Hepatocellular carcinoma (HCC) occurs mostly in individuals with cirrhosis, which is why the guidelines of the most important scientific societies indicate that these patients are included in surveillance programs through the repetition of an ultrasound examination every 6 months. The aim is to achieve early identification of the neoplasia in order to increase the possibility of curative therapies (liver transplantation, surgery or local ablative therapies) and to increase patient survival. HCC nodules arising in cirrhotic livers show characteristic angiographic behavior that can be evaluated with dynamic multidetector computed tomography and dynamic magnetic resonance imaging (MRI). However, the use of these techniques in real life is often hindered by the lack of uniform terminology in reporting and in the interpretation of the exams reflected in the impossibility of comparing examinations performed in different centers and/or at different times. Liver Imaging Reporting and Data System^® was created to standardize reporting and data collection of computed tomography and MRI for HCC. In some cases HCC arises in patients with healthy livers and, although there is evidence that angiographic behavior is not different from cirrhotic patients in this clinical situation, the guidelines still indicate the execution of a biopsy. Frequent use of palliative therapeutic techniques such as transarterial chemoembolization, transarterial radioembolization or administration of antiangiogenic drugs (sorafenib) poses problems of interpretation of the therapeutic response with repercussions on the subsequent choices that have been attempted to resolve with the use of stringent criteria such as Modified Response Evaluation Criteria In Solid Tumors.

Chronic infection of hepatitis B virus (HBV) or/and hepatitis C virus (HCV) is one of major risk factors in the development of the hepatocellular carcinoma. Recent studies had shown the capacity of viral proteins in inducing the presence of the population of so-called the cancer stem cells (CSC). The integration of HBV S and X gene in the host genome indicates its direct oncogenicity. In addition, the presence HBV and HCV proteins were shown to modulate intracellular molecular pathways and epigenetic modification. This review summarizes current literature regarding direct oncogenic properties of HBV and HCV in the initiation of CSC both in in vitro and in vivo studies.

Recent clinical trials and new agents have permitted greater clarity in the choice of effective agents for that majority of patients with hepatocellular carcinoma who have advanced disease at diagnosis and thus cannot be offered potentially curative resection, ablation or liver transplantation. The main treatment for these patients remains chemoembolization, although evidence for selective internal radiation therapy (SIRT) with SIR-Spheres or Theraphere, is beginning to suggest that the results with this may be comparable with less toxicity. Patients who have failed chemoembolization or SIRT or have metastatic disease at presentation are suitable for the multikinase inhibitor sorafenib (nexavar) or newly-approved lenvatinib (lenvima) as first line therapies. The choice between which of them to use first is not currently clear. Patients who have failed sorafenib can be offered a choice of FDA-approved regorafenib (stivarga) or immune checkpoint inhibitor nivolumab (opdivo) as second line agents. For that considerable percent of patients presenting with macroscopic portal vein thrombosis, the choice appears to be between multikinase inhibitor or SIRT, given the potential toxicity of chemoembolization in this setting. However, considering the potency of both nivolumab and regorafenib and the pipeline of new agents such as atezolizumab (tecentriq) in current clinical trials, including new immune checkpoint inhibitors, this landscape may change within a couple of years, especially if new evidence arises for the superior effectiveness of combinations of any of these agents over single agents.

Patients with hepatocellular carcinoma (HCC) often present with underlying liver disease and significant comorbidities, limiting treatment tolerance. With the development of improved toxicity models and highly conformal radiation delivery systems, external beam radiotherapy has become a valuable treatment option for liver cancer. Using cutting edge technology, stereotactic ablative radiotherapy (SABR) allows for the delivery of ablative doses in few fractions while sparing uninvolved liver tissue. This approach permits dose escalation and precise tumor targeting with minimal risk of radiation induced liver disease. This review clarifies SABR’s role alongside liver-directed treatments such as radiofrequency ablation, transarterial radioembolization, and transarterial chemoembolization in the management of HCC. It also examines the promising potential of SABR combined with immunotherapy to treat advanced HCC.

Aim: Hepatocellular carcinoma (HCC) has emerged as one of the most commonly diagnosed forms of human cancer; yet, the current treatment for HCC is less effective than those used against other cancers. Transcription factor p53 induces cell cycle arrest and apoptosis in response to DNA damage and cellular stress, thereby playing a critical role in protecting cells from malignant transformation. The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53, conferring tumor development and survival.

Methods: In this work, we firstly explored the feasibility of antagonists targeting the p53-binding domains of MDM2 and MDMX as a potential method for HCC therapy via the survival rate analysis in The Cancer Genome Atlas. Moreover, we developed a novel stapling strategy for peptide drug design using the reaction between mercapto group and bromine to crosslink the side chains of the two Cys at (i, i+4) positions, and apply it to a series of peptides derived from a dodecameric peptide antagonist of both MDM2 and MDMX, termed p53-MDM2/MDMX inhibitor (PMI).

Results: Notably, all of these stapled peptides can compete with p53 for MDM2 or MDMX binding as the similar affinity as PMI. More importantly, this stapling functionally rescued PMI that, on its own, failed to activate p53 because of its poor membrane permeability and susceptibility to proteolytic degradation.

