Aim: Eligibility for liver transplantation for hepatocellular carcinoma (HCC) is currently based on single-dimension, diameter measurements on cross-sectional imaging, as specified by various selection criteria. This does not account for significant differences in shape, and therefore tumour volume, between patients. This study investigated whether one-dimensional selection criteria disadvantages patients by not considering volume.

Methods: Patient data were collected retrospectively from a prospectively maintained database. Tumours were measured on both computer tomography (CT) and magnetic resonance imaging (MRI). Tumour volume was measured using two methods; semi-automated planimetry and the ellipsoid volume formula. Statistical analysis was performed using SPSS.

Results: A total of 313 patients with HCC were assessed for liver transplantation. For this study, patients who underwent transplantation (n = 89) and those who did not based on tumour size (n = 33) were included. In total, 213 tumours were measured, showing excellent correlation between CT and MRI (R² = 0.83). The majority of tumour nodules (94%) were ellipsoid not spherical. Volumetric measurements of the 84 tumours that did not meet diameter-based Milan criteria confirmed that 76% would have been within a theoretical volume allowance based on Milan criteria diameters.

Conclusion: This study shows that a significant number of patients deemed outside conventional diameter-based Milan criteria have smaller tumour volumes than those considered within criteria. It appears that those with ellipsoid rather than spherical tumours may be disadvantaged by current size-based criteria. Further research using a contemporary patient cohort who have had the benefit of advancements in non-surgical treatments for HCC is required.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver condition worldwide due to the global proliferation of obesity, which has become an insidious healthcare epidemic. While nonalcoholic fatty liver is recognized as a multi-system disease, benign and pernicious in its unfolding, nonalcoholic steatohepatitis is the more severe form progressing from cirrhosis to hepatocellular carcinoma. Unfortunately, liver biopsy - beset by many limitations - is the only accurate diagnostic tool setting the benchmark for a plethora of non-invasive biomarkers which have so far proved limited in their reliability and take-up. As a result, we need better diagnostic and prognostic tools to aid in the identification and stratification of patients at risk of disease progression in order to enhance treatment and monitoring strategies. In this review, we explore the performance as well as pros and cons of three novel technologies that could have the potential to become the next generation in NAFLD diagnostic testing. To harness these technologies, however, we suggest that more work needs to be done to refine and validate the technology features under review, while suggesting ways in which personalized medicine could be mobilized to discover the next generation in non-invasive diagnostics.

Hepatocellular carcinoma (HCC) accounts for 75%-85% of all primary liver cancers and is the leading cause of cancer-related deaths. China accounts for almost half of the global incidence and deaths of HCC. The poor response of chemotherapeutics and targeted drugs may be due to the drug resistance, heterogeneity of HCC, severe chronic liver damage and cirrhosis. Restoration of the liver microenvironment changes caused by chronic injury is crucial. Immunotherapy recently seems to show promise for the treatment of HCC induced by inflammatory injury. However, the unique liver immune system and resident immune tolerance state also pose a challenge for HCC immunotherapy. Different combinations of strategies have been developed for enhancement of HCC treatment. Here, we will discuss the immune microenvironment and progression of immunotherapy and combination therapeutic strategies for HCC.

Background: The impact of sarcopenia on the outcome of patients with cirrhosis who undergo liver transplantation (LT) has been analysed in heterogeneous cohorts with mixed results. We sought to determine the prevalence and the impact of pre-LT sarcopenia on morbidity and mortality after LT in a cohort of patients with cirrhosis with and without hepatocellular carcinoma (HCC).

Methods: Patients with cirrhosis who underwent LT between 2010 and 2016 at Padua University Hospital were retrospectively evaluated. Using image software analysis, cross-sectional area of skeletal muscle at 3rd lumbar vertebra was measured and skeletal muscle index (SMI) was calculated. Sarcopenia was defined by SMI < 50 cm²/m² in males and < 39 cm²/m² in females, respectively. Primary outcome was post-LT survival. Secondary outcomes included hospitalization length and post-LT complications.

Results: 197 patients were included, of whom, 122 (62%) had sarcopenia. Demographics and severity of cirrhosis were comparable in patients with vs. without sarcopenia. Overall survival was similar between the groups. When survival analysis was adjusted for severity of liver disease, sarcopenia was associated with a significantly reduced survival in decompensated (80% vs. 91%, 1-year post-LT; P = 0.04) but not in compensated (93% vs. 90%, 1-year post-LT; P = 0.7) patients. In patients with HCC, sarcopenia was associated with a trend towards lower survival but only in those with HCC beyond Milan criteria. Among secondary outcomes, bacterial infections were more frequent in patients with vs. without sarcopenia (50% vs. 35%; P = 0.02), whereas hospitalization length and other complications were comparable between the groups.

Conclusion: Sarcopenia is a common finding in patients awaiting LT and, in those with decompensated cirrhosis, it is associated with reduced survival after transplantation.

Aim: Laparoscopic liver resection (LLR) has been recognized as a minimally invasive surgery offering disease curability for liver tumors. Moreover, recent publications suggest that the systematic liver resections including hemi-hepatectomies have been performed safely in high volume centers. We describe our indication, standardized technique, and surgical outcome for totally laparoscopic hemi-hepatectomy (TLHH). Moreover, we hypothesize that TLHHs can be performed feasibly, as well as discuss the technical correspondence of technically difficult cases which have marginal indication for TLHHs.

Methods: From September 2008 to July 2020, in total, 488 cases of liver resections including 222 cases of LLR were performed in our institution. We invented the favorable indication of TLHHs of locally resectable tumors without involvement of tumor to hepatic hilus, confluence of hepatic veins, inferior vena cava, or extrahepatic organs, in patients with sufficient hepatic functional reserve for hemi-hepatectomies. Among 21 TLHHs for liver tumors performed during study period, there were cases which derogate favorable indications; however, they might have been able to undergo TLHHs. We divided these cases into “difficult indication group (DIG)” (10 of 21 cases) and “favorable indication group (FIG)”; compared them on perioperative background, surgical outcome; and discussed the technical correspondence of TLHHs on DIG.

Results: There were no significant differences in patient’s background and operative outcome. Operative duration, blood loss, and postoperative morbidity tended to be larger in DIG, mainly due to tumor factor, than in FIG. However, TLHHs were performed without any severe perioperative complications beyond Clavien-Dindo grade IIIb or mortality.

Conclusion: We believe that hemi-hepatectomies can safely be stylized by totally laparoscopic fashion and correspondence for difficulty can be made through technical standardization.

Hepatocellular carcinoma (HCC) is the most common type of primary liver malignancy and the fourth leading cause of cancer-related deaths globally. HCC is often diagnosed in late stage, difficult to treat, and has poor prognosis with a median survival of 6-20 months. Innate and adaptive immunity play a pivotal role in determining tumor control versus progression. Genomic instability and abnormal signaling in the setting of chronic liver inflammation lead to tumorigenesis. Tumor progression occurs due to a sustained inflammatory response that promotes fibrogenesis and angiogenesis. This review discusses the key innate and adaptive cellular players that mediate the anti-tumor response. This review explores the complex interactions that occur within the tumor microenvironment and their clinical implications. HCC is a fastidious malignancy that is able to evade and downregulate the host immune response. Mechanisms of how this occurs are discussed, along with how they may be exploited in the development of novel therapeutics. From our research, it appears that striking a balance between immunotolerance and a robust immune response may yield the best prognosis. This review assesses major and recent developments in HCC immunotherapy, including adoptive cell therapy, cancer vaccines, and targeted therapy such as checkpoint inhibitors. Overall, the importance of the immune response in determining outcomes for HCC cannot be understated. Improved animal models and better characterization of the tumor microenvironment are needed. We determine that a better understanding of the HCC immune profile would facilitate advancements in diagnosis, monitoring, and ultimately treatment.

Risk prediction modelling for hepatocellular carcinoma (HCC) has been the focus of research in the last decade. The prediction models would help HCC risk stratification, so that patients at high risk of HCC would be able to receive more appropriate management and HCC surveillance. These models were mostly developed in treatment-naïve chronic hepatitis B patients in the early days. In recent years, more prediction models were derived and validated in patients who have received antiviral treatment, which account for the majority of patients who are at increased risk of HCC. Various statistical tests are adopted in developing and validating a risk prediction model - commonly Cox proportional hazards regression, time-dependent receiver operating characteristic (ROC) curve and area under the ROC curve. Even in well-validated models, there may be some pitfalls, e.g., generalizability and clinical applicability. The future direction of prediction model development should be directed towards a more personalised approach. Continuous optimisation of the predictive accuracy of the models would be achieved by involving more serial and dynamic parameters.

Mutations involving CTNNB1, the gene encoding beta-catenin, and other molecular alterations that affect the Wnt/beta-catenin signaling pathway are exceptionally common in hepatocellular carcinoma. Several of these alterations have also been associated with scarcity of immune cells in the tumor microenvironment and poor clinical response to immune checkpoint inhibitor therapy. In light of these associations, tumor biomarkers of beta-catenin status could have the potential to serve as clinical predictors of immunotherapy outcome. This editorial review article summarizes recent pre-clinical and clinical research pertaining to associations between beta-catenin activation and diminished anti-tumor immunity. Potential non-invasive biomarkers that may provide a window into this oncogenic mechanism of immune evasion are also presented and discussed.

Hepatocellular carcinoma (HCC), especially hepatitis B virus (HBV)-related, remains a major cause of cancer-related mortality worldwide. Unless there is early detection with curative treatment, the 5-year survival rate of advanced HCC is less than 15%. The preventive strategies for HBV-related HCC are thus urgently needed to reduce the global burden of this disastrous cancer. Primary prevention involves the avoidance of viral infection through hepatitis B vaccination and interruption of viral transmission from patients with chronic HBV infection. Universal neonatal hepatitis B vaccination program has successfully reduced the prevalence of HBV carriage rate as well as HCC incidence in vaccinated cohorts. However, HBV elimination is still difficult to achieve. Regarding secondary prevention, long-term treatment with nucleos(t)ide analogues has been proven to reduce the risk of HBV-related HCC. Individual risk stratification and a periodic HCC surveillance in these patients could facilitate early HCC diagnosis. Finally, tertiary prevention can also be achieved by life-long treatment with NAs to reduce the risk of HCC recurrence after curative treatment of primary HCC. Challenges ahead include the fact that HBV is not yet curable by current antiviral agents. Combination therapy with direct anti-HBV agents and host-targeting immunomodulatory agents is under active development. In addition, HCC risk cannot be eliminated even in patients with HBsAg seroclearance or functional cure. Therefore, HCC surveillance is strongly recommended for every patient with chronic HBV infection.

