The application of minimally invasive liver surgery (MILS) in the field of living donor hepatectomy has been exceedingly slow, and its impact is limited to a handful of centers worldwide. Widespread adoption has been primarily hampered by the technical limitations of laparoscopy, namely rigid instrumentation, suboptimal optics, and a seemingly steep learning curve. These deficiencies are magnified in the donor hepatectomy operation wherein the parenchyma and vasculature must be handled atraumatically to produce a pristine allograft fit for implantation. Donor safety concerns and medicolegal ramifications are also cited as impediments to MILS in donor surgery. In 2013, our institution embraced a purely laparoscopic approach to living donor left lateral sectionectomy, and it quickly became our default technique. However, with donor hemi-hepatectomy, we gravitated to the robotic surgical system as our preferred modality. Herein, we describe our experience with minimally invasive donor hepatectomy, which we now universally offer to all living donors. Our extensive familiarity with robotic donor hepatectomy will provide the reader with an instructive perspective on the attributes and merits of the robotic approach. With appropriate collaboration and proctorship, we believe that the robotic platform will actualize a more rapid and widespread adoption than that experienced with the purely laparoscopic technique.
Hepatocellular carcinoma remains a prominent cause of cancer-related mortality globally. Transarterial yttrium-90 radioembolization is a versatile therapy and plays an important role in the treatment of hepatocellular carcinoma. This review summarizes the establishment of radioembolization in the hepatocellular carcinoma treatment paradigm, treatment considerations across cancer stages, and recent advances in evidence.
Global prevalence of non-alcoholic fatty liver disease (NAFLD) and of NAFLD-hepatocellular carcinoma (HCC) is estimated to grow in the next years. The burden of NAFLD and the evidence that NAFLD-HCC arises also in non-cirrhotic patients, explain the urgent need of a better characterization of the molecular mechanisms involved in NAFLD progression. Obesity and diabetes cause a chronic inflammatory state which favors changes in serum cytokines and adipokines, an increase in oxidative stress, DNA damage, and the activation of multiple signaling pathways involved in cell proliferation. Moreover, a role in promoting NAFLD-HCC has been highlighted in the innate and adaptive immune system, dysbiosis, and alterations in bile acids metabolism. Several dietary, genetic, or combined mouse models have been used to study nonalcoholic steatohepatitis (NASH) development and its progression to HCC, but models that fully recapitulate the biological and prognostic features of human NASH are still lacking. In humans, four single nucleotide polymorphisms (PNPLA3, TM6SF2, GCKR, and MBOAT7) have been linked to the development of both NASH and HCC in cirrhotic and non-cirrhotic patients, whereas HSD17B13 polymorphism has a protective effect. In addition, higher rates of somatic ACVR2A mutations and a novel mutational signature have been recently discovered in NASH-HCC patients. The knowledge of the molecular pathogenesis of NAFLD-HCC will be helpful to personalized screening programs and allow for primary and secondary chemopreventive treatments for NAFLD patients who are more likely to progress to HCC.
When do you need to take biopsies of the liver, and what information will you get is the topic of this review on hepatocellular carcinoma (HCC). If, clinically, the differential diagnosis of HCC after imaging is suggested, a biopsy has become obligatory as a diagnostic confirmation of HCC in the non-cirrhotic liver prior to definitive therapeutic interventions, as well as in a palliative therapy concept. In the case of hepatic lesions with an uncharacteristic contrast uptake, a biopsy should be performed immediately to confirm the diagnosis of HCC. After diagnosing HCC, a treatment strategy is evaluated. Further, the biopsy, or in case of surgical treatment, the resected tissue, shows us the different subtypes of HCC, with the steatohepatitic subtype being the most common and the lymphocyte-rich subtype being the least common. Further, the histological grade of HCC is determined according to the grading system of the WHO or the Edmonson and Steiner System. Through biopsies, HCC can be differentiated from intrahepatic cholangiocarcinoma or combined hepatocellular-cholangiocarcinoma or metastases of other malignant tumors, especially metastases of the gastrointestinal tract. In summary, biopsies are fundamental in the diagnosis of HCC.
Cholangiocarcinoma (CC) is a malignancy with a very heterogeneous spectrum of morphopathological and prognostic characteristics. Diagnostic imaging is fundamental for early detection, preoperative staging, and resectability assessment, as well as early recognition of prognostic factors. Radical surgical treatment is limited by disease stage and technical feasibility. Interventional radiology has acquired a critical function in addressing disease control and survival improvement through loco-regional therapies, specifically in the setting of intrahepatic CC. In this review, we will describe the current state of art of diagnostic imaging, focusing on intrahepatic CC and proximal extrahepatic CC, and delineate the available loco-regional therapies strategies for unresectable intrahepatic CC.