Conclusion: Taken together, this work not only illustrates that the restoration of p53 is a potentially feasible program for HCC therapy, but promises an important new tool for peptide drug discovery and development for a variety of human diseases.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide and despite improvement in therapeutic approaches, prognosis remains poor. This can be partly attributed to the fact that the majority of HCCs are diagnosed at intermediate or advanced stages. Availability of circulating biomarkers able to detect HCC at early stages could improve patients’ prognosis. At present, however, alpha fetoprotein or des-g-carboxyprothrombin are unable to reliably detect HCC at early stages and better circulating biomarkers are needed. Circulating tumor DNA (ctDNA) and non-coding RNAs (ncRNAs) are emerging as promising biomarkers to achieve the goal. Genetic and epigenetic alterations in ctDNA allow to pinpoint tumor-specific biomarkers, reveal tumor heterogeneity, help monitor tumor evolution over time and assess therapy efficacy. It remains to be fully evaluated the possibility of detecting these biomarkers at early tumor stages. Circulating ncRNAs are quantitative biomarkers with potential use in diagnostic, prognostic and predictive clinical settings. They may help to reveal HCC at early stages. However, because of heterogeneous and sometimes conflicting reported results, they still require validation and standardization of pre-analytical and analytical approaches before clinical applications could be envisaged.

Non-alcoholic fatty liver disease has become the leading chronic liver disease in the developed world, with a prevalence of 6%-35%. Its pathological spectrum ranges from simple steatosis (non-alcoholic fatty liver) to different degrees of inflammation and liver cell damage [non-alcoholic steatohepatitis (NASH)]. NASH has gained attention in recent years because of its association with hepatocellular carcinoma (HCC). Although the occurrence of HCC is more frequent in the presence of cirrhosis, studies have shown that hepatic carcinogenesis may also develop in the context of NASH without association with advanced fibrosis, as well as from simple steatosis. Evidence of the onset of HCC in the absence of cirrhosis is of concern, since recent surveillance and screening guidelines for liver cancer do not include this population subgroup. Therefore, it is imperative that new effective screening and monitoring measures for HCC, or even the reformulation of these recommendations, be taken to handle these patients considered to be at high risk. The present paper aims to review the literature on the occurrence of HCC in patients with NASH with or without cirrhosis. In addition, we report a case showing the development of HCC in a patients with NASH without cirrhosis.

Through several studies exploiting next-generation sequencing, we are obtaining a clearer picture of the complex genetic and molecular landscape of hepatocellular carcinoma (HCC). Consistent with the findings of other cancer types, telomerase reverse transcriptase (TERT) promoter mutations have been frequently reported in HCC. C228T and C250T are two major types of hot spot mutations in the TERT promoter region. Besides, in hepatitis B virus (HBV)-related HCC cases, the TERT promoter is recurrently interrupted by integration of HBV DNA. TERT promoter mutations are thought to be an early event in HCC carcinogenesis, and they are significantly associated with disease progression. In this review, we provide an updated overview of the somatic mutations in the TERT promoter region and discuss their possible roles in the development of HCC.

Despite of the advances in clinical imaging and applied research in proteomic biomarkers, liver cancer, especially hepatocellular carcinoma remains detected at the very late and advanced stages when curable treatments are unavailable and ineffective. In this regard, there are still huge unmet medical needs in developing and clinically validating those high-potential protein biomarkers preferably in liquid biopsy samples. This review provides a glimpse of emerging biomarkers together with detection tools and techniques which are potentially commercially available to the markets. We also discuss several diagnostic biomarkers having therapeutic potential for developing first-in-class medicines.

Hepatitis B virus (HBV) infection is still a severe health problem in the world, and chronic hepatitis B (CHB) is the major cause of serious HBV-related complications, including fibrosis, hepatic failure, and hepatocellular carcinoma. It is difficult for CHB patients to achieve complete cure as the currently available antiviral drugs can hardly eradicate covalently closed circular DNA (cccDNA) in the infected liver. Since detecting intrahepatic cccDNA needs invasive procedure, it is urgent to find a noninvasive indicator to reflect the activity of cccDNA. Recently, growing numbers of studies have indicated that serum HBV RNA could be regarded as a new biomarker for CHB activity. In order to illustrate the molecular biology and clinical characteristics of HBV RNA, we systematically reviewed the latest research to summarize the role of HBV RNA in HBV replication and pathogenicity, and to better estimate its potential function as a remarkable biomarker in clinical application. Meanwhile, we will also point out the deficiencies of current research, and discuss the future direction of HBV RNA study.

Screening for liver cancer (hepatocellular carcinoma) in China started in early 1970s with the application of alpha-fetoprotein (AFP) in high-incidence regions. It has been extended to nationwide areas, emerging from the concepts of conducting screening in populations at-risk with positive hepatitis B surface antigen to the practice programs in rural and urban areas, and finally to the development of recommendations to guide medical practice for health care providers. The implementation of screening for liver cancer has resulted in earlier detection and hence the early curable treatment for patients who have gained short- or long-term survival, and even reduction in mortality rates, although these outcomes are more anecdotal than rigorously evidence-based. AFP or ultrasound examination has been considered as sensitive and specific methods for early detection but are with limitations. The combined use of these two modalities for screening populations at-risk every six months seems to have been reached consensus. The feasibility of screening for liver cancer is still debated because of differing opinions and even opposition to the choice of targeted sub-populations, the intrinsic necessity, and the contributions of the main risk factors among Western countries and China/Asian areas. Yet, the over 51% of global burden of liver cancer is in China, the solution to the early detection and treatment of liver cancer should fully consider the actual situation in China. The effectiveness of screening for liver cancer is worthy of anticipation.

