Mutations in MPV17 lead to severe mitochondrial DNA depletion syndrome (MTDPS). All known p.R50W variants in MPV17 are lethal. The homozygous variant p.R50Q in MPV17 among patients with Navajo neurohepatopathy is known to allow longer survival, although heterozygous variants p.R50Q have not been reported. This is the first clinical report in compound heterozygosity MPV17 mutation (p.R50W/p.R50Q). Three siblings were admitted due to multiple hepatic nodules; none presented neurological abnormalities. However, they suffered from severe hypoglycemia and cyclic vomiting. The diagnosis of MPV17-related MTDPS was confirmed by detection of a compound heterozygous MPV17 mutation (p.R50W/p.R50Q), and striking reduction of hepatic mitochondrial DNA. One patient developed pediatric-onset of hepatocellular carcinoma. Notably, all patients survived for extended periods, including two patients who received liver transplantation, which contrasted the high mortality rate associated with p.R50W mutations, as previously reported. The p.R50Q mutation might be associated with longer survival and improved liver transplantation outcomes.

Aim: We aimed to further investigate the role of hepcortespenlisimut-L (Hepko-V5 or V5), a new oral immunotherapy developed by us, for hepatocellular carcinoma (HCC) indication.

Methods: The interim data from ongoing Phase III placebo-controlled, randomized trial were evaluated on the initial group of patients in advanced stage of HCC with emphasis on liver function and tumor marker alpha-fetoprotein levels. Additionally, an in vitro study was undertaken to elucidate the mechanism of action of V5 by measuring with flow cytometry the expression of cytokines such as IL-2, INF-γ, and TNF-α and cell activation markers CD69 and Ki67 on CD4- and CD8-positive lymphocytes isolated from peripheral blood of healthy volunteers.

Results: As early as one month after treatment initiation, there was a clear improvement in alanine transaminase, aspartate transaminase, alkaline phosphatase, and bilirubin levels among HCC patients who received daily dose of V5, but not in the placebo group. Additionally, alpha-fetoprotein (AFP) levels among V5 recipients decreased, while in the placebo group they rose. Clinical results are in line with in vitro observations indicating immune activation, as evidenced by many-fold enhancement of CD69, Ki67, and INF-γ expression and at the same time marked anti-inflammatory effect resulting in 10-fold decrease in TNF-α output and lack of influence on IL-2 production.

Conclusion: Hepcortespenlisimut-L, a tableted oral formulation derived from heat-inactivated pooled blood of patients with HCC and viral hepatitis shows beneficial clinical effect, as demonstrated by improvement in liver function and reduction of tumor marker AFP levels. These correlate with in vitro observations showing potent activation of the immune response and pronounced oral tolerance effect.

Aim: Patients with chronic hepatitis C virus (HCV) infection who develop hepatocellular carcinoma (HCC) soon after treatment with direct antiviral agents (DAA) may have been harboring hitherto hidden tumors. If this were true, they should have a lower sustained viral response (SVR) rate, since active HCC hampers DAA efficacy. We aimed to verify this hypothesis.

Methods: We included all patients who attended an HCV clinic, provided that they: (1) had no previous history of HCC; (2) had received at least one DAA dose; and (3) had been followed-up clinically and ultrasonographically for at least six months after concluding DAA.

Results: The study population included n = 789 patients (55% males, median age 62 years). A median of 9.3 months (8.8-11.9) after concluding DAA, n = 19 (2.4%) patients were discovered to harbor HCC. In comparison to all others, patients with HCC were more commonly male (84% vs. 54%, P = 0.009), obese (47% vs. 17%, P = 0.002), and cirrhotic (95% vs. 35%, P < 0.001) and had less commonly achieved an SVR (68% vs. 98%, P < 0.001). Moreover, they had a trend for being less commonly treatment naïve (58% vs. 67%, P = 0.051). Based on multivariate analysis, the independent predictors of HCC were male sex (P = 0.031), cirrhosis (P = 0.004), obesity (P = 0.006), and failure to achieve an SVR (P < 0.001).

Conclusion: Lack of achieving SVR is a strong independent predictor of development of HCC early after treatment of hepatitis C with DAA. Treatment failure should further alert clinicians to the possibility of this dreadful complication.

As the world population is continuously aging, the number of older patients requiring liver surgery is also on the rise. Data have shown that age should not be a limiting factor for liver resection, as it cannot accurately predict postoperative outcomes. Instead, frailty can serve as a more reliable measure of the patient’s overall health and functional reserves. Several frailty assessment tools have been implemented for preoperative risk stratification before liver surgery, and higher scores have commonly been associated with postoperative morbidity, mortality, and length of hospital stay. However, no consensus has been reached on the most useful screening tool. Future studies should focus on comparing the currently available assessment tools, constructing a liver resection-specific tool, and assessing the role of frailty assessment tools in preoperative patient optimization.

Currently, alcoholic liver disease (ALD) is one of the most prevalent chronic liver diseases worldwide, representing one of the main etiologies of cirrhosis and hepatocellular carcinoma (HCC). Although we do not know the exact mechanisms by which only a selected group of patients with ALD progress to the final stage of HCC, the role of the gut microbiota within the progression to HCC has been intensively studied in recent years. To date, we know that alcohol-induced gut dysbiosis is an important feature of ALD with important repercussions on the severity of this disease. In essence, an increased metabolism of ethanol in the gut induced by an excessive alcohol consumption promotes gut dysfunction and bacterial overgrowth, setting a leaky gut. This causes the translocation of bacteria, endotoxins, and ethanol metabolites across the enterohepatic circulation reaching the liver, where the recognition of the pathogen-associated molecular patterns via specific Toll-like receptors of liver cells will induce the activation of the nuclear factor kappa-B pathway, which releases pro-inflammatory cytokines and chemokines. In addition, the mitogenic activity of hepatocytes will be promoted and cellular apoptosis will be inhibited, resulting in the development of HCC. In this context, it is not surprising that microbiota-regulating drugs have proven effectiveness in prolonging the overall survival of patients with HCC, making attractive the implementation of these drugs as co-adjuvant for HCC treatment.

Coffee, a popular drink around the world, is composed of a complex mix of biologically active molecules, including caffeine, chlorogenic acid, and diterpenes. These compounds have antioxidant, anti-inflammatory, antifibrotic, and anticarcinogenic properties, which may explain observational data showing that coffee drinkers have lower rates of chronic liver disease, including cirrhosis and hepatocellular carcinoma (HCC). Recent studies have also shown that coffee consumption may also increase patient survival before and after liver transplantation. The mechanism by which coffee consumption protects against HCC is not clear; however, its relevant role has been demonstrated. This literature review article focuses on the role of coffee consumption in protecting against the development of HCC. Methodology: Scientific articles indexed through PubMed, including Medline, Scielo, and Lilacs, published in English were used as search methods. The terms used in English were: “hepatocellular carcinoma” or “Liver cancer” or “HCC” and “coffee”. According to the study design or review article, cross-sectional, longitudinal, or descriptive investigations were included, showing site and year of publication until 2019.

Hepatocellular carcinoma (HCC) is a major and increasing cause of clinical and economic burden worldwide. Now that there are effective therapies to control or eradicate viral aetiologies, the landscape of HCC is changing with alcoholic and metabolic liver diseases becoming major catalysts. The pathogenesis of HCC is complex and incompletely understood, hampering improvements in therapy. Animal models are essential tools for advancing study on the cellular and molecular processes in HCC and for screening potential novel therapies. Many models of hepatocarcinogenesis have been established using various methods including genetic engineering, chemotoxic agents and dietary manipulation to direct implantation of tumour cells. However, none of these can accurately replicate all features found in human diseases. In this review, we provide an overview of different mouse models of HCC with a particular focus on cancer arising from alcoholic liver disease, non-alcoholic fatty liver disease and hereditary haemochromatosis. We also highlight their strengths and limitations and provide perspectives for future study.

Hepatocellular carcinoma (HCC) is a significant global health problem with high morbidity and mortality. Its incidence is increasing exponentially worldwide with a close overlap between annual incidence and death rates. Even though significant advances have been made in HCC treatment, fewer than 20% of patients with HCC are suitable for potentially curative treatment. Hereditary hemochromatosis (HH) is an important genetic risk factor for HCC. HH is an autosomal recessive disorder of iron metabolism, characterised by elevated iron deposition in most organs including the liver, leading to progressive organ dysfunction. HCC is a complication of HH, nearly always occurring in patients with cirrhosis and contributes to increased mortality rates. Identifying the susceptibility of development of HCC in HH patients has gained much traction. This review summarises the current knowledge with regard to the association of HH and HCC in order to encourage further research. In this review, we focus particularly on HFE gene-related HH. Herein, we highlight and discuss emerging clinical research which addresses the prevalence of HCC in HH patients and the coincidence of HH with other risk factors for HCC development. We also focus on the therapeutic tools in the management of HCC associated with HH.

Direct-acting antivirals (DAAs) have been introduced for the treatment of hepatitis C virus, and the sustained virological response rate after DAAs was reported to be over 95%. Because of the high sustained virological response rate, the risk of hepatocellular carcinoma (HCC) was expected to be reduced. However, an unexpected high risk of HCC recurrence after DAA treatment was reported, and thus the dispute about the association of DAA and HCC arose. The present article reviews the interplay between DAAs and HCC.

Aim: To evaluate wether it is safe and meaningful to treat octogenarians with microwave ablation for hepatocellular carcinoma. With an ageing population being healthier than previous generations, old limits for treating disease founded on patient age need to be revised. One of the most common tumour related death causes is hepatocellular carcinoma (HCC). With the development of minimally invasive therapies with curative potential, new ground is being broken offering treatments to older patients in the hope of achieving prolongation and better quality of life.

Methods: In this retrospective single centre study of patients having a first microwave ablation therapy for HCC in a national referral centre for ablative liver treatments, septuagenarians (n = 161, age 70-80) were compared with octogenarians (n = 32, age 80-90).

Results: Octogenarians selected for microwave ablation of HCC at a regional multidisciplinary team conference have similar outcomes as their younger control group. Survival, complications and length of stay are not different.

Conclusion: Octogenarians who are fit for ablative treatment of HCC should not be disqualified on grounds of age, recognising that this group has an obvious immortality, or lead-time, bias as well as a probable selection bias in part explaining their good results.

Aim: We aimed to study the clinical and pathological characteristics of liver transplant recipients with hepatocellular carcinoma recurrence.

Methods: We reviewed the data for 26 patients who had tumor recurrence after deceased donor liver transplant for hepatocellular carcinoma at the Johns Hopkins Hospital from January 2005 to December 2015.