Aim: To describe the current practise of living donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC), including the patient selection criteria, surgical techniques, management of small-for-size syndrome, postoperative complications, and the results of our units, in the Liver Transplant Centre of Queen Mary Hospital, Hong Kong, one of the high-volume centres for LDLT in Asia.
Methods: Our centre practises careful selection for HCC patients using the University of California, San Francisco (UCSF) criteria, supplemented by alpha-fetoprotein level and the model for end-stage liver disease score. Slight flexibility is offered to enthusiastic donors and recipients in LDLT while balancing the risks and benefits. We pioneered in using the extended right lobe graft and the novel hepatic venoplasty technique, which lessen the risk of hyperperfusion and small-for-size syndrome with improved overall recipient survival. Data were collected prospectively and presented as the mean values and ranges, or the number of patients in proportion of total patient population.
Results: Of our patients, 74.9% met the UCSF criteria, and 64.5% met the Milan criteria. A 5-year overall and disease-free survival rate of 78.9% and 76.3% were achieved.
Conclusion: LDLT is an ideal treatment for HCC in Hong Kong with regard to the critical organ shortage and high demand for transplantation. The current surgical techniques and post-transplant surveillance contribute to the positive outcome.
Treatment modalities for hepatocellular carcinoma (HCC) vary from surgical techniques and interventional radiologic strategies to systemic therapy. For the latter, the use of immune checkpoint inhibitors (ICIs) has gained popularity due to successful trials showing increased survival. In patients who have undergone liver transplantation, recurrence of HCC poses a significant challenge. There is indeed considerable debate on the efficacy and safety of ICI use in liver transplant recipients due to competing immune interests in maintaining a healthy graft and combating the tumor. Recent reports and case series have highlighted a role for the type of immune therapy, timing of therapy, tissue expression of PD-1 and modulation of immunosuppression, in the understanding of the efficacy and risks of ICIs for HCC in liver transplant. In this article, we appraise the available literature on the usage of ICIs for HCC in liver transplant recipients and provide perspectives on immune concerns as well as potential recommendations to consider during the management of such complex cases.
Aim: Genetic polymorphisms of human leukocyte antigen (HLA) class II molecules are associated with chronic hepatitis B virus (HBV) infection. We aimed to investigate the impacts of HLA-II haplotypes on viral evolution and the risks of HBV-caused liver diseases.
Methods: HLA-DR-DQ-DP haplotypes were estimated in 1210 healthy controls, 296 HBV clearance subjects, 301 asymptomatic hepatitis B surface antigen carriers, 770 chronic hepatitis B patients, 443 HBV-related liver cirrhosis (LC) patients, and 1037 HBV-related hepatocellular carcinoma (HCC) patients. HBV mutations were determined by sequencing. The associations of HLA-DR-DQ-DP haplotypes with viral mutations and the risks of liver diseases were assessed by multivariate logistic regression.
Results: Compared to HBV-free subjects, the haplotypes CCAACG, CCGACG, TCAATA, and TCGATA were associated with decreased HCC risk, with an odds ratio (OR) [95% confidence interval (CI)] of 0.62 (0.40-0.95), 0.60 (0.39-0.92), 0.73 (0.54-0.98), and 0.58 (0.42-0.78), respectively. CCAACG, CCGACG, and TCAATA were significantly associated with decreased frequencies of the HCC-risk HBV mutations: preS1 deletion, APOBEC-signature HBV mutations in the core promoter and preS regions, A51C/T, G104C/T, and G146C/T. TCGATA and TTAACG were associated with increased LC risk, with an OR (95%CI) of 1.54 (1.03-2.30) and 2.23 (1.50-3.33), respectively. However, TCGATA and TTAACG were not consistently associated with the cirrhosis-risk HBV mutations.
Conclusion: CCAACG, CCGACG, and TCAATA are inversely associated with HCC risk, possibly because they are involved in creating an immune microenvironment attenuating the generation of HCC-risk HBV mutations. TCGATA and TTAACG might predispose the polarity of immunity towards Th17 isotype related to LC.
Aim: The purpose of this study is to assess the benefit of laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) given recurrence and future need for liver transplantation (LT).