Aim: This meta-analysis was designed to compare the effectiveness of the combination of transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) vs. that of TACE alone in hepatocellular carcinoma (HCC) tumors larger than 5 cm.

Methods: PUBMED, CNKI, and CBM were searched for all related randomized controlled trials (RCTs) up until October 22, 2018. Eleven studies were identified that compared TACE with RFA vs. TACE alone for HCC treatment. Tumor response rate, the proportion of patients with either complete or partial shrinkage of tumors, and survival rate were the major evaluation indices.

Results: Meta-analysis data revealed that TACE with RFA showed significantly better tumor response rate (risk ratio (RR) = 1.452, 95% confidence interval (CI): 1.308-1.610, P < 0.001) and 1-year overall survival rate (RR = 1.412, 95% CI: 1.249-1.596, P < 0.001) than that of TACE alone treatment.

Conclusion: The data of our study indicates that TACE combined with RFA in the treatment of HCC larger than 5 cm is an effective comprehensive interventional therapy.

Hepatocellular carcinoma (HCC) is often associated with pre-existing chronic liver pathologies of different origin infections of hepatitis B virus (HBV) and hepatitis C virus. Clinically, the diagnosis and therapy for HCC are very important for the prognosis of patients. However, current methods for HCC diagnosis and therapy have no an optimal accuracy due to the tumor heterogeneity and the frequent late diagnosis. This review summarizes the new advances in molecular diagnosis and therapy of HCC, based on the recent novel biomarkers and new therapeutic strategies for HCC, including alpha-fetoprotein-L3, glypican-3, heat shock protein 90, dickkopf WNT signaling pathway inhibitor 1, paraoxonase 1, highly up-regulated in liver cancer. Moreover, epigenetic regulation, signal pathway, cellular and molecular targets for the immunotherapy, tumor microenviroment and genome sequencing analysis may serve as the molecular expression signatures in clinical practice. For promising new treatment strategy of HCC, targeting molecular therapy based on the restoration of tumor suppressor genes lost and inhibition of oncogenic genes is attractive. The new clinical trials for other molecular-targeted agents, including pembrolizumab, nivolumab, tivantinib, lenvatinib, cabozantinib, and ramucirumab, are ongoing in clinic. Interestingly, anti-HBV drugs display an amazing therapy for HBV-related HCC. In future, the global determination of more biomarkers may provide new insights into the diagnosis of HCC. More importantly, the diagnostic markers should be used to trace patient’s follow-up disease progression, guiding doctors to judge and prescribe drugs for status of an illness, prognosis and other processes.

In multistep hepatocarcinogenesis, sizable lesions can precede the development of hepatocellular carcinoma (HCC). These lesions are currently classified as low grade (LG)- and high grade (HG)-dysplastic nodules. Following international guidelines recommending the surveillance of cirrhotic patients, a growing number of 1-2 cm hepatocellular nodules are recognized including early hepatocellular carcinoma (eHCC) and DN the latter accounting for as many as 70% of nodules < 1 cm. HG-DN are currently considered the most advanced HCC precursors. The histological diagnosis of low-grade dysplastic nodule (LG-DN), high- grade dysplastic nodule (HG-DN) and eHCC in small liver biopsies requires a comprehensive stepwise morphological and immunocytochemical approach. By imaging the differential diagnosis among these lesions is a challenge. According to vascular enhancement at dynamic computed tomography (CT) or magnetic resonance imaging (MRI) these precursors are classified as hypo-vascular/indeterminate nodules even though distinction between LG-DN and HG-DN is almost impossible. The introduction of gadoexetic acid-enhanced MRI has represented an extremely important advance in this field allowing a better differentiation of dysplastic lesions from eHCC and progressed HCC. Additional MRI features as diffusion-weighted imaging further improved diagnostic accuracy of imaging. According to Liver Imaging Reporting and Data System (LI-RADS), either CT/MRI or Contrast-Enhanced Ultrasound LI-RADS, the dysplastic lesions should be categorized as LR-3 or LR-4. Natural history of these lesions confirmed that HCC can develop from HG-DN but which nodule and when it will undergo malignant transformation is not predictable. The search and validation of radiological and tissue markers able to select lesions more prone to HCC development, is currently underway. Whether and how HG-DN should be ablated or closely followed up is currently debated.

Aim: The increased risk of hepatocellular carcinoma (HCC) recurrence in hepatitis C virus (HCV)-infected patients treated with direct-acting antivirals (DAAs) after curative treatment for HCC is controversial. The purpose of this study was to examine the risk of HCC recurrence after DAA therapy.

Methods: We conducted a retrospective cohort study of 312 consecutive patients with HCV-related HCC who received DAA therapy in participating institutions between September 2014 and July 2016. All patients received curative hepatectomy or radio-frequency ablation. We calculated the annual incidence of HCC recurrence after DAA therapy and identified the risk factors for HCC recurrence using Cox regression models.

