Surveillance and diagnosis of hepatocellular carcinoma in patients with cirrhosis

Early identification of hepatocellular carcinoma (HCC) is more frequent because of surveillance programs for HCC worldwide. The optimal strategy of surveillance in cirrhosis is a current topical issue. In terms of diagnosis, recent advances in non-invasive imaging technology, including various techniques of harmonic ultrasound, new ultrasound contrast agents, multi-slice helical computed tomography and rapid high quality magnetic resonance, have all improved the accuracy of diagnosis. Consequently the role of liver biopsy in diagnosis of HCC has declined. The imaging diagnosis relies on the hallmark of arterial hypervascularity with portal venous washout. However, with recent advances in genomics and proteomics a great number of potential serum and tissue markers have been identified and are being developed as new candidate markers for both diagnosis and prognosis of hepatocellular carcinoma, and may increase the need for liver biopsy.     

Biomarkers in hepatocellular carcinoma: an overview

Introduction: Current methods for HCC diagnosis have not an optimal diagnostic accuracy. The detection of more than one biomarker seems to improve their individual performance and provide an accurate HCC diagnosis approach. Individual gene expression seems to influence whether or not the treatment is successful, since several molecules have interfere with cancer associated pathways and have been related to poor prognosis which condition the lack of effective treatment options.

Areas covered: Novel biomarkers have been proposed as a useful tool in each patient prognosis. This article aims to review the recent evidence based on HCC biomarkers which seems to have a regulative role according to tumor cell development leading to a specific biological response. Epigenetic regulation, miRNAs, and genome sequencing analysis propose molecular expression signatures as novel biomarkers which allowed achieve the major goal for the use of biomarkers in clinical practice. Moreover, a deeper analysis for determine the diagnostic accuracy of biomarkers has been made.

Expert commentary: To improve of methodological designs and sample sizes are needed in order to support the role of biomarkers in HCC. Furthermore, is necessary to consider HCC etiologies and all clinic disease context to carried out clinical phase studies to thrust biomarkers application.     

Human microbiome is a diagnostic biomarker in hepatocellular carcinoma

Background:Hepatocellular carcinoma(HCC)is the third leading cause of cancer mortality worldwide.Increasing evidence indicates a close relationship between HCC and the human microbiota.Herein,we reviewed the important potential of the human microbiota as a diagnostic biomarker of HCC.Data sources:Several innovative studies have investigated the characteristics of the gut and oral micro-biomes in patients with HCC and proposed that the human microbiome has the potential to be a diag-nostic biomarker of HCC.Literature from February 1999 to February 2019 was searched in the PubMed database using the keywords"microbiota"or"microbiome"or"microbe"and"liver cancer"or"hepato-cellular carcinoma",and the results of clinical and experimental studies were analyzed.Results:Specific changes occur in the human microbiome of patients with HCC.Moreover,the gut mi-crobiome and oral microbiome can be used as non-invasive diagnostic biomarkers for HCC.Furthermore,they also have certain diagnostic potential for precancerous diseases of HCC.The diagnostic potential of the blood microbiota and ascites microbiota in HCC will be gradually discovered in the future.Conclusions:The human microbiome is valuable to the diagnosis of HCC and provides a novel strategy for targeted therapy of HCC.The human microbiome may be widely used in the diagnosis,treatment and prognosis for multiple system diseases or cancers in the future.     

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.     