Methods: Data on liver resections were gathered from the Istituto di Ricovero e Cura a Carattere Scientifico-Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione (IRCCS-ISMETT) from 2003-2021. A retrospective analysis of 1408 consecutive adult patients who had a liver resection was performed with categorization based on the underlying disease process. A sub-analysis studied the 291 patients who had an LLR with an intention to transplant approach after LLR.
Results: From 2012 to 2020, ISMETT’s mean annual LLR rate was 45%. Data suggests that a laparoscopic approach to iterative surgical treatment for HCC has demonstrated protective benefits. Compared to open surgery or LT, LLR is protective against the risk of de-listing, post-transplant patient death, tumor recurrence, adhesions, and bleeding in a cirrhotic patient. Kaplan Meier’s analysis showed no difference between post-LT survival curves for those with prior open abdominal surgery or LLR (P = 0.658).
Conclusion: Laparoscopic surgery has important protective advantages over laparotomy surgery for the surgical treatment of HCC, particularly since treatment is not always curative. LLR can be considered a bridge therapy for transplantation, ensuring less crowding of waiting lists, a desirable condition in areas of donor storage.
Hepatocellular carcinoma (HCC) is among the leading causes of cancer incidence and mortality worldwide. Surveillance of individuals with cirrhosis or other conditions that confer a high risk of HCC development is essential for early detection and improved overall survival. Biannual ultrasonography with or without alpha-fetoprotein is widely recommended as the standard method for HCC surveillance, but it has limited sensitivity in early disease and may be inadequate in certain individuals. This review article will provide a comprehensive overview of the current landscape of HCC surveillance, including the rationale and indications for HCC surveillance, standard methods for HCC surveillance, and their strengths/limitations. Alternative surveillance methods such as the role of cross-sectional imaging, emerging circulating biomarkers, as well as the problem of under-utilization of HCC surveillance and surveillance-related harms will also be discussed in this review.
Cholangiocarcinoma (CCA), an aggressive tumor originating from both intra- and extra-hepatic biliary cells, represents an unmet need in liver oncology, as treatment remains largely unsatisfactory. A typical feature of CCA is the presence of a complex tumor microenvironment (TME) composed of neoplastic cells, a rich inflammatory infiltrate, and cancer-associated fibroblasts and desmoplastic matrix that makes it extremely chemoresistant to traditional chemotherapeutic drugs. In this review, we describe the cell populations within the TME, in particular those involved in the innate and adaptive immune response and how they interact with tumor cells and with matrix proteins. The TME is crucial for CCA to mount an immune escape response and is the battlefield where molecularly targeted therapies and immune therapy, particularly in combination, may actually prove their therapeutic value.
Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are first-line antiviral therapies for patients with chronic hepatitis B (CHB) and reduce the risk of disease progression and liver-related complications, as well as improve survival by effectively suppressing viral replication. Nevertheless, since the first publication in 2019 on a lower risk of hepatocellular carcinoma (HCC) in Korean patients receiving TDF than those receiving ETV, the topic has remained a hot and unsettled debate. Multiple studies and meta-analyses have yielded conflicting results. As HCC takes time to develop, studies are mainly observational to benefit from a larger sample size and longer follow-up that provides a higher statistical power to compare the two treatments. However, TDF was available to CHB patients a few years later than ETV in most countries, thus leading to a difference in follow-up duration. Moreover, despite studying the same topic, the difference in data sources and available parameters, inclusion and exclusion criteria, and use of statistical methods complicated the interpretation and comparison of the findings and contributed to between-study heterogeneity in meta-analyses. This review describes some caveats in interpreting and comparing the results from these observational studies and meta-analyses. Future studies should explore better designed observational studies with high-quality data sources, and aggregation of patient data in meta-analysis to tackle between-study heterogeneity.
A paper published several years ago suggested that tenofovir disoproxil fumarate (TDF) was superior to entecavir (ETV) for reducing the risk of hepatocellular carcinoma (HCC). Since then, many observational studies have been conducted comparing TDF and ETV. Many studies in Asia demonstrated similar HCC risks between ETV and TDF groups. Similarly, recent studies involving Caucasian and European did not observe any differences in HCC risk between these groups. In this article, we briefly review studies that compared the incidence rates of HCC between ETV and TDF and discuss potential reasons for the discrepant results.
The epidemiological features of hepatocellular carcinoma have changed significantly in the last decades. While for a long-time viral hepatitis and alcohol consumption have been the leading risk factors, the current spread of obesity and type 2 diabetes has contributed to the emergence of non-alcoholic fatty liver disease (NAFLD) worldwide, which has become the leading chronic liver disease as well as one of the main etiologies of hepatocellular carcinoma (HCC), especially in western countries. In this review, we resume the latest data about the epidemiology of metabolic liver disease and HCC arising from NAFLD and discuss the main clinical and molecular features leading to the progression of liver disease and the development of HCC in NAFLD. The emerging concept of metabolic associated fatty liver disease and its association with the development of HCC are also introduced.
