How to assess the efficacy or failure of targeted therapy:deciding when to stop sorafenib in hepatocellular carcinoma

Sorafenib is thus far the only systemic treatment for hepatocellular carcinoma(HCC) based on the results of two randomized controlled trials performed in Western and in Eastern countries, despite a poor response rate(from 2% to 3.3%) following conventional evaluation criteria. It is now recognized that the criteria(European Association of the Study of the Liver criteria, modified response evaluation criteria in solid tumors) based on contrast enhanced techniques(computed tomography scan, magnetic resonance imaging) aimed to assess the evolution of the viable part of the tumor(hypervascularized on arterial phase) are of major interest to determine the efficacy of sorafenib and of most antiangiogenic drugs in patients with HCC. The role of alphafetoprotein serum levels remains unclear. In 2016, in accordance with the SHARP and the Asia-Pacific trials, sorafenib must be stopped when tolerance is poor despite dose adaptation or in cases of radiological and symptomatic progression. This approach will be different in cases of available second-line therapy trials. Some recent data(in renal cell carcinoma) revealed that despite progression in patients who received sorafenib, this drug can still decrease tumor progression compared to drug cessation. Then, before deciding to continue sorafenib post-progression or shift to another drug, knowing other parameters of post-progression survival(Child-Pugh class, Barcelona Clinic Liver Cancer, alphafetoprotein, post-progression patterns in particular, the development of extrahepatic metastases and of portal vein thrombosis) will be of major importance.     

Imaging response predictors following drug eluting beads chemoembolization in the neoadjuvant liver transplant treatment of hepatocellular carcinoma

BACKGROUND Drug-eluting bead transarterial chemoembolization(DEB-TACE) is an endovascular treatment to release chemotherapeutic agents within a target lesion,minimizing systemic exposure and adverse effects to chemotherapeutics.Therefore, identifying which patient characteristics may predict imaging response to DEB-TACE can improve treatment results while selecting the best candidates. Predictors of the response after DEB-TACE still have not been fully elucidated. This is the first prospective study performed with standardized DEBTACE technique that aim to identify predictors of radiological response,assessing patients clinical and laboratory characteristics, diagnostic imaging and intraprocedure data of the hepatocellular carcinoma treated in the neoadjuvant context for liver transplantation.AIM To identify pre-and intraoperative clinical and imaging predictors of the radiological response of drug-eluting bead transarterial chemoembolization(DEB-TACE) for the neoadjuvant treatment of hepatocellular carcinoma(HCC).METHODS This is prospective, cohort study, performed in a single transplant center, from2011 to 2014. Consecutive patients with HCC considered for liver transplant who underwent DEB-TACE in the first session for downstaging or bridging purposes were recruited. Pre and post-chemoembolization imaging studies were performed by computed tomography or magnetic resonance. The radiological response of each individual HCC was evaluated by objective response using m RECIST and the percentage of necrosis.RESULTS Two hundred patients with 380 HCCs were examined. Analysis of the objective response(nodule-based analysis) demonstrated that HCC with pseudocapsules had a 2.01 times greater chance of being responders than those without pseudocapsules(P = 0.01), and the addition of every 1 mg of chemoembolic agent increased the chance of therapeutic response in 4%(P 0.001). Analysis of the percentage of necrosis through multiple linear regression revealed that the addition of each 1 mg of the chemoembolic agent caused an average increase of 0.65%(P 0.001) in necrosis in the treated lesion, whereas the hepatocellular carcinoma with pseudocapsules presented 18.27%(P 0.001) increased necrosis compared to those without pseudocapsules.CONCLUSION The presence of a pseudocapsule and the addition of the amount of chemoembolic agent increases the chance of an objective response in hepatocellular carcinoma and increases the percentage of tumor necrosis following drug-eluting bead chemoembolization in the neoadjuvant treatment,prior to liver transplantation.     