Aim: Robotic liver resection (RLR) is a new platform for minimally invasive hepatobiliary surgery. Minimally invasive surgery can confer benefits to patients with hepatocellular carcinoma (HCC), which is mostly associated with underlying chronic liver disease. Despite the inherent functional merits of robotics for surgical techniques, the clinical advantages of hepatectomy are not well defined. Therefore, we reviewed the short-term and long-term surgical results of 57 HCC cases in 46 patients who underwent RLR at our institution.

Methods: We evaluated the feasibility and safety of robotic anatomic liver resection for HCC by comparing the results of the anatomic resection (AR) group (n = 23) and non-anatomic resection (NAR) group (n = 34).

Results: Overall (n = 57), the liver-specific console time was 487 min, blood loss was 194 g, and there was one open conversion (2%). Postoperative data showed acceptable hepatic functional recovery, with a major complication rate of 11% and no 90-day mortality. Compared to NAR, AR was associated with longer operative and console times, more blood loss, and worse postoperative liver function, thus reflecting the greater extent and complexity of hepatectomies for more advanced-stage tumors than NAR. Nonetheless, major complication rate, mortality rate, length of hospital stay, and R0 resection rate were comparable between groups. Long-term results were comparable to those of previously reported hepatectomies for HCC and were similar between groups.

Conclusion: RLR including AR may be a safe and feasible form of hepatectomy for select patients with HCC.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder worldwide. It comprises a spectrum of conditions that range from steatosis to non-alcoholic steatohepatitis, with progression to cirrhosis and hepatocellular carcinoma. Currently, there is no FDA-approved pharmacological treatment for NAFLD. The pathogenesis of NAFLD involves genetic and environmental/host factors, including those that cause changes in intestinal microbiota and their metabolites. In this review, we discuss recent findings on the relationship(s) of microbiota signature with severity of NAFLD and the role(s) microbial metabolites in NAFLD progression. We discuss how metabolites may affect NAFLD progression and their potential to serve as biomarkers for NAFLD diagnosis or therapeutic targets for disease management.

Chronic infection of the liver by the hepatitis B virus (HBV) is associated with increased risk for developing hepatocellular carcinoma (HCC). A multitude of studies have investigated the mechanism of liver cancer pathogenesis due to chronic HBV infection. Chronic inflammation, expression of specific viral proteins such as HBx, the integration site of the viral genome into the host genome, and the viral genotype, are key players contributing to HCC pathogenesis. In addition, the genetic background of the host and exposure to environmental carcinogens are also predisposing parameters in hepatocarcinogenesis. Despite the plethora of studies, the molecular mechanism of HCC pathogenesis remains incompletely understood. In this review, the focus is on epigenetic mechanisms involved in the pathogenesis of HBV-associated HCC. Epigenetic mechanisms are dynamic molecular processes that regulate gene expression without altering the host DNA, acting by modifying the host chromatin structure via covalent post-translational histone modifications, changing the DNA methylation status, expression of non-coding RNAs such as microRNAs and long noncoding RNAs, and altering the spatial, 3-D organization of the chromatin of the virus-infected cell. Herein, studies are described that provide evidence in support of deregulation of epigenetic mechanisms in the HBV-infected/-replicating hepatocyte and their contribution to hepatocyte transformation. In contrast to genetic mutations which are permanent, epigenetic alterations are dynamic and reversible. Accordingly, the identification of essential molecular epigenetic targets involved in HBV-mediated HCC pathogenesis offers the opportunity for the design and development of novel epigenetic therapeutic approaches.

Laparoscopic liver resection (LLR) has expanded to include major liver resection and systematic resection as the techniques have advanced. Regardless of the oncological significance of anatomical resection, dissection of the intersegmental plane is useful in liver resection because it makes liver dissection easier and does not leave an ischemic area. In laparoscopic surgery, the hepatic vein can be exposed with less bleeding than in open surgery because bleeding can be controlled by pneumoperitoneum pressure. Therefore, the hepatic vein is a useful indicator to guide the dissected surface and to determine the depth. However, the basic technique of exposing the hepatic vein during LLR is required. The hepatic vein root can be approached using either a cranial or dorsal approach, with the dorsal approach providing the favorable view characteristic of laparoscopy. Selecting the dissection layer with the Laennec’s capsule of the hepatic vein roots in mind is also a useful technique to ensure more reliable dissection of the hepatic vein. We summarize previous reports on techniques for facilitating LLR using the hepatic vein as a guide and outline the role of each hepatic vein type. Although there are many reports of procedures using the hepatic vein as a guide, the terminology of the approach awaits standardization in the future.

Aim: Simple, rapid, and non-invasive methods for the early diagnosis of non-alcoholic steatohepatitis (NASH) in patients with fatty liver are an unmet need in clinical practice. Transient elastography (TE), commonly used for measuring liver stiffness (LS), which is significantly influenced by both liver fibrosis and inflammation is a promising tool.

Methods: We studied retrospectively the impact of TE in a cohort of 98 consecutive asymptomatic patients with fatty liver who underwent a liver biopsy [21 non-alcoholic fatty liver (NAFL) and 77 NASH] and TE on the same day at the Hepatology Unit of University Hospital of Pisa. Patients positive for HBsAg, anti-HCV, HIV, autoantibodies, drug-induced liver disease, Wilson’s disease, hemochromatosis, alpha-1 antitrypsin deficiency, type 2 diabetes, or neoplasia were excluded.

Results: NAFL patients were younger (42.5 years vs. 47.7 years, P = 0.02) and with lower BMI (25.5 kg/m² vs. 28.8 kg/m², P < 0.001) than NASH patients. TE was higher in NASH than NAFL patients (8.1 kPa vs. 5.4 kPa, P = 0.01). Age, BMI, TE, and total/LDL cholesterol were statistically significantly different between NAFL and NASH patients, but with multivariate analysis only BMI (P = 0.009) and TE (P = 0.031) were independent predictors of NAFL/NASH with AUROCs of 0.771 and 0.754, respectively. A score combining TE and BMI (TE*BMI) showed the best AUROC (0.817, by De Long test, P = 0.01) to differentiate NAFL/NASH (P = 0.005).

Conclusion: Ultrasound based LS measure qualifies as a candidate tool for the early screening of NASH in fatty liver patients provided that its measure is properly standardized and tested in large prospective studies enrolling patients with different clinical and histological features.

Non-alcoholic fatty liver disease (NAFLD) is one of the most prominent causes of liver-related morbidity in the Western world. NAFLD is a chronic disease characterised by accumulation of triglycerides in hepatocytes. Upon damage, hepatocytes drive regeneration to sustain homeostasis of the liver. However, 30-40 years of ongoing replication induced by chronic lipid damage and oxidative stress increase senescence of the hepatocytes. At this stage, activation of a reserve compartment is seen, known as the hepatic progenitor cells (HPCs). HPCs are bipotent cells which can differentiate into hepatocytes or cholangiocytes depending on the underlying aetiology in order to facilitate liver regeneration. Activation of HPCs is observed as ductular reaction (DR), comprising an expansion of transit amplifying cells of the terminal branches of the biliary tree. DR is usually observed in advanced NAFLD but is also associated with histological severity and distinct molecular profiles. In this context, information about HPCs and their activation in the form of DR may add a both diagnostic and prognostic values when assessing NAFLD patients. In this review, we analyse HPCs characteristics and development, and the clinical impact of their activation in subjects with NAFLD.

The liver is bestowed with an extraordinary regenerative capability, which is accomplished by a well-coordinated cellular and molecular response at different phases of regeneration. Metabolism, as the primary function of liver, displays various alterations as a consequence of hepatic insufficiency from an injury. These metabolic perturbations are physiologically relevant for promoting hepatocellular proliferation and regeneration. On the other hand, proliferation of otherwise quiescent hepatocytes and accompanied regeneration are regulated by transient, but precisely regulated transcriptional reprogramming. This phase- cell- and time-specific gene expression is controlled by epigenetic mechanisms. Hence, both metabolic and epigenetic changes regulate liver regeneration events. But the cross-talk between metabolic and epigenetic changes for a successful liver regeneration needs to be explored. Since most of the enzymatic players of epigenetic mechanisms rely upon metabolites for their substrates and co-factors, we expect a highly coordinated inter-dependence between metabolism and epigenetics during liver regeneration too. In the present review, we discuss various metabolic and epigenetic regulatory mechanisms for liver regeneration, and put forward the possible metabolic-epigenetic-liver regeneration link for a better understanding of the process and identification of novel targets for liver-related diseases in clinical settings.

The age-adjusted incidence of primary liver cancer (PLC) has been declining in China. However, PLC cases in China account for 55% globally. The disease burden is still high and the five-year survival rate has not improved significantly in the past two decades. This guideline outlines PLC screening in populations with high risk, both in the hospital and community settings. Liver cirrhosis and chronic hepatitis B are the main causes of PLC in China. For better PLC surveillance and screening in clinical practices, it is recommended that these populations be stratified into four risk levels, namely, low-, intermediate-, high-, and extremely high-risk. A lifelong surveillance is suggested for those with risks of PLC. The intervals and tools for surveillance and screening are recommended based on risk levels. Abdominal ultrasonography combined with serum alpha-fetoprotein tests (routine surveillance) is recommended every 6 months for high risk PLC. Routine surveillance every 3 months and enhanced CT/MRI examinations every 6-12 months is recommended for those with extremely high risk of PLC. The surveillance interval can be extended to one year or longer for those with low or intermediate risk because the annual incidence of low risk PLC is relatively low. The cost-effectiveness of these recommendations remains to be evaluated.