Hepatocellular carcinoma (HCC) was the sixth most common cancer and the third cause of cancer-related deaths worldwide in 2020. Liver resection and transplantation remain the cornerstone for patients with early-stage disease and represent the only option for potential cure in HCC. However, fewer than 10% of patients are considered suitable for surgery at the time of diagnosis. Locoregional therapies, defined as minimally invasive image-guided liver tumour-directed procedures, are integral to in the management of HCC. This review discusses the role of locoregional therapies in HCC management in the emergence of immune and systemic treatments.
Aim: Safety and efficacy evidence of drug-eluting-microspheres trans-arterial chemoembolization (DEM-TACE) in patients with hepatocellular carcinoma (HCC) and trans-jugular intrahepatic portosystemic shunt (TIPS) is lacking. The aim of this retrospective study was to report the safety and efficacy of DEM-TACE procedures performed with microspheres smaller than 300 μm in patients with HCC and TIPS in a high-volume transplant center.
Methods: Embolization was standardized by initiating DEM-TACE with microspheres smaller than 100 μm, and if stasis was not achieved, adjunctive embolization with 100-300 or 200 μm microspheres was administered. With regards to efficacy, the oncological response was evaluated and categorized according to mRECIST criteria at 1, 3-6, 9-12, and 15-18 months. Reporting the safety profile, detailed laboratory analysis was performed before, at 36-48 h, and 30-60 days after the procedure. Adverse events (AEs) were recorded; post-embolic syndrome was defined as the onset of fever/nausea/pain after the procedure. Late onset hepatobiliary complications were evaluated by follow-up imaging with computed tomography or magnetic resonance (CT/MR).
Results: From December 2007 to November 2020, 17 HCC patients (25 HCC nodules) with patent TIPS underwent 20 DEM-TACE. Embolization was performed only with microspheres smaller than 100 μm in 3/20 DEM-TACE (15%); adjunctive embolization with 100-300 or 200 μm microspheres was required in 17/20 DEM-TACE (85%). Reported early AEs were post-embolic syndrome (9/20; 45%) all of grade 1-2, late AEs were asymptomatic acute liver bile duct injury (2/20; 10%), and in one case we observed hepatic abscess (1/20; 5%) resulting in death due to sepsis. With regards to efficacy, the oncological response was evaluated and categorized according to mRECIST criteria. Complete response (CR) at 1, 3-6, 9-12, and 15-18 months was 52%, 50%, 50%, and 50%, respectively. Objective response (CR + partial response) at 1, 3-6, 9-12, and 15-18 months was 95%, 71%, 70%, and 50%, respectively.
Conclusion: DEM-TACE with drug-eluting-microspheres smaller than 300 μm can be performed in appropriately selected patients with TIPS.
Aim: We aimed to analyze temporal trends in mortality from intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma in selected countries worldwide.
Methods: Official death certification data for ICC and ECC and populations estimates for 29 countries worldwide (17 from Europe, 8 from the Americas, and 4 from Australasia) and for Hong Kong Special Administrative Region of the People’s Republic of China (SAR), from 1995 to 2018, were extracted from the World Health Organization and the Pan American Health Organization databases. Age-standardized mortality rates were computed. A joinpoint regression analysis was performed.
Results: In both sexes, ICC mortality rates increased in most countries considered, including the USA, the UK, and Australia; in some countries, including Italy and France, the increasing trends leveled off over the most recent years. In men, around 2016, the highest rates (1.7-2.3/100,000) were observed in Hong Kong SAR, Portugal, France, Spain, Australia, Austria, the UK, and Canada; Latin American countries and some eastern European countries had the lowest rates (0.2-0.8/100,000). A similar pattern was observed in women, but with lower rates (from 1.7/100,000 in Hong Kong SAR to 0.14/100,000 in Argentina). ECC mortality declined in most European and Australasian countries, but it tended to increase in Americas. In both sexes, rates were below 1/100,000 around 2016, with the only exceptions being Japan (2.6/100,000 men and 1.2/100,000 women) and Hungary (1.5/100,000 men and 1.1/100,000 women).
Conclusion: ICC mortality increased in most areas of the world, likely due to increased prevalence of risk factors and improved cancer