Liver transplantation for hepatocellular carcinoma: Where do we stand?

Hepatocellular carcinoma represents an important cause of morbidity and mortality worldwide. It is the sixth most common cancer and the fourth leading cause of cancer death. Liver transplantation is a key tool for the treatment of this disease in human therefore hepatocellular carcinoma is increasing as primary indication for grafting. Although liver transplantation represents an outstanding therapy for hepatocellular carcinoma, due to organ shortage, the careful selection and management of patients who may have a major survival benefit after grafting remains a fundamental question. In fact, only some stages of the disease seem amenable of this therapeutic option, stimulating the debate on the appropriate criteria to select candidates. In this review we focused on current criteria to select patients with hepatocellular carcinoma for liver transplantation as well as on the strategies (bridging) to avoid disease progression and exclusion from grafting during the stay on wait list. The treatments used to bring patients within acceptable criteria (down-staging), when their tumor burden exceeds the standard criteria for transplant, are also reported. Finally, we examined tumor reappearance following liver transplantation. This occurrence is estimated to be approximately 8%-20% in different studies. The possible approaches to prevent this outcome after transplant are reported with the corresponding results.     

Improving definition of the term “synchronous liver metastases” from colorectal cancer

正The liver is the most frequent site of metastasis in colorectal cancer with up to a quarter of patients having liver metastases at the time of initial diagnosis and a further third subsequently developing liver lesions.~([1])Patients who present with metastatic liver disease after treatment of the primary(termed metachronous disease)receive care focused on this new metastatic disease.~([2])In contrast,the management of patients who present with colorectal cancer and concurrent liver     

Liver transplantation for malignancy:current treatment strategies and future perspectives

In 1967,Starzl et al performed the first successful liver transplantation for a patient diagnosed with hepatoblastoma.In the following,liver transplantation was considered ideal for complete tumor resection and potential cure from primary hepatic malignancies.Several reports of liver transplantation for primary and metastatic liver cancer however showed disappointing results and the strategy was soon dismissed.In1996,Mazzaferro et al introduced the Milan criteria,offering liver transplantation to patients diagnosed with limited hepatocellular carcinoma.Since then,liver transplantation for malignant disease is an ongoing subject of preclinical and clinical research.In this context,several aspects must be considered:(1)Given the shortage of deceased-donor organs,long-term overall and disease free survival should be comparable with results obtained in patients transplanted for nonmalignant disease;(2)In this regard,living-donor liver transplantation may in selected patients help to solve the ethical dilemma of optimal individual patient treatment vs organ allocation justice;and(3)Ongoing research focusing on perioperative therapy and antiproliferative immunosuppressive regimens may further reduce tumor recurrence in patients transplanted for malignant disease and thus improve overall survival.The present review gives an overview of current indications and future perspectives of liver transplantation for malignant disease.     

Recent advances in recurrent hepatocellular carcinoma therapy

Hepatocellular carcinoma(HCC) is the most prevalent form of primary liver cancer, accounting for 75%-85% of cases. Although treatments are given to cure early-stage HCC, up to 50%-70% of individuals may experience a relapse of the illness in the liver after 5 years. Research on the fundamental treatment modalities for recurrent HCC is moving significantly further. The precise selection of individuals for therapy strategies with established survival advantages is crucial to ensuring better outcom...     

Clinical features and management of primary sclerosing cholangitis

Primary sclerosing cholangitis is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts,resulting in cirrhosis and need for liver transplantation and reduced life expectancy.The majority of cases occur in young and middle-aged men,often in association with inflammatory bowel disease.The etiology of primary sclerosing cholangitis includes immune-mediated components and elements of undefined nature.No effective medical therapy has been identified.The multiple complications of primary sclerosing cholangitis include metabolic bone disease,dominant strictures,bacterial cholangitis,and malignancy,particularly cholangiocarcinoma,which is the most lethal complication of primary sclerosing cholangitis.Liver transplantation is currently the only life-extending therapeutic alternative for patients with end-stage disease,although recurrence in the allografted liver has been described.A PSC-like variant attracting attention is cholangitis marked by raised levels of the immunoglobulin G4 subclass,prominence of plasma cells within the lesions,and steroid responsiveness.     

Obesity and cholangiocarcinoma

It is estimated that about half of the population in developed countries are either overweight or obese.In some developing nations obesity rates have increased to surpass those seen in Western countries.This rate increase in obesity has many implications as obesity has been associated with numerous negative health effects including increased risks of hypertension,diabetes,cardiovascular disease,stroke,liver disease,apnea,and some cancer types.Obesity is now considered to be one of the major public health concerns facing the society.Cholangiocarcinomas(bile duct cancers) are malignant tumors arising from cholangiocytes inside or outside of the liver.Although cholangiocarcinomas are relatively rare,they are highly lethal.The low survival rate associated with cholangiocarcinoma is due to the advanced stage of the disease at the time of diagnosis.Prevention is therefore especially important in this cancer type.Some data suggest that the incidence of cholangiocarcinoma in the western world is on the rise.Increasing rate of obesity may be one of the factors responsible for this increase.Determining whether obesity is a risk factor for cholangiocarcinoma has significant clinical and societal implications as obesity is both prevalent and modifiable.This paper seeks to provide a summary of the current knowledge linking obesity and cholangiocarcinoma,and encourage further research on this topic.     