Hepatocellular carcinoma (HCC) is increasing in prevalence and has the potential to be a highly lethal malignancy. Patients with early-stage HCC have potentially curative therapeutic options, but treatments for more advanced HCC were limited until recently. Historically, tyrosine kinase inhibitors have been used in both the first- and second-line treatment of patients with advanced HCC; however, given HCC’s highly immune-responsive origins, immunotherapy is proving to be a promising systemic therapy in the frontline as well as later lines of treatment. Notably, recent studies of the novel antibody therapy combination atezolizumab (anti-PD-L1) and bevacizumab demonstrated unprecedented, practice-changing efficacy in the advanced HCC setting and led to its Food and Drug Administration approval. Although such landmark studies offer new treatment options for patients with HCC, the role of potential biomarkers to monitor immunotherapy response is largely unknown and undergoing exploration.

Different strategies have been used to induce preoperative liver hypertrophy and reduce the risk of postoperative liver failure. Those have included both radiological-interventional and surgical strategies, such as portal and hepatic vein embolization, 2-stage hepatectomy and associated liver partition with portal vein ligation for staged hepatectomy (ALPPS). Herein, we describe the case of a patient with a large right liver hepatocellular carcinoma not amenable to liver transplantation, with HBV-related chronic hepatitis and a small future liver remnant (FLR), who underwent a multistep approach to ensure a safe major laparoscopic resection with an adequate FLR.

Hepatocellular carcinoma (HCC) is the fifth most widespread cancer responsible for one fourth of cancer-related deaths globally. Persistent infection with hepatitis B virus (HBV) remains the main cause of HCC summing up to 50% of its causative etiology. Our recent studies, supported by findings from others, uncovered that HBV and its close relative woodchuck hepatitis virus (WHV) integrate into hepatocyte genome almost immediately, hence in minutes after infection. Retrotransposons and genes with translocation potential were found to be frequent sites of HBV insertions, suggesting a mechanism of HBV DNA spread across liver genome from the earliest stages after virus invasion. Many other genes were identified as the sites of early hepadnavirus merges in human hepatocyte-like lines infected de novo with HBV and in natural woodchuck WHV infection model. It was uncovered that head-to-tail joins (HTJs) prevail among the earliest virus-host fusions, implying their formation via the non-homologous-end-joining (NHEJ) pathway. Overlapping homologous junctions resulting from the micro-homology-mediated-overlapping-joining (MHMOJ) were rarely detected. Formation of the initial HTJs coincided with strong induction of reactive oxygen species (ROS) and transient appearance of inducible nitric oxide (iNOS). This was accompanied by cell DNA damage and activation of the poly(ADP-ribose) polymerase 1 (PARP1)-mediated host DNA repair machinery, which may explain predominant HTJ format of the first virus-host fusions. Identification of initial integration sites and resulting alterations in hepatocyte phenotype may pave a way to discovery of reliable markers of HBV-triggered HCC, including HCC resulting from occult HBV infection. Our research strongly argues that HBV is an ultimate human carcinogen capable of initiation of a pro-oncogenic process immediately after first contact with a susceptible host.

The goal of antiviral treatment for chronic hepatitis B (CHB) is to reduce the risk of liver-related complications, including liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). It is not possible to eliminate hepatitis B virus from the host with currently available antiviral treatments; hence, a realistic goal is to decrease the risk of HCC as much as possible with an appropriate and timely antiviral treatment. For the past decades, real-world evidence has enlarged the field of CHB research. Presently, there is mounting evidence that randomized clinical trials are not technically and ethically possible to conduct. In this review, we focus on secondary prevention by antiviral treatment in patients with CHB, mainly based on real-world evidence.

Currently, laparoscopic liver resections are routinely performed at an increasing number of centres and has extended to include major liver resections as well as more challenging segments of the liver. We believe that patient positioning and port placement is a critical yet under described component of successful laparoscopic liver resection to achieve optimal visualisation and allow for an ergonomic and safe dissection. In this article, we describe the advantages of various types of patient positioning as well as provide illustrations for an array of trocar configurations previously described in literature. Whilst there is no universally accepted standardization of port placement for various resection types, this descriptive article can serve as a guide for the various possibilities of port configurations that can be individually adapted by surgeons based on their preference as well as the patient’s physique and anatomy.

Hepatitis B infection (HBV) is one of the most common causes of hepatocellular carcinoma (HCC) worldwide. The age of occurrence, prognosis and incidence vary dramatically depending on the region of the world. This geographic variation is largely dependent on the contrasting incidence of HBV, age of transmission of the virus, the timing of integration into the human genome, and different HBV genotypes, as well as environmental factors. It results in a wide difference in viral interaction with the immune system, genomic modulation and the consequent development of HCC in an individual. In this review, we describe many factors implicated in HCC development, provide insight regarding at-risk populations and explain societal recommendations for HCC surveillance in persons living with HBV in different continents of the world.

We present a fully laparoscopic partial RALPPS (radiofrequency-assisted liver partition with portal vein ligation for staged hepatectomy) on a cirrhotic 71-year-old man with a bifocal hepatocellular carcinoma. The patient’s liver was preoperatively studied through a CT-guided 3D-reconstruction. During stage-1, the right portal vein was ligated and injected with alcohol distally; the vascular limit between the right and left anterior sectors was defined through the systemic infusion of indocyanine green for a negative staining. Hence, laparoscopic ablations, guided by luminescence and checked with intraoperative ultrasounds, were performed. After 55 days, the future liver remnant increased from 28.6% to 46.3%, allowing a laparoscopic RALPPS stage-2. Fully laparoscopic RALPPS technique shows several advantages compared to the original procedure, especially in patients with cirrhosis. The avoidance of liver transection during stage-1 reduced blood loss and intraabdominal adhesions, and it eliminated the risk of biliary fistulae and allowed an easier liver transection during stage-2.

Aim: In this systematic review, guidelines on non-alcoholic fatty liver disease (NAFLD) were evaluated, aiming at a guideline synthesis focusing on diagnosis and staging.

Methods: A systematic literature search was conducted on any relevant database or institutional website to find guidelines on NAFLD assessment intended for clinical use on humans, in English, published from January 2010 to August 2020. Included guidelines were appraised using the AGREE II Instrument; those with higher scores and intended for use in adult patients were included in a comparative analysis.

Results: Fourteen guidelines were included in the systematic review, eight of which reached an AGREE II score sufficiently high to be recommended for clinical use, of which one developed for pediatric patients only. British and North American guidelines received the highest scores. Most guidelines recommend a screening or case-finding approach in patients with metabolic risk factors who are at increased risk of steatohepatitis or fibrosis. Ultrasound is mostly recommended to confirm steatosis, while the presence of metabolic syndrome, liver function tests, fibrosis scores, and elastographic techniques may help in selecting high-risk patients to be referred to the hepatologist, who may consider liver biopsy, although referral criteria for liver biopsy are not clearly defined. Most guidelines identify the development of noninvasive tests to replace liver biopsy as a research priority.

Conclusion: Several high-quality guidelines exist for NAFLD assessment, with no complete agreement on whether to screen high-risk patients and on the tests and biomarkers suggested to stratify patients and select those to be referred to liver biopsy.

Hepatocellular carcinoma (HCC) is a malignant neoplasm associated with significant mortality worldwide. The most commonly applied curative options include liver resection and liver transplantation (LT). Advances in technology have led to the broader implementation of minimally invasive approaches for liver surgery, including laparoscopic, hybrid, hand-assisted, and robotic techniques. Laparoscopic liver resection for HCC or living donor hepatectomy in LT for HCC are considered to be feasible and safe. Furthermore, the combination of laparoscopy and LT is a recent impressive and promising achievement that requires further investigation. This review aims to describe the role of minimally invasive surgery techniques utilized in LT for HCC.

Despite the development of surrogate non-invasive methods, histological evaluation remains an important tool for reliable classification, grading and staging, as well as prognosis in non-alcoholic fatty liver disease (NAFLD). However, histological evaluation has been criticised because it requires a liver biopsy, its propensity for sampling, and inter-observer variation. This article highlights the future developments in the morphological interpretation of liver biopsy in NAFLD, so as to aid in improving its diagnostic and prognostic utility.

Aim: Rituximab is administered for ABO blood type incompatibility or donor-specific anti-HLA (human leukocyte antigen) antibody-positive liver transplantation (LT). However, the impact of rituximab administration on hepatocellular carcinoma (HCC) recurrence over a long term period remains unclear. The present study aimed to retrospectively investigate the impact of rituximab-based prophylaxis on HCC recurrence after living donor LT (LDLT).

Methods: A total of 117 patients who had undergone LDLT for HCC at Kyoto University between February 2006 and October 2018 were retrospectively enrolled for this study. Overall survival (OS) and the recurrence rate (RR) for HCC after LDLT were examined in patients who received rituximab (rituximab group: n = 31) vs. those who did not (control group: n = 86). Additional analyses were conducted as per the Milan criteria, the University of California San Francisco extended criteria (single tumor ≤ 6.5 cm, or ≤ 3 nodules with the largest tumor ≤ 4.5 cm, and total tumor diameter ≤ 8 cm), and the Kyoto criteria (KC) [maximum size ≤ 5 cm, number ≤ 10, des-gamma-carboxy prothrombin (DCP) ≤ 400]. Moreover, we analyzed risk factors associated with HCC recurrence with a focus on pretransplant factors.

Results: The one-, three-, and five-year (1/3/5-y) OS and RR for all patients were 89%/81%/79% and 5%/9%/11%, respectively. The 1/3/5-y OS and 1/3/5-y RR in the rituximab group vs. the control group were 87%/77%/69% and 4%/4%/8% vs. 89%/82%/82% and 5%/11%/12%, respectively (P = 0.11 and P = 0.55, respectively). In the subgroup analysis stratified by the selection criteria, the RR was comparable between groups. The number of patients with non-recurrence-related death tended to be higher in the rituximab group than the control group. Multivariate analysis identified maximum tumor size (P = 0.003) and preoperative treatment (P = 0.024) as independent risk factors for HCC recurrence.