Results: In total, 88% of recipients were males. The mean age was 59 years. On explant, poor differentiation was detected in 43%, while 73% had microvascular invasion. Overall, 62% were diagnosed to be outside of Milan criteria. Out of these, 15% met the criteria for downstaging. Twenty (77%) patients had pre-transplant alpha fetoprotein levels ≥ 20 ng/mL. In 54% of patients, the location of hepatocellular carcinoma (HCC) recurrence was extrahepatic, followed by intrahepatic in 31% and both intra- and extrahepatic in 15%. The post-transplant tumor recurrence was diagnosed at a mean of 427 days (range 34-1502). Fifty percent of HCC recurrences were diagnosed within one year following liver transplant. Twenty (77%) patients received treatment for their recurrent HCC: external radiation (n = 10), surgical resections (n = 8; brain 4, spine 2, bone 1, and Whipple surgery 1), sorafenib (n = 7), locoregional therapy (n = 5). Overall, 24 out of 26 (92%) recipients died within four years after the transplant.

Conclusion: HCC recurrence after liver transplant is infrequent. More than fifty percent of HCC recurrences following liver transplant are extrahepatic. Despite better recipient selection for liver transplant, the curative options are limited in recurrent cases and associated with extremely poor outcomes.

Aim: The aim of the present study was to evaluate the characteristics of the magnetic resonance imaging features of hepatocellular carcinoma (HCC) that developed early after the eradication of hepatitis C virus (HCV) by direct-acting antiviral (DAA) treatment.

Methods: This study included 26 patients who achieved sustained viral response with DAA and developed HCC thereafter within one year (DAA-SVR HCC). The radiologic characteristics of these patients were evaluated by contrast-enhanced magnetic resonance imaging, including diffusion-weighted imaging (DWI) and T2-weighted imaging (T2WI). For comparison, 80 HCC patients with positive HCV RNA (HCV-positive HCC) were included. Among 42 patients where tumor biopsy was available, histological grade and radiologic findings were compared.

Results: The rates of high intensity on DWI and T2WI were significantly higher in DAA-SVR HCC compared to HCV-positive HCC (DWI: 100% vs. 67.5%, P < 0.001; T2WI: 92.6% vs. 67.5%, P = 0.01). HCC with high intensity on DWI or T2WI was more likely to have moderately or poorly differentiated HCC compared to well-differentiated HCC (DWI: 69.7% vs. 30.3%, P = 0.02; T2WI: 66.7% vs. 27.3%, P = 0.03).

Conclusion: High intensity on DWI and hyperintensity on T2WI were distinctive features of HCC that developed within one year after the end of DAA treatment.

Ageing population of first world economies pose unique challenges to surgical community. Enhanced recovery after surgery protocols and pathways do not attempt to optimize or enhance physical function of patients by customized program of physical activity. Increasingly, prehabilitation programs (PP) have gained momentum in orthopaedics, urology, colorectal surgery and hepatopancreaticobiliary surgery. Current evidence of PP in various elective surgical procedures have shown improved outcomes with minimal to none drawback or harm. There is emerging evidence of role of PP in elective liver resection. The aim of this paper is to review the basis of PP and share local multidisciplinary team protocol specifically customized to frail and elderly population - Recovery Of Surgery in Elderly.

Cancer is a major cause of death worldwide. Hepatocellular carcinoma (HCC) is one of the malignancies with the highest mortality-to-incidence ratio (> 0.9), and in some countries this value is up to 1. Unfortunately, many patients are diagnosed at advanced stages of the disease. Therefore, HCC early markers, as well as novel therapeutic approaches, are urgently needed. HCC is the main type of liver cancer and it is associated with different factors including alcohol use, viral infections, and fatty liver disease. A significant percentage of HCC patients previously had liver cirrhosis. Several ion channels have been proposed as novel potential markers and therapeutic targets for diverse cancers including HCC. Here, we review most of the findings associating ion channel expression with HCC and its etiological factors, as well as some possible pro-tumorigenic mechanisms of action for ion channels in HCC. Novel therapies for HCC treatment and prevention are also discussed. Ion channel targeting offers a plethora of opportunities for HCC prevention, early diagnosis, and therapy that may help to reduce the extremely high mortality-to-incidence ratio of this malignancy.

Hepatocellular carcinoma (HCC) is one of the most common solid tumors with poor clinical prognosis. Novel therapeutic regimens are urgently required for patients with advanced HCC. Both pre-clinical and clinical studies suggest immunotherapy as an attractive alternative for advanced HCC treatment. Natural killer (NK) cells and CD8⁺ T cells are the most important cytotoxic immune cells involved in cancer treatment and elimination. Reinvigorating the anticancer activity of NK and CD8⁺ T cells is the fundamental guarantee for the success of immunotherapy in advanced HCC treatment. Therefore, in this review, we aim to summarize the characteristics and roles of NK and CD8⁺ T cells in HCC development, describe the frontiers of immunotherapy for advanced HCC based on immune checkpoint inhibitors and adoptive cell transfer, and discuss their limitations and scope for future improvement.

Aim: Despite the high cure rate of interferon-free directly acting antivirals (DAAs) for chronic hepatitis C (CHC) patients, the treatment efficacy for patients with preexisting hepatocellular carcinoma (HCC) remains undefined. We aimed in the present study to address the issue by using novel DAAs in treating CHC patients who were adherent to treatment in Taiwan.

Methods: CHC patients with or without HCC were consecutively enrolled. The primary objective was sustained virological response (SVR) defined as undetectable HCV RNA throughout 12 weeks of a post-treatment follow-up period (SVR12). Only patients with available SVR12 were enrolled for final analysis.

Results: A total of 1237 patients (1113 non-HCC, 101 inactive HCC and 23 active HCC) were enrolled. The overall SVR12 rate was 98.9%, and was similar between HCV patients with and without pre-existing HCC (98.4% vs. 98.9%, P = 0.64). While HCC patients were classified as those who had active or inactive HCC, the SVR12 was also similar between patients with and without active HCC (95.7% vs. 99.0%, P = 0.34). Among the 101 patients without viable HCC at the time of DAA initiation, eighty-four patients exhibited curative therapy and the other 17 patients experienced HCC recurrence before DAAs. Among the 23 patients with viable HCC at the time of DAA treatment, 10 patients had received curative therapy for HCC whereas the remaining 13 patients had HCC that was never cured. The SVR12 rates were also similar among the four subpopulations, being 98.8% (83/84), 100% (17/17), 90% (9/10) and 100% (13/13) respectively.

Conclusion: CHC patients with HCC who were adherent to potent DAAs achieved similar SVR12 rate compared to those without HCC and could be effectively treated.

The estimated number of people with active hepatitis C virus infection worldwide is about 70 million. The estimated number of people with active hepatitis C virus infection worldwide is about 70 million. Approximately 30% of infected individuals develop cirrhosis, whilst some develop liver cancer, the fifth most common cancer worldwide. Currently available treatments, high-efficacy antiviral agents mostly short-term (8-12 weeks) and pangenotypic, have efficacy rates of over 96%. Some patients, especially those with cirrhosis, develop primary liver cancer even after effective hepatitis C virus treatment. In order to diagnose hepatocellular carcinoma early, patients at risk should be enrolled in a surveillance program.

Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of liver disease worldwide, and represents an increasingly important cause of hepatocellular carcinoma (HCC). As the prevalence of NAFLD has increased, the burden of NAFLD-related HCC has been rising in parallel. This is particularly evident in Western countries, where NAFLD is estimated to account for 10%-59% of all HCC. NAFLD-related HCC can occur in the presence or absence of cirrhosis, and, while those with cirrhosis remain at the greatest risk, factors such as steatohepatitis, age, genetic polymorphisms, type 2 diabetes mellitus and obesity also appear have an impact on the risk of developing HCC in NAFLD. In this review, we present the epidemiology of NAFLD-related HCC from a Western perspective, highlighting gaps in current knowledge and future directions for research in this field.

The Liver Imaging Reporting and Data System (LI-RADS) provides a stepwise algorithmic approach that is proven to be highly accurate in diagnosing hepatocellular carcinoma (HCC) in patients at risk. An essential and early step in the algorithm is the diagnosis of malignancies other than HCC, such as cholangiocarcinoma and combined tumors, by application of LR-M features and criteria. The LR-M category captures most non-HCC malignancies and some atypical HCCs. The exclusion of non-HCC malignancies is important for maintaining the high specificity of the LR-5, definite HCC category. This review provides an overview of the approach to diagnosing non-HCC malignancies using LI-RADS CT/MRI and contrast enhanced ultrasound algorithms.

Hepatocellular carcinoma (HCC) is the most common cancer associated with chronic liver disease and cirrhosis. The most common cause of HCC is chronic hepatitis C virus infection and many studies in Europe, Asia and North America have focused on its etiology, epidemiology, diagnostic tools, and therapeutic options. However, little is known about these issues in Latin America. The aim of this review is to address these aspects of HCC in Latin America. The main risk factors associated with developing HCC in this region are: age, concomitant cirrhosis, hepatitis C infection, obesity and hereditary disease such as hemochromatosis. On the other hand, screening tests and diagnostic methods of HCC are mostly serum alpha fetoprotein quantification, liver ultrasound, computed tomography, magnetic resonance, and histopathology. Novel diagnostic methods include gut microbiota analysis and the use of nanotechnology and they continue to be tested. Finally, according to the Barcelona Clinic Liver Cancer, curative treatments used in HCC patients are mainly liver resection, liver transplantation, and local ablation, each with advantages and disadvantages. In conclusion, clear strategies are urgently needed to understand the extent of HCC and related problems in this part of the world. This review provides greater knowledge of HCC for the proper design of preventive programs by taking into consideration specific characteristics of our population. Also, this review allows for an understanding of individualizing treatments according to the patient’s needs.

The increased incidence of hepatocellular carcinoma (HCC) in the last several decades in the United States and worldwide has partly resulted from an increase in hepatitis C virus (HCV) infection. HCV carcinogenesis is speculated to be indirectly related to multiple steps from inflammation to fibrosis and advanced fibrosis/cirrhosis over 20 or more years. However, the direct carcinogenic potential from HCV may explain HCC occurring in non-cirrhotic HCV patients. Highly potent direct-acting antivirals (DAAs) in recent years have changed hepatitis C treatment significantly and have resulted in the sustained virologic response (SVR) rate exceeding 90%. Although initial reports concerned the increase in de novo and recurrent HCC associated with DAAs, more recent studies showed that DAA-induced SVR on the contrary reduced risk of HCV-associated HCC without increasing its recurrence. The International Consortium of Hepatitis C Therapeutic Registry and Research Network (HCV-TARGET) database and other resources of HCV patients treated with DAA collectively in the near future most likely will be able to show definitive evidence on the risk of HCC occurrence and recurrence after DAA with SVR. The long-term risk of HCC in chronic hepatitis C patients with advanced fibrosis or cirrhosis remains high after DAAs with SVR. Thus, HCC surveillance on this sub-group of patients is important for early detection and intervention of HCC.

Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the second leading cause of cancer-related death. Hepatitis C virus and mainly hepatitis C virus-related cirrhosis is the chief risk factor for HCC. Many direct-acting antivirals are available for the eradication of hepatitis C virus with remarkable results in terms of virological response and with optimal safety profile. Notably, some authors have suggested that viral eradication due to these new drugs might favor both occurrence and recurrence of HCC. The exact biological mechanisms of carcinogenesis in this specific setting have not been well identified, but it has been suggested that adjustments in immune surveillance and increase in vascular endothelial growth factor expression could have a chief role. Remarkably, after publication of many large studies and meta-analyses, we can affirm that there is no increased risk on a population basis. Nonetheless, on an individual basis, sustained virological response due to direct-acting antivirals may facilitate HCC onset in some specific subgroups of patients. Among them, we could point out patients with activated neoangiogenesis but also subjects with particularly severe metabolic imbalance.

Hepatocellular carcinoma (HCC) is a deadly malignancy which typically occurs in the context of chronic liver inflammation. Chronic hepatitis B virus (HBV) infection is considered a major global cause of HCC development. At the moment, liver transplantation is the only curative modality for HBV-associated HCC. However, some patients develop HBV-HCC recurrence after liver transplantation, leaving them with very limited therapeutic options. Adoptive cell therapy with HBV-specific T cell receptor (TCR) that redirects T cells against HCC relapses has shown promising results in such HBV-HCC patients. In this mini-review, we discuss the application of this personalized T cell therapy, and highlight mRNA electroporation as an efficient tool for engineering safe and efficient TCR-redirected T cells for the treatment of liver transplant patients with HBV-HCC metastasis.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the liver, with poor prognosis and high mortality. Traditional treatments for patients with HCC have shown poor efficacy especially for advanced liver cancer. Compared with other organs, the liver has more natural immune cells such as Kupffer cells, natural killer cells and natural killer T cells. Immunotherapy for liver cancer has become the focus in current research. The theoretical basis of immunotherapy rests on immune tolerance and suppression in the tumor microenvironment. Common immunotherapy methods include vaccines, cytokines, adoptive cell therapies, immune checkpoint inhibitors, and oncolytic viruses. Compared with traditional treatment, immunotherapy can enhance the body’s immune function, delay tumor progression, and prolong survival. This article reviews the HCC microenvironment and immunotherapy both in the clinical and basic research aspects.

Most patients diagnosed with hepatocellular carcinoma (HCC) present with advanced or metastatic disease. The lack of therapeutic options in the treatment of advanced HCC accounts for its high mortality and recurrence rate. HCC is known as an immunogenic tumor, which develops in chronically inflamed livers. Anti-PD-1/PD-L1 antibodies (immune checkpoint inhibitors, ICB) were approved by the FDA to treat advanced HCC in patients previously treated with sorafenib as a second line. This has opened up a new era of anticancer treatment, although the response rate of HCC to anti-PD-1/PD-L1 antibodies is only around 20%. Other than ICB treatment, adoptive cell transfer, dendritic cell-based vaccines and oncolytic therapy are currently under clinical trials. In this review, different immunotherapy approaches for HCC is presented. Current knowledge on the mechanisms of action for each approach is discussed and relevant, ongoing clinical trials are presented. We also discuss the future of immunotherapy and combination treatment for HCC patients.

The recurrence rate after primary resection for hepatocellular carcinoma (HCC) has been reported to be up to 80%. There is no consensus or guideline about the best treatment option for such recurrent HCC (rHCC). It is therefore of paramount importance to select patients for suitable treatment due to the high risk of associated morbidity and mortality. In this paper, we review the literature on treatment for rHCC and propose a strategy based on the best evidence available. Even in rHCC, it is still possible to achieve cure and good survival rates through careful patient selection. Repeat hepatectomy is recognized as a feasible and safe procedure even in cirrhotic patients and should be considered as the best option with curative intent when the patient is fit enough. Greater adoption of minimally-invasive liver surgery could have the potential to increase the number of candidate patients with rHCC for repeat resection in the next few years. Liver transplantation offers longer disease-free survival compared to repeat resection, curing the underlying cirrhosis, but is not widely available due to organ shortage. When surgery is not feasible, locoregional treatments such as radiofrequency ablation and transarterial chemoembolization have an important role for patients who cannot tolerate repeat hepatectomy and are not suitable for transplantation. For advanced cases, systemic therapy could be considered.

Hepatitis B virus (HBV) infection remains the most important risk factor for hepatocellular carcinoma (HCC) worldwide and nonalcoholic fatty liver disease (NAFLD) has developed as major etiology of chronic liver diseases, cirrhosis and eventually HCC in the last decades. Although nucleos(t)ide analogs are recommended as the first-line drug for patients with chronic hepatitis B, incomplete eradication of HBV serves as an obstacle for effective cure of chronic hepatitis B and even HCC. NAFLD refers to a spectrum of hepatic metabolic disorders, compromised with multi-system diseases. Considering the specificity of hepatocytes and enrichment of immune cells in liver, this review aims to summarize the mechanisms of direct pro-tumorigenesis to hepatocytes induced by HBV infection and abnormal lipid metabolism, and indirect oncogenic processes mediated by immune cells. We also discuss similarities and differences of immune cells between HBV- and NAFLD-HCC and finally focus on the novel immunotherapies concerning preclinical and clinical studies for liver cancer.

The COVID-19 pandemic has led to the greatest worldwide health crisis in decades. The number of infected patients with severe SARS-CoV-2 (COVID-19) disease has overwhelmed the capacity of almost all health care systems around world. Hypoalbuminemia has now been reported in patients with severe disease seeking help in the emergency room because of COVID-19 infection. In the past, hypoalbuminemia was considered to be a negative prognostic marker, not only in patients with chronic liver disease, but also in patients with SARS and MERS infections. Albumin is the major serum protein synthesized by the liver. A low serum albumin level is an ominous clinical sign. Introduction of amino acids to a patient’s diet is of fundamental importance to hepatic albumin synthesis in different clinical situations. This highlights the importance of nutritional support during the early phases of COVID-19-infection. Furthermore, albumin synthesis in the hepatocyte is downregulated at a pretranslational level by the direct interaction of the major acute-phase cytokines which are released into the circulation during the cytokine “storm” induced by the viral effects on the lungs. Both mechanisms contribute to severe hypoalbuminemia which, combined with massive fluid losses due to the fever, is responsible for severe hypovolemia and shock commonly observed in patients with COVID-19 in critical care settings.

Nonalcoholic fatty liver disease and its evolutive form nonalcoholic steatohepatitis (NASH) are nowadays the second/third cause of chronic liver disease worldwide, and their prevalence and incidence are rapidly increasing in parallel to the burden of diabetes and obesity. Hepatocellular carcinoma (HCC) due to NASH (HCC-NASH) has become the major cause of HCC and is now one of the major indications for liver transplant in Western countries, after that due to HCV infection. NASH occurs both in the presence and absence of liver cirrhosis. In this review, we describe the epidemiology of HCC related to metabolic liver disease: not only NASH-HCC but also type 2 diabetes mellitus and obesity-related HCC. Some new practical guidelines for screening and surveillance of patients with metabolic diseases at risk for HCC are also discussed.

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver with a high mortality rate. Heterogeneity is the main biological characteristic of HCC, which manifests through the different biological behaviors of each phenotype and ultimately, affects patient prognosis and treatment efficacy. Various aggressive biological behaviors are considered to be associated with the poor prognosis of HCC patients including poor differentiation, microvascular invasion, intracellular fat accumulation, invasive growth, bile duct invasion or tumor thrombosis, and tumor spread and metastasis, and have been reported as prognostic biomarkers. In addition, HCC results from multifactor synergistic damage, and various factors related to genetics, molecular pathology and immunohistochemistry such as β-catenin, Ki67, cytokeratin-19, and epithelial cell adhesion molecule have an impact on HCC differentiation and prognosis. This article is an overview of the biological behaviors that lead to poor prognosis of HCC, and the roles of morphological and quantitative noninvasive imaging biomarkers in the evaluation and prediction of these behaviors. Some common biomarkers related to genetics, molecular pathology and immunohistochemistry are also briefly summarized. It is hoped that this review will provide clinicians and radiologists with an update on the development of liver imaging, and provide directions for the combination of radiology, genetics, molecular pathology and histopathology to better predict the prognosis of HCC patients.

Hepatitis C Virus (HCV) infection constitutes a significant burden to world health, leading to liver cirrhosis and hepatocellular carcinoma (HCC). In the past decades, pegylated interferon combined with ribavirin has been used extensively for HCV treatment, and interferon (IFN) is thought to have antitumor property. Direct-acting antivirals (DAAs) have fundamentally changed HCV therapy, due to their high efficacy and tolerability. However, recent studies have reported relatively high rates of HCC occurrence, and recurrence, following successful HCV treatment using DAAs. These studies were grossly underpowered due to their retrospective design, lack of untreated or IFN controls, small sample size, and limited patient follow-up time. From then, many retrospective and prospective cohort studies with larger size and longer follow-up duration after DAAs therapy have been published. These studies showed that treatment with DAAs can reduce the risk of HCC compared to no treatment, didn’t increase the risk of HCC compared to IFN-based therapy after adjusting for the potential confounders of these two groups, and DAAs-induced sustained virological response decreased the risk of HCC compared to DAAs treatment failure. In conclusion, DAAs treatment doesn’t appear to increase the development of HCC, even in cirrhotic patients. However, cirrhotic patients should be monitored for the development of HCC during and after DAAs treatment.

Post-hepatectomy liver failure (PHLF) is associated with great morbidity and mortality after resection of hepatocellular carcinoma. Previous studies have underlined that advanced age could be a potential factor influencing post-operative complications and long-term survival.

In the past, candidates for resection were based on the Child-Pugh classification, the predictive value of which was rather low. The selection of patients undergoing resection in Western countries is based on the assessment of portal hypertension (PH), which is clinically assessed by measurement of the hepatic venous pressure gradient, an invasive and costly process. Thus, there have been several attempts to identify the best non-invasive test (NIT) to accurately predict PHLF. Most biochemical NITs for the prediction of PHLF are focused on evaluation of underlying liver cirrhosis and PH. Amongst them, FIB-4, which also includes the patient’s age, seems to have more robust supporting results. In Europe and the USA., the most tested and reliable NIT for predicting PHLF is the evaluation of liver stiffness measurement, which is also influenced by age. Imaging parameters are promising tools which are used only in specialized centers however, and when available. Liver volume parameters, as well as contrast-enhanced data, demonstrate good accuracy in predicting PHLF. In this scenario, the evaluation of sarcopenia and bone mineral density through contextual imaging allows the delineation of PHLF in at-risk elderly patients. Further studies focused on parameters for the evaluation of PHLF in elderly patients are needed.