Lentiviral-mediated microRNA-26b up-regulation inhibits proliferation and migration of hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is a frequently occurred malignancy worldwide with a high mortality. The treatment for HCC is still controversial. Emerging evidences have demonstrated that microRNAs (miRs) play a role in HCC. This study aims to investigate the effects of lentiviral-mediated miRNA-26b (miR-26b) on the proliferation and metastasis of HCC cells. The normal hepatic cell line HL-7702 and HCC cell lines HepG2 (without metastatic potential), SMMC-7721 (with low metastatic potential) and MHCC97H (with high metastatic potential) were purchased for our experiment. The lentiviral-mediated miR-26b overexpression (miR-26b-LV) and low expression (sh-miR-26b) were constructed to transfect the cells. The miR-26b expression and expressions of Karyopherin α-2 (KPNA2), matrix metalloproteinase 1 (MMP-1), MMP-7 and MMP-14 were determined by RT-qPCR and western blot analysis. The proliferation and metastasis of transfected HCC cells were detected by MTT and Transwell assay respectively. The miR-26b expressions were decreased significantly in MHCC97H cells. With lentiviral-mediated miR-26b overexpression, the proliferation and migration of HepG2, MHCC97H and SMMC-7721 cells were decreased significantly. The RT-qPCR and western blot analysis results revealed that the mRNA and protein expressions of KPNA2, MMP-1, MMP-7 and MMP-14 were decreased by lentiviral-mediated miR-26b overexpression. All the above indexes in the HepG2, MHCC97H and SMMC-7721 cells treated by sh-miR-26b exhibited opposite trends. These results show that overexpressed miR-26b could inhibit the proliferation and metastasis of HCC cells significantly, which provides a novel target and theoretical foundation for the treatment of HCC.     

肝细胞癌组织miRNA-155水平变化及其对预后的影响

目的 观察肝细胞癌（HCC）组织miRNA-155水平变化,并分析其对患者预后的意义。方法 2013年1月~2014年5月我院诊治的50例HCC患者,取手术切除的癌组织,另取50例正常肝组织作为对照组,采用荧光定量PCR法检测组织miRNA-155水平。结果 正常肝组织miRNA-155水平（1.06±0.1）明显低于HCC癌组织,10例Ⅰ级、15例Ⅱ级、12例Ⅲ级和13例Ⅳ级HCC 组织miRNA-155水平分别为（2.04±0.82）、（3.02±1.20）、（4.20±1.84）和（6.24±2.36）;miRNA-155低水平HCC患者生存率（24.00%）明显高于miRNA-155高水平患者（9.24%,P<0.05）;在不同分级HCC（14.26月对9.02月）、不同肿瘤大小（15.68 月对10.02月）、肿瘤是否转移（8.20 月对14.46月）、是否静脉侵犯（9.36 月对14.36月）、肿瘤分化程度（15.20月对7.84月）和miRNA-155水平高低（7.86月对16.32月）患者间生存期均存在明显差异（P<0.05）;肿瘤大小（>5 cm,HR=1.46,P=0.038）、肿瘤转移（是,HR=1.72,P=0.026）、静脉侵犯（是,HR=1.46,P<0.001）、肿瘤分化（高分化,HR=1.33,P=0.012）和miRNA-155（高水平,HR=1.65,P<0.001）均为影响HCC患者预后的独立危险因素（P<0.05）。结论 肝癌组织miRNA-155水平明显高于正常肝组织,且高水平的miRNA-155为HCC患者预后的独立危险因素。结果表明,miRNA-155水平高低可评估HCC患者预后,可考虑将其作为评估HCC患者预后的独立预测因子之一。     

circZFR promotes cell proliferation and migration by regulating miR-511/AKT1 axis in hepatocellular carcinoma

