Metastatic human hepatocellular carcinoma models in nude mice and cell line with metastatic potential

Metastatic human HCC model is needed for the studies on mechanism and intervention of metastatic recurrence. By using orthotopic implantation of histologically intact tissues of 30 surgical specimens, a patient-like metastatic model of human HCC in nude mice (LCI-D20) and a low metastatic model of human HCC in nude mice (LCI-D35) have been established. All mice with transplanted LCI-D20 tumors exhibited extremely high metastatic ability including spontaneous metastasis to liver, lungs, lymph nodes and peritoneal seeding. Remarkable difference was also found in expression of some of the invasiveness related genes and growth factors between the LCI-D20 and LCI-D35 tumors. PAI-1 increased gradually following tumor progression in LCI-D20 model, and correlated with tumor size and AFP level. Phasic expression of tissue intercellular adhesion molecule-1 in this model was also observed. Using corneal micropocket model, it was demonstrated that the vascular response induced by LCI-D20 tumor was stronger than that induced by LCI-D35 tumor. Similar report on metastatic human HCC model in nude mice and human HCC cell line with metastatic potential was rarely found in the literature. This LCI-D20 model has been widely used for the studies on intervention of metastasis, including anti-angiogenesis,antisense approach, metalloproteinase inhibitor, differentiation inducer, etc. It is concluded that the establishment of metastatic human HCC model in nude mice and human HCC cell line with metastatic potential will provide important models for the in vitro and in vitro study of HCC invasiveness, angiogenesis as well as intervention of HCC recurrence.

Targeting Effect Study of ￣(3) H-Mitoxantrone Nanosphereson Hepatocellular Carcinoma(HCC) Model in Nude Mice

The distribution of ￣(3)H-mitoxantrone polybutyl cyanoacrylate nanospheres(￣(3)H-DHAQ-PBCA-NS)in the viscera,muscle and tumors of human hepatocellular carcinoma (HCC)model in nude mice was studied with liquid scintillation counting techniique. The results showed that the ￣(3)H-DHAQ-PBCA-NS had remarkable liver targeting effect. The content of ￣(3)H-DHAQ-PBCA-NSin liver and heterotopic liver tumor was found to be 71.31±10. 49% of total amount of drug in animal body. It was also found that the content of ￣(3)H-DHAQ-PBCA-NS in liver was higher than that in liver tissue, and the content of ￣(3)H-DHAQ-PBCA-NS in annpit tumor was higher than that in armpit muscle tissue,but had no significant difference;It provides an ideal preparation for the DHAQ admini-stration.

A modified rat model for hepatocellular carcinoma

BACKGROUND: Rat hepatocellular carcinoma ( HCC ) model which has a high analogy to clinical liver cancer is of great value in understanding the pathogenesis and evolution of liver cancer, in searching effective anti-cancer treat- ments ( drug, hepatectomy and liver transplantation ), and designing cancer prevention strategies. In this study we es- tablished a modified rat model of hepatocellular carcinoma to enhance rats' physique and surgical endurance. METHODS: Wistar rats were fed with diethylnitrosamine (DENA) by three methods for evaluation of general condi- tions for 130 days: Doppler ultrasonographic measurement, laparotomy and histopathological examination. RESULTS: No rat died in control group ( group A) and modified DENA-induction-HCC group ( group C), but 6 deaths in classical DENA-induction-HCC group (group B) (survival rate 80%). All survived rats in groups B and C de- veloped diffusive hepatocellular carcinoma and liver cirrho- sis. General appearance of rats in the group C was better than that in the group B. CONCLUSION: With good general conditions for surgery, the modified rat model for hepatocellular carcinoma has a high carcinogenic rate and a high survival rate.