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm worldwide. Recurrence of HCC after resection or loco-regional therapies represents an important clinical issue as it affects up to 70% of patients. This can be divided into early or late, if it occurs within or after 24 months after treatment, respectively. While the predictive factors for early recurrence are mainly related to tumour biology (local invasion and intrahepatic metastases), late recurrences are mainly related to de novo tumour formation. Thus, it is important to recognize these factors prior to any treatment in each patient, in order to optimize the treatment strategy and follow-up after treatment. The aim of this review is to summarize the current evidence available regarding predictive factors for the recurrence of HCC, according to the different therapeutic strategies available. In particular, we will discuss the role of new ultrasound-based techniques and biological features, such as tumor-related and circulating biomarkers, in predicting HCC recurrence. Recent advances in imaging-related parameters in computed-tomography scans and magnetic resonance imaging will also be discussed.

Aim: This study aimed to compare mini-invasive liver resection (MILR) (laparoscopic/robotic approach) and open liver resection (OLR) for hepatocellular carcinoma (HCC) in elderly patients with regard to clinical and oncological outcomes through a comprehensive systematic review.

Methods: The MEDLINE and Cochrane Library electronic databases were systematically searched from 2009 to December 2019 to identify relevant English written studies comparing MILR and OLR. The main endpoints were Child-Pugh score, serum total bilirubin level, comorbidity, presence/absence of cirrhosis, minor/major resection, challenge segment approach, operative time, estimated intraoperative blood loss, liver failure rate, morbidity according to the Clavien-Dindo classification, length of hospital stay (LOS), postoperative mortality, number of lesions, tumor size, readmission rate, recurrence rate and survival at 1, 3 and 5 years after operation. Meta-analyses provided pooled relative risks and mean differences for these outcomes. Cut-off for “elderly age” was set at 65 years old.

Results: Eight studies that evaluated 3051 patients who underwent liver resection for HCC, with 950 undergoing MILR and 2101 OLR, were included after the screening process. Blood loss, morbidity, and LOS showed statistical significance in favor of MILR. In particular, with respect to OLR, MILR decreased on average blood loss by 161.43 mL (95%CI: 250.24-72.61), risk of morbidity by 42% (P < 0.01), LOS by 4 days (95%CI: 7-2), postoperative mortality risk by 47% (although not significantly, P = 0.06). Major resections were significantly more common in the OLR group (P < 0.0001). Recurrence, although not significant (P = 0.06), must also be emphasized. The two surgical approaches were comparable with regard to the other outcomes investigated.

Conclusion: Meta-analyses confirmed the advantages of MILR in terms of short perioperative outcomes, where it may promote the extension of liver resection to HCC patients with borderline liver function. MILR may be considered an important treatment option with significant benefits in the elderly and fragile patients. However, large well-designed prospective comparative studies or randomized controlled trials would be necessary to further confirm our conclusions.

Worldwide, nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions and in parallel, hepatocellular carcinoma (HCC) has become one of the fastest growing cancers. Epidemiological studies have not only shed light on the prevalence and incidence of the disease but have also unmasked important environmental risk factors, including the role of diabetes and dyslipidemia in disease pathogenesis. Genetic association studies have identified single nucleotide polymorphisms implicated in NAFLD-HCC, many of which are part of lipid metabolism pathways. Through these clinical studies and subsequently, translational and basic research, the role of statins as a chemoprotective agent has also emerged with ongoing clinical trials assessing their utility in HCC prevention and treatment. In this review, we summarize the recent epidemiological studies describing the burden of NAFLD-HCC in different patient populations and countries. We discuss the genetic and environmental risk factors for NAFLD-HCC and highlight the chemoprotective role of statins and aspirin. We also summarize what is known about NAFLD-HCC in the cirrhosis and non-cirrhosis populations and briefly address the role of surveillance in NAFLD-HCC patients.

Liver cancer is the second leading cause of cancer deaths in men worldwide, and the 6th and 7th cause of cancer deaths in men and women in developed countries. 70%-90% of primary liver cancer is hepatocellular carcinoma. Hepatitis B or C viruses and chronic inflammation due to alcohol intake are the main risk factors for hepatocellular carcinoma. One of the key approaches for the early detection of hepatocellular carcinoma is to understand the specific imaging findings of liver nodules in the multi-step hepatocrcinogenesis process. In this article, we review the imaging findings of multistep hepatocarcinogenesis, with a focus on the early detection of malignant, cirrhotic nodules with CT and MRI.

Portal vein thrombosis (PVT) is a common complication after splenectomy, causing a possible negative impact on the prognosis of patients with liver cirrhosis. However, the risk factors of PVT are not completely clear. Many factors are related to the occurrence of postoperative PVT, such as hemodynamic changes, splenomegaly, splenectomy, coagulation and anticoagulation disorder, liver cirrhosis, platelet count, D-dimer level, infection, inflammation, and other factors.Hemodynamic changes are mainly caused by thicker portal and splenic vein diameters, larger spleen, slower portal vein blood flow rate, lower portal vein pressure before and after surgery, etc. It is timely detection and advanced prevention that really matter in reducing PVT incidence and improving patient prognosis. We systematically reviewed the researches on the risk factors and therapies of PVT to provide useful information on a comprehensive understanding for researchers.

Immunotherapy is revolutionizing the clinical management of cancer patients by modulating T cells and natural killer cells. Dendritic cells (DCs) have the capacity to orchestrate the expansion and function of these effector cells both in lymphoid and non-lymphoid tissues of cancer patients. Distinct subtypes of DCs have various capacities to prime and activate different T cell responses. Here, we review conventional type 1 dendritic cells (cDC1s) and their crucial role in protective anti-tumor immunity. Targeting cDC1s as a cancer vaccine against the development of hepatocellular carcinoma will be discussed.

Hepatocellular carcinoma (HCC) is a common malignant tumor in China. After years of efforts, there has been great progress in the management of liver cancer, but overall, it is still not ideal. At present, there are many therapies for liver cancer, including surgical resection, transcatheter arterial chemoembolization (TACE), ablation, molecular targeted therapy, stereotactic body radiation therapy, chemotherapy, immunotherapy, and so on. Studies have reported that TACE combined with radiotherapy can shrink the tumor, and some of the remainder will be resectable, resulting in cure. For HCC with tumor thrombus, the tumor thrombus was reduced and then resected after neoadjuvant radiotherapy. The survival time of the patients with portal vein tumor thrombus was significantly longer than that of the patients without neoadjuvant radiotherapy. Large liver cancer will be reduced to small liver cancer after comprehensive treatment, which can be transformed into stereotactic radiotherapy or radiofrequency ablation, and can also be palliative to radical treatment. Individualized and multidisciplinary therapy for liver cancer is the direction of future development. More clinical evidence-based level of radiotherapy treatment of liver cancer should be done in the future.

Hepatocellular carcinoma (HCC) is one of the malignant tumors with higher incidence and mortality worldwide. Recently, significant progress has been made in uncovering immunotherapy in HCC, for instance programmed death-1, cytotoxic T-lymphocyte antigen 4, chimeric antigen receptor T-cell therapy, T cell receptor T cell therapy, dendritic cell vaccine, and cytokine-induced killer cells. This paper reviews the advances in immunotherapy and focuses on the results of many of preclinical studies and clinical trials in the field, as well as some of the promising therapeutic strategies for HCC in the future.

Aim: β-catenin activation is known to promote liver regeneration and play a role in the pathogenesis of liver cancer. Recently, we detected intranuclear inclusions (NI) in hepatocellular carcinoma (HCC) containing degenerated cell organelles and lysosomal proteins and delimited by a completely closed nuclear membrane. The presence of NI was positively associated with patient survival. The aim of the current study was to investigate a possible association between proteins of the Wnt/β-catenin pathway with NI morphology and survival.

Methods: We examined NI in 72 paraffin-embedded specimens of HCC. Immunohistochemistry (IHC) and immunofluorescence (IF) were performed to investigate the content and shape of NI. β-catenin gene (CTNNB1 ) mutations were analyzed by next generation sequencing.

Results: We detected the accumulation of β-catenin and glutamine synthetase (a target gene of β-catenin) proteins within NI. Further, we found immunopositivity for the lysine demethylase KDM2A in NI. KDM2A is known to be involved in β-catenin degradation. We detected significant associations between the presence of β-catenin and autophagy-associated proteins in NI. Double-IF revealed co-localization of β-catenin and p62 in the same NI. Kaplan-Meier survival analysis showed that the presence of NI containing KDM2A protein accumulations displayed a significant benefit in overall survival.

Conclusion: We detected accumulations of β-catenin and proteins associated with the Wnt/β-catenin pathway partly together with autophagy-associated proteins in the same inclusion. Our finding that KDM2A immunopositivity within NIs was associated with favorable clinical outcomes and suggests a biological significance of NI.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, with increasing incidence worldwide. Alcohol-related cirrhosis (AC) accounts for 30% of the global incidence of HCC and HCC-related deaths. With the decline of hepatitis C virus (HCV) and decreasing HCV-related HCC, AC will soon become the leading cause of HCC. Excess alcohol consumption (> 80 g per day for > 10 years) increases the risk of HCC by 5-fold. However, only up to 35% of excessive drinkers develop cirrhosis and its associated HCC risk. Individual variation in susceptibility to HCC is known, but there is limited information to predict who among the patients is at high risk of progressing to HCC. Clinical risk factors for HCC include male gender, older age, severity of cirrhosis, obesity and presence of type 2 diabetes. In addition to ethnic variability in HCC risk, genetic variants are known to alter the risk of alcohol-related HCC. For example, single nucleotide polymorphisms in PNPLA3 (rs738409, C>G) and TM6SF2 (rs58542926, C>T) increase the risk of AC-related HCC, whereas HSD17B13 (T>A) reduces the risk for HCC. Studies have also confirmed PNPLA3 and TM6SF2 to be independent risk factors for AC-related (but not HCV-related) HCC. Combining genetic risk factors with phenotypic/clinical risk factors has been explored for stratification of patients for HCC development. Risk allele rs378409-G in PNPLA3 when combined with phenotypic/clinical risk factors (BMI, age, sex) has enabled HCC risk stratification of AC patients into low-, intermediate- and high-risk subgroups. Similarly, a combination of the two genetic variants PNPLA3-G and TM6SF2-T has been independently associated with risk of HCC onset. Using a polygenic risk score approach of incorporating several genetic variants, prognostic performance of polygenic risk score that included PNPLA3 rs378409 and TM6SF2 rs58542926 improved HCC prediction better than with either variant alone. Incorporating new variants and risk factors has the potential to build better algorithms/models to predict onset, early diagnosis and treatments for AC-related HCC. However, clinical usefulness of these approaches is yet to be determined.