Results: The median age was 74 years old, and a sustained virological response was achieved by 288 patients. The 3-year-overall survival rate was 95.4% in a median follow-up period of 855 days. HCC recurred in 135 patients. The 1-, 2- and 3-year recurrence rates were 18.3%, 38.8% and 55.4%, respectively. A multivariate analysis revealed that the following factors were associated with HCC recurrence: multiple tumors at the first HCC treatment [hazard ratio (HR) = 2.21; 95%CI: 1.41-3.49], a history of multiple treatments for HCC (HR = 1.97; 95%CI: 1.28-3.02), and α-fetoprotein (AFP-L3) ≥ 10% at the initiation of DAA therapy (HR = 4.74; 95%CI: 2.10-10.7).

Conclusion: Among patients treated with DAAs after the curative treatment of HCC, multiple tumors at the first HCC treatment, multiple prior HCC treatments and a high AFP-L3 level before DAA therapy were associated with recurrence, and the rate of recurrence was comparable to that before the DAA era.

Aim: According to the current guidelines, transarterial chemoembolization (TACE) remains the first-line therapies for hepatocellular carcinoma (HCC) patients at Barcelona Clinic Liver Cancer (BCLC) B-stage and sorafenib is a small molecule target drug for BCLC C-stage. In clinical practice, clinicians have attempted to use stereotactic body radiation therapy (SBRT) plus TACE for treating intermediate- to advanced-stage HCC. However, the therapeutic effects are still inconsistent. This meta-analysis was conducted to elucidate the validity and safety of the combination therapy of SBRT plus TACE in the patients with intermediate-to advanced-stage HCC.

Methods: PubMed, MEDLINE, Web of Science, China Biology Medicine, Chinese Knowledge resources integrated and Chinese Scientific Journal Full-Text Database was searched from their inception date to November 2018. The survival rates (half-year, one-year and two-year) were analyzed and compared between the observation groups and the control groups. The negative conversion rate of AFP and the total effective rate were also assessed. Risk ratios (RR) and 95%CI were calculated to express therapeutic effects.

Results: A total of 1,210 patients from 13 eligible studies were included. The cooperation of TACE and SBRT notably ameliorated the whole survival rates of half-year, one-year, two-year, the negative conversion rate of AFP, and the total effective rate, compared with TACE or SBRT monotherapy [RR (the total effective rate), 1.412, 95%CI: 1.309-1.523, P < 0.001], [RR (half-year survival rate), 1.196, 95%CI: 1.121-1.276, P < 0.001], [RR (one-year survival rate), 1.327, 95%CI: 1.236-1.424, P < 0.001], [RR (two-year survival rate), 1.479, 95%CI: 1.284-1.703, P < 0.001] and [RR (negative conversion rate of AFP), 1.756, 95%CI: 1.502-2.059, P < 0.001]. Sensitivity analysis supported the above results.

Conclusion: Combination therapy of SBRT and TACE provides survival benefits in intermediate-to advanced-stage HCC patients compared to monotherapy of SBRT or TACE.

Aim: Immune checkpoint inhibitors (ICIs) are proven to be an effective way to treat the disease of hematologic malignancies. But there is still plenty of uncertainty about the effectiveness of ICIs on hepatocellular carcinoma. The Meta-analysis was conducted to evaluate the efficacy and safety of ICIs treatment in patients with HCC.

Methods: Four electronic databases, including PubMed, Embase, Cochrane database, and ClinicalTrials.gov, were systematically retrieved for relevant observational studies published before November 1, 2018. The objective response rate (ORR) and adverse events were analyzed. Meta and Metafor Packages in R were utilized to accomplish meta proportion analysis.

Results: A total of 462 patients from 7 studies were included in this meta-analysis. The pooled estimated ORR of ICIs was 19.8% (95% CI 16.4% to 23.7%). No substantial heterogeneity was observed among studies (Q = 2.0427, P = 0.92, I² = 0.0%). The common adverse events on any grade were saw in increased AST (22.7%, 95%CI 13.8% to 35.2%), fatigue (20.9%, 95%CI 10.9% to 36.3%), rash (18.5%, 95%CI 8.9% to 34.4%) and pruritus (17.3%, 95%CI 13.5% to 21.8%). Increased AST (9.9%, 95%CI 4.4% to 21.0%) and increased ALT (5.8%, 95%CI 3.7% to 8.9%) were the most common adverse events on grade greater than 3.

Conclusion: Although ICIs treatment has a certain efficacy on liver cancer, it also causes some adverse events which should be noticed by clinicians.

Contrast-enhanced ultrasound (CEUS) with pure blood stream contrast agents allow the study of blood supply of focal liver lesions and especially of hepatocellular carcinoma (HCC) in cirrhosis. Its sensitivity and specificity in diagnosis of small tumors is very high. This review summarizes the recent results on CEUS with SonoVue, which is one of the second generation contrast agents, in the diagnosis of early HCC in cirrhosis emphasizing its increasing role in routine clinical practice.