BackgroundEmerging data suggest the crucial regulatory roles of circular RNAs (circRNAs) in hepatocellular carcinoma (HCC). However, the pathophysiology role of circZFR in HCC remains largely unknown.AimsThis study aims to disclose the functions of circZFR in HCC progression and its potential molecular mechanism.MethodscircZFR and miR-511 were identified by qRT-PCR. Colony formation assay, wound-healing assay, transwell assay, and flow cytometry assay were performed to determine the cell proliferation, migration, invasion and apoptosis. Western blotting and immunohistochemistry (IHC) were utilized to evaluate the expression level of AKT1, GSK3β, β-catenin and cascades of proliferation-related proteins both in vitro and in vivo. Dual luciferase reporter assay was conducted to evaluate the interactions among circZFR, miR-511 and AKT1.ResultsThe expression of circZFR was enhanced and the expression of miR-511 was down-regulated in HCC tissues and cells. Functionally, circZFR silencing or miR-511 overexpression suppressed cell proliferation, migration and invasion, and induced apoptosis of HCC cells. Mechanistically, circZFR acted as a miR-511 sponge to up-regulate its target gene AKT1, which activated cascades of proliferation-related proteins (c-Myc, cyclin D1, Survivin and Bcl-2). Furthermore, depletion of circZFR inhibited tumorigenesis and decreased the expression level of AKT1 in xenograft models.ConclusioncircZFR promotes HCC progression by directly down-regulating miR-511 to activate AKT1 signaling, suggesting that circZFR is a potential target in HCC treatment. Targeting circZFR may provide therapeutic benefits for HCC.     

血浆Ki67联合miRNA-26 b检测诊断肝细胞癌价值分析

目的 探讨肝细胞癌(HCC)患者血浆Ki67和miRNA-26b水平变化,分析其诊断效能.方法 我院收治的HCC患者90例和乙型肝炎肝硬化患者60例,采用RT-qPCR检测血浆Ki67和miRNA-26b水平,采用ROC曲线分析血浆Ki67和miRNA-26b水平诊断HCC的效能.结果 HCC患者血浆Ki67水平为[1...     

DNA methylation,microRNAs,and their crosstalk as potential biomarkers in hepatocellular carcinoma

Epigenetic alterations have been identified as a major characteristic in human cancers.Advances in the field of epigenetics have contributed significantly in refining our knowledge of molecular mechanisms underlying malignant transformation.DNA methylation and microRNA expression are epigenetic mechanisms that are widely altered in human cancers including hepatocellular carcinoma(HCC),the third leading cause of cancer related mortality worldwide.Both DNA methylation and microRNA expression patterns are regulated in developmental stage specific-,cell type specific-and tissue-specific manner.The aberrations are inferred in the maintenance of cancer stem cells and in clonal cell evolution during carcinogenesis.The availability of genome-wide technologies for DNA methylation and microRNA profiling has revolutionized the field of epigenetics and led to the discovery of a number of epigenetically silenced microRNAs in cancerous cells and primary tissues.Dysregulation of these microRNAs affects several key signalling pathways in hepatocarcinogenesis suggesting that modulation of DNA methylation and/or microRNA expression can serve as new therapeutic targets for HCC.Accumulative evidence shows that aberrant DNA methylation of certain microRNA genes is an event specifically found in HCC which correlates with unfavorable outcomes.Therefore,it can potentially serve as a biomarker for detection as well as for prognosis,monitoring and predicting therapeutic responses in HCC.     

Biological markers of hepatocellular carcinoma for use as selection criteria in liver transplantation

The Milan criteria (MC) have been widely accepted as an effective way of selecting patients with early‐stage hepatocellular carcinoma (HCC) for curative liver transplantation (LT). However, since a substantial subset of HCC patients exists that is beyond the MC but with the potential for good outcomes after LT, several institutions have recently proposed new extended criteria. To explore optimal criteria that can reasonably predict the risk of recurrence, it is considered that new markers of biological behavior are needed in addition to morphological tumor size and number. Several promising candidates for such biological markers have been reported, including serum tumor markers such as alpha‐fetoprotein and des‐gamma‐carboxy prothrombin, inflammatory markers such as C‐reactive protein and neutrophil‐to‐lymphocyte ratio, response to pre‐transplant treatments for bridging therapy or down‐staging, and fluorine‐18‐fluorodeoxyglucose positron emission tomography. However, the role of these biological markers in patient selection criteria for LT has yet to be clarified. This review article aims to summarize the results of recent reported studies and to display perspectives for the establishment of optimal criteria that incorporate such biological markers.     