Cholangiocarcinoma： A compact review of the literature

Cholangiocarcinoma （CC） is a devastating cancer arising from biliary epithelia. Unfortunately, the incidence of this disease is increasing in Western countries. These tumors progress insidiously, and liver failure, biliary sepsis, malnutrition and cancer cachexia are general modes of death associated with this disease. To date, no established therapy for advanced disease has been established or validated. However, our knowledge in tumor biology is increasing dramatically and new drugs are under investigation for treatment of this notorious tumor. In clinical practice, there are better diagnostic tools in use to facilitate an earlier diagnosis of CC, at least in those patients with known risk factors. CC is resectable for cure in only a small percentage of patients. Preoperative staging for vascular and biliary extension of CC is very important in this tumor. Laparoscopy and recently endosonography seem to protect against unnecessary laparotomies in these patients. During the last 15 years, aggressive surgical approaches, including combined liver resections and vascular reconstructive surgical expertise, have improved survival in patients with CC. Surgery is contraindicated in CC cases having primary sclerosing cholangitis （PSC）. Although CC was previously consid- ered a contraindication to liver transplantation, new cautious protocols, including neo-adjuvant chemoradiation therapies and staging procedures before the transplantation, have made it possible to achieve longterm survival after liver transplantation in this disease. New ablative therapies with photodynamic therapy,intraductal high-intensity ultrasonography and chemotherapy-impregnated plastic biliary endoprosthesis are important steps in the palliative management of extra- hepatic CCs. Radiofrequency and chemo-embolization methods are also applicable for intra-hepatic CCs as palliative modes of treatment. We need more prospective randomized controlled trials to evaluate the role of the new emerging therapies for CC patients.     

Non-invasive tests for the prediction of primary hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of the most common malignancies in the world and it is one of the main complications of cirrhosis and portal hypertension. Even in the presence of a well-established follow-up protocol for cirrhotic patients, to date poor data are available on predictive markers for primary HCC occurrence in the setting of compensated advanced chronic liver disease patients(c ACLD). The gold standard method to evaluate the prognosis of patients with c ACLD, beyond liver fibrosis assessed with histology, is the measurement of the hepatic venous pressure gradient(HVPG). An HVPG ≥10 mm Hg has been related to an increased risk of HCC in c ACLD patients.However, these methods are burdened by additional costs and risks for patients and are mostly available only in referral centers. In the last decade increasing research has focused on the evaluation of several, simple, non-invasive tests(NITs) as predictors of HCC development. We reviewed the currently available literature on biochemical and ultrasound-based scores developed for the noninvasive evaluation of liver fibrosis and portal hypertension in predicting primary HCC. We found that the most reliable methods to assess HCC risk were the liver stiffness measurement, the aspartate aminotransferase to platelet ratio index score and the fibrosis-4 index. Other promising NITs need further investigations and validation for different liver disease aetiologies.     

Multimodal imaging evaluation in staging of rectal cancer

Rectal cancer is a common cancer and a major cause of mortality in Western countries.Accurate staging is essential for determining the optimal treatment strategies and planning appropriate surgical procedures to control rectal cancer.Endorectal ultrasonography(EUS)is suitable for assessing the extent of tumor invasion,particularly in early-stage or superficial rectal cancer cases.In advanced cases with distant metastases,computed tomography(CT)is the primary approach used to evaluate the disease.Magnetic resonance imaging(MRI)is often used to assess preoperative staging and the circumferential resection margin involvement,which assists in evaluating a patient’s risk of recurrence and their optimal therapeutic strategy.Positron emission tomography(PET)-CT may be useful in detecting occult synchronous tumors or metastases at the time of initial presentation.Restaging after neoadjuvant chemoradiotherapy(CRT)remains a challenge with all modalities because it is difficult to reliably differentiate between the tumor mass and other radiation-induced changes in the images.EUS does not appear to have a useful role in post-therapeutic response assessments.Although CT is most commonly used to evaluate treatment responses,its utility for identifying and following-up metastatic lesions is limited.Preoperative high-resolution MRI in combination with diffusion-weighted imaging,and/or PET-CT could provide valuable prognostic information for rectal cancer patients with locally advanced disease receiving preoperative CRT.Based on these results,we conclude that a combination of multimodal imaging methods should be used to precisely assess the restaging of rectal cancer following CRT.     