The occurrence of three primary malignancies in a single patient is an infrequent phenomonen with an estimated occurrence at 0.1%. Notably, patients with hepatocellular carcinoma (HCC) are particularly unlikely to develop extrahepatic primary malignancies. In this light, we present a case of patient with chronic hepatitis B who developed HCC, as well as two other primary malignancies. This case exhibits an exceedingly rare combination of cancers, underlining the importance of continued cancer surveillence in those with a history of primary malignancy.

Re-irradiation (Re-RT) in liver tumours is rarely reported owing to poor tolerance of liver and high incidence of radiation induced liver disease incidence. Fiducial based robotic radiosurgery allows to deliver high dose radiation to the liver tumour and restricts the dose to healthy uninvolved liver, thereby increasing the potential for Re-RT. Tolerance to radiation is low for entire liver and hence re-radiation is a challenge. On the other hand, as regenerative potential of hepatocytes is rapid, replacement of necrotic liver tissue occurs with regenerated hepatocytes. These regenerated hepatocytes are radiation naïve, do not have “memory” of radation therapy treatment and hence have potential of Re-RT. We are reporting a series of two breast cancer patients presented with liver oligometastasis treated with fiducial based CyberKnife system (CK). Both the patients were treated multiple times with CK and had long-term survival (> 2 years) without any clinical features of radiation induced liver injury. Appropriately selected patients are suitable for multiple sessions of CK for liver lesions with long-term outcome.

Hepatocellular carcinoma (HCC) is the most recurrent hepatic malignancy and the third in the cancer-related casualties in the west. The frequently-documented causes of HCC are chronic liver infections by hepatitis B virus or hepatitis C virus, nonalcoholic fatty liver disease, cirrhosis, exposure to aflatoxins and tobacco smocking, etc. Clinical presentation of this fatal disease ranges from asymptomatic to upper abdominal pain or common health conditions like weight loss or lethargy. Among current surveillance strategy for suspected patients, liver imaging and serum alpha fetoprotein estimation has been regularly recommended. However, sensitivity of this diagnostic methodology especially in early detections, often suffers from compromised sensitivity and selectivity. Various image based and serological biomarkers for HCC has been introduced in recent decades with varied sensitivity as stand-alone or combined diagnostic protocol. The current article will review the status of HCC diagnosis with respect to common diagnostic protocol, and upcoming novel biomarkers.

Aim: Chronic persistent hepatitis B virus carriers are generally asymptomatic until the advanced stage of the disease. The “Hepatitis B-Carrier Clinics” of Chang Gung Memorial Hospital has been using alpha-fetoprotein (AFP) and liver ultrasound for early detection of hepatocellular carcinoma (HCC) in hepatitis B surface antigen (HBsAg) carriers since 1980.

Methods: We evaluated the results of surveillance between 1980 and 2012 by collecting clinic data, matched cancer registry status, and national mortality database status.

Results: Of 15,235 HBsAg carriers, 238 instances of HCC (1.5% or 156.2/100,000 person-years) were detected over a mean follow-up period of 10.0 ± 7.6 years. There were more men (89.1%) and patients with liver cirrhosis (70.2%) in the HCC group (P < 0.001), and both the initial and maximal alanine aminotransferase (ALT) levels were higher in this group (P < 0.001). One hundred and thirty cases of HCC (54.6%) were identified during regular follow-up sessions, 55 (23.1%) were detected after the regular schedule had lapsed (“out-of-schedule”), and 53 (22.3%) were lost to follow-up completely. The mean tumor size was smaller in the regular group than in the out-of-schedule group (2.72 cm vs. 4.59 cm, P < 0.001), and the survival rate was higher (43.8% vs. 30.9%, P < 0.001).

Conclusion: The incidence of HCC was relatively low in the HBsAg-Carrier Clinics cohort. Surveillance for early diagnosis of HCC improved the survival of high-risk HBsAg carriers. To ensure cost-effectiveness, we suggest using different screening strategies according to the individual risk of hepatocarcinogenesis.

Liver cancer stem cells (LCSCs), a small subpopulation that constitutes liver cancer heterogeneity, play a vital role in cancer initiation, invasion, recurrence, metastasis, and resistance to chemo-radiotherapy. It is believed that therapies targeting LCSCs can improve the efficacy of conventional chemotherapy and radiotherapy by completely eliminating tumors while preventing recurrence. Therefore, during last decades, numerous surface markers for LCSCs have been identified and characterized in many subtypes of liver cancer, especially in hepatocellular carcinoma (HCC). These well-recognized surface markers significantly promote the therapeutic efficacy that identifies, targets and destroys LCSCs. Meanwhile, there have been intensive studies that aim to investigate the molecular mechanism of how stemness contributes to liver cancer relapse, recurrence and resistance. However, liver cancer stemness seems to be regulated by a hierarchical organization and crosstalk of a wide variety of signaling pathways. Using individual or few LCSC surface markers may not be able to completely reveal the intrinsic stemness hierarchy. From an integrated perspective, understanding of recent advances in LCSC surface markers remains important and urgent. In this review, we concentrate on demonstrating the indispensable roles of LCSC surface markers in identification and characterization of multiple cancer stages including initiation, invasion, metastasis, resistance and highlighting the cutting-edge therapeutic strategies against cancer stem cells in HCC.