Survivin-positive circulating tumor cells as a marker for metastasis of hepatocellular carcinoma

BACKGROUNDCirculating tumor cells (CTCs) and survivin are indicators for tumor stage and metastasis, as well as epitheliomesenchymal transition, in various cancers, including hepatocellular cancer (HCC). AIMTo explore the potential of survivin-positive CTCs, specifically, as a marker for tumor progression in HCC patients.METHODSWe examined the survivin expression pattern in CTCs obtained from 179 HCC patients, and investigated the in vitro effects of survivin silencing and overexpression on the proliferation and invasion of HCC cells. CTC count and survivin expression in patient samples were examined using RNA in situ hybridization.RESULTSAll 179 patients were positive for CTC markers, and 94.41% of the CTCs were positive for survivin. The CTC and survivin-positive CTC counts were significantly higher in the HCC patients than in the normal controls, and were significantly associated with tumor stage and degree of differentiation. Further, survivin overexpression was found to induce HepG2 cell proliferation, reduce apoptosis, and improve invasive ability.CONCLUSIONSurvivin shows upregulated expression (indicative of anti-apoptotic effects) in HCC. Thus, survivin-positive CTCs are promising as a predictor of HCC prognosis and metastasis, and their accurate measurement may be useful for the management of this cancer.     

Current biomarkers for hepatocellular carcinoma: Surveillance,diagnosis and prediction of prognosis

Biomarkers for surveillance, diagnosis and prediction of prognosis in patients with hepatocellular carcinoma(HCC) are currently not ready for introduction into clinical practice because of limited sensitivity and specificity. Especially for the early detection of small HCC novel biomarkers are needed to improve the current effectiveness of screening performed byultrasound. The use of high-throughput technologies in hepatocellular research allows to identify molecules involved in the complex pathways in hepatocarcinogenesis. Several invasive and non-invasive biomarkers have been identified already and have been evaluated in different clinical settings. Gene signatures with prognostic potential have been identified by gene expression profiling from tumor tissue. However, a single "all-in-one" biomarker that fits all-surveillance, diagnosis, prediction of prognosis-has not been found so far. The future of biomarkers most probably lies in a combination of non-invasive biomarkers, imaging and clinical parameters in a surveillance setting. Molecular profiling of tumorous and non-tumorous liver tissue may allow a prediction of prognosis for the individual patient and hopefully clear the way for individual treatment approaches. This article gives an overview on current developments in biomarker research in HCC with a focus on currently available and novel biomarkers, in particular on micro RNA.     

Serum biomarkers and risk of hepatocellular carcinoma recurrence after liver transplantation

Liver transplantation(LT) is the only potentially curative treatment for selected patients with cirrhosis and hepatocellular carcinoma(HCC) who are not candidates for resection. When the Milan criteria are strictly applied, 75% to85%of 3-to 4-year actuarial survival rates are achieved, but up to 20% of the patients experience HCC recurrence after transplantation. The Milan criteria are based on the preoperative tumor macromorphology, tumor size and number on computed tomography or magnetic resonance imaging that neither correlate well with posttransplant histological study of the liver explant nor accurately predict HCC recurrence after LT, since they do not include objective measures of tumor biology. Preoperative biological markers, including alpha-fetoprotein, desgamma-carboxiprothrombin or neutrophil-to-lymphocyte ratio and platelet-tolymphocyte ratio, can predict the risk for HCC recurrence after transplantation.These biomarkers have been proposed as surrogate markers of tumor differentiation and vascular invasion, with varied risk magnitudes depending on the defined cutoffs. Different studies have shown that the combination of one or several biomarkers integrated into prognostic models predict the risk of HCC recurrence after LT more accurately than Milan criteria alone. In this review, we focus on the potential utility of these serum biological markers to improve the performance of Milan criteria to identify patients at high risk of tumoral Published online: January 27, 2019 recurrence after LT.Liver transplantation(LT) is the only potentially curative treatment for selected patients with cirrhosis and hepatocellular carcinoma(HCC) who are not candidates for resection. When the Milan criteria are strictly applied, 75% to85%of 3-to 4-year actuarial survival rates are achieved, but up to 20% of the patients experience HCC recurrence after transplantation. The Milan criteria are based on the preoperative tumor macromorphology, tumor size and number on computed tomography or magnetic resonance imaging that neither correlate well with posttransplant histological study of the liver explant nor accurately predict HCC recurrence after LT, since they do not include objective measures of tumor biology. Preoperative biological markers, including alpha-fetoprotein, desgamma-carboxiprothrombin or neutrophil-to-lymphocyte ratio and platelet-tolymphocyte ratio, can predict the risk for HCC recurrence after transplantation.These biomarkers have been proposed as surrogate markers of tumor differentiation and vascular invasion, with varied risk magnitudes depending on the defined cutoffs. Different studies have shown that the combination of one or several biomarkers integrated into prognostic models predict the risk of HCC recurrence after LT more accurately than Milan criteria alone. In this review, we focus on the potential utility of these serum biological markers to improve the performance of Milan criteria to identify patients at high risk of tumoral recurrence after LT.     