Conclusion: Rituximab administration does not seem to affect HCC recurrence after LDLT.

Coffee is one of the most widely consumed beverages worldwide. It is a complex chemical mixture composed of thousands of physiologically active compounds, including caffeine, chlorogenic acid, and diterpenes (cafestol and kahweol). Recently, coffee has emerged as a beverage with various health benefits, in particular in liver disease. Several epidemiological and observational studies demonstrated an inverse association between coffee consumption and primary liver cancer risk. The biological mechanisms underlying the hepatoprotective effect of coffee are still not completely understood. This article reviews the current available literature about the association between coffee consumption and hepatocellular carcinoma risk and the proposed mechanisms by which coffee exerts its chemopreventive properties.

Nonalcoholic fatty liver disease is a major contributor to chronic liver disease worldwide, and 10%-20% of nonalcoholic fatty liver progresses to nonalcoholic steatohepatitis (NASH). Astaxanthin is a kind of natural carotenoid, mainly derived from microorganisms and marine organisms. Due to its special chemical structure, astaxanthin has strong antioxidant activity and has become one of the hotspots of marine natural product research. Considering the unique chemical properties of astaxanthin and the complex pathogenic mechanism of NASH, astaxanthin is regarded as a significant drug for the prevention and treatment of NASH. Thus, this review comprehensively describes the mechanisms and the utility of astaxanthin in the prevention and treatment of NASH from seven aspects: antioxidative stress, inhibition of inflammation and promotion of M2 macrophage polarization, improvement in mitochondrial oxidative respiration, regulation of lipid metabolism, amelioration of insulin resistance, suppression of fibrosis, and liver tumor formation. Collectively, the goal of this work is to provide a beneficial reference for the application value and development prospect of astaxanthin in NASH.

Hepatocellular carcinoma (HCC) located in caudate lobectomy is not common, but caudate lobectomy is associated with technical difficulty and high degree of operative risk due to deep location of the caudate lobe and surrounding major vasculature. Recently, with advances in technology and accumulation of techniques, minimal invasive surgery has been widely performed in the field of liver surgery. However, laparoscopic isolated caudate lobectomy is still technically challenging which requires in-depth knowledge of the anatomy of the caudate and extensive experience in laparoscopic liver surgery. This review focuses on the surgical techniques and outcomes of laparoscopic isolated caudate lobectomy. Although it is difficult to make conclusion regarding oncologic outcome because only a few studies with limited case numbers have reported oncologic outcome of laparoscopic isolated caudate lobectomy for HCC, laparoscopic approach could be performed safely with several benefits and become a favorable method for isolated caudate lobectomy, especially for surgeons with relatively large experience in laparoscopic liver surgery.

Despite universal vaccination and antiviral therapies being available for decades, chronic hepatitis B (CHB) remains the leading primary liver disease for liver transplantation in many parts of the Asia-Pacific region. The main indications include decompensated cirrhosis, severe acute flares, and hepatocellular carcinoma. Liver transplantation is not a sterilizing cure for CHB infection, therefore long-term antiviral prophylaxis is required. As the virus is never completely eradicated after transplant, the main goal of antiviral prophylaxis is to prevent reactivation, rather than recurrence or reinfection. Current available antiviral prophylaxis using nucleos(t)ide analogs (NUCs) ± hepatitis B immunoglobulin (HBIG) are highly effective in preventing HBV reactivation after liver transplantation. Only NUCs with high potency and high barriers to resistance should be used, as there is still a risk of developing resistance and subsequent virological rebound and reactivation for older NUCs. Over the past decade, there has been a trend towards using less HBIG, with HBIG-free regimens showing excellent long-term outcomes and survival. Although cessation of prophylaxis may be feasible in a highly selected group, this should only be attempted within clinical trial settings, and life-long prophylaxis is still recommended. Future novel agents may restore the immune control of HBV, whereby antiviral therapy can be safely discontinued.

This article synthesises the current evidence on the risk of de novo extrahepatic cancer in people living with a liver transplant after hepatocellular carcinoma, the risk factors for cancer, and the recommended approaches to cancer prevention and surveillance. People living with a transplanted liver have an elevated risk of cancer and cancer death, and the indication for transplantation does not markedly alter the cancer risk. The excess risk of cancer is double that of the age- and sex-matched general population. Virus-related cancers, especially non-Hodgkin lymphoma, Kaposi sarcoma, Merkel cell carcinoma, oral, and anogenital cancers occur at increased risk, as do cancers causally associated with high prior sun exposure, smoking and excessive alcohol consumption, including skin, oesophageal, larynx, lung, kidney, and bladder cancer. The risk of incident breast and prostate cancer is not increased. Cancer-related deaths largely mirror that for cancer incidence, and extend to include the more common malignancies such as breast, colorectal, prostate cancer and non-melanoma skin cancer. As medical immunosuppression is the principal risk factor for cancer, the regimen should be reviewed on a regular basis to achieve immunosuppression minimisation. An individual, risk-based approach to cancer screening according to test characteristics and personal and family cancer history, medical history, lifestyle factors, and life expectancy is recommended. Multicomponent interventions may achieve the best results in supporting the adoption and maintenance of cancer risk-reducing behaviours. Regular, empowering patient counselling and education is a cornerstone for the care of people living with a liver transplant.

Glycine N-methyltransferase (GNMT) exerts a pivotal role in the methionine cycle and, consequently, contributes to the control of methylation reactions, and purine and pyrimidine synthesis. Numerous observations indicate that GNMT is a tumor suppressor gene, but the molecular mechanisms of its suppressive action have only been partially unraveled to date. Present knowledge indicates that GNMT acts through both epigenetic and genetic mechanisms. Among them are the decrease of AKT signaling through the inhibition of the RAPTOR/mTOR complex and the interaction of GNMT with the PTEN inhibitor, PREX2. Furthermore, GNMT is a polycyclic aromatic hydrocarbon-binding protein and a mediator of the induction, by polycyclic hydrocarbons of the cytochrome P450-1A1 gene, whose polymorphism is involved in favoring different types of cancers. Finally, GNMT suppresses the expression of the transcription factor NRF2, whose overexpression is associated with HCC development. These findings suggest a multifaceted suppressor mechanism of the GNMT gene.

In the last few years, there has been a significant widening of the landscape of systemic therapy for unresectable hepatocellular carcinoma (HCC) patients. After the landmark drug sorafenib, several other molecules have been approved for treatment in first-line (lenvatinib) and second-line (regorafenib, cabozantinib, and ramucirumab) regimens. Very recently, another important step forward has been made with the demonstration that the combination of an anti-programmed death ligand 1 and an anti-vascular endothelial growth factor (atezolizumab + bevacizumab) provides better survival results compared to sorafenib, thus becoming the new paradigm in first-line treatment of HCC. In consideration of this rapidly evolving situation, with the availability of many potential active drugs, the American Society of Clinical Oncology recently published a guideline in order to advise on the selection of systemic treatment options. However, also considering the uncertainties and the unmet needs in the current treatment of patients with advanced liver cancer is mandatory.

Aim: The microbiome has been shown to be pivotal in the development of metabolic associated fatty liver disease (MAFLD). Few have examined the relationship of the microbiome specifically with steatosis grade. Therefore, our aim was to characterize the association of the microbiome with MAFLD steatosis severity while adjusting for metabolic comorbidities including diabetes.

Methods: We enrolled patients with MAFLD at the West Los Angeles Veterans Affair Hospital. All patients underwent ultrasound elastography, fasting serum collection, and fecal sampling for 16S sequencing. We examined the associations of microbial diversity and composition with advanced steatosis, defined as a CAP score of ≥ 300 dB/m, with or without the presence of metabolic comorbidities.

Results: Seventy-five patients were enrolled. African American were less likely to have advanced steatosis than either Hispanics or Whites (P = 0.001). Patients with more advanced steatosis had higher fasting serum triglyceride (192.6 ± 157.1 mg/dL vs. 122.5 ± 57.4 mg/dL), HbA1c (6.7% ± 1.4% vs. 6.1% ± 0.8%), transaminases, and were more likely to have metabolic syndrome (52.4% vs. 24.2%, P = 0.02). Advanced steatosis and diabetes were associated with altered microbial composition. Bacteroides was negatively associated with advanced steatosis while Megasphaera was positively associated with steatosis. Akkermansia was negatively associated with diabetes, while Anaerostipes and Parabacteroides were positively associated with diabetes.

Conclusion: Diabetes and metabolic syndrome are associated with hepatic steatosis severity in MAFLD patients and both advanced steatosis and comorbid diabetes are independently associated with microbiome changes. These results provide insight into the role of the gut microbiome in MAFLD associated with metabolic syndrome.

Subtypes of hepatocellular carcinoma are important for 2 primary reasons: they help improve diagnostic accuracy, as different subtypes have their own diagnostic pitfalls; they are an important building block to the personalization of patient care, as subtypes are enriched for shared genetic changes and biological associations. The most common subtype of hepatocellular carcinoma is steatohepatitic hepatocellular carcinoma (SH-HCC), a subtype that is strongly linked to tumorigenesis in the setting of the metabolic syndrome and metabolic-associated liver disease (MAFLD) and/or alcoholic hepatitis. SH-HCC shows macrovesicular steatosis, balloon cells, Mallory hyaline, intratumoral inflammation, and intratumoral fibrosis. This review examines the historical development of this subtype and explores in detail the histological features that are used to define SH-HCC. The strongest molecular correlates to-date include a low frequency of CTNNB1 mutations and possible activation of the IL6/JAK/STAT pathway. In addition, critical unresolved questions are discussed in detail to refine the histological definition of SH-HCC, including the minimal histological thresholds needed to make the diagnosis, as well as whether or not SH-HCC currently is a mixed category of tumors, containing some tumors where the distinctive morphology is driven by tumor-specific genetic changes, and other tumors where the findings are an epiphenomenon, a reflection of metabolic or alcohol-associated fatty liver disease, and not necessarily of genetic/epigenetic changes.