Surveillance for hepatocellular carcinoma in chronic liver disease:Evidence and controversies

Primary liver cancer is the sixth most common cancer in the world and the third cause of cancer-related death.Hepatocellular carcinoma(HCC)represents more than90%of primary liver cancers and generally occurs in patients with underlying chronic liver disease such as viral hepatitis,hemochromatosis,primary biliary cirrhosis and non-alcoholic steatohepatitis.Especially cirrhotic patients are at risk of HCC and regular surveillance could enable early detection and therapy,with potentially improved outcome.We here summarize existing evidence for surveillance including ultrasound,other radiological modalities and various serum biomarkers,and current international guideline recommendations for surveillance.Ultrasound andα-fetoprotein(alone or in combination)are most frequently used for surveillance,but their sensitivities and specificities are still far from perfect,and evidence for surveillance remains weak and controversial.Various other potential surveillance tools have been tested,including serum markers as des-carboxyprothrombin,lectin-boundα-fetoprotein,and(most recently)circulating TIE2-expressing monocytes,and radiological investigations such as computed tomographyscan or magnetic resonance imaging-scan.Although early results appear promising,these tools have generally been tested in diagnostic rather than surveillance setting,and in most cases,no detailed information is available on their cost-effectiveness.For the near future,it remains important to define those patients with highest risk of HCC and most benefit from surveillance,and to restrict surveillance to these categories.     

肝癌动物模型的研究进展

原发性肝癌是最常见的恶性肿瘤之一.由于其死亡率高,现已有很多研究为其临床的治疗提供基础依据.在这些研究中,肝癌动物模型的使用很广泛.以下我们回顾现今常用的肝癌动物模型,并对未来肝癌动物模型的发展做一重点介绍.     

Transposon mouse models to elucidate the genetic mechanisms of hepatitis B viral induced hepatocellular carcinoma

The major type of human liver cancer is hepatocellular carcinoma(HCC), and there are currently many risk factors that contribute to this deadly disease. The majority of HCC occurrences are associated with chronic hepatitis viral infection, and hepatitis B viral(HBV) infection is currently a major health problem in Eastern Asia. Elucidating the genetic mechanisms associated with HBV-induced HCC has been difficult due to the heterogeneity and genetic complexity associated with this disease. A repertoire of animal models has been broadly used to study the pathophysiology and to develop potential treatment regimens for HBVassociated HCC. The use of these animal models has provided valuable genetic information and has been an important contributor to uncovering the factors involved in liver malignant transformation, invasion and metastasis. Recently, transposon-based mouse models are becoming more widely used in liver cancer research to interrogate the genome by forward genetics and also used to validate genes rapidly in a reverse genetic manner. Importantly, these transposon-based rapid reverse genetic mouse models could become crucial in testing potential therapeutic agents before proceeding to clinical trials in human. Therefore, this review will cover the use of transposon-based mouse models toaddress the problems of liver cancer, especially HBVassociated HCC occurrences in Asia.     

Mouse models of pancreatic cancer

Pancreatic cancer is one of the most lethal of human malignancies ranking 4th among cancer-related death in the western world and in the United States, and potent therapeutic options are lacking. Although during the last few years there have been important advances in the understanding of the molecular events responsible for the development of pancreatic cancer, currently specific mechanisms of treatment resistance remain poorly understood and new effective systemic drugs need to be developed and probed. In vivo models to study pancreatic cancer and approach this issue remain limited and present different molecular features that must be considered in the studies depending on the purpose to fit special research themes. In the last few years, several genetically engineered mouse models of pancreatic exocrine neoplasia have been developed. These models mimic the disease as they reproduce genetic alterations implicated in the progression of pancreatic cancer. Genetic alterations such as activating mutations in KRas, or TGFb and/or inactivation of tumoral suppressors such as p53, INK4A/ARF BRCA2 and Smad4 are the most common drivers to pancreatic carcinogenesis and have been used to create transgenic mice. These mouse models have a spectrum of pathologic changes, from pancreatic intraepithelial neoplasia to lesions that progress histologically culminating in fully invasive and metastatic disease and represent the most useful preclinical model system. These models can characterize the cellular and molecular pathology of pancreatic neoplasia and cancer and constitute the best tool to investigate new therapeutic approaches, chemopreventive and/or anticancer treatments. Here, we review and update the current mouse models that reproduce different stages of human pancreatic ductal adenocarcinoma and will have clinical relevance in future pancreatic cancer developments.     