Contribution of alpha-fetoprotein in liver transplantation for hepatocellular carcinoma

Alpha-fetoprotein(AFP) is the main tumor biomarker available for the management of hepatocellular carcinoma(HCC). Although it is neither a good screening test nor an accurate diagnostic tool for HCC, it seems to be a possible prognostic marker. However, its contribution in liver transplantation for HCC has not been fully determined, although its use to predict recurrence after liver transplantation has been underlined by international societies. In an era of organ shortages, it could also have a key role in the selection of patients eligible for liver transplantation. Yet unanswered questions remain. First, the cut-off value of serum AFP above which liver transplantation should not be performed is still a subject of debate. We show that a concentration of 1000 ng/m L could be an exclusion criterion, whereas values of 15 ng/m L indicate patients with an excellent prognosis whatever the size and number of tumors. Monitoring the dynamics of AFP could also prove useful. However, evidence is lacking regarding the values that should be used. Today, the real input of AFP seems to be its integration into new criteria to select patients eligible for a liver transplantation. These recent tools have associated AFP values with morphological criteria, thus refining pre-existing criteria, such as Milan, University of California, San Francisco, or "up-to-seven". We provide a review of the different criteria submitted within the past years. Finally, AFP can be used to monitor recurrence after transplantation, although there is little evidence to support this claim. Future challenges will be to draft new international guidelines to implement the use of AFP as a selection tool, and to determine a clear cut-off value above which liver transplantation should not be performed.     

MicroRNA4293基因多态性与女性肝癌易感性相关

目的研究microRNA-4293的SNP(rs12220909)与原发性肝癌易感性的关系。方法收集人体血液样本1788份,样本取自健康对照者884名,原发性肝癌患者904例。抽提血液样本中基因组DNA,应用MassARRAY法对microRNA-4293的SNP(rs12220909)位点进行基因分型;应用二元逻辑回归法分析microRNA-4293的SNP(rs12220909)位点与肝癌易感性之间的关系。结果女性肝癌患者microRNA-4293的SNP(rs12220909)中CC基因型较健康对照组显著增加(P=0.04),在HBV相关肝癌中显著性进一步增加(P=0.02),提示CC基因可能增加女性肝癌尤其是HBV相关肝癌的易感性。而在男性患者中,microRNA-4293的SNP(rs12220909)与肝癌易感性并不相关(P=0.33)。结论microRNA-4293的SNP(rs12220909)与女性肝癌易感性相关。     

Implications of biomarkers in human hepatocellular carcinoma pathogenesis and therapy

Hepatocellular carcinoma(HCC)is one of the most frequent tumors worldwide and accounts for approximately one-third of all malignancies.In the past decade,advances have been made to improve the prognosis of HCC,including improvement in the clinical diagnosis of early-stage HCC using molecular biomarkers and molecular-targeted therapy to treat advanced HCC.However,the diagnosis,pathogenesis and targeted therapy of HCC are not completely independent,and should be comprehensively studied.For example,a number of tumor markers provide useful clinical information not only for prognosis,but also in pathogenesis and treatment efficacy.Therefore,this review will focus on the role of several specific biomarkers implicated in the pathogenesis of HCC and several promising molecular-targeted drugs that target the biomarkers of HCC.     