Surgical resection or radiofrequency ablation (RFA) is considered first-choice treatment for small hepatocellular carcinomas (HCCs). When a patient has a small HCC that is inoperable or unsuitable for RFA, what are alternative treatments? Some oncologists recommend transarterial chemoembolization (TACE), chemotherapy, molecular-targeted therapy, or immunotherapy. However, these treatments have minimally beneficial effects in small HCCs. Stereotactic body radiation therapy (SBRT) is a liver-directed radical therapy for small HCCs, with treatment outcomes similar to those for surgical resection or RFA, but many oncologists do not comprehend its efficacy or accept this therapy. We herein discuss 11 typical patients who received SBRT for various indications: refusal to undergo resection or RFA; surgical resection or RFA considered difficult or unfeasible; residual cancer after surgical resection or RFA or incomplete iodized oil retention after TACE; or tumor recurrence after resection or RFA. We describe each case, including the radiation field, tumor radiation dose, and response to SBRT in both the tumor and liver parenchyma. These clinical data should help readers understand this new therapeutic technique. We also conducted a literature review and found evidence to support survival benefit with SBRT, including good three- and five-year overall survival rates. The purpose of this article is to encourage readers to accept the concept that SBRT is a low-toxicity and effective therapeutic option for patients with small HCCs, which offers substantial local control and improved overall survival, especially for patients with a tumor that is unresectable or unsuitable for RFA, residual tumor after local therapy, or intrahepatic recurrent tumor.

The use of stereotactic body radiotherapy (SBRT) in hepatocellular carcinoma (HCC) has increased over the past few decades. Thus, accurate evaluation of post-SBRT treatment response is essential to avoid over-treatment of responders as well as missing the opportunity to salvage non-responders. There are some intricate imaging differences after liver SBRT compared to those observed after conventional fractionated radiotherapy and other locoregional treatment. We aim to review the imaging changes that occur following SBRT for HCC and their potential clinical implications.

With the development of second-generation contrast agents and advancement in contrast harmonic imaging, contrast-enhanced ultrasonography (CEUS) now has the capacity to sensitively and accurately show tumor vascularity. Therefore, marked improvements have been achieved in the diagnosis of focal liver lesions(FLLs), including hepatocellular carcinoma (HCC), by US. In contrast to other agents, Kupffer cells in liver sinusoids take up Sonazoid. Two contrast enhancement phases occur in CEUS with Sonazoid: a vascular phase and Kupffer phase. Images obtained in the Kupffer phase have higher diagnostic sensitivity for hepatic malignancies because the majority of these malignancies do not contain Kupffer cells. Dynamic images obtained in the vascular phase markedly narrow the clinical differential diagnoses of FLLs. The sustainable detection of inconspicuous HCC, adequate guidance of ablation therapy, and accurate assessment of treatment responses in HCC are all facilitated by Sonazoid. The principles, clinical applications, and techniques of CEUS with Sonazoid in the diagnosis of HCC will be reviewed herein.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and usually arises in cirrhotic livers. Increasingly, it is diagnosed in non-cirrhotic livers. A variety of risk factors and etiologies can trigger the development of HCC in non-fibrotic and non-cirrhotic backgrounds. The most important causes are metabolic syndrome and hepatitis B virus infection. Postulated pathogenetic mechanisms are direct carcinogenesis, chronic liver injury and repair cycles, and genetic/epigenetic aberrations. Histopathology has a very important role in the diagnosis of non-cirrhotic HCC. Gross features of non-cirrhotic HCC are quite different from HCC originating in a cirrhotic background. Microscopic characteristics are similar to a classical HCC. However, certain histological variants show a predilection to occur in non-cirrhotic livers. These encompass fibrolamellar, scirrhous, steatohepatitic and mixed hepato-cholangiocarcinoma subtypes. Due to the non-cirrhotic background, adenoma, metastasis and most of the other non-neoplastic and neoplastic conditions enter the differential diagnosis. Genomic studies and morpho-molecular classifications of HCC provide further understanding of the molecular pathogenesis of non-cirrhotic HCC. This group however, has rarely been exclusively studied. This review offers an update of etiology, patho-molecular characteristics and differential diagnosis of HCC arising in non-cirrhotic backgrounds.

Occult hepatitis B infection (OBI) is characterized by absent hepatitis B surface antigen (HBsAg), low or undetectable serum hepatitis B viral DNA (HBV-DNA), and detectable DNA in the liver. There is debate over whether OBI increases the risk of hepatocellular carcinoma (HCC). We present a patient with negative HBsAg and a large HCC tumor who underwent a large right hepatic lobectomy. Initially, the etiology of HCC was unknown, but through more sensitive molecular testing, it was believed to be due to OBI. In this case report, we discuss the patient’s clinical course, the effect of antiviral therapy, mechanism of carcinogenesis in OBI, and the need for more rigorous HBV DNA assay testing for the detection of OBI.

Liver transplant (LT) is the curative treatment for patients with hepatocellular carcinoma (HCC). Bridge therapies are local treatments given to patients on the LT waitlist, to prevent tumor progression and to reduce the dropout rate. Case presentation: We reported a 40-year-old man diagnosed with Barcenola-Clinic Liver Cancer BCLC intermediate stage HCC and Child-Pugh A5 hepatitis B virus cirrhosis who underwent combined bridge therapies to LT. Firstly, the patient received transarterial chemoembolization (TACE) for two times and showed a partial response. Then he underwent stereotactic body radiation therapy (SBRT) with a total dose of 45 Gy in 3 fractions. Three months later, the tumor size and serum protein induced by Vitamin K absence or antagonists-II, alpha fetoprotein levels decreased gradually. In June 2019 a suitable donor was found and his LT was successfully performed. Conclusion: We propose that a combination of TACE and SBRT was feasible as bridge therapy for HCC patients on the LT waitlist.

Liver transplantation (LT) provides an excellent option for the long-term survival of patients with unresectable hepatocellular carcinoma (HCC) based on the Milan criteria. Despite careful selection of patients, HCC may still recur after LT, which represents the most important negative predictor of post-transplant survival. The growing demand for LT in HCC has led to the expansion of patient selection criteria, with a resultant increase in the risk of post-transplant HCC recurrence. Numerous tumor and host factors predict HCC recurrence. The morphological, histological, and serological characteristics of tumors in predicting HCC recurrence have been extensively studied. Furthermore, the type and duration of anticancer response before LT has also been considered a surrogate marker of tumor aggressiveness and is associated with the risk of recurrence. The demographic and clinical characteristics of recipients, as well as the type and duration of exposure to immunosuppressive therapy, represent the main host-related risk factors. Many studies have attempted to describe predictive models for the risk of HCC recurrence, considering evaluable parameters both before and after LT. Although many models have been proposed, relatively few have been externally validated on different patient populations. This paper aims to comprehensively summarize the available data on the predictive factors of HCC recurrence after LT, and to examine and discuss those that have been externally validated.

The Liver Imaging Reporting and Data System (LI-RADS) is a comprehensive and robust system which provides an algorithmic approach to stratify the probability of hepatocellular carcinoma (HCC) for each observation found in patients at risk for HCC. LI-RADS uses a standardized terminology and approach to improve communication between the radiologist and clinicians. LI-RADS version 2018 is noteworthy for its adoption by the American Association for the Study of Liver Disease into its HCC practice guidance. This manuscript provides an overview of the history of LI-RADS, reviews the Computed tomography/magnetic resonance imaging diagnostic algorithm, highlights the key diagnostic criteria for each category, and discusses the advantage of incorporating LI-RADS in clinical practice.

Aim: To describe the global pattern and trend of liver cancer survival, using data from the population-based studies or cancer registration.

Methods: By searching CNKI, Wanfang Data, PubMed, Web of Science, EMBASE and SEER. All population-based survival studies of liver cancer from 1 January 2000 to 30 April 2020 were collected and evaluated by patient gender, time period, and country. The overall or age-standardized five-year relative survival rate was used to describe the pattern and changes in liver cancer survival over the past decades.

Results: Globally, the highest age-standardized five-year relative survival rate was observed in Italy (18.0%, 2005-2007) and the highest overall five-year relative survival rate was observed in Korea (34.6%, 2012-2016), when compared to other countries. The most remarkable increase in overall five-year relative survival rate can be seen in Korea (from 10.7% during 1993-1995 to 34.6% during 2012-2016). In general, worldwide, the five-year relative survival rate of younger patients with liver cancer was higher than old people. For most countries, the five-year relative survival rate of liver cancer was slightly higher in women than in men. In China, the overall five-year relative survival rate of liver cancer in Taiwan was higher than that in other areas, while Cixian of Hebei and Qidong of Jiangsu were lower.

Conclusion: Over the past decades, the survival rates of liver cancer have gradually improved, but great variations are also observed globally. Worldwide, younger patients with liver cancer have experienced a better prognosis. Gender disparity in liver cancer survival was not obvious.

Contrast-enhanced ultrasound (CEUS) is a powerful imaging modality for the diagnosis of focal liver lesions, including hepatocellular carcinoma (HCC). The American College of Radiology Contrast-Enhanced Ultrasound Liver Reporting and Data System (CEUS LI-RADS®) was created as a standardized reporting system to facilitate consistent and high-quality technique, interpretation, reporting, and data collection for CEUS diagnosis of HCC. This article describes the history and background of CEUS LI-RADS®, its major concepts and algorithm, and the differences between CEUS LI-RADS® and CT/MRI LI-RADS®.

Aim: To validate a novel Japanese indication criteria for liver transplantation (LT) for hepatocellular carcinoma (HCC), i.e., the 5-5-500 criteria (nodule size ≤ 5 cm in diameter, nodule number ≤ 5, and alfa-fetoprotein (AFP) value ≤ 500 ng/mL) and the Japanese double eligibility criteria (DEC) (patients meeting the Milan or the 5-5-500 criteria) in the University of Tokyo cohort. The usefulness of biomarkers in predicting the recurrence of HCC was also verified.

Methods: The overall survival and recurrence rates of patients meeting the Milan, 5-5-500, and the Japanese DEC were compared among 153 patients who underwent living donor LT (LDLT) between 1996 and 2019. A receiver-operating characteristics curve analysis was conducted to evaluate the usefulness of AFP, lens culinaris agglutinin-reactive fraction of AFP, des-gamma-carboxy prothrombin, neutrophil-lymphocyte ratio, and the platelet-lymphocyte ratio to detect recurrence.