Our comprehensive review focuses on the treatment of hepatitis C virus in the context of hepatocellular carcinoma and vice versa, highlighting the ongoing complexity of this clinical scenario. There remain multiple unanswered questions when considering the management of these complex patients and, with a rapidly-changing treatment landscape for both chronic hepatitis C and hepatocellular carcinoma, these questions are only going to grow. Treatment timing, interactions and the impact of one disease condition on the other are vitally important, though guidance generally remains non-specific, suggesting that we make these decisions on a case-by-case basis. We focus on the current evidence for managing these cases, depending on disease stage and treatment type.

Aim: Hepatitis C virus (HCV) is the leading cause of hepatocellular carcinoma (HCC) in the United States. Achieving sustained viral response with interferon (IFN) treatment reduces the risk from 3%-5% to 0.5%-1% annually. Several studies reported unexpectedly high rates of HCC after treatment with direct-acting antivirals (DAAs). The aim of our study was to compare HCC rates in DAA-, IFN-treated and untreated populations.

Methods: A literature search was conducted using ScienceDirect, Ovid®, Web of Science and MEDLINE through January 2019. Studies were included if they measured rates of de novo or recurrent HCC (following curative treatment) in HCV-infected persons. We included 138 studies (n = 177,512). Simple pooling of data and meta-analysis were performed, using the random effects method.

Results: Mean age was higher in the DAA-treated vs. IFN-treated group (58.4 years vs. 52.6 years; P = 0.0073), as were diabetes prevalence (34.5% vs. 11.7%; P ≤ 0.001) and incident cirrhosis (47.8% vs. 34.2%, P = 0.0017). The incidence rate of de novo HCC was 2.01/100 person-years (py) (95%CI: 1.38, 2.67) in the DAA group and 1.45/100py (95%CI: 0.98, 1.94) in the IFN-treated group. HCC recurred at 16.76/100py (95%CI: 10.75, 22.91) in the DAA-treated group vs. 20.04/100py (95%CI: 2.58, 45.21) after IFN. After adjusting for factors such as age and cirrhosis, the hazard ratio was 0.58 (95%CI: 0.20, 1.07) for HCC occurrence and 0.59 (95%CI: 0.24, 1.03) for HCC recurrence after DAA treatment compared to IFN-based treatment.

Conclusion: We did not find evidence for increased rates of HCC in DAA-treated compared with IFN-treated patients. Compared to those treated with IFN, older patients with additional risk factors for HCC were treated with DAAs. This imbalance appears to explain the higher numerical incidence of HCC among DAA-treated patients.

Hepatocellular carcinoma (HCC) is the most lethal and common type of liver cancer with limited treatment options at the advanced stage. The use of immune checkpoint inhibitor (ICI) based immunotherapy is exponentially increasing in the treatment of patients with advanced solid tumors. The expression of immune checkpoints on tumor cells leading to lower activity of T-cells is one of the major mechanisms of immune escape. Checkpoint blockade immunotherapies with antibodies against PD-1, PD-L1 or CTLA-4 are being investigated in clinical trials in HCC patients. ICIs have improved survival in patients with inoperable advanced stage HCC where other curative treatments are not applicable. However, the response rates remain low with only a small subset of patients responding to this therapy. There is an unmet need to identify predictive markers to select those HCC patients who would benefit from ICI therapies. Importantly, epithelial-to-mesenchymal transition (EMT), a major process driving HCC invasion and metastasis by regulating the phenotypic cellular switching from epithelial to mesenchymal state, has been implicated as a resistance mechanism associated with ICI therapies. The role of EMT as a regulator of immune checkpoint molecule in HCC is just emerging. However, the consequence of EMT as a resistance mechanism in HCC patients undergoing ICI treatments remains unexplored. In this review, we summarize the recent clinical studies with ICIs in HCC and highlight the trials underway featuring novel monotherapies and combinatorial approaches based on immune and non-immune therapies. We will discuss the ongoing efforts to discover new immune checkpoint molecules in HCC as potential drug targets. We also highlight the role of EMT in facilitating therapy resistance in HCC treated with ICIs and discuss potential strategies to circumvent resistance in ICI treated HCC patients.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is associated with high mortality. The currently used methods for diagnosing HCC, including imaging modalities and liver biopsy, detect tumors at a relatively advanced stage or are invasive. Non-invasive biomarkers are urgently needed to facilitate screening and early diagnosis of HCC, as well as treatment monitoring and detection of tumor recurrence. Liquid biopsy, the analysis of blood or other body fluids to obtain genetic and epigenetic information, has historically been applied to other types of cancer including breast and prostate cancer. Over the past few decades, liquid biopsy analysis has shed significant insights on genetic and epigenetic aberrations in HCC detectable in peripheral blood. Aberrations in nucleic acids found circulating freely in body fluids or contained within extracellular vesicles such as exosomes or microvesicles show potential clinical utility as non-invasive biomarkers. In this review, we present available literature on cell-free nucleic acids in the diagnosis of HCC.

Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) worldwide. The recent advancement of direct-acting Antiviral Agents (DAAs) in hepatitis C therapy, resulted in sustained virological response rates of over 90% in treated patients in different stages of liver fibrosis. The efficacy of DAAs treatment has also been confirmed in real-life cohorts that include subjects with decompensated cirrhosis and therefore seems a promising step to a significant reduction in the recurrence of HCC in patients who achieved complete destruction of the HCC nodules by local therapy. We present a 72-year old patient with HCV-related liver cirrhosis who successfully responded to DAAs treatment after complete destruction of an early HCC nodule.

Aim: Survival in patients with hepatocellular carcinoma (HCC) is impacted by stage of liver disease, tumor characteristics, and HCC surveillance in high-risk individuals. Factors associated with HCC tumor growth rate (TGR) and its influence on recurrence-free survival after treatment was investigated.

Methods: TGR was calculated in 164 HCC patients with chronic viral hepatitis who had two consecutive magnetic resonance imaging or computed tomography scans ≥ 30 days apart prior to treatment and who were followed prospectively to determine the rates of recurrence-free survival.

Results: The median TGR in 164 patients was 17.8% per month (mean 33.3% per month). Regression tree analysis indicated that the top three predictors of TGR were alpha-fetoprotein (AFP) levels (≥ 16.7 ng/mL), platelet counts (≥ 140,000 mm³), and serum albumin level (< 3.55 g/dL). The regression tree identified patient groups with TGRs ranging from 0.65% to 39.4% per month. At a median follow-up of 22 months, the overall recurrence-free survival was 53.8%. The Cox model with backwards AIC search identified TGR (HR = 1.34, P = 0.029), age > 56 years (HR = 1.08, P = 0.072), hepatitis C virus (HR = 1.44, P = 0.091), macrovascular invasion (HR = 1.94, P = 0.092), and the most definitive treatments (orthotopic liver transplantation, HR 0.14, P < 0.001; surgical resection, HR = 0.54, P = 0.072; radiofrequency ablation, HR = 0.58, P = 0.060) as independent predictors of recurrence-free survival. For all treatment modalities, slow TGR was significant for prolonged survival (P = 0.029). The poorest survival rates were observed in patients with fast TGRs treated by transarterial chemoembolization.

Conclusion: The TGR correlated with AFP, platelet count, and albumin level. Patients with fast TGRs had shorter recurrence-free survival after HCC treatments. TGR is a potential imaging biomarker to predict clinical outcomes in HCC.

Hepatocellular carcinoma (HCC) carries an unfavorable prognosis and novel therapeutic strategies are needed. Until now, only few systemic agents have improved survival in patients with advanced stage disease. Immunotherapy changed the landscape in several tumor types by producing unprecedented clinical outcomes with a favorable safety profile. Liver presents a particular immune-suppressive microenvironment and HCC develops in a background of chronic inflammation in the vast majority of cases. In this regard, immunotherapy may be a suitable strategy. Preliminary research focused on therapies involving immune cells and anti-tumor immune response for HCC has shown encouraging preliminary results. Immune checkpoint inhibitors, such the anti-PD-1/PD-L1 monoclonal antibodies, have provided durable responses in patients with advanced stage disease, although the pioneers phase III trials did not confirm survival superiority over the available agents. Cancer vaccines, adoptive cellular therapies and combinations of local modalities with immunotherapy are promising approaches under active research.

Aim: Long-term survival after hepatocellular cancer (HCC) is difficult to achieve likely related to recurrence. This study aimed to identify factors that were predictive of 10-year survival after the diagnosis of HCC.

Methods: In a prospectively collected database of 1374 HCC cases (1993-2019), we identified 70 patients who survived over 10 years regardless of treatment. We then identified 164 patients in the entire cohort who either had liver resection or transplant, and died before 10 years. Demographics, tumor characteristics, treatment, recurrence and treatment of recurrence were compared.

Results: Of the 10-year survivors, 36 underwent transplant, 27 had liver resection and 7 patients had only locoregional therapy. Compared to the non-survivors, the 10-year survivors were younger and had fewer comorbidities or recurrence, smaller tumor size, lower AST, ALT, AFP, platelets, neutrophil-to-lymphocyte ratio. Multivariate analysis showed only age and diabetes to be negative predictors. Recurrence occurred in 24 survivors (34.3%) with mean time to recurrence with standard deviation 57.1 ± 42.6 months compared to 80 non-survivors (48.7%) with mean time to recurrence of 15.3 ± 14.8 months. For hepatic resection, 10-year survivors had longer time to recurrence compared to non-survivors (median: 31.3 months).

Conclusion: Long-term survivors mostly occur after resection or transplant, but 10% of our cohort survived 10 years with only locoregional therapy. Underlying health status maybe an important predictor of 10-year survival for patients receiving liver resections. Recurrence of HCC occurs in both 10-year survivors and non-survivors, but later recurrence with aggressive treatment of the recurrence may allow for 10-year survival.

Aim: To determine the computed tomography (CT) features of non-alcoholic fatty liver disease (NAFLD) associated hepatocellular carcinoma (HCC).

Methods: In this institutional review board approved study, we reviewed 38 patients with NAFLD (68.4% male; mean age 63 years) with histology confirmed HCC and triphasic liver CT. CT images were independently reviewed by four readers blinded to clinical and pathology data. The reviewers assessed HCC for arterial phase hyper enhancement (APHE), portal venous phase washout (PVWO), delayed phase washout (DPWO), and enhancing capsule. Features of cirrhotic morphology and portal hypertension (PH) were also evaluated. The final CT features were determined by majority and a fifth reader reviewed cases lacking majority. Inter-rater agreement was determined by prevalence-adjusted kappa.