Radiomics: A radiological evidence-based artificial intelligence technique to facilitate personalized precision medicine in hepatocellular carcinoma

The high postoperative recurrence rates in hepatocellular carcinoma (HCC) remain a major hurdle in its management. Appropriate staging and treatment selection may alleviate the extent of fatal recurrence. However, effective methods to preoperatively evaluate pathophysiologic and molecular characteristics of HCC are lacking. Imaging plays a central role in HCC diagnosis and stratification due to the non-invasive diagnostic criteria. Vast and crucial information is hidden within image data. Other than providing a morphological sketch for lesion diagnosis, imaging could provide new insights to describe the pathophysiological and genetic landscape of HCC. Radiomics aims to facilitate diagnosis and prognosis of HCC using artificial intelligence techniques to harness the immense information contained in medical images. Radiomics produces a set of archetypal and robust imaging features that are correlated to key pathological or molecular biomarkers to preoperatively risk-stratify HCC patients. Inferred with outcome data, comprehensive combination of radiomic, clinical and/or multi-omics data could also improve direct prediction of response to treatment and prognosis. The evolution of radiomics is changing our understanding of personalized precision medicine in HCC management. Herein, we review the key techniques and clinical applications in HCC radiomics and discuss current limitations and future opportunities to improve clinical decision making.     

Biomarkers for the early diagnosis of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the fifth most common cancer and the second leading cause of cancer-related deaths worldwide. Although the prognosis of patients with HCC is generally poor, the5-year survival rate is 70% if patients are diagnosed at an early stage. However, early diagnosis of HCC is complicated by the coexistence of inflammation and cirrhosis. Thus, novel biomarkers for the early diagnosis of HCC are required. Currently, the diagnosis of HCC without pathological correlation is achieved by analyzing serum α.fetoprotein levels combined with imaging techniques. Advances in genomics and proteomics platforms and biomarker assay techniques over the last decade have resulted in the identification of numerous novel biomarkers and have improved the diagnosis of HCC. The most promising biomarkers,such as glypican-3, osteopontin, Golgi protein-73 and nucleic acids including microRNAs, are most likely to become clinically validated in the near future. These biomarkers are not only useful for early diagnosis of HCC, but also provide insight into the mechanisms driving oncogenesis. In addition, such molecular insight creates the basis for the development of potentially more effective treatment strategies. In this article,we provide an overview of the biomarkers that are currently used for the early diagnosis of HCC.     

New indexes derived from routine blood tests and their clinical application in hepatocellular carcinoma

Considerable efforts have been made in the diagnosis and treatment of hepatocellular carcinoma (HCC), but the prognosis of patients with HCC remains poor. The development of officious and easy-to-use indicators that are applicable to all levels of hospitals for the diagnosis, prognosis and risk prediction of HCC may play an important role in improving the current undesirable situation. The occurrence of HCC can cause a series of local and systemic changes, involving liver function, inflammation, immunity, and nutrition, which can be reflected in routine clinical indicators, especially laboratory metrics. A comprehensive analysis of these routine indicators is capable of providing important information for the clinical management of HCC. Routine clinical indicators are daily medical data that are readily available, easily repeatable, and highly acceptable, which has attracted clinicians to derive a number of comprehensive indexes from routine clinical indicators by means of four arithmetic operations, scoring system, and mathematical modeling. These indexes integrate several clinical indicators into a new single indicator that performs better than any of original individual indicators in the risk prediction, clinical diagnosis and prognostic evaluation of HCC and is easy to use. Herein, we reviewed recent indexes derived from routine clinical indicators for the diagnosis, prognosis and risk prediction of HCC.     

Hepatocellular carcinoma tumour markers: Current role and expectations

Tumour markers could be helpful along the continuum of care for patients with hepatocellular carcinoma; however, there is insufficient data for routine use of most current biomarkers in clinical practice. Therefore, the backbone of early detection, diagnosis and treatment response for hepatocellular carcinoma remains imaging-based. Alpha fetoprotein is the best studied of all biomarkers and may be of benefit for early detection when used in combination with ultrasound. Several other biomarkers, including AFP-L3, DCP, osteopontin, and GP73, are also being evaluated for early detection of hepatocellular carcinoma in phase III biomarker studies. Serum and tissue-based biomarkers and genomics may aid in HCC diagnosis, prognosis, and treatment selection; however, further studies are needed to better characterize their accuracy and potential role in clinical practice.     