Results: The 5-year recurrence rate for all patients, those meeting the Japanese DEC, 5-5-500 criteria, and the Milan criteria was 10.9%, 9.2%, 7.4%, and 7.6%, respectively. Compared with the conventional Milan criteria, the 5-5-500 criteria and the Japanese DEC could increase the number of eligible LDLT candidates by 6.1% and 11.4%. Among five biomarkers, the area under the curve value of AFP was the highest (0.852).

Conclusion: The results suggest that the 5-5-500 criteria and the Japanese DEC are the appropriate selection criteria for patients with HCC in LDLT. Among five biomarkers investigated, AFP was most reliable to predict HCC recurrence, which justified the utilization of AFP in the 5-5-500 criteria and the Japanese DEC.

Imaging plays a notable role in hepatocellular carcinoma (HCC) surveillance, diagnosis, and treatment response assessment. Whereas HCC surveillance among at-risk patients, including those with cirrhosis, has traditionally been ultrasound-based, there are increasing data showing that this strategy is operator-dependent and has insufficient sensitivity when used alone. Several novel blood-based and imaging modalities are currently being evaluated to increase sensitivity for early HCC detection. Multi-phase computed tomography (CT) or contrast-enhanced magnetic resonance imaging (MRI) should be performed in patients with positive surveillance tests to confirm a diagnosis of HCC and perform cancer staging, as needed. HCC is a unique cancer in that most cases can be diagnosed radiographically without histological confirmation when demonstrating characteristic features such as arterial phase hyperenhancement and delayed phase washout. The Liver Imaging Reporting and Data System offers a standardized nomenclature for reporting CT or MRI liver findings among at-risk patients. Finally, cross-sectional imaging plays a critical role for assessing response to any HCC therapy as well as monitoring for HCC recurrence in those who achieve complete response.

Liver metastases can present synchronously or at different time points. While systemic therapy continues to be the mainstay of treatment for patients with liver metastases, it is unlikely to completely eradicate the disease. Surgical “metastectomy” for patients with limited metastatic burden, particularly from colorectal cancers, has been shown to improve survival. However, owing to medical co-morbidities or tumour location, not all patients are eligible for surgical resection. In recent years, there has been an increase in the use of non-surgical techniques, including high dose radiation using stereotactic body radiotherapy, or brachytherapy, to ablate liver metastases. The purpose of this narrative review is to describe the role of radiotherapy in the management of liver metastases, both for local ablation and symptom palliation. We will elaborate on the techniques used, patient selection process, expected outcomes and toxicities based on the current literature.

Non-invasive imaging is the current method of choice for the characterization of frequently discovered focal liver disease. Although historically, contrast-enhanced computed tomography (CT) and magnetic resonance (MR) scans have been selected for this purpose, contrast-enhanced ultrasound (CEUS) now offers a less expensive and safer method to acquire the same information. Performed with the intravenous injection of a microbubble contrast agent, CEUS provides some unique advantages that make it a valuable addition to an imaging toolbox. CEUS is performed in dynamic real-time, providing superior temporal resolution compared to other modalities and allowing detection of enhancement regardless of its timing or duration. CEUS is performed with a purely intravascular contrast agent, providing accurate depiction of the presence of microbubbles in the circulation in all phases of imaging. This compares with CT and MR contrast agents, which have a well-recognized interstitial phase. Resulting discordant imaging may occur especially in the portal venous phase, when CT and MR may show pseudoenhancement from interstitial contrast, while CEUS will accurately show washout in malignant tumors. Lastly, the contrast specific software used to perform CEUS has an excellent subtraction technique, which produces a contrast only image with high sensitivity to enhancement in thin septations and small nodules. CEUS makes a positive contribution to liver mass characterization in any situation.

Hepatocellular carcinoma (HCC) is the fourth leading global cause of tumor-related mortality. HCC has a high prevalence in patients with chronic liver diseases, and it mostly results from cirrhosis caused by infection with blood-borne viruses. Despite the implementation of various diagnostic and prevention strategies, the rates of new HCC cases and mortality are increasing globally due to the aging and growth of the world population as well as their increased exposure to dominant risk factors like alcohol, hepatitis B and C, and clinical correlates of metabolic syndrome. Modeling studies indicate that sanitation practices, implementation of vaccination programs against hepatitis B, and expanded recognition and treatment of patients with chronic hepatitis B and C could greatly contribute to the eradication of viral hepatitis B and C. While the availability of generic antiviral drugs could partially overcome the bottleneck represented by the lack of resources in low and middle-income countries, where viral hepatitis is the leading cause of liver cancer, the enthusiasm for the prevention of liver cancer through antiviral therapy is mitigated by the risk of cancer in many patients who are treated late in the hepatitis course. The present work aimed to review in detail the various types, epidemiology, and carcinogenesis mechanisms of viral infections that are associated with a significantly increased risk for the development of HCC.

This review focuses on emerging abbreviated magnetic resonance imaging (AMRI) surveillance of patients with chronic liver disease for hepatocellular carcinoma (HCC). This surveillance strategy has been proposed as a high-sensitivity alternative to ultrasound for identification of patients with early-stage HCC, particularly in patients with cirrhosis or obesity, in whom sonographic visualization of small tumors may be compromised. Three general AMRI approaches have been developed and studied in the literature - non-contrast AMRI, dynamic contrast-enhanced AMRI, and hepatobiliary phase contrast-enhanced AMRI - each comprising a small number of selected sequences specifically tailored for HCC detection. The rationale, general technique, advantages and disadvantages, and diagnostic performance of each AMRI approach is explained. Additionally, current gaps in knowledge and future directions are discussed. Based on emerging evidence, we cautiously recommend the use of AMRI for HCC surveillance in situations where ultrasound is compromised.

Hepatocellular carcinoma (HCC) is a poor prognosis tumor when not accessible to potentially curative treatments such as surgical resection, thermal ablations or liver transplantation. Systemic cytotoxic chemotherapies have shown inconsistent clinical benefit. In 2007, sorafenib, a tyrosine kinase inhibitor (TKI), was the first systemic therapy able to significantly improve the outcome of HCC patients non-eligible for curative or loco-regional therapies, despite a modest tolerance and low tumor objective response rate (ORR). Among the newer TKIs approved after 2017, lenvatinib was the first to show a striking ORR and demonstrate non-inferiority vs. sorafenib in the first-line setting. Furthermore, phase 3 trials showed the benefit of other TKIs, regorafenib and cabozantinib, and the anti-angiogenic ramucirumab monoclonal antibody, in systemic second-line therapy. Immune checkpoint inhibitors targeting PD1, achieved striking tumor shrinkage in some patients in monotherapy, seeming to be associated with exciting outcomes. Unfortunately, this occurred in too few patients to improve the median overall survival. More recently, the combination of anti-angiogenic drugs targeting the liver microenvironment with PD-1/PD-L1 inhibitors, such as the combination of bevacizumab and atezolizumab, proved to be substantially effective in phase 3, and other combinations of PD-1/PD-L1 and CTLA-4 inhibitors or TKIs have raised a lot of hopes for the systemic treatment of HCC.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is associated with poor clinical prognosis, which is mainly caused by tumor recurrence and metastasis. Circulating tumor cells (CTCs) are tumor cells shed into the bloodstream and regarded as the “seeds” of tumor recurrent or metastatic lesions. Over the past decade, the clinical value of CTC analysis has been extensively explored. CTC analysis is a representative form of liquid biopsy, offering a novel solution that can bypass the problems of invasive biopsy procedures, enabling comprehensive, non-invasive, and real-time disease monitoring. In HCC, CTC analysis has facilitated early detection and prognosis prediction, as well as treatment monitoring and therapeutic intervention guiding. In this review, we summarize available literature and provide an overview of CTC biology, detection technologies, and clinical applications in the diagnosis, prognosis prediction, and personalized treatment of HCC.

Worldwide, hepatocellular carcinoma (HCC) is a frequent complication of liver diseases and remains a major cause of cancer-related mortality. In addition, the prevalence of nonalcoholic steatohepatitis (NASH) as prerequisite of hepatocarcinogenesis, even in the absence of cirrhosis, is rising rapidly. The early detection of HCC has been crucial in improving the survival outcomes of those patients. However, in the mostly obese NASH population, diagnostic sensitivity of ultrasound-based HCC screening approaches is limited. On the other hand, biomarkers for HCC show promising potential to improve early detection, providing reproducible, investigator-independent results that can be used either alone or integrated with other biomarkers for scoring models. In the past, validation has been limited due to a lack of prospective longitudinal cohort studies. At present, large-scale retrospective phase-III- biomarker- development gives hope for the availability of biomarker-based screening approaches in the near future. This review focuses on the potential impact of biomarkers on surveillance strategies, potentially allowing for earlier HCC diagnosis.

Computed tomography (CT) and magnetic resonance imaging (MRI) are commonly used modalities for the imaging based diagnosis and staging of hepatocellular carcinoma (HCC). The Liver Imaging Reporting and Data System (LI-RADS) was initially released in 2011 in an effort to standardize the interpretation and reporting of these studies in patients at increased risk for the development of HCC. With the release of LI-RADS v2018, LI-RADS has reached two important milestones - 10 years since the formation of the American College of Radiology supported LI-RADS committee and integration of LI-RADS into the 2018 American Association for the Study of Liver Disease practice guidance for HCC. In this article, we will discuss recent changes to LI-RADS with v2018, technical recommendations for the performance of CT and MRI in patients at risk for HCC, and critical imaging features in the LI-RADS algorithm.

Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of liver disease in many parts of the world, causing considerable liver-related (steatohepatitis, cirrhosis, liver failure and hepatocellular carcinoma) and extra-hepatic morbidity and mortality (mainly cardiovascular disease, chronic kidney disease or certain types of extra-hepatic cancers). Recently, based on insights gained from the past two decades, an international panel of experts from 22 countries has taken the initiative to propose a new name and definition for NAFLD in adult individuals - that is, metabolic dysfunction-associated fatty liver disease. This proposed change in nomenclature is not simply a semantic revision, but may facilitate improved diagnosis of this common liver disease for health promotion, case identification, patient awareness, ongoing clinical trials and health services delivery. The aim of this commentary is to discuss the proposal for a change in nomenclature of this common and burdensome liver disease and to address the “pros and cons” for changing the name according to the perspective of different stakeholders.

Aim: To test the efficacy and safety of liver stereotactic body radiation therapy (SBRT) in patients who harbor adverse factors.

Methods: We retrospectively evaluated the outcomes of liver SBRT in a single cancer center. We invented criteria consisting of two physical factors and two tumor factors to measure the treatment difficulty in each case. The clinical outcomes and toxicity were evaluated by stratification of the harboring factors.