Results: Mean HCC size was 3.6 ± 2.8 cm (range, 1.1-16.0 cm). The HCCs showed APHE in 92.1%, PVWO in 55.3%, DPWO in 81.6%, and enhancing capsule in 44.7%. Cirrhotic morphology was present in 65.8% and PH in 63.2%. Inter-rater agreement was moderate to almost perfect for APHE (0.74-1.0), cirrhosis (0.79-0.89), and PH (0.79-0.95), weak to perfect for DPWO (0.47-0.95) and poor for PVWO (0-0.42).

Conclusion: NAFLD associated HCC demonstrate less frequent portal venous washout on CT which may affect their imaging diagnosis.

Alcoholic hepatocellular carcinoma (AHCC) represents a lethal stage, emerging in the course of severe injurious stages of alcoholic liver disease including cirrhosis. AHCC only affects a few alcohol consumers, certainly not all individuals who consume large amounts of alcohol over a long period of time, suggesting a role of yet unknown genetic risk or protection factors. Most likely, hepatic DNA is ultimately involved, attacked by intermediate products derived from reactive oxygen species (ROS) generated from cytochrome P450 2E1 of the NADPH and oxygen dependent microsomal ethanol-oxidizing system whereby ethanol is metabolized. Ethanol and acetaldehyde are activated to procarcinogens, to be promoted to ultimate carcinogens by ROS and causatives for AHCC instead of any other putative chemical contained in alcoholic beverages. Prevention of HCC associated with cirrhosis is best accomplished by early recognition of alcohol abuse at the stage of alcoholic fatty liver rather than alcoholic hepatitis (AH) or alcoholic steatohepatitis (ASH), leading to the advice of consequent abstinence from alcohol. Abstinence early started effectively prevents AHCC development, as opposed to late begin of abstinence that lacks risk reduction. Although drug therapy may partially be effective in AH or ASH, no established drug options are available for a realistic therapy of AHCC. Liver transplantation is controversially discussed and can be considered, but may be an option for only a few patients on a case by case base. In conclusion, AHCC results from a ROS dependent conversion of ethanol and acetaldehyde to procarcinogens as promoters of AHCC.

Hepatocellular carcinoma (HCC) is one of the top-ranking cancers worldwide and in Southeast Asia. The high propensity for tumor recurrence, distant metastasis and chemoresistance remain major hurdles in the treatment of HCC. With advances on genetics and genomics research, molecular targeted therapies are emerging as a hope for better disease control. On the histological perspective, microscopic review of clinical samples has led to subclassification of HCC and establishment of new entities. In this review, latest understanding on macrotrabecular-massive HCC, steatohepatitic HCC, lymphocyte-rich HCC, scirrhous HCC, fibrolamellar carcinoma and combined hepatocellular-cholangiocarcinoma will be discussed, emphasizing on the clinical relevance of these pathological entities. Further delineation of the histological, immunohistochemical, molecular and biological phenotypes of primary liver cancer would to further enhance an integrated morphological-molecular classification that better predicts clinical outcome and guides clinical management.

Non-alcoholic fatty liver disease (NAFLD) and its advanced complication, non-alcoholic steatohepatitis (NASH), have become leading causes of hepatocellular carcinoma (HCC) worldwide. In this review, we discuss the role of metabolic, gut microbial, immune and endocrine mediators which promote the progression of NAFLD to HCC. In particular, this progression involves multiple hits resulting from lipotoxicity, oxidative stress, inhibition of hepatic autophagy and inflammation. Furthermore, dysbiosis in the gut associated with obesity also promotes HCC via induction of proinflammatory cytokines and Toll like receptor signalling as well as altered bile metabolism. Additionally, compromised T-cell function and impaired hepatic hormonal action promote the development of NASH-associated HCC. Lastly, we discuss the current challenges involved in the diagnosis and treatment of NAFLD/NASH-associated HCC.

Along with the changes in our food culture and lifestyle, conditions such as obesity, diabetes mellitus, and metabolic syndrome have been on the rise, and the incidence of nonalcoholic fatty liver disease (NAFLD), which is closely related to these diseases, has also increased rapidly. Despite being a risk factor for the development of hepatocellular carcinoma (HCC), NAFLD has no established screening method, and HCC originating from NAFLD often tends to be discovered in its advanced and symptomatic stages, which has become an important clinical problem. Even though the carcinogenicity rate among the entire population of NAFLD patients is not high compared to that of patients with viral hepatitis, since HCC also often develops from non-cirrhotic livers, it is difficult to narrow down the cases that need to be under surveillance. Going forward, it will be important to clarify the clinical characteristics and genetic background of NAFLD-related HCC and establish not only a useful surveillance method but also preventive methods.

Transcatheter arterial chemoembolization has become an established drug delivery system for palliative or bridging treatment of hepatocellular carcinoma. Over the last two decades, various research and developments have taken place to improve the transcatheter arterial chemoembolization procedure from both a clinical and a technical perspective. This review article aims to provide an update on the technical developments over the last decade.