Genetic profiling of human hepatocellular carcinoma

The underlying molecular basis for the heterogeneity in human liver cancer, hepatocellular carcinoma (HCC), is largely unknown. As with most other human cancers, the heterogeneous nature of HCC has hampered both treatment and prognostic predictions. Global gene expression profiling of human cancers is a promising new technology for refining the diagnosis and prognosis of HCC as well as for identifying potential therapeutic targets. Improved molecular characterization of HCC from gene expression profiling studies will undoubtedly improve the prediction of treatment responses, improve the selection of treatments for specific molecular subtypes of HCC, and ultimately improve the clinical outcome of HCC patients. We review the recent advances in gene expression profiling of HCC and discuss the biological and clinical insights obtained from these studies.     

Hepatocellular carcinoma: Review of disease and tumor biomarkers

Hepatocellular carcinoma(HCC) is a common malignancy and now the second commonest global cause of cancer death. HCC tumorigenesis is relatively silent and patients experience late symptomatic presentation. As the option for curative treatments is limited to early stage cancers, diagnosis in non-symptomatic individuals is crucial. International guidelines advise regular surveillance of high-risk populations but the current tools lack sufficient sensitivity for early stage tumors on the background of a cirrhotic nodular liver. A number of novel biomarkers have now been suggested in the literature, which may reinforce the current surveillance methods. In addition, recent metabonomic and proteomic discoveries have established specific metabolite expressions in HCC, according to Warburg's phenomenon of altered energy metabolism. With clinical validation, a simple and non-invasive test from the serum or urine may be performed to diagnose HCC, particularly benefiting low resource regions where the burden of HCC is highest.     

Integration of genomic information in the clinical management of HCC

Molecular profiling of hepatocellular carcinoma (HCC) is enabling the advancement of novel approaches to disease diagnosis and management. Accurate prognosis prediction in HCC is specially critical. Clinical staging systems for HCC support clinical decision-making (e.g., BCLC algorithm) might be complemented by molecular-based information in the near future. Molecular signatures derived from tumour and non-tumour samples are associated with patient recurrence an outcome. Single nucleotide polymorphisms have been linked with HCC development. Next generation sequencing studies have brought to light the genomic diversity of this disease. Gens recurrently altered in HCC and susceptible to be targeted belong to signalling pathways including telomere maintenance, cell cycle, chromatin remodelling, Wnt/beta-catenin, RAS/RAF/MAPK and PI3K/AKT/mTOR pathways. Oncogenic loops are unknown but might include some of the already discovered aberrations. Despite the intratumoral heterogeneity observed in HCC tumours, studies including large number of samples can identify key genetic drivers and contribute to the development of novel treatments and a personalized medicine.     

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.     

Diagnosis of hepatocellular carcinoma: role of tumor markers and liver biopsy

Early diagnosis of hepatocellular carcinoma (HCC) has a significant impact on survival by implementation of effective treatment strategies, including hepatic resection, locoregional ablative therapy, and liver transplantation. The use of serum tumor markers and biopsy are particularly important for diagnosis of small hepatic lesions with atypical features on imaging studies. α-Fetoprotein remains the most frequently used tumor marker for the diagnosis of HCC. The development of novel serum biomarkers for HCC, identification of molecular markers for tissue immunohistochemistry, and emergence of new diagnostic techniques such as proteomic profiling may improve the early detection rate of HCC in the future.     