With the highest annual fatality ratio (mortality-to-incidence ratio), reported for a human cancer, hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related deaths worldwide and its distribution is not uniform. In Sub-Saharan Africa (SSA), HCC is the second leading cause of cancer-related deaths for men and the fourth for women in 2020, with average age-standardised mortality rates of 8.2 and 4.2 per 100,000 persons/year, respectively. In this region, HCC presents in younger age groups and has a median survival rate of ~3-4 months. The major risk factors for HCC include viral [hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus (HDV)] and environmental [dietary aflatoxin and iron overload] factors, with more than 50% being attributable to HBV, which is endemic in SSA. HCC control efforts in SSA are faced with a number of unique challenges, including resource restrictions, a paucity of good data, few cancer registries, inaccessibility of treatment for HBV and HCV, co-infection with human immunodeficiency virus (HIV), exposure to co-carcinogen aflatoxin B1, unique (sub)genotypes of HBV and changing natural history and aetiology of HCC as a result of antiretroviral therapy rollout for HIV and changing lifestyles. These unique features of HCC in SSA, together with the challenges faced in its prevention and appropriate public health intervention, diagnosis and treatment, all suggest that HCC in SSA is deserving of an in depth understanding by further focused research. Considerable motivation of policymakers, work and resources are required to reduce the burden of this cancer on the subcontinent.

Primary liver cancers constitute the fourth leading cause of cancer mortality worldwide, due to their high morbidity, late diagnosis and lack of effective treatments. Hepatocellular carcinoma (HCC) represents 80% and cholangiocarcinoma (CCA) 15% of liver cancers. Several genetic and epigenetic gene alterations (e.g., TERT, TP53 or CTNNB1) are HCC drivers, although many additional gene alterations contribute to HCC initiation and/or progression. Rho and Ras GTPases have been widely implicated in tumorigenesis and their activators (GEFs) have recently emerged as putative key players in liver cancer. The Ras GEF, C3G (RAPGEF1), a GEF mainly for Rap proteins, has recently been uncovered as a relevant gene in HCC. Its upregulation promotes tumor growth, although a decrease in C3G levels favors migration/invasion and lung metastasis. Rap1A/1B/2A/2B are overexpressed in HCC tumors, but their effects are controversial and not equivalent to those of C3G. The C3G partner, CRKL, is also overexpressed in HCC, promoting proliferation, migration and invasion. Various Rho GEFs are also deregulated in liver cancer. Tiam1 and Tiam2 expression is upregulated in HCC, promoting proliferation, migration and metastasis. In addition, ARHGEF-10L/9/19/39 are overexpressed in HCC tumors, facilitating migration, invasion, metastasis and proliferation. Another Rho GEF, Vav2, is also involved in metastasis. Little is known about the participation of these GEFs and GTPases in CCA. However, analysis of cancer databases uncovered deregulations or genetic alterations in several of these genes, in both CCA and HCC. Hence, GEFs function appear essential for liver homeostasis, although future studies are needed to define their precise function in liver cancer.

Following injury such as partial hepatectomy, the liver activates its response to proliferate and repopulate the lost liver mass. This process is associated with the re-expression of pro-regenerative genes that are controlled epigenetically. While epigenetic control of gene expression can be observed in many forms (DNA methylation, histone modification, chromatin remodeling, etc.), this review will focus on the role of regulators of DNA methylation in the concept of cell proliferation and progression and its relevance to tissue regeneration. Obligate proteins UHRF1 and DNMT1 are key players in the maintenance of methylation in the process of DNA replication. Both proteins have a well-established role in cell proliferation, progression and methylation maintenance, and are indicators of the stress response. Understanding how these regulatory mechanisms function is crucial in determining clinical applications on restoring lost tissue in the liver as a result of infection, toxins, or other liver pathologies.

Liver transplantation for the autoimmune liver diseases (AILD), which includes autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), is indicated in the setting of decompensated cirrhosis, liver failure, and hepatocellular carcinoma (HCC). The risk of HCC is thought to be low in AILD, though data on the risk factors and predictors of HCC are limited in this population. Recurrence of AILD can occur in over half of the patients, complicating the post-transplant course. The pathogenesis of recurrent AILD involves a complex interaction of genetic and environmental influences, as well as a variety of clinical risk factors. Graft and patient survival are negatively impacted by recurrent AILD and the optimal approach to the treatment of AILD recurrence is the subject of ongoing research. This review will address the current literature on the risk of HCC in AILD, as well as the development and management of recurrent AILD post-liver transplantation.

Despite hepatocellular carcinoma’s position as the second most common pediatric liver tumor, it is a rare tumor in children warranting international collaboration to improve outcomes. Few cases diagnosed in earlier stages, when confined to the liver and responding to systemic treatment or with resectable metastases, may be cured by complete resection and/or orthotopic transplantation. Complete resection is the only chance for cure; therefore, all attempts should be made to make these options available. Despite modest progress in locoregional treatments, these serve in most cases as palliative treatment or as a bridge to definitive treatment at best. Currently used systemic treatments have response rates below 50%. Five-year survival in advanced stages is below 30%. The international Paediatric Hepatic International Tumour Trial trial is evaluating novel systemic treatments in pediatric hepatocellular carcinoma. Patients suffering from these tumors likely benefit from targeted treatment based on molecular aberrations corresponding with tumor subtype.

Aim: In the Japanese study group for Pediatric Liver Tumor (JPLT) studies, the survival of patients with hepatoblastoma (HB) was improved by cisplatin/pirarubicin-based chemotherapy with combined surgical resection. We aimed to clarify whether marginal positive resection is correlated with the prognosis of HB patients from the JPLT-2 study (1999-2012).

Methods: Of the 361 JPLT-2 patients, we excluded 4 who died before surgery, 14 inoperable following preoperative chemotherapy, and 6 macroscopically positive resections and analyzed local recurrence and survival rates in 337 patients who underwent primary resection including liver transplantation.

Results: The five-year event-free survival (EFS) and overall survival (OS) rates were 76.0% and 87.7% in patients (n = 312) with complete resection of their primary tumors and 59.1% and 83.0% in those (n = 25) with microscopically margin-positive resection (microMPR), respectively. Among patients without distant metastasis, the five-year EFS and OS rates were 81.4% and 90.8% in those (n = 263) with complete resection vs. 62.5% and 90.9% in those (n = 22) with microMPR, respectively. The EFS, but not OS, was significantly lower (P < 0.05) in patients with microMPR vs. complete resection. The local recurrence rate was significantly different (chi-square = 12.11, P < 0.01) between the two groups.

Conclusion: In patients administered cisplatin/pirarubicin-based chemotherapy, the presence of microMPR influenced local recurrence but not outcome. Advance of liver surgery including LT correlated with improving of resection rates. The presence of microMPR influenced the local recurrence but not the outcome in the JPLT-2 study. The outcome of patients with microMPR might depend on the postoperative treatment and/or tumor biology rather than occurrence of recurrence.

Aim: To elucidate the role and efficacy of laparoscopic liver resection for elderly patients with hepatocellular carcinoma (HCC).

Methods: A retrospective comparative analysis was performed between laparoscopic and open liver resection operated from year 2008 to 2018. Consecutive HCC patients aged 65 or above at the time of operation were recruited. Patients with recurrent HCC and/or alternative pathology were excluded. Short-term and long-term outcomes between the laparoscopic and the open group were compared. Propensity score matching of patients in a ratio of 1:2 was conducted before comparison.

Results: A total of 911 patients underwent hepatectomy for primary HCC from 2008 to 2018. Among them, 320 elderly patients aged over 65 years old were eligible for analysis. Heterogeneities between laparoscopic and open groups were identified namely pre-operative albumin level, aspartate transaminase, and magnitude of hepatectomy (major vs. minor). After propensity score matching of 1:2, 46 patients in the laparoscopic group and 92 patients in the open group were included for comparison. The laparoscopic group had less blood loss (326 mL vs. 735 mL; P < 0.001), shorter operative time (223 min vs. 324 min; P < 0.001), and shorter hospital stay (6.3 days vs. 10.5 days; P < 0.001). No significant differences in postoperative morbidity and hospital mortality were noted between the groups. For oncological outcome, the laparoscopic group had a superior disease-free survival (59.7% vs. 44.5%; P = 0.041), and a trend towards better overall survival compared with the open group. (78.4% vs. 64.8%; P = 0.110).

Conclusion: Laparoscopic liver resection is a safe approach for elderly patients with HCC with benefits from faster recovery and better oncological outcomes.

Non-alcoholic fatty liver disease (NAFLD), which is considered a liver phenotype of metabolic diseases, is becoming a major cause of chronic liver disease. Multiple factors influence and interact with each other in a complex manner to form this pathological condition. As evidenced by low-grade chronic inflammation in obesity, which is a basic pathological feature of NAFLD, immune cell infiltration can occur in various organs, and immune cell infiltration into the liver plays an important role in the development of steatohepatitis. In recent years, an increasing number of reports indicate the involvement of innate immunity and adaptive immunity in the pathogenesis of NAFLD. CD4⁺ T-cells, which serve as an essential and complex element of the immune system and major regulators of host health and disease, are differentiated into functional T helper 1 (Th1), Th2, Th9, Th17, Th22, T follicular helper, and regulatory T-cells upon antigen stimulation in a special cytokine environment. In NAFLD patients, various pathological conditions such as obesity, diabetes, dyslipidemia, and adipose tissue inflammation coexist. Hence, T-cells can be affected by each of these pathological conditions. This review covers and discusses the reports on NAFLD and its associated pathologies as well as their effects on CD4⁺ T-cells.

Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized public health problem worldwide. To emphasize the close pathophysiological links between NAFLD and overweight/obesity, insulin resistance, and related metabolic comorbidities, a consensus statement of international experts in 2020 has recommended to replace the old acronym NAFLD with “metabolic dysfunction-associated fatty liver disease” (MAFLD). A set of “positive” criteria to diagnose MAFLD, regardless of daily alcohol consumption, has also been proposed. A “positive” definition of MAFLD and its special focus on the metabolic causative drivers of this liver disease is expected to reduce patient confusion on disease etiology, which can, in turn, improve the identification and awareness of this common and burdensome liver disease among both primary care physicians and specialists. However, the proposal to change the terminology from NAFLD to MAFLD is still under intense discussion, as also recently highlighted by a panel of international experts (led by Dr. Polyzos and Mantzoros), which is the main topic of discussion of this commentary. Further studies are required to better understand whether, and how, the proposed changes to the diagnostic criteria for MAFLD may impact on the risk of adverse hepatic and extra-hepatic clinical outcomes.

Hepatocellular carcinoma (HCC) is one of the most common indications for liver transplantation (LT). With expanding criteria and increasing number of transplants, post-transplant recurrence of HCC remains an important cause for concern and portends a poor survival in these patients. Traditionally, HCC recurrence post-LT has been notoriously difficult to manage and their outcomes dismal. A better understanding of the tumour biology and its interplay with the immune system, combined with newer oncological interventions has allowed for improved survivals in these patients. A useful classification of HCC recurrence is where it is divided into oligo-recurrence and disseminated recurrence. This system helps strategize their multi-disciplinary management algorithm and prognosticate outcomes. We provide an overview of the factors which may predict recurrence and summarise the current evidence on the management of post-LT HCC recurrence.

A deeper understanding of the genetic and molecular basis of hepatoblastoma (HB) has fueled the hope to help in identifying genes and signaling pathways that are amenable to therapeutic intervention. However, it has become clear that HB is a genetically very simple cancer and that rather alterations of the transcriptome or epigenome will facilitate a more stratified and rationalized approach to current therapeutics. In this review, we discuss recent findings on genomic, transcriptomic, and epigenomic data and their potential to serve as biomarkers and predictors of patient’s outcome. We also describe the state of the art in HB experimental biology, the in vitro and in vivo HB models that are currently available, and their use to improve our understanding of this disease and identify new treatment options.

Radiological assessment is evolving rapidly, including in paediatric liver tumour surgery. There are advancements in the fields of conventional radiology, 3D imaging and preoperative planning. This article presents the current research in paediatric liver imaging for liver tumour surgery and shows the results of a systematic search in computer-aided liver surgery in children. Sixteen original papers were found. We summarise the progress made and offer the directions in which further research could go. Computer-assisted surgery is a promising field for research and clinical application.

Immuno-oncology, particularly with the development of immune checkpoint inhibitors (ICIs), has become a front-line category of cancer-directed therapy, including in the treatment of hepatocellular carcinoma (HCC). While liver transplant (LT) offers a potential cure for HCC, the use of ICIs is a topic of safety concern both pre- and post-transplant due to the risk of donor graft rejection. Nonetheless, some scenarios for which the therapeutic effects of ICI may be highly beneficial include the downstaging of unresectable HCC pre-transplant, or the treatment of recurrent HCC and secondary malignancies post-transplant. In this review, we explored the evidence surrounding the use of ICI in the peri-transplant setting, including safety and efficacy. In a comprehensive review of 28 cases of ICI use post-transplant, we found graft rejection in 9 of 28 cases (32%). Some factors that may increase the risk of rejection include younger age, less time between LT and ICI therapy, and PD-1/PD-L1 expression in the donor graft (particularly when using anti-PD-1/anti-PD-L1 ICIs). Despite these concerns, we relay a case of successful HCC downstaging with nivolumab and subsequent LT. We also describe several cases of response to ICIs post-LT (7 of 28 cases) among a group that is often heavily pre-treated. We conclude that ICIs are valuable options in the peri-transplant setting that have demonstrated promising efficacy based on case reports. Controlled clinical trials are needed to further investigate the conditions that may allow safe delivery of these therapies.

Liver disease accounts for approximately 2 million deaths per year worldwide with cirrhosis, viral hepatitis, and malignancy being the most common causes. Consequently, the regenerative capacity of the liver is a topic of extreme interest in the search for curative therapies to end-stage liver disease. Mesenchymal stem cells (MSCs) have emerged as a promising new therapy for hepatic regeneration. MSCs have multiple properties that make them an appropriate treatment option for liver disease including easy accessibility, targeted migration, immunomodulatory potential and antifibrotic/antioxidant effects. Additionally, MSCs have potential clinical applications in acellular therapy and tissue engineering. Liver regeneration with concurrent attenuation of liver injury makes MSCs a compelling therapeutic target in the setting of severe liver disease. This review outlines the mechanisms of MSC-driven liver regeneration and suggests potential clinical applications.

Surgical resection and chemotherapy are the mainstay of the treatment for undifferentiated embryonal sarcoma of the liver. Whether neoadjuvant chemotherapy should be systematically performed is a matter of debate; perioperative morbidity and mortality should be carefully weighed against chemotherapy-associated complications. In order to manage undifferentiated embryonal sarcoma of the liver and to allow for accurate outcome analysis, there is a clear need for standardization of disease extent as well as for a risk stratification system, including the PRETEXT grouping system, patient age, and tumor size.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. In recent years, the metabolic syndrome epidemic is changing the etiological landscape of HCC, with metabolic liver disease comprising an exponentially increasing proportion of HCC cases. In this review, we discuss HCC in the context of metabolic syndrome, including its epidemiology, its unique clinical and pathological characteristics, and its multifactorial pathogenesis. We also discuss HCC prevention and management as relates to these patients.

Aim: Transarterial chemoembolisation (TACE) is recommended therapy for intermediate-stage hepatocellular carcinoma (HCC). However, the wide variations in outcomes reflect significant heterogeneity of this patient group. We evaluated the prognostic factors associated with survival in a real-world setting to identify those at high risk of a poor outcome.

Methods: Patients with HCC who underwent initial TACE at six tertiary hospitals between 2009 to 2014 were included via an extensive search of hospital databases and electronic medical records. Overall survival (OS) was measured from the date of initial treatment to the date of death or last follow-up. Univariate and multivariate Cox regression analyses were used to assess the effects of baseline variables on post-TACE survival.

Results: The majority of the 431 eligible patients were Caucasian (80%), male (87%), with a mean age of 66 years and had alcohol-related cirrhosis (43%). Most were Child-Pugh A (69%) with BCLC stage A (59%) or B (35%) disease, with a median OS of 28 months. On multivariate analysis, pre-treatment ascites (P = 0.001) and larger HCC (P < 0.001) were associated with worse overall survival, while higher serum albumin (P < 0.001) and HBV (P = 0.005) were associated with improved survival.

Conclusion: Patients with advanced liver disease, including the presence of ascites and lower serum albumin, as well as those with greater tumour burden, have poorer outcomes following TACE treatment. Such findings provide a better understanding of the variation in survival after TACE and are helpful in facilitating selection and timely stage migration of patients undergoing this therapy.

Primary sclerosing cholangitis (PSC) is a rare disease that may well be notified as a premalignant condition due to the increased cancer risk. The risk is highest for hepatobiliary cancer and increased by 28-398 times compared to the general population. When comorbidity with inflammatory bowel disease exists, the risk for colorectal cancer is increased 5-12 times and may even be higher after liver transplantation. The cancer risk estimates have decreased with time but vary according to study design. More recent population-based studies have approximated lower cancer risk than previous studies. Higher awareness and earlier detection of PSC together with increased surveillance over time may have influenced risk estimates. Surveillance for PSC patients is recommended for early tumor detection in both the liver and colon to enable curative treatment. The evidence for the efficacy of surveillance for early detection of hepatobiliary cancer is weak and an accepted common strategy worldwide is lacking. The high risk of hepatobiliary cancers has been confirmed repeatedly and future studies in PSC should focus on individualizing follow-up strategies and treatment.

Progressively, as chemotherapy has become more effective, more children with liver malignancies are amenable to liver transplantation, and indications have expanded from a limited range of cases (mostly hepatoblastoma) to a range of other unresectable malignant liver tumors; as a result, more children with hepatocellular carcinoma are also now proposed to transplantation, even and often outside the Milan criteria, for a cure. Recent series have highlighted that patient and graft survivals after transplantation for hepatoblastoma and hepatocellular carcinoma have improved in the last decade. Although consensus has not yet been reached about transplantation as a possible cure for other tumor types than hepatoblastoma and hepatocellular carcinoma, liver transplantation, generally speaking, has become an important pillar in the management of pediatric liver malignancies. Remaining limitations and inquiries relate to patient selection (in term of selection criteria considering the risk of recurrence), the role and usefulness of chemotherapy after transplantation, or the best immunosuppression strategy to both protect renal function and improve outcome. Although some prospective studies are on the way regarding these aspects, more studies are needed to explore this rapidly changing aspect of care.

Aim: We wished to establish 3D organoid-like hepatocellular carcinoma (HCC) models from HCC cell lines.

Methods: Hep3B, Huh7, HepG2, SNU398, SNU449, and SNU475 cell lines were inoculated into Matrigel and grown up to 9 days in hepatocyte specific or standard RPMI media. Spheroid formation was followed by light microscopy. Matrigel scaffolds were immobilized and embedded in paraffin, and sections were subjected to H&E and immunohistochemical staining for different hepatobiliary biomarkers. Stained material was examined under light microscopy and micro photo were taken.

Results: Organoid-like structures were obtained successfully from all selected cell lines except mesenchymal-like SNU475 cells. Hep3B, Huh7, and HepG2 cell lines from hepatoblast-like sub-group formed compact 3D colonies and showed hepatocyte-like morphology and staining with different hepatocyte lineage markers as well as hepatobiliary progenitor markers. SNU398 and SNU449 cell lines from mesenchymal-like group formed irregular and loose 3D colonies that expressed vimentin homogeneously, but also several epithelial and hepatocyte lineage markers. The pattern of biomarker expression was unique for each cell line tested. Such features, not observed in tested monolayer cultures were confirmed with single-cell derived Hep3B cells.

Conclusion: We described experimental conditions to obtain organoid-like structures from five different HCC cell lines representing hepatoblast-like and mesenchymal-like subgroups. These models are useful as an alternative to monolayer cultures to study phenotypic features of HCC cells. Our detailed analysis of biomarker expression in five different organoid-like structures provide convincing evidence for highly specific phenotypic features of these cell lines although they share some common or subtype-restricted features also.