Assessment of KL-6 as a tumor marker in patients with hepatocellular carcinoma

AIM: To investigate the clinical significance of KL-6 as a tumor marker of HCC in two different ethnic groups with chronic liver disease consecutively encountered at outpatient clinics. METHODS: Serum KL-6 was measured by the sandwich enzyme immunoassay method using the KL-6 antibody (Ab) as both the capture and tracer Ab according to the manufacturer's instructions (Eisai, Tokyo, Japan). Assessment of alpha fetoprotein (AFP) and protein induced vitamin K deficiency or absence (PIVKA-Ⅱ) was performed in both groups using commercially available kits. RESULTS: A significantly higher mean serum KL-6 (556±467 U/L) was found in HCC in comparison with non-HCC groups either with (391±176 U/L; P<0.001) or without (361±161 U/L; P<0.001) liver cirrhosis (LC). Serum KL-6 level did not correlate with either AFP or PIVKA-Ⅱ serU/Levels. Using receiver operating curve analysis for KL-6 as a predictor for HCC showed that the area under the curve was 0.574 (95%CI = 0.50-0.64) and the KL-6 level that gave the best sensitivity (61%) was found to be 334 U/L but according to the manufacturer's instructions; a cut-off point of 500 U/L was used that showed the highest specificity (80%) in comparison with AFP and PIVKA-Ⅱ (78% vs 72% respectively). Combining the values of the three markers improved specificity of AFP for HCC diagnosis from 78% for AFP alone; 93% for AFP plus PIVKA-Ⅱ to 99% for both plus KL-6 value (P<0.001). Mean serum alkaline phosphatase level was significantly higher in KL-6 positive (564±475) in comparison with KL-6 negative (505±469) HCC patients (P = 0.021), but such a difference was not found among non-HCC corresponding groups. CONCLUSION: KL-6 is suggested as a tumor for HCC. Its positivity may reflect HCC-associated cholestasis and/ or local tumor invasion.     

Role of biomarkers in the prediction and diagnosis of hepatocellular carcinoma

The prevalence of hepatocellular carcinoma (HCC) has progressively increased in recent years and is now the fifth and the second most common cancer in the World and in Egypt, respectively. Much work has focused in the development of assays for detecting hepatic carcinogensis before the observance of hepatic focal lesions. Particular attention has been directed towards HCC-specific biomarkers for use in the early diagnosis of HCC and in the confirmation of radiological studies. Although a number of biomarkers have been identified, none have been considered reliable indicators of early HCC lesions. This review presents a few of the most relevant HCC biomarkers and suggests improvements to the accuracy of diagnostic assays through their combined use. Furthermore, we present an algorithm for the biomarker-based diagnosis of HCC and highlight its important role in the early prediction of HCC.     

Assessment of the correlation between serum prolidase and alpha-fetoprotein levels in patients with hepatocellular carcinoma

