body:'\nGiacomelli, R. and Pistolesi, E. (1934). “Aerodynamic theory." Div. D.(ed. Wm. F. Durand). Berlin: Springer\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Mohamed Yehia Zakaria",address:"zakaria@mtc.edu.eg",affiliation:'
Aircraft Mechanics Department, Military Technical College, Cairo, Egypt
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This chapter discusses general features of CMVI in dogs focusing on recent advances in diagnosis and treatment.",book:{id:"5469",slug:"canine-medicine-recent-topics-and-advanced-research",title:"Canine Medicine",fullTitle:"Canine Medicine - Recent Topics and Advanced Research"},signatures:"Sang-II Suh, Dong-Hyun Han, Seung-Gon Lee, Yong-Wei Hung, Ran\nChoi and Changbaig Hyun",authors:[{id:"13534",title:"Prof.",name:"Changbaig",middleName:null,surname:"Hyun",slug:"changbaig-hyun",fullName:"Changbaig Hyun"},{id:"371146",title:"Dr.",name:"Sang-II",middleName:null,surname:"Suh",slug:"sang-ii-suh",fullName:"Sang-II Suh"},{id:"371147",title:"Dr.",name:"Dong-Hyun",middleName:null,surname:"Han",slug:"dong-hyun-han",fullName:"Dong-Hyun Han"},{id:"371148",title:"Dr.",name:"Seung-Gon",middleName:null,surname:"Lee",slug:"seung-gon-lee",fullName:"Seung-Gon Lee"},{id:"371149",title:"Dr.",name:"Yong-Wei",middleName:null,surname:"Hung",slug:"yong-wei-hung",fullName:"Yong-Wei Hung"},{id:"371150",title:"Dr.",name:"Ran",middleName:null,surname:"Choi",slug:"ran-choi",fullName:"Ran Choi"}]},{id:"52484",title:"Infectious Causes of Abortion, Stillbirth and Neonatal Death in Bitches",slug:"infectious-causes-of-abortion-stillbirth-and-neonatal-death-in-bitches",totalDownloads:2818,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Problems in gestational development in dogs can be determined by infectious and non‐infectious causes. Among the non‐infectious causes, trauma during pregnancy, genetic characteristics of the animal, deficit nutrition, thyroid dysfunction, maternal problems and hormonal disorders are found. The majority of the cases are in relation to infectious diseases, one should consider viral, bacterial, fungal and protozoal, which can interfere directly or indirectly in the foetal development. The progression of foetal development may be affected by the direct action of the microorganisms to overcome the placenta, but they are also able to affect pregnancy and release placental toxins by inflammatory processes and, may still cause maternal pathologies, which entail problems such as hyperthermia, hypoxia and endotoxemia, which can result in abortion. Several diseases can trigger pregnancy loss in dogs. This action can be direct by microorganisms, as well as indirectly triggering other problems that lead to abortion. This chapter discusses the infectious aetiologies of reproductive failures (abortion, stillbirth and neonatal death) in bitches.",book:{id:"5469",slug:"canine-medicine-recent-topics-and-advanced-research",title:"Canine Medicine",fullTitle:"Canine Medicine - Recent Topics and Advanced Research"},signatures:"João Marcelo Azevedo de Paula Antunes, Débora Alves de Carvalho\nFreire, Ilanna Vanessa Pristo de Medeiros Oliveira, Gabriela Hémylin\nFerreira Moura, Larissa de Castro Demoner and Heider Irinaldo\nPereira Ferreira",authors:[{id:"191197",title:"Ph.D.",name:"João",middleName:null,surname:"Antunes",slug:"joao-antunes",fullName:"João Antunes"},{id:"191203",title:"MSc.",name:"Débora Alves",middleName:null,surname:"De Carvalho Freire",slug:"debora-alves-de-carvalho-freire",fullName:"Débora Alves De Carvalho Freire"},{id:"191204",title:"MSc.",name:"Ilanna Vanessa",middleName:null,surname:"Pristo De Medeiros Oliveira",slug:"ilanna-vanessa-pristo-de-medeiros-oliveira",fullName:"Ilanna Vanessa Pristo De Medeiros Oliveira"},{id:"191205",title:"BSc.",name:"Gabriela Hémylin",middleName:null,surname:"Ferreira Moura",slug:"gabriela-hemylin-ferreira-moura",fullName:"Gabriela Hémylin Ferreira Moura"},{id:"191207",title:"Dr.",name:"Larissa",middleName:null,surname:"De Castro Demoner",slug:"larissa-de-castro-demoner",fullName:"Larissa De Castro Demoner"},{id:"194801",title:"MSc.",name:"Heider Irinaldo Pereira",middleName:null,surname:"Ferreira",slug:"heider-irinaldo-pereira-ferreira",fullName:"Heider Irinaldo Pereira Ferreira"}]},{id:"28674",title:"Atresia Ani in Dogs and Cats",slug:"atresia-ani-in-dogs-and-cats",totalDownloads:15480,totalCrossrefCites:1,totalDimensionsCites:2,abstract:null,book:{id:"1667",slug:"a-bird-s-eye-view-of-veterinary-medicine",title:"A Bird's-Eye View of Veterinary Medicine",fullTitle:"A Bird's-Eye View of Veterinary Medicine"},signatures:"Lysimachos G. 