Results: A total of 24 (23 hepatocellular carcinoma and 1 intrahepatic cholangiocarcinoma) patients were eligible for this study, with a median follow-up duration of 18 months. Of all eligible patients, 21 patients (88%) had one or more factors. The local control, progression-free survival, and overall survival rates for all patients at 2 years were 89%, 42%, and 76% respectively. In the patients with physical and tumor adverse factors, local control/progression-free survival/overall survival rates at 2 years were 100%/42%/69% and 80%/23%/78%, respectively. The subgroup of 11 patients with 2 or more factors showed comparable local control rate at 2 years to the subgroup of 13 patients with 0 to 1 factors (100% vs. 86%, P = 0.59). One patient (4.2%) experienced a decline in the Child-Pugh score by 2 points at 3 months after the treatment. Grade 2 to 3 gastrointestinal toxicity was observed in three patients.

Conclusion: SBRT showed a high local control rate with acceptable toxicity for the group of liver cancer patients harboring both physical and tumor adverse factors as long as conducted following patient selection and dose constraints that were used in this study.

Aim: Inflammation-based markers, such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), have recently been used as prognostic indicators in hepatocellular carcinoma (HCC). We aimed to determine whether NLR and PLR may predict response to yttrium-90 transarterial radioembolization (TARE) as primary treatment for HCC.

Methods: We performed a retrospective review of a prospectively collected database of HCC cases (1994-2019) and selected patients who received TARE as primary treatment (n = 42). Laboratory studies were used to calculate NLR and PLR. Response to TARE was determined using the modified response evaluation criteria in solid tumors (mRECIST). Patients were classified as non-responders (stable or progressive disease) or responders (partial or complete response) to treatment based on mRECIST.

Results: Receiver operating characteristic curves identified a pre-treatment NLR cutoff of ≥ 2.83 and a pre-treatment PLR cutoff of ≥ 83 for predicting non-response to treatment. Pre-treatment NLR ≥ 2.83 was the only significant predictor of non-response to TARE in multivariate logistic regression analysis (odds ratio 7.83, P = 0.036). On time to progression analysis, both pre-treatment NLR ≥ 2.83 and pre-treatment PLR ≥ 83 were associated with a higher proportion of tumor progression at 6 months post-treatment (43.6% vs. 10.0%, P = 0.014, log-rank) and (38.6% vs. 0%, P = 0.010, log-rank), respectively.

Conclusion: NLR confers prognostic value and may be superior to PLR in determining response to TARE as primary treatment for HCC. Future studies are necessary to validate these findings in a larger cohort.

Hepatocellular carcinoma (HCC) has one of highest mortalities globally amongst cancers, but has limited therapeutic options once in the advanced stage. Hepatitis B or C virus infection are the most common drivers for HCC carcinogenesis, triggering chronic liver inflammation and adding to the complexity of the immune microecosystem of HCC. The emergence of immunotherapy has afforded a new avenue of therapeutic options for patients with advanced HCC with a history of hepatitis B or C virus infection. This article reviews the change of immunity elicited by hepatitis B or C virus infection, the immune feature of HCC, and the clinical evidence for immunotherapy in advanced HCC and discusses future directions in this field.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases and is related to unhealthy lifestyle habits, characterized by a diet rich in sugars and fats leading to excessive calorie intake, and lack of exercise. In recent years, there is a growing incidence of this pathology, raising the attention of hepatologists, endocrinologists, diabetologists, and nutritionists. In this context, the alimentary regimen adopted by patients with NAFLD has become an increasingly scrutinised parameter. Diet is now considered a crucial factor in the treatment of NAFLD since it has been observed that some functional foods play a beneficial role. These include coffeewhose health effects have already been amply demonstrated. Here we describe the beneficial effects of coffee consumption reported in the NAFLD literature.

Patients with unresectable cholangiocarcinoma (CCA) face a poor prognosis, and there are few effective treatment options for the disease. The standard of care for patients with locally advanced or metastatic CCA is chemotherapy with a gemcitabine-based doublet. Unfortunately, the clinical benefit obtained with these regimens is modest, with a median overall survival of about one year. For CCA that is chemotherapy-refractory or recurs after first-line chemotherapy, the treatment options are even more limited, and no relevant randomized controlled data are available. In recent years, molecular profiling has shed light on the molecular basis of CCA and identified subgroups of patients that might benefit from a personalized treatment approach. These efforts resulted in the recent FDA approval of the fibroblast growth factor receptor (FGFR) inhibitor, pemigatinib, as a second-line treatment for patients with advanced CCA harboring an FGFR2-fusion or rearrangement. Several other targeted agents also are under evaluation in patients with CCA, of which the isocitrate dehydrogenase inhibitor has had the most promising results. Finally, immunotherapy is being explored as a new treatment approach for advanced CCA patients; indeed, the immune checkpoint inhibitor pembrolizumab can already be used to treat CCAs that are mismatch repair deficient. This review is a comprehensive overview of the treatment options for CCA and offers a glimpse into what the future could hold for these patients.

Aim: We analysed outcomes using multimodality therapy in patients with hepatocellular carcinoma (HCC) recurrence post living donor liver transplantation (LDLT).

Methods: Of 2363 LDLT’s performed between 2005 to mid 2018, 435 (18.4%) were for HCC within our expanded selection criteria (absence of extrahepatic disease and vascular invasion, irrespective of tumor size and number). Survival after recurrence, and prognostic factors for these patients were studied.

Results: Of 435 LDLT patients, 51% had HCC beyond Milan and 43% beyond UCSF criteria at the time of LDLT. pre-LT AFP > 100 ng/mL and tumour FDG-18 PET avidity predicted overall survival (OS), whereas pre-LT AFP > 100 ng/mL, UCSF criteria, and FDG-18 PET avidity predicted recurrence-free survival. Hundred patients (23%) developed HCC recurrence at a median time of 16 months (range 2-108 months) post LDLT. Lungs (53%), liver (37%), and bone (21%) were the most common sites of recurrence. Ninety-five patients received tyrosine kinase inhibitors (TKI) after recurrence and 62 received mTOR inhibitors (protocol-based after LDLT, or post recurrence). Surgical resection of metastases was performed in 14 patients, 15 received stereotactic body radiotherapy, and 18 underwent ablation (radiofrequency, microwave ablation, transarterial chemoembolisation, or percutaneous ethanol injection). One- and 3-yr OS after recurrence were 57%, and 24% respectively, with a maximum post recurrence survival of 7.5 years. HCC recurrence within one year after LDLT (P = 0.004, HR = 2.38, 95%CI: 1.325-4.276), AFP > 200 ng/mL at the time of recurrence (P =0.02, HR = 2.075, 95%CI: 1.121-3.841), and recurrence at multiple sites (P = 0.047, HR = 1.831, 95%CI: 1.009-3.321) were poor prognostics factors for post recurrence survival. Multimodality management of recurrence using combined medical, surgical, ablative treatments and radiotherapy significantly improved survival compared to the use of TKI’s or mTORi’s alone, or in combination.

Conclusion: In patients accepted for LDLT beyond the conventional size-number criteria, even after HCC recurrence, an aggressive approach using multimodality therapy, when possible, aids in further prolongation of survival.

Aim: To compare the phenotype of lean versus overweight (OW) and obese (OB) subjects with non-alcoholic fatty liver disease (NAFLD) across multiple continents.

Methods: A retrospective study of histologically defined subjects from a single center each in France (Fr), Brazil (Br), India (In) and United States (US) was performed.

Results: A total of 70 lean [body mass index (BMI) < 25 kg/m²] subjects (Fr:Br:In:US: 16:19:22:13) with NAFLD were compared to 136 OW (BMI > 25 kg/m², BMI < 29 kg/m²) (n = 28:33:52:23) and 224 OB subjects (BMI > 29 kg/m²) (n = 81:11:22:103). Lean French subjects had the lowest incidence of type 2 diabetes while those from Brazil (P < 0.01) had the highest. Lean subjects had similar low-density lipoprotein-cholesterol, but higher high-density lipoprotein-cholesterol compared to obese subjects in all regions. In both lean and obese subjects, there were both insulin-sensitive and insulin-resistant subjects. Lean French subjects were most insulin-sensitive while those from Brazil were mostly insulin-resistant. For each weight category, subjects from India were more insulin-sensitive than those from other regions. Disease activity increased from lean to overweight to obese in France but was similar across weight categories in other regions.

Conclusion: The phenotype of NAFLD in lean subjects varies by region. Some obese subjects with NAFLD are insulin-sensitive. We hypothesize that genetics and region-specific disease modifiers account for these differences.

Liver cancer accounts for 4.7% of all newly diagnosed cancers and 8.2% of cancer deaths annu-ally. Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. There are 2 curative strategies in HCC: resection and transplant. Unfortunately, 50% of patients who undergo resection will relapse in 2 years and many patients on transplant lists become ineligible for transplant due to disease progression. The majority of patients still require systemic therapies. Tyrosine kinase inhibitors have successfully extended the overall survival in patients with hepa-tocellular carcinoma. However, these treatments have been noted to cause severe side effects in-cluding liver toxicity, hypertension, gastrointestinal toxicity and cutaneous adverse effects. This article will focus on the adverse skin reactions seen during the treatment of hepatocellular carci-noma by various tyrosine kinase inhibitors. The focus will be symptomatology, management, and whether the development of cutaneous toxicities can be prognostic.

Familial clustering of hepatitis B surface antigen carriers (HBsAg) and hepatocellular carcinoma (HCC) has led to the evaluation of the role of genetics in hepatitis B-related diseases. Consistent reports indicate that the HLA-DP and -DQ loci are associated with persistent hepatitis B virus (HBV) infection. However, for hepatocarcinogenesis, existing studies have low power and conflicting data. Global single nucleotide polymorphism (SNP) data was collected from the 1000 Genomes Project and correlated with local epidemiological information. Southeastern Asia has a higher prevalence of HBsAg than Northeastern Asia; this was used in the evaluation of persistent HBV infection. The higher incidence of HCC in West Africa compared with East Africa was used in the evaluation of hepatocarcinogenesis. The allele frequencies for SNPs were significantly different between East Asians and Africans. Therefore, SNPs that have been identified in persistent HBV infections in East Asia may not be completely applicable in Africa. SNPs in NTCP, CTF19, and the HLA-DQ and -DP loci showed North-to-South allele frequency changes in East Asia. These findings confirm the role of genetics in persistent HBV infection. Some of the SNPs in the HLA loci show a trend of West-to-East allele frequency changes in Africa, indicating they may participate in hepatocarcinogenesis. Among the non-HLA related SNPs, rs2596542 in MICA shows a strong trend of allele frequency changes and is correlated with HCC incidence in Africa. SNPs in KIF1, IL-1A, and STAT4 also show, albeit with low statistical power, allele frequency trends compatible with HCC incidence. Taken together, there are strong correlations between background genetics in HLA-DP and -DQ loci with persistent HBV infection and hepatocarcinogenesis. The correlations were weak-positive in non-HLA loci.