AIM: To determine the predictive value of increased prolidase activity that reflects increased collagen turnover in patients with hepatocellular carcinoma(HCC).METHODS: Sixty-eight patients with HCC(mean age of 69.1 ± 10.1), 31 cirrhosis patients(mean age of59.3 ± 6.3) and 33 healthy volunteers(mean age of51.4 ± 12.6) were enrolled in this study. Univariate and multivariate analysis were used to evaluate the association of serum α-fetoprotein(AFP) values with HCC clinicopathological features, such as tumor size,number and presence of vascular and macrovascular invasion. The patients with HCC were divided into groups according to tumor size, number and presence of vascular invasion(diameters; ≤ 3 cm, 3-5 cmand ≥ 5 cm, number; 1, 2 and ≥ 3, macrovascular invasion; yes/no). Barcelona-clinic liver cancer(BCLC)criteria were used to stage HCC patients. Serum samples for measurement of prolidase and alphafetoprotein levels were kept at-80 ℃ until use.Prolidase levels were measured spectrophotometrically and AFP concentrations were determined by a chemiluminescence immunometric commercial diagnostic assay.RESULTS: In patients with HCC, prolidase and AFP values were evaluated according to tumor size, number,presence of macrovascular invasion and BCLC staging classification. Prolidase values were significantly higher in patients with HCC compared with controls(P 0.001). Prolidase levels were significantly associated with tumor size and number(P 0.001, P = 0.002,respectively). Prolidase levels also differed in patients in terms of BCLC staging classification(P 0.001).Furthermore the prolidase levels in HCC patients showed a significant difference compared with patients with cirrhosis(P 0.001). In HCC patients grouped according to tumor size, number and BCLC staging classification, AFP values differed separately(P = 0.032,P = 0.038, P = 0.015, respectively). In patients with HCC, there was a significant correlation(r = 0.616; P 0.001) between prolidase and AFP values in terms of tumor size, number and BCLC staging classification,whereas the presence of macrovascular invasion did not show a positive association with serum prolidase and AFP levels.CONCLUSION: Considering the levels of both serum prolidase and AFP could contribute to the early diagnosing of hepatocellular carcinoma.     

Inflammatory markers as selection criteria of hepatocellular carcinoma in living-donor liver transplantation

AIM:To investigate that inflammatory markers can predict accurately the prognosis of hepatocelluar carcinoma(HCC)patients in living-donor liver transplantation(LDLT).METHODS:From October 2000 to November 2011,224 patients who underwent living donor liver transplantation for HCC at our institution were enrolled in this study.We analyzed disease-free survival(DFS)and overall survival(OS)after LT in patients with HCC and designed a new score model using pretransplant neutrophil-lymphocyte ratio(NLR)and C-reactive protein(CRP).RESULTS:The DFS and OS in patients with an NLR level≥6.0 or CRP level≥1.0 were significantly worse than those of patients with an NLR level<6.0 or CRP level<1.0(P=0.049,P=0.003 for NLR and P=0.010,P<0.001 for CRP,respectively).Using a new score model using the pretransplant NLR and CRP,we can differentiate HCC patients beyond the Milan criteria with agood prognosis from those with a poor prognosis.CONCLUSION:Combined with the Milan criteria,new score model using NLR and CRP represent new selection criteria for LDLT candidates with HCC,especially beyond the Milan criteria.     

Controversies regarding and perspectives on clinical utility of biomarkers in hepatocellular carcinoma

The prevalence of hepatocellular carcinoma (HCC) worldwide parallels that of persistent infection with the hepatitis B virus (HBV) and/or hepatitis C virus (HCV). According to recommendations by the World Health Organization guidelines for HBV/HCV, alpha-fetoprotein (AFP) testing and abdominal ultrasound should be performed in routine surveillance of HCC every 6 mo for high-risk patients. These examinations have also been recommended worldwide by many other HCC guidelines over the past few decades. In recent years, however, the role of AFP in HCC surveillance and diagnosis has diminished due to advances in imaging modalities. AFP was excluded from the surveillance and/or diagnostic criteria in the HCC guidelines published by the American Association for the Study of Liver Diseases in 2010, the European Association for the Study of the Liver in 2012, and the National Comprehensive Cancer Network in 2014. Other biomarkers, including the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), des-γ-carboxyprothrombin, Dickkopf-1, midkine, and microRNA, are being studied in this regard. Furthermore, increasing attention has focused on the clinical utility of biomarkers as pre-treatment predictors for tumor recurrence and as post-treatment monitors. Serum and tissue-based biomarkers and genomics may aid in the diagnosis of HCC, determination of patient prognosis, and selection of appropriate treatment. However, further studies are needed to better characterize the accuracy and potential role of these approaches in clinical practice.