经肝动脉化疗栓塞术联合射频消融治疗

近年来在原发性肝癌治疗领域中新兴治疗方法层出不穷,但由于病变多发生于进展期肝病或肝硬化的基础上,导致原发性肝癌仍然是一种难治性恶性肿瘤。外科手术切除及肝移植虽是根治性治疗方法,但由于移植相关问题的复杂性及原发性肝癌本身的隐匿性,使得上述两种治疗方法并不能适用于大多数患者。而近些年随着设备和技术水平的提高,原发性肝癌的介入治疗得到了越来越多的重视,这其中应用最为广泛的就是经肝动脉化疗栓塞术（TACE）和经皮肝穿刺射频消融（RFA）。主要讨论上述两种介入疗法联合应用治疗原发性肝癌的有效性、可行性,以及近年来介入治疗在原发性肝癌治疗领域的研究进展。     

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.     

Mouse models for the study of HCV infection and virus-host interactions

Hepatitis C virus (HCV) is a major cause of chronic liver disease including steatosis, cirrhosis and hepatocellular carcinoma. The development of transgenic mice expressing HCV proteins and the successful repopulation of SCID/Alb-uPA mice with human hepatocytes provides an important tool for unraveling virus-host interactions in vivo. Several of these mouse models exhibit aspects of HCV-related liver disease. Thus, these in vivo models play an important role to further understand the pathogenesis of HCV infection and to evaluate the pre-clinical safety and efficacy of new antiviral compounds against HCV. This review summarizes the most important mouse models currently used to study HCV pathogenesis and infection. Finally, the perspective of these models for future HCV research as well as the design of novel small animal models is discussed.     

Hepatocellular carcinoma in non-cirrhotic liver: A comprehensive review

Hepatocellular carcinoma(HCC) is the most common type of primary liver cancer, which in turns accounts for the sixth most common cancer worldwide.Despite being the 6 th most common cancer it is the second leading cause of cancer related deaths. HCC typically arises in the background of cirrhosis, however,about 20% of cases can develop in a non-cirrhotic liver. This particular subgroup of HCC generally presents at an advanced stage as surveillance is not performed in a non-cirrhotic liver. HCC in non-cirrhotic patients is clinically silent in its early stages because of lack of symptoms and surveillance imaging; and higher hepatic reserve in this population. Interestingly, F3 fibrosis in non-alcoholic fatty liver disease, hepatitis B virus and hepatitis C virus infections are associated with high risk of developing HCC. Even though considerable progress has been made in the management of this entity, there is a dire need for implementation of surveillance strategies in the patient population at risk, to decrease the disease burden at presentation and improve the prognosis of these patients. This comprehensive review details the epidemiology, risk factors, clinical features,diagnosis and management of HCC in non-cirrhotic patients and provides future directions for research.     

Models of ovarian cancer--are we there yet?

Ovarian cancer is the most lethal of all gynecological cancers and arises most commonly from the surface epithelium. Successful clinical management of patients with epithelial ovarian cancer is limited by the lack of a reliable and specific method for early detection, and the frequent recurrence of chemoresistant disease. Experimental models are of crucial importance not only to understand the biological and genetic factors that influence the phenotypic characteristics of the disease but also to utilize as a basis for developing rational intervention strategies. Ovarian cancer cell lines derived from ascites or primary ovarian tumors have been used extensively and can be very effective for studying the processes controlling growth regulation and chemosensitivity or evaluating novel therapeutics, both in vitro and in xenograft models. While our limited knowledge of the initiating events of ovarian cancer has restricted the development of models in which the early pathogenic events can be studied, recent advances in the ability to manipulate gene expression in ovarian surface epithelial cells in vitro and in vivo have begun to provide insights into the molecular changes that may contribute to the development of ovarian cancer. This review highlights the strengths and weaknesses of some of the current models of ovarian cancer, with special consideration of the recent progress in modeling ovarian cancer using genetically engineered mice.     

Murine models of acute neuronopathic Gaucher disease

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the glucosidase, beta, acid (GBA) gene that encodes the lysosomal enzyme glucosylceramidase (GCase). GCase deficiency leads to characteristic visceral pathology and, in some patients, lethal neurological manifestations. Here, we report the generation of mouse models with the severe neuronopathic form of GD. To circumvent the lethal skin phenotype observed in several of the previous GCase-deficient animals, we genetically engineered a mouse model with strong reduction in GCase activity in all tissues except the skin. These mice exhibit rapid motor dysfunction associated with severe neurodegeneration and apoptotic cell death within the brain, reminiscent of neuronopathic GD. In addition, we have created a second mouse model, in which GCase deficiency is restricted to neural and glial cell progenitors and progeny. These mice develop similar pathology as the first mouse model, but with a delayed onset and slower disease progression, which indicates that GCase deficiency within microglial cells that are of hematopoietic origin is not the primary determinant of the CNS pathology. These findings also demonstrate that normal microglial cells cannot rescue this neurodegenerative disease. These mouse models have significant implications for the development of therapy for patients with neuronopathic GD.