Aim: Only patients with good liver function {[Child-Pugh (CP)] A class} were eligible for trials testing sorafenib as first-line treatment of hepatocellular carcinoma (HCC); nevertheless, the drug was authorized without restrictions based on liver function. Therefore, we planned to test sorafenib efficacy and safety in patients with HCC and deteriorated liver function (CP-B).

Methods: This was an open-label, multicenter, randomized phase 3 trial. Patients with HCC, no previous systemic therapy, and CP-B score 7-9 were assigned 1:1 to best supportive care alone (control arm) or with standard dose sorafenib (experimental arm). Overall survival (OS) was the primary endpoint. To detect a 0.70 HR of death, with 80% power, and two-tailed α error 0.05, 234 events were required. The study closed prematurely because of slow accrual. Descriptive analyses are reported.

Results: From 2012 to 2017, 13 Italian centers randomized 35 patients. In total, 28 deaths were recorded, 12 without and 16 with sorafenib; median OS was 4.9 (95%CI: 1.2-5.6) and 3.5 months (95%CI: 1.3-5.3), respectively. At least one severe adverse event was reported in 2/15 (13.3%) without and 9/17 (52.9%) patients with sorafenib.

Conclusions: This trial failed its planned enrolment goal, showing the difficulty in performing clinical trials with drugs already registered with a label broader than what available evidence supports.

Aim: Previous studies have demonstrated the racial disparities of new incidence and mortality rate of hepatocellular carcinoma (HCC) patients, but the racial differences in the tumor characteristics causing these disparities remain unclear.

Methods: We collected genomic mutation profile of 589 HCC patients, including Asian-Korea (n = 231), Asian-TCGA (n = 156), White-TCGA (n = 176), and Black-TCGA (n = 16). We applied a non-negative factorized matrix algorithm to decipher the mutational signatures of HCC patients, compared racial differences of mutational signature, performed molecular subtyping analysis of HCC patients based on their composition of mutational signatures, and evaluated their influence on clinical outcome.

Results: Asian patients showed a significantly higher level of SBS96F-aristolochic acid exposure signature related to the widespread usage of Chinese herbs in East Asia, and they also showed higher SBS96B-MMR at T > C mutations but lower SBS96D-MMR at C > T mutations than White patients, suggesting the heterogeneous mechanisms related to defective DNA mismatch repair across races. Asian-Korea patients showed a significantly higher SBS96C-tobacco chewing and aflatoxin exposure than the other three populations, indicating the higher levels of aflatoxin contamination in food and environment in this area. The SBS96G-Unclear signature was also observed to be significantly higher in Asian-Korea patients, and their dominated subgroup patients showed better prognosis for both disease-free and overall survival probability.

Conclusion: Our study found racial differences of mutational signatures to be associated with differences in diverse genetic backgrounds and environmental factors, which might help guide the personalized treatment of HCC patients.

According to the Barcelona Clinic Liver Cancer (BCLC) staging system, surgical resection is recommended only for BCLC-0 and BCLC-A hepatocellular carcinoma (HCC). Nevertheless, several investigators have recently advocated for widening the resection criteria for HCC to select patients with BCLC-B and less frequently BCLC-C tumors. The available studies have reported a 5-year survival rate ranging from 25% to 63% following resection of select patients with multinodular HCC. The role of liver resection for macrovascular invasive HCC still remains unclear. The present review aimed to summarize the available evidence regarding the outcomes of patients who underwent resection for BCLC-B/C HCC as well as highlight the proposed criteria for resection beyond the current BCLC guidelines.

The resectability of hepatocellular carcinoma (HCC) has been assessed based on the liver functional test, the liver volume of the future liver remnant (FLR), and, more recently, the functional liver volume of FLR. Liver volume is estimated via multi-detector computed tomography and three-dimensional image visualization technologies, and functional liver volume is investigated via ^99mTc-galactosyl human serum albumin scintigraphy, ^99mTc-mebrofenin hepatobiliary scintigraphy, and gadoxetic acid-enhanced magnetic resonance imaging. Several special techniques have been developed to promote FLR hypertrophy, thus allowing for safe hepatectomy. As an interventional technique, portal vein embolization (PVE) is essential, and, along with transarterial chemoembolization or hepatic vein embolization, this is beneficial in promoting a much larger FLR. Dual embolization is recommended for patients with very small FLR or with PVE failure. Radioembolization by Yttrium-90 microspheres (i.e., radiation lobectomy) can help in achieving FLR hypertrophy and has an anticancer effect on HCC. Transarterial chemoembolization on PVE has a similar anticancer effect. Surgical procedures, such as two-stage hepatectomy as well as associated liver partition and portal vein ligation for staged hepatectomy, are somewhat invasive. Therefore, they should be applied as a salvage procedure for patients with HCC who had inadequate response to the interventional approach. However, the best approach should be selected mainly based on the functional volume of FLR and the patients’ condition; in addition, the resources of each facility should be considered.

Hepatoblastoma (HB) is the most frequent pediatric primary liver tumor. When the tumoral lesions can be resected, prognosis is generally favorable. However, there is a significant number of cases in which resection is not possible at diagnosis, and patients usually receive neo-adjuvant cisplatin-based chemotherapy prior to surgery. Unfortunately, some HBs develop resistance to initial chemotherapy or after recurrence, progressing to metastatic disease. Moreover, long-term side effects of chemotherapy remain a serious concern. Understanding the molecular bases of HB development and progression is thus essential for the identification of more efficacious therapies. HBs have a very low mutational burden, and the most frequent mutations occur in the CTNN1B gene (> 80% of cases) and to a lesser extent in NFE2L2 (~10% of cases). These observations suggest that other pathogenic processes besides genetic mutations may play a role in HB tumorigenesis. Epigenetic mechanisms encompass a variety of molecular processes with a tremendous potential to regulate gene expression. They include the covalent modifications of DNA and histones, the activity of enzymatic chromatin remodelers, and the expression of non-coding RNAs. Dysregulation of epigenetic processes has clearly become a hallmark of cancer. Regarding HB, recent studies have explored its epigenetic landscape, the expression of specific epigenetic effectors, and the tumorigenic consequences of epigenetic alterations. The reversible nature of most epigenetic modifications and the possibility to target non-coding RNAs may pave the way for new therapeutic avenues in HB. Here, we summarize and discuss the most relevant findings in this less explored aspect of HB.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death not only in the United States but in the world. One of the curative treatment options for early-stage HCC is surgical resection, which can be divided into two approaches: anatomic and nonanatomic. The theoretical advantage of anatomic liver resection is excising the entire primary tumor along with adjacent liver parenchyma containing micrometastases that reside in the surrounding portal tributaries. However, the superiority of anatomic vs. nonanatomic liver resection in patients with HCC is controversial. While this is a feasible strategy for patients with preserved liver function, it may not be ideal for patients with cirrhosis, who rely on parenchymal-sparing or nonanatomic approaches to maximize their future liver remnant and prevent post-operative liver failure. This review identifies and critically analyzes the evidence for anatomic vs. nonanatomic liver resection for HCC.

Hepatocellular carcinoma (HCC) is a highly lethal malignancy, and few patients are candidates for curative-intended therapies. The mainstay of curative treatment in HCC is surgical resection, ablation, and transplantation. However, rates of recurrence are high, and there is no established approach to reduce the risk of recurrence and mortality. We discuss the available data and current landscape of (neo)adjuvant therapies aimed at decreasing recurrence risk and improving overall survival, including liver-directed therapies, tyrosine kinase inhibitors, and immunotherapy. Neoadjuvant strategies aimed at downstaging advanced HCC to enable local treatment and minimize the risk of recurrence using novel agents are also a topic of interest in current research. The improvements achieved in the advanced stages with immune-checkpoint inhibitors are priming ongoing trials that address potential future directions for both adjuvant and neoadjuvant strategies that may change the treatment paradigm of HCC in the near future.

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, and surgical resection offers an opportunity for cure in patients fortunate enough to have tumors amenable to resection. Unfortunately, recurrence rates are as high as 70% five years after resection, and recurrent disease proves to be a major obstacle to improving prognosis. Many adjuvant treatments have been utilized after resection in hopes of improving survival and have failed. This review outlines previous adjuvant strategies for patients with resected HCC and discusses potential steps forward to finding a successful adjuvant therapy.

Twenty years ago, hematologists introduced imatinib, a tyrosine kinase inhibitor (TKI), as a long-term oral systemic therapy for patients suffering from chronic myeloid leukemia (CML) and gastrointestinal stroma tumor (GIST) (400 mg/day) who have normal liver function. The mechanism of action of imatinib was considered to be the specific interruption of the activation of the BCR-ABL kinase in CML patients and the autoactivated c-kit-tyrosine kinase in GIST patients. After the first successful long-term treatment of a c-kit-positive HCC patient with imatinib, 10 further patients with unresectable HCC were treated in Göttingen. After 18 months of therapy (200 mg/day), four patients remained alive. The first approval of a TKI, sorafenib, occurred in 2008 and several other TKIs have been approved since for patients with advanced HCC and CHILD A cirrhosis. As immune cells of the tumoral microenvironment (c-kit positive or PD-1- and PD-L1 positive) can contribute to cancer cell survival, it could be assumed that those cells are the real target not only of TKIs but also of recently approved monoclonal antibodies. In fact, histological studies of the first treated GIST in Finland and the first HCC patient treated in Göttingen showed similar results, acellular necrotic material. As most patients with HCC are older than those recruited for the studies published thus far and systemic therapy duration is quite short, imatinib at a lower dose (200 mg/day) may be an additional alternative in long-term treatment of HCC/cholangiocellular carcinoma in patients unfit for resection or transplantation and who are unresponsive or intolerant of other treatments.

Aim: Nonalcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is projected to become the leading indication for liver transplantation. Previous studies indicate that tumor growth rates (TGR) may predict survival and were helpful in determining HCC surveillance intervals. Therefore, we aimed to determine its usefulness in predicting clinical outcomes and treatments.