代谢组学在肝细胞癌标志物研究中的应用

代谢组学技术作为一种新的组学研究手段,能够揭示肝细胞癌(HCC)发生发展过程中的代谢谱差异,成为HCC生物标志物研究的热点。简述了代谢组学在HCC诊断中的意义,概括了HCC相关的生物标志物的代谢组学研究,这些研究主要以血清、尿液及肝组织代谢物为对象,通过动物实验和临床研究两个方面进行。指出分析和监视HCC发生发展过程中相应代谢物的变化,对于患者的个体化治疗具有重要价值。     

蛋白芯片技术对肝细胞癌组织蛋白谱的建立及标志蛋白的筛选

目的:应用表面增强激光解吸附电离飞行时间质谱技术(SELDI-TOF-MS)对肝细胞癌组织的蛋白表达谱进行分析,从中筛选出标记蛋白.方法:采用CM10芯片及SELDI-TOF-MS技术对肝细胞癌组织26例和肝硬化组织18例进行蛋白指纹图谱检测分析;比较高、中、低分化肝细胞癌组织,不同TNM分期肿瘤以及AFP阴、阳性肝细胞癌组织的蛋白表达差异,所得结果均采用Biomarker Wizard软件进行分析;通过查询蛋白库,对特定分子质量所对应的标记蛋白进行初步确定.结果:肝细胞癌和肝硬化组织蛋白表达图谱之间存在16个稳定的标志蛋白,7个蛋白在肝细胞癌组织中表达上调.9个蛋白在肝细胞癌组织中表达下调,其中4.7 kDa,7.2 kDa和9.8 kDa蛋白峰差异性最明显;中分化和高分化肝细胞癌之间存在11个标志蛋白;通过查询蛋白库ExPasy并进行筛选,初步确定特定分子质量所对应的蛋白.结论:采用SELDI-TOF-MS技术,证实在肝细胞癌组织中存在多种高度特异性低分子蛋白.     

MicroRNAs as possible biomarkers for diagnosis and prognosis of hepatitis B- and C-related-hepatocellular-carcinoma

Aim of the present review is to summarize the current knowledge about the potential relationship between miRNAs and hepatitis B virus (HBV)-hepatitis C virus (HCV) related liver diseases. A systematic computer-based search of published articles, according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis Statement, was performed to identify relevant studies on usefulness of serum/plasma/urine miRNAs, as noninvasive biomarkers for early detection of HBV and HCV-induced hepatocellular carcinoma (HCC) development, as well as for its prognostic evaluation. The used Medical Subject Headings terms and keywords were: “HBV”, “HCV”, “hepatocellular carcinoma”, “microRNAs”, “miRNAs”, “diagnosis”, “prognosis”, “therapy”, “treatment”. Some serum/plasma miRNAs, including miR-21, miR-122, mi-125a/b, miR-199a/b, miR-221, miR-222, miR-223, miR-224 might serve as biomarkers for early diagnosis/prognosis of HCC, but, to date, not definitive results or well-defined panels of miRNAs have been obtained. More well-designed studies, focusing on populations of different geographical areas and involving larger series of patients, should be carried out to improve our knowledge on the potential role of miRNAs for HCC early detection and prognosis.     

Liquid biopsy in patients with hepatocellular carcinoma: Circulating tumor cells and cell-free nucleic acids

Hepatocellular carcinoma(HCC), with its high incidence and mortality rate, is one of the most common malignant tumors. Despite recent development of a diagnostic and treatment method, the prognosis of HCC remains poor. Therefore, to provide optimal treatment for each patient with HCC, more precise and effective biomarkers are urgently needed which could facilitate a more detailed individualized decision-making during HCC treatment, including the following; risk assessment, early cancer detection, prediction of treatment or prognostic outcome. In the blood of cancer patients, accumulating evidence about circulating tumor cells and cell-free nucleic acids has suggested their potent clinical utilities as novel biomarker. This concept, so-called "liquid biopsy" is widely known as an alternative approach to cancer tissue biopsy. This method might facilitate a more sensitive diagnosis and better decision-making by obtaining genetic and epigenetic aberrations that are closely associated with cancer initiation and progression. In this article, we review recent developments based on the available literature on both circulating tumor cells and cell-free nucleic acids in cancer patients, especially focusing on Hepatocellular carcinoma.