Prediction models of hepatocellular carcinoma development in chronic hepatitis B patients

Chronic hepatitis B virus(HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma(HCC). Applying the same strategies for antiviral therapy and HCC surveillance to all chronic hepatitis B(CHB) patients would be a burden worldwide. To properly manage CHB patients, it is necessary to identify and classify the risk for HCC development in such patients. Several HCC risk scores based on risk factors such as cirrhosis, age, male gender, and high viral load have been used, and have negative predictive values of ≥ 95%. Most of these have been derived from, and internally validated in, treatment-na?ve Asian CHB patients. Herein, we summarized various HCC prediction models, including IPM(Individual Prediction Model), CU-HCC(Chinese University-HCC), GAG-HCC(Guide with Age, Gender, HBV DNA, Core Promoter Mutations and Cirrhosis-HCC), NGM-HCC(NomogramHCC), REACH-B(Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B), and Page-B score. To develop a noninvasive test of liver fibrosis, we also introduced a new scoring system that uses liver stiffness values from transient elastography, including an LSM(Liver Stiffness Measurement)-based model, LSM-HCC, and mR EACH-B(modified REACH-B).

Hepatocellular carcinoma mouse models:Hepatitis B virusassociatedhepatocarcinogenesis and haploinsufficienttumor suppressor genes

The multifactorial and multistage pathogenesis of hepatocellular carcinoma(HCC)has fascinated a wide spectrum of scientists for decades.While a number of major risk factors have been identified,their mechanistic roles in hepatocarcinogenesis still need to be elucidated.Many tumor suppressor genes(TSGs)have been identified as being involved in HCC.These TSGs can be classified into two groups depending on the situation with respect to allelic mutation/loss in the tumors:the recessive TSGs with two required mutated alleles and the haploinsufficient TSGs with one required mutated allele.Hepatitis B virus(HBV)is one of the most important risk factors associated with HCC.Although mice cannot be infected with HBV due to the narrow host range of HBV and the lack of a proper receptor,one advantage of mouse models for HBV/HCC research is the numerous and powerfulgenetic tools that help investigate the phenotypic effects of viral proteins and allow the dissection of the dose-dependent action of TSGs.Here,we mainly focus on the application of mouse models in relation to HBV-associated HCC and on TSGs that act either in a recessive or in a haploinsufficient manner.Discoveries obtained using mouse models will have a great impact on HCC translational medicine.

Zebrafish as a disease model for studying human hepatocellular carcinoma

Liver cancer is one of the world's most common cancers and the second leading cause of cancer deaths. Hepatocellular carcinoma(HCC), a primary hepatic cancer, accounts for 90%-95% of liver cancer cases. The pathogenesis of HCC consists of a stepwise process of liver damage that extends over decades, due to hepatitis, fatty liver, fibrosis, and cirrhosis before developing fully into HCC. Multiple risk factors are highly correlated with HCC, including infection with the hepatitis B or C viruses, alcohol abuse, aflatoxin exposure, and metabolic diseases. Over the last decade, genetic alterations, which include the regulation of multiple oncogenes or tumor suppressor genes and the activation of tumorigenesis-related pathways, have also been identified as important factors in HCC. Recently, zebrafish have become an important living vertebrate model organism, especially for translational medical research. In studies focusing on the biology of cancer, carcinogen induced tumors in zebrafish were found to have many similarities to human tumors. Several zebrafish models have therefore been developed to provide insight into the pathogenesis of liver cancer and the related drug discovery and toxicology, and to enable the evaluation of novel smallmolecule inhibitors. This review will focus on illustrativeexamples involving the application of zebrafish models to the study of human liver disease and HCC, through transgenesis, genome editing technology, xenografts,drug discovery, and drug-induced toxic liver injury.

Anticancer Effect of PS-T on the Experimental Hepatocellular Carcinoma

Objective: To apply PS-T in di?erent phases of carcinoma formation and development, and research the mechanism of anti-carcinoma of PS-T in the cytological level. Methods: N-nitrosodiethylamine (DENA) and CCl4 were applied jointly to duplicate the rat hepatocirrhosis and hepatic cancer model. The rats were divided into 7 groups and were administrated via nasal-stomach tube with PS-T in di?erent phases to interfere the cancer genesis and development. All the rats were killed in 20 weeks for pathological observation. Results: The loss of body weight of rats slowed down in the PS-T-treated group, and the carcinogenesis rate was signi?cantly decreased correspondingly. PS-T could also inhibit the carcinogenesis by supressing the hepatocirrhosis, which showed the positive correlation between the curative e?ect and the curative period. Conclusion: Application of PS-T during cancer induction showed a signi?cant e?ect on preventing and supressing cancer. PS-T might be an ideal drug for clinical anti-cancer therapy. And it will be a main drug in both combined and single treatments for tumor.