Since the Milan Criteria (MC) were adopted in many countries as the allocation policy criteria for patients with hepatocellular carcinoma to be transplanted, many groups started to expand it to provide a chance for patients with tumors outside the MC who could achieve similar survival rates. With the scarcity of deceased donors, Asian countries improved the results with living donor liver transplantation, allowing patients outside MC to be transplanted with a living donor. Newer prognostic models and a more profound understanding of tumor behavior are targeting better patient selection. Currently, patients are unevenly selected for liver transplantation and mostly separated into those fulfilling the MC and transplanted with a deceased donor and those with expanded criteria and transplanted with a living donor. In this paper, insight is brought into this debate.

Liver transplantation (LT) is the treatment of choice for patients with hepatocellular carcinoma (HCC) and underlying liver disease. Given the organ scarcity, LT for patients with HCC have been restricted to those patients associated with the highest survivals. However, many patients with extended criteria HCC can still benefit from LT, but due to deceased organ shortage, they are not offered that opportunity. Living donor liver transplantation (LDLT) emerged as a successful strategy to overcome organ shortage around the world and as LDLT experience grows, this technique might offer the opportunity to expand the indications of LT to patients with advanced HCC. Therefore, since LDLT is not competing for deceased donor organs, many patients with extended criteria HCC who could still benefit from transplantation may have access to this treatment option. In this review, we will discuss the role of LDLT for patients with advanced-stage HCC and how LDLT allows for safe expansion of HCC transplant criteria.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related death worldwide. Surgical resection is still regarded as the first choice of treatment for HCC. With advances in technology and techniques, minimally invasive surgery has now become the standard of care in almost every field in general surgery, including hepatectomy surgery. This review focuses on the latest advances in minimally invasive surgical treatment of HCC, including laparoscopic hepatectomy (LH), robotic hepatectomy (RH) and other minimally invasive treatment technologies. Although some limitation in LH or RH exists, these minimally invasive techniques may be performed for hepatectomy with benefits, and have a promising future. With the development of technology and the improvement of surgical operations, patients will benefit from this.

Nonalcoholic fatty liver disease (NAFLD) is linked to abdominal obesity, insulin resistance and type 2 diabetes mellitus (T2DM). The association of NAFLD with T2DM is bidirectional. In fact, evidence suggests that abdominal obesity, T2DM and metabolic syndrome play a part in the development and progression of NAFLD. Alternatively, NAFLD is associated with an increased risk of having T2DM and metabolic syndrome. According to this background, it is unsurprising that patients with T2DM patients also have a higher prevalence of NAFLD than those with no T2DM, as well as an increased risk of developing liver-related and extrahepatic complications, mainly cardiovascular and renal diseases. Seeing the relationship of NAFLD with insulin resistance, obesity and T2DM, recent consensus proposes a change in nomenclature from NAFLD to metabolic associated fatty liver disease. In this review, we will discuss the prevalence and incidence of NAFLD (as detected by imaging techniques or liver biopsy) in patients with type T2DM with particular regard to hepatic and extrahepatic complications.

Although liver resection (LR) is often adopted to recurrent hepatocellular carcinomas, risks of complications and conversion reportedly increase in laparoscopic repeat LR (LRLR). The indication is not agreed upon even with the recent advances of laparoscopic LR. We conducted an international propensity score matching study of LRLR and open repeat LR for hepatocellular carcinoma with 1,582 patients from 42 world centers. Propensity-score matched LRLR patients have smaller blood loss and longer operation time than open repeat LR patients. Median overall survival time was 8.94 years in open and 12.55 years in LRLR; although the difference was not significant, the P-value was 0.0855 and the better curve of LRLR is clearly separated from that of open. In our institution, we experienced 34 LRLR and 12 cases of three times or more repeat LR until 2019. There are no significant differences in operation time, blood loss, hospital stay, conversion, and morbidity rates among first, second, and third or higher laparoscopic LR, which is different from the open situation. However, postoperative bile leakage and intraoperative bleeding causing conversion did happen in the cases with repeat extended exposure of Glissonian pedicle. LRLR is feasible for selected patients. However, the procedure is under developing stage and further accumulation of experiences and evaluation are needed.

The tumor suppressor p53 is a key player in the control of genomic integrity and homeostasis in connection with p63 and p73, the two other members of the p53 family. Loss of functional p53 leads to the proliferation and survival of mature cells and progenitor or stem cells that accumulate genetic alterations, thus favoring tumorigenesis. p53 loss of function, observed in a wide variety of human tumor types, is frequently caused by missense mutations more frequently found in the DNA binding domain, but can also be due to the expression of a plethora of viral and cellular negative regulators. Human hepatocellular carcinoma (HCC) represents a specific situation, first because the TP53 gene mutations pattern exhibits a “hot spot” rarely found in other tumor types that is linked to Aflatoxin B1 exposure and, second, because many HCCs do not exhibit any TP53 mutation. Here, we provide an overview of the current knowledge about the inhibition of p53 functions by the N-terminal (ΔN) truncated forms of the family, and their role in the emergence and maintenance of pre-malignant cells with stem cell characteristics and in HCC development. We focus in particular on the Nanog-IGF1R-ΔNp73 axis that is associated with stem-like features in HCC cells and that may provide an attractive new therapeutic target and help to develop new biomarkers for HCC risk stratification, as well as preventive strategies.

Repeat liver resection (RLR) is an effective treatment approach for recurrent hepatocellular carcinoma (HCC) and can provide acceptable long-term outcomes in select patients. Recent randomized controlled trials comparing RLR with radiofrequency ablation revealed that the latter approach was associated with a higher rate of early recurrence compared with RLR. With recent advances in laparoscopic liver resection (LLR), RLR has been increasingly performed using laparoscopy. Several propensity score-matched studies reported that laparoscopic RLR achieved lower blood loss and shorter hospital stays compared to open RLR. However, laparoscopic RLR requires more advanced techniques because of adhesions formed after the previous liver resection, changes in anatomical landmarks, and deformity of the remnant liver. The recently described difficulty classification of laparoscopic RLR is based on five factors including type of previous liver resection (open or laparoscopic), number of previous liver resections, surgical procedure used in previous liver resections, tumor location in previous liver resections, and difficulty score of LLR for recurrent HCC. We reviewed the available literature to summarize available evidence suggesting that laparoscopic RLR might be considered a more minimally invasive surgical treatment approach for recurrent HCC as long as the indication for laparoscopic RLR is carefully determined.

Despite the fact that non-alcoholic fatty liver disease (NAFLD) and its severe clinical forms [non-alcoholic steatohepatitis (NASH) and NASH-cirrhosis] are highly prevalent in the general population, there are no licensed drugs for NAFLD, and lifestyle intervention remains the only treatment accepted by international guidelines. This is despite massive investments in research by pharmaceutical companies. In the presence of type 2 diabetes, novel anti-diabetic drugs offer an opportunity to reduce the burden of NAFLD, by adequate control of glucose and lipid metabolism, also reducing the risk of NASH progression, advanced fibrosis, and finally hepatocellular carcinoma. We extensively reviewed the literature, based either on registration studies, ad hoc randomized studies or real-world data, to define the effectiveness of anti-diabetic drugs in the treatment of NAFLD and prevention of hepatocellular carcinoma (HCC). Metformin provides the best evidence for decreased risk of HCC, pioglitazone was associated with decreased progression to fibrosis, glucagon-like peptide-1 receptor agonists offer a possible opportunity to reduce NAFLD progression coupled with a definite protection for cardiovascular outcomes, and sodium-glucose cotransporter-2 inhibitors are likely to reduce lipid burden, simultaneously reducing the risk of progressive renal and heart failure. For the latter two drug classes, the effects on NAFLD might largely explained by decreased body weight, in keeping with the beneficial effects of intensive lifestyle intervention.

Nonalcoholic fatty liver disease (NAFLD) exhibits sexual dimorphism, with men being more exposed than women to the risk of simple steatosis, nonalcoholic steatohepatitis fibrosis, and hepatocellular carcinoma (HCC), while the protection conferred to women seemingly disappears with aging and reproductive senescence (i.e., menopause). HCC, the most common primary liver cancer, which carries an ominous prognosis, may result from various genetic and non-genetic risk factors. NAFLD is now projected to become the most common cause of HCC. HCC also exhibits a definite sexual dimorphism in as much as it has a worldwide high male-to-female ratio. In this review article, we focus on sex differences in the epidemiological features of HCC. Moreover, we discuss sex differences in the clinical outcome and molecular pathobiology of NAFLD-HCC. By highlighting the research gaps to be filled, the aim of this review is to prompt future research of sex differences in HCC and facilitate developing personalized cancer prevention strategies, detection, and treatments to achieve better patient outcomes in NAFLD-HCC, considering sex differences in HCC pathobiology.

The epidemiology of nonalcoholic fatty liver disease goes hand-in-hand with the obesity pandemic. The pathogenesis of fatty liver has shifted from an hepatocentric view to an adipocentric view, in which the overloaded adipose tissue spills out lipids that spread to ectopic tissues and organs such as the liver, elicits inflammation, and changes its adipokines profile promoting insulin resistance and the metabolic syndrome. Up to 40% of nonalcoholic fatty liver disease (NAFLD) patients are not obese and up to 20% are actually lean. Furthermore roughly 10% of lean subjects have NAFLD. In fact, adiposopathy can occur in patients with normal weight, and it is associated with expansion of metabolically active visceral fat and a qualitatively different adipose tissue that becomes overwhelmed after challenged by a mildly positive energy balance. This defines the concept of personal fat threshold that when exceeded results in metabolic dysfunction. Overweight/obese persons have higher probability of exceeding that threshold, explaining why adiposopathy/metabolic syndrome/NAFLD is more frequent in the obese. In this article, the epidemiology, pathogenesis, and management of patients with lean NAFLD are reviewed with an emphasis on reconciling the concepts of NAFLD in its relationship with adiposity and of NAFLD in lean individuals.

Non-alcoholic fatty liver disease (NAFLD) is estimated to affect 25% of the worldwide population, and is the leading cause of chronic liver disease in developed countries. Genetic research on NAFLD has included heritability studies, candidate gene studies, familial aggregation studies, and genome-wide association studies (GWAS). Next-generation sequencing approaches, such as whole-genome sequencing and whole-exon sequencing, are emerging as the post-GWAS era of genetic research. However, GWAS remains more practical for elucidating the genetic factors related to NAFLD, which is affected by thousands of common genetic variants and does not follow Mendelian inheritance. In the present review, we summarize the current knowledge regarding five GWAS-identified genetic loci that are associated with NAFLD. We also discuss the relationships between NAFLD-predisposing polymorphisms and cardiovascular disease, and potential applications for these identified genetic loci.