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The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. 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Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:6,paginationItems:[{id:"22",title:"Applied Intelligence",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",isOpenForSubmission:!0,editor:{id:"27170",title:"Prof.",name:"Carlos",middleName:"M.",surname:"Travieso-Gonzalez",slug:"carlos-travieso-gonzalez",fullName:"Carlos Travieso-Gonzalez",profilePictureURL:"https://mts.intechopen.com/storage/users/27170/images/system/27170.jpeg",biography:"Carlos M. Travieso-González received his MSc degree in Telecommunication Engineering at Polytechnic University of Catalonia (UPC), Spain in 1997, and his Ph.D. degree in 2002 at the University of Las Palmas de Gran Canaria (ULPGC-Spain). He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"26",title:"Machine Learning and Data Mining",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",isOpenForSubmission:!0,editor:{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. His research interests include intelligent and embedded systems.",institutionString:"Universidad Autonoma de Queretaro",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null},{id:"27",title:"Multi-Agent Systems",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",isOpenForSubmission:!0,editor:{id:"148497",title:"Dr.",name:"Mehmet",middleName:"Emin",surname:"Aydin",slug:"mehmet-aydin",fullName:"Mehmet Aydin",profilePictureURL:"https://mts.intechopen.com/storage/users/148497/images/system/148497.jpg",biography:"Dr. Mehmet Emin Aydin is a Senior Lecturer with the Department of Computer Science and Creative Technology, the University of the West of England, Bristol, UK. His research interests include swarm intelligence, parallel and distributed metaheuristics, machine learning, intelligent agents and multi-agent systems, resource planning, scheduling and optimization, combinatorial optimization. Dr. Aydin is currently a Fellow of Higher Education Academy, UK, a member of EPSRC College, a senior member of IEEE and a senior member of ACM. In addition to being a member of advisory committees of many international conferences, he is an Editorial Board Member of various peer-reviewed international journals. He has served as guest editor for a number of special issues of peer-reviewed international journals.",institutionString:null,institution:{name:"University of the West of England",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:20,paginationItems:[{id:"82526",title:"Deep Multiagent Reinforcement Learning Methods Addressing the Scalability Challenge",doi:"10.5772/intechopen.105627",signatures:"Theocharis Kravaris and George A. Vouros",slug:"deep-multiagent-reinforcement-learning-methods-addressing-the-scalability-challenge",totalDownloads:19,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Multi-Agent Technologies and Machine Learning",coverURL:"https://cdn.intechopen.com/books/images_new/11445.jpg",subseries:{id:"27",title:"Multi-Agent Systems"}}},{id:"82196",title:"Multi-Features Assisted Age Invariant Face Recognition and Retrieval Using CNN with Scale Invariant Heat Kernel Signature",doi:"10.5772/intechopen.104944",signatures:"Kamarajugadda Kishore Kumar and Movva Pavani",slug:"multi-features-assisted-age-invariant-face-recognition-and-retrieval-using-cnn-with-scale-invariant-",totalDownloads:14,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Pattern Recognition - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11442.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}},{id:"82063",title:"Evaluating Similarities and Differences between Machine Learning and Traditional Statistical Modeling in Healthcare Analytics",doi:"10.5772/intechopen.105116",signatures:"Michele Bennett, Ewa J. 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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. 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We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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