Construction of a risk score prognosis model based on hepatocellular carcinoma microenvironment

BACKGROUND Hepatocellular carcinoma(HCC)is a common cancer with a poor prognosis.Previous studies revealed that the tumor microenvironment(TME)plays an important role in HCC progression,recurrence,and metastasis,leading to poor prognosis.However,the effects of genes involved in TME on the prognosis of HCC patients remain unclear.Here,we investigated the HCC microenvironment to identify prognostic genes for HCC.AIM To identify a robust gene signature associated with the HCC microenvironment to improve prognosis prediction of HCC.METHODS We computed the immune/stromal scores of HCC patients obtained from The Cancer Genome Atlas based on the ESTIMATE algorithm.Additionally,a risk score model was established based on Differentially Expressed Genes(DEGs)between high and lowimmune/stromal score patients.RESULTS The risk score model consisting of eight genes was constructed and validated in the HCC patients.The patients were divided into high-or low-risk groups.The genes(Disabled homolog 2,Musculin,C-X-C motif chemokine ligand 8,Galectin 3,B-cell-activating transcription factor,Killer cell lectin like receptor B1,Endoglin and adenomatosis polyposis coli tumor suppressor)involved in our risk score model were considered to be potential immunotherapy targets,and they may provide better performance in combination.Functional enrichment analysis showed that the immune response and T cell receptor signaling pathway represented the major function and pathway,respectively,related to the immune-related genes in the DEGs between high-and low-risk groups.The receiver operating characteristic(ROC)curve analysis confirmed the good potency of the risk score prognostic model.Moreover,we validated the risk score model using the International Cancer Genome Consortium and the Gene Expression Omnibus database.A nomogram was established to predict the overall survival of HCC patients.CONCLUSION The risk score model and the nomogram will benefit HCC patients through personalized immunotherapy.

Establishment of NOD/SCID mouse models of human hepatocellular carcinoma via subcutaneous transplantation of histologically intact tumor tissue

Hepatocellular carcinoma （HCC） is one of the most deadly human cancers, but it is very difficult to establish an animal model by using surgical specimens. In the present experiment, histologically intact fresh surgical specimens of HCC were subcutaneously transplanted in non-obese diabetic/severe combined immunodeficienccy （NOD/SCID） mice. The biological characteristics of the original and the corresponding transplanted tumors and cell lines were investigated. The results showed that 5 new animal models and 2 primary cell lines were successfully established f^om surgical specimens. Hematoxylin-eosin staining showed that xenografts retained major histological features of the original surgical specimens. The two new cell lines had been cultivated for 3 years and successively passaged for more than 100 passages in vitro. The morphological characteristics and biologic features of the two cell lines were genetically similar to the original tumor. The subcutaneous transplant animal models with histologically intact tumor tissue and primary cell lines could be useful for in vivo and in vitro testing of anti-cancer drugs and be ideal models to study various biologic features of HCC.

Early detection of hepatocellular carcinoma co-occurring with hepatitis C virus infection: A mathematical model