Methods: We conducted a retrospective study of hepatitis B, C and NAFLD-HCC cases. TGR was measured using 2-consecutive pre-treatment contrast-enhanced imaging studies ≥ 25 days apart. A multivariate regression model was used to determine predictors of TGR. In addition, the Cox regression model was used to evaluate the relationship between TGR and overall survival.

Results: From 2000-2019, the study cohort comprised 38, 60, and 47 HBV, HCV, and NAFLD patients, respectively, with TGRs. NAFLD-HCC tumor size was inversely correlated to the extent of liver disease as measured by Child-Pugh score (7.2 cm in non-cirrhosis; 3.7 cm, 2.6 cm, and 2.1 cm in Child A, B, and C, respectively; P < 0.001). After adjusting for baseline characteristics, the TGR per month was fastest in HBV (9.4%, 95%CI: 6.3%-12.5%) compared to HCV (4.9%, 95%CI: 2.8%-7%) and NAFLD patients (3.6%, 95%CI: 1.6%-6.7%). Predictors of TGR included elevated AFP, low albumin, and smaller tumor size. Fast TGR in viral etiologies had higher mortality [adj. hazard ratio (HR) = 2.6, 95%CI: 1.2-5.7, P = 0.02] than slow TGRs, independent of treatments. Fast TGR in NAFLD had a trend towards higher mortality (HR = 3.6, 95%CI: 0.95-13.3, P = 0.059).

Conclusion: NAFLD-HCC patients have more indolent growths than viral-related HCC TGRs. The addition of TGR as a biomarker may assist in stratifying treatment options.

Biliary tract cancers are a wide group of heterogeneous neoplasms of the biliary tree, composed of intrahepatic cholangiocarcinoma perihilar bile duct cancer and distal bile duct cancer, according to location. The variability in location reflects the different morphologies and molecular alterations. In particular, intrahepatic peripheral mass forming cholangiocarcinoma is represented by the “small duct type” cholangiocarcinoma, which is different from the “large duct type” cholangiocarcinoma that, although intrahepatic, behaves similar to extrahepatic bile duct cancers, perihilar and distal ones. Recently, molecular targetable alterations, mainly FGFR2 fusions and IDH1 mutations, have been described, mostly in the intrahepatic “small duct type” subgroup and have opened the way, together with rarer targetable alterations, for personalisation of therapy also in these aggressive neoplasms.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disorder worldwide. It comprises simple steatosis and non-alcoholic steatohepatitis (NASH), which can further progress to cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD involves genetic, environmental, and endocrine factors, and several molecular mechanisms have been identified. In this review, we discuss the recent findings on the role of autophagy, in particular lipophagy and mitophagy, in hepatic lipid oxidation. We discuss the pre-clinical and clinical evidence suggesting that impairment of autophagy exacerbates NAFLD progression and restoration of autophagy exerts beneficial effects on NAFLD. We discuss how thyroid hormone (TH) simultaneously regulates lipophagy, mitophagy, and mitochondrial biogenesis to increase β-oxidation of fatty acids and reduce steatosis in the liver. Lastly, we discuss the recent clinical progress in using TH or thyromimetics in treating NAFLD/NASH.

Biliary tract cancers are a relatively rare heterogenous group of malignancies, including gallbladder cancer, intrahepatic, perihilar, and distal cholangiocarcinoma. Most patients are diagnosed with locally advanced or metastatic disease, and survival outcomes remain poor. This is also the case in the relatively few who undergo curative surgery. Efforts to improve patient survival outcomes have focussed on adjuvant and neoadjuvant chemotherapy and chemoradiotherapy. Adjuvant trials investigating the efficacy of systemic chemotherapy have primarily been negative to date, with challenges including compliance, recruitment rate, percentage of node-positive and R1 resections, and tumor heterogenicity observed. As reported in BILCAP, adjuvant capecitabine is currently considered the standard of care in many countries and guidelines, while chemoradiotherapy improves R1 outcomes as observed in the phase II trial SWOG S0809. Trials are ongoing to elicit the ideal combination of adjuvant treatment. Evidence for neoadjuvant chemotherapy continues to be based on retrospective analysis and a few phase II trials, with observed downstaging to surgery and improved R1 resection rates documented. This review documents the current evidence for systemic chemotherapy in adjuvant and neoadjuvant treatment of biliary tract cancers and highlights the ongoing clinical trials.

In patients with chronic hepatitis B (CHB), entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are equally recommended as first-line treatment by the international guidelines. These two drugs have shown similar short and intermediate clinical outcomes, including virologic, biochemical, and histologic responses. However, there is considerable controversy as to whether ETV and TDF differ in reducing the risk of hepatocellular carcinoma (HCC) in patients with CHB despite many observational studies and meta-analyses being published. In this review, we summarize recent evidence comparing the preventive effects of these two drugs against HCC from the perspective that TDF is associated with a lower risk of HCC compared with ETV in patients with CHB.

Cholangiocarcinoma (CCA) is a rare but lethal tumor that arises from the intrahepatic, perihilar, or extrahepatic bile ducts. Complete surgical resection remains the only chance at long-term survival. Unfortunately, most cases of CCA are clinically silent until late in the disease process, and, combined with the lack of effective screening tests, many CCAs present as unresectable tumors. CCA workup typically includes a multiphasic chest, abdominal, and pelvic imaging, liver function tests, and tumor markers (CEA, CA 19-9). Tissue diagnosis is encouraged but not always necessary. In certain situations, esophagogastroduodenoscopy, colonoscopy, and mammography are recommended. If resectable, intrahepatic CCAs and perihilar CCAs require a hepatectomy ranging from a wedge resection to an extended hepatectomy with reconstruction depending on the location and tumor size. In certain specialized centers, portal vein and hepatic artery reconstruction can be performed with good outcomes and acceptable morbidity. For resectable extrahepatic CCAs, a pancreaticoduodenectomy is recommended. Traditionally, few effective adjuvant options have existed for patients after surgery. However, recent randomized controlled trials support the use of either adjuvant chemotherapy or chemoradiation therapy after surgical resection. In select patients, intra-arterial therapy options such as transarterial chemoembolization, hepatic artery infusion therapy, or yttrium-90 radioembolization, as well as liver transplant, are effective treatment modalities. Improved surgical techniques, regionalization of care to high-volume centers, and appropriate application of preoperative optimization techniques have safely expanded the candidates of potentially resectable patients and improved patient outcomes.

Biliary tract cancers (BTCs) are usually diagnosed at an advanced stage and have a dismal prognosis. The treatment of advanced disease is mainly based on systemic chemotherapy, which is demonstrated to improve survival in the first- and second-line setting. Following the results of phase III clinical trials, the combination of cisplatin and gemcitabine is the regimen of choice in the frontline, while 5-fluorouracil plus oxaliplatin is considered the standard after first-line progression in unselected patients. Recent advances in molecular biology have unravelled the molecular heterogeneity of BTCs and identified patient subgroups harbouring unique molecular aberrations such as isocitrate dehydrogenase (IDH) mutations and fibroblast growth factor receptor (FGFR) fusions that can be targeted by specific agents. This knowledge has opened the way to personalised medicine in BTCs. Molecules targeting IDH and FGFR are currently approved for the treatment of advanced, refractory, intrahepatic cholangiocarcinoma. Beyond targeted therapies, novel combinatorial approaches that target the immune microenvironment and the crosstalk between cancer and stroma are being explored based on strong preclinical rationale. This review discusses the current therapeutic opportunities for the management of patients with advanced BTCs and provides an overview of the promising new strategies on the horizon with a particular focus on ongoing clinical trials.

Survival in patients with transfusion-dependent thalassemias (TDT) has increased, and complications such as hepatocellular carcinoma (HCC) are emerging. Risk factors include viral infection, mainly hepatitis C virus (HCV), iron overload, the presence of cirrhosis, and immune dysregulation. Median survival after HCC occurrence has been estimated at 12 months, while data regarding the incidence of HCC in this population are minimal. Implementing effective hepatitis B virus (HBV)/HCV antiviral treatment and universal HBV vaccination programs is expected to decrease the risk for hepatocarcinogenesis substantially. Significant hemosiderosis and hepatic fibrosis are common in patients with TDT despite chelation therapy and have been correlated with HCC development. Thus, iron overload should be monitored with liver iron concentration and ferritin levels, and effective chelation therapy should be applied. In addition, all TDT patients, particularly those with cirrhosis, should be under surveillance every six months with abdominal ultrasound ± alpha-fetoprotein levels, as this combination seems to provide better sensitivity for early HCC detection.

Aim: We sought to identify predictors of progression of an indeterminate observation (LI-RADS 3) to hepatocellular carcinoma (LI-RADS 5).

Methods: Imaging reports with LI-RADS (LR) assignments were identified among patients at the University of Washington, 2013-2017. Patients with an LR3 lesion and follow-up scan within 1 year of LR3 lesion date were included (n = 313). Features of interest were abstracted from chart review. Survival analyses employing interval censoring were performed, with variables potentially predictive of LR3 progression identified in univariate analyses. Backwards elimination (P < 0.05) was used to obtain the final multivariate model.

Results: 20.4% of LR3 lesions progressed to LR5; 73% remained LR3, 8% LR4. The cohort was predominantly male (61%), Caucasian (54%), older than 55 (63%). 47% had a history of hepatitis C virus (HCV), 33% with alcohol abuse, not mutually exclusive. Alpha-fetoprotein (AFP) at the time of LR3 scan was low if available (39% with AFP < 5, 29% unknown). CT was the most common exam (56%). Men (HR = 2.0, P = 0.02), earlier scan year (HR = 0.47 per year, P < 0.0001), and older age (HR = 1.48, P = 0.03), appeared as predictors of LR progression in the final model. HCV and alcohol use were more common among men but did not appear to explain the difference in LR progression by sex.

Conclusion: Our analysis is an early exploration of characteristics that may predict the risk of progression of an LR3 observation to hepatocellular carcinoma. Future efforts may allow for risk stratification to identify high-risk indeterminate lesions that may benefit from earlier intervention or more frequent surveillance.