AIM: To develop a mathematical model for the early detection of hepatocellular carcinoma (HCC) with a panel of serum proteins in combination with α-fetoprotein (AFP).METHODS: Serum levels of interleukin (IL)-8, soluble intercellular adhesion molecule-1 (sICAM-1), soluble tumor necrosis factor receptor II (sTNF-RII), proteasome, and β-catenin were measured in 479 subjects categorized into four groups: (1) HCC concurrent with hepatitis C virus (HCV) infection (n = 192); (2) HCV related liver cirrhosis (LC) (n = 96); (3) Chronic hepatitis C (CHC) (n = 96); and (4) Healthy controls (n = 95). The R package and different modules for binary and multi-class classifiers based on generalized linear models were used to model the data. Predictive power was used to evaluate the performance of the model. Receiver operating characteristic curve analysis over pairs of groups was used to identify the best cutoffs differentiating the different groups.RESULTS: We revealed mathematical models, based on a binary classifier, made up of a unique panel of serum proteins that improved the individual performance of AFP in discriminating HCC patients from patients with chronic liver disease either with or without cirrhosis. We discriminated the HCC group from the cirrhotic liver group using a mathematical model (-11.3 + 7.38 × Prot + 0.00108 × sICAM + 0.2574 × β-catenin + 0.01597 × AFP) with a cutoff of 0.6552, which achieved 98.8% specificity and 89.1% sensitivity. For the discrimination of the HCC group from the CHC group, we used a mathematical model [-10.40 + 1.416 × proteasome + 0.002024 × IL + 0.004096 × sICAM-1 + (4.251 × 10-4) × sTNF + 0.02567 × β-catenin + 0.02442 × AFP] with a cutoff 0.744 and achieved 96.8% specificity and 89.7% sensitivity. Additionally, we derived an algorithm, based on a binary classifier, for resolving the multi-class classification problem by using three successive mathematical model predictions of liver disease status.CONCLUSION: Our proposed mathematical model may be a useful method for the early detection of different statuses of liver disease co-occurring with HCV infection.

Validated model for prediction of recurrent hepatocellular carcinoma after liver transplantation in Asian population

BACKGROUND Liver transplantation(LT) is regarded as the best treatment for both primary and recurrent hepatocellular carcinoma(HCC). Post-transplant HCC recurrence rate is relatively low but significant, ranging from 10%-30% according to different series. When recurrence happens, it is usually extrahepatic and associated with poor prognosis. A predictive model that allows patient stratification according to recurrence risk can help to individualize post-transplant surveillance protocol and guidance of the use of anti-tumor immunosuppressive agents.AIM To develop a scoring system to predict HCC recurrence after LT in an Asian population.METHODS Consecutive patients having LT for HCC from 1995 to 2016 at our hospital were recruited. They were randomized into the training set and the validation set in a60:40 ratio. Multivariable Cox regression model was used to identity factors associated with HCC recurrence. A risk score was assigned to each factor according to the odds ratio. Accuracy of the score was assessed by the area under the receiver operating characteristic curve.RESULTS In total, 330 patients were eligible for analysis(183 in training and 147 invalidation). Recurrent HCC developed in 14.2% of them. The median follow-up duration was 65.6 mo. The 5-year disease-free and overall survival rates were78% and 80%, respectively. On multivariate analysis, alpha-fetoprotein > 400 ng/mL [P = 0.012, hazard ratio(HR) 2.92], sum of maximum tumor size and number(P = 0.013, HR 1.15), and salvage LT(P = 0.033, HR 2.08) were found to be independent factors for disease-free survival. A risk score was calculated for each patient with good discriminatory power(c-stat 0.748 and 0.85, respectively,in the training and validation sets). With the derived scores, patients were classified into low-(0–9), moderate-(> 9–14), and high-risk groups(> 14), and the risk of HCC recurrence in the training and validation sets was 10%, 20%, 54%(cstat 0.67) and 4%, 22%, 62%(c-stat 0.811), accordingly. The risk stratification model was validated with chi-squared goodness-of-fit test(P = 0.425).CONCLUSION A validated predictive model featuring alpha-fetoprotein, salvage LT, and the sum of largest tumor diameter and total number of tumor nodule provides simple and reliable guidance for individualizing postoperative surveillance strategy.

Research Progress in Animal Models of Hepatocellular Carcinoma

[Objective] To establish good animal models of hepatocellular carcinoma （HCC） and serve treatment of HCC in humans. [Method] Several common animal models of HCC were introduced briefly. [Result] The commonly used animal models include C57BL/6J mouse model of or- thotopic HCC induced with Hepa1-6 cells, nude mouse model of HCC constructed with Hep_G2 cell lines, rat HCC model constructed through direct transplantation or direct injection, HU-PBL-SCID mice modal, and other transplanted HCC models or genetic HCC models. [ Conclusion] Animal model is an important means and platform for experimental studies. To establish animal models of HCC is of important significance for studies on pathogenesis, diagnosis and treatment of HCC.

Detection and characterization of hepatocellular carcinoma in rats with liver cirrhosis:diagnostic value of combined use of MR positive and negative contrast agents

BACKGROUND: Gadolinium-enhanced multi-phase dynamic imaging has improved the accuracy of the diagnosis of hypervascular hepatocellular carcinoma (HCC), but using gadolinium-enhanced dynamic imaging alone is problematic in evaluating hypovascular HCC. This work aimed at evaluating the combined use of superparamagnetic iron oxide (SPIO)-enhanced and gadolinium set in distinguishing HCCs from regenerative nodules (RNs) in a rat model induced by diethylnitrosamine (DEN). METHODS: DEN-induced HCC model rats (n=40) and control rats (n=10) were studied. From weeks 16 to 19 after DEN administration, 4 animals were scanned every week. The hepatic changes were tested with a 1.5 Tesla magnet, and MR images of SPIO-enhanced and gadolinium set were obtained. According to the pathologic changes, the tumorigenesis was divided into HCC and RN (diameter of nodules >= 3 mm). Diagnostic accuracy of the combined SPIO-enhanced and gadolinium set and the gadolinium set alone was evaluated using receiver-operating characteristic curves. Sensitivity and specificity of the combined SPIO-enhanced and gadolinium set and the gadolinium set alone were calculated. RESULTS: The listed tests were completed in 29 rats (21 treated and 8 controls). One hundred and six nodules (82 HCCs, 24 RNs) were analyzed. The Az value and sensitivity with the combined SPIO-enhanced and gadolinium set (Az 0.94, sensitivity 0.96) were higher than those with the gadolinium set alone (Az 0.92, sensitivity 0.89). Using the combined SPIO-enhanced and gadolinium set led to detection of 6 nodules which were negative in the gadolinium set alone and 3 nodules were correctly characterized. CONCLUSION: Using the combined SPIO-enhanced and gadolinium set improved the detectability of HCCs and the SPIO-enhanced imaging compensated for the gadolinium set in differentiating HCCs from RNs in a rat model.

End-stage liver disease score and future liver remnant volume predict post-hepatectomy liver failure in hepatocellular carcinoma

BACKGROUND Hepatocellular carcinoma(HCC)is the world’s sixth most common malignant tumor and the third cause of cancer death.Although great progress has been made in hepatectomy,it is still associated with a certain degree of risk of posthepatectomy liver failure(PHLF),which extends the length of hospital stay and remains the leading cause of postoperative death.Studies have shown that assessment of hepatic functional reserve before hepatectomy is beneficial for reducing the incidence of PHLF.AIM To assess the value of model for end-stage liver disease(MELD)score combined with standardized future liver remnant(sFLR)volume in predicting PHLF in patients undergoing hepatectomy for HCC.METHODS This study was attended by 238 patients with HCC who underwent hepatectomy between January 2015 and January 2018.Discrimination of sFLR volume,MELD score,and sFLR/MELD ratio to predict PHLF was evaluated according to the area under the receiver operating characteristic curve.RESULTS The patients were divided into two groups according to whether PHLF occurred after hepatectomy.The incidence of PHLF was 8.4%in our research.The incidence of PHLF increased with the decrease in sFLR volume and the increase in MELD score.Both sFLR volume and MELD score were considered independent predictive factors for PHLF.Moreover,the cut-off value of the sFLR/MELD score to predict PHLF was 0.078(P<0.001).This suggests that an sFLR/MELD≥0.078 indicates a higher incidence of PHLF than an sFLR/MELD<0.078.CONCLUSION MELD combined with sFLR is a reliable and effective PHLF predictor,which is superior to MELD score or sFLR volume alone.

Three-dimensional morphometric analysis for hepatectomy of centrally located hepatocellular carcinoma:A pilot study

AIM: To describe a three-dimensional model(3DM) to accurately reconstruct anatomic relationships of centrally located hepatocellular carcinomas(HCCs).METHODS: From March 2013 to July 2014, reconstructions and visual simulations of centrally located HCCs were performed in 39 patients using a 3D subject-based computed tomography(CT) model with customdeveloped software. CT images were used for the 3D reconstruction of Couinaud's pedicles and hepatic veins, and the calculation of corresponding tumor territories and hepatic segments was performed using Yorktal DMIT software. The respective volume, surgical margin, and simulated virtual resection of tumors were also estimated by this model preoperatively. All patients were treated surgically and the results were retrospectively assessed. Clinical characteristics, imaging data, procedure variables, pathologic features, and postoperative data were recorded and compared to determine the reliability of the model.RESULTS: 3D reconstruction allowed stereoscopic identification of the spatial relationships between physiologic and pathologic structures, and offered quantifiable liver resection proposals based on individualized liver anatomy. The predicted values were consistent with the actual values for tumor mass volume(82.4 ± 109.1 m L vs 84.1 ± 108.9 m L, P = 0.910), surgical margin(10.1 ± 6.2 mm vs 9.1 ± 5.9 mm, P = 0.488), and maximum tumor diameter(4.61 ± 2.16 cm vs 4.53 ± 2.14 cm, P = 0.871). In addition,the number and extent of portal venous ramifications, as well as their relation to hepatic veins, were visualized. Preoperative planning based on simulated resection facilitated complete resection of large tumors located in the confluence of major vessels. And most of the predicted data were correlated with intraoperative findings.CONCLUSION: This 3DM provides quantitative morphometry of tumor masses and a stereo-relationship with adjacent structures, thus providing a promising technique for the management of centrally located HCCs.

“Metroticket” predictor for assessing liver transplantation to treat hepatocellular carcinoma:A single-center analysis in China's Mainland

AIM:To validate the"Metroticket"predictor using a large cohort of liver transplantation(LT)patients with hepatocellular carcinoma(HCC)in China.METHODS:In total,230 cases of LT for HCC treatment at our center,from July 2000 to August 2008,were included in the present study.The predicted 1-,3-and 5-year post-LT survival rates were calculated using the Metroticket model(http://89.96.76.14/metroticket/calculator/).The predicted and observed long-term survival rates were then compared and analyzed.RESULTS:The predicted survival rates for all 230cases,as calculated by the Metroticket model,were64.7%and 56.2%at 3 and 5 years,respectively,and the observed survival rates for these patients were71.3%and 57.8%,respectively.For the 23 cases with macrovascular invasion,the predicted 5-year survival rate was 43.5%,whereas the observed 5-year survival rate was only 8.7%.For the 42 cases with microvascular invasion but an absence of macrovascular invasion,the predicted 5-year survival rate was 44.9%,and the observed 5-year survival rate was 50%.For the remaining 165 patients without any vascular invasion,the predicted 5-year survival rate was 65.8%,and the observed 5-year survival rate was 66.7%.CONCLUSION:The Metroticket model can be used to accurately predict survival in HCC-related LT cases with an absence of macrovascular invasion.

Seven-senescence-associated gene signature predicts overall survival for Asian patients with hepatocellular carcinoma

BACKGROUND Cellular senescence is a recognized barrier for progression of chronic liver diseases to hepatocellular carcinoma(HCC). The expression of a cluster of genes is altered in response to environmental factors during senescence. However, it is questionable whether these genes could serve as biomarkers for HCC patients.AIM To develop a signature of senescence-associated genes(SAGs) that predicts patients' overall survival(OS) to improve prognosis prediction of HCC.METHODS SAGs were identified using two senescent cell models. Univariate COX regression analysis was performed to screen the candidate genes significantly associated with OS of HCC in a discovery cohort(GSE14520) for the least absolute shrinkage and selection operator modelling. Prognostic value of this seven-gene signature was evaluated using two independent cohorts retrieved from the GEO(GSE14520) and the Cancer Genome Atlas datasets, respectively.Time-dependent receiver operating characteristic(ROC) curve analysis was conducted to compare the predictive accuracy of the seven-SAG signature and serum α-fetoprotein(AFP).RESULTS A total of 42 SAGs were screened and seven of them, including KIF18 B, CEP55,CIT, MCM7, CDC45, EZH2, and MCM5, were used to construct a prognostic formula. All seven genes were significantly downregulated in senescent cells andupregulated in HCC tissues. Survival analysis indicated that our seven-SAG signature was strongly associated with OS, especially in Asian populations, both in discovery and validation cohorts. Moreover, time-dependent ROC curve analysis suggested the seven-gene signature had a better predictive accuracy than serum AFP in predicting HCC patients' 1-, 3-, and 5-year OS.CONCLUSION We developed a seven-SAG signature, which could predict OS of Asian HCC patients. This risk model provides new clinical evidence for the accurate diagnosis and targeted treatment of HCC.

Magnetic resonance imaging of hepatocellular carcinoma induced by diethylnitrosamine in Sprague-Dawley rats

Diethylnitrosamine (DENA) is able to induce various benign and malignant liver lesions in rats with a high success rate and a low mortality rate. It provides a more appropriate model that better simulates the various lesions occurring in humans than the usual model of tumor implantations. The aim of the present study was to evaluate MRI liver examination in Sprague-Dawley(SD) rats as a routine method to detect hepatocellular carcinoma (HCC) nodules induced by DENA and to follow up their growth. METHODS:Hepatic carcinogenesis was induced in 80 male SD rats using oral DENA solution. All animals were imaged for liver tumor detection with a 1.5 Tesla magnet (Siemens Sonata,Erlangen, Germany) using correspondence scan parameters and a radio-frequency knee coil. Macroscopic examinations were performed along the axial MRI sections to evaluate magnetic resonance imaging (MRI) findings, and histopathological assessment was also performed. RESULTS:No false negative results were obtained on MR images. Hepatic tumors in 72 rats were confirmed macro-scopically and 68 rats were detected by MRI till the 20th week. The smallest and the largest nodules detected by MRI were 2 mm and 37 mm in diameter respectively. The agreement rate of MRI with macroscopic observation was 39. 1% and 97. 4% respectively for 2 mm to 5 mm and more than 5 mm nodules. CONCLUSIONS:The hepatic tumor induced by DENA provides a more representative range of tumors for imaging diagnosis and interventional treatment. MRI is the best approach for scrutinizing pathological changes of rat livers in the period of observation.

Hepatocellular carcinoma and non-alcoholic steatohepatitis:The state of play

Hepatocellular carcinoma(HCC) is now the fifth cancer of greatest frequency and the second leading cause of cancer related deaths worldwide. Chief amongst the risks of HCC are hepatitis B and C infection, aflatoxin B1 ingestion, alcoholism and obesity. The latter can promote non-alcoholic fatty liver disease(NAFLD), that can lead to the inflammatory form non-alcoholic steatohepatitis(NASH), and can in turn promote HCC. The mechanisms by which NASH promotes HCC are only beginning to be characterized. Here in this review, we give a summary of the recent findings that describe and associate NAFLD and NASH with the subsequent HCC progression. We will focus our discussion on clinical and genomic associations that describe new risks for NAFLD and NASH promoted HCC. In addition, we will consider novel murine models that clarify some of the mechanisms that drive NASH HCC formation.

Risk of hepatocellular carcinoma after hepatitis C virus cure

Hepatitis C virus(HCV)is a significant cause of hepatocellular carcinoma(HCC).The direct-acting antivirals marked a new era of HCV therapy and are associated with greater than 95%cure rate.Successful treatment of chronic hepatitis C greatly reduces the risk of HCC.A proportion of patients,especially those with pre-existing cirrhosis,remain at risk for HCC despite sustained virologic response(SVR).Diabetes mellitus,hepatic steatosis,alcohol consumption and lack of fibrosis regression are associated with risks of HCC after HCV cure.Noninvasive modalities such as aspartate aminotransferase to platelet ratio index and fibrosis-4 index and transient elastography have been used to monitor hepatic fibrosis.More recently,various fibrosis scores have been combined with clinical parameters and other novel biomarkers to predict risks of HCC for patients who achieved SVR.These models still need to be validated and standardized prior to applying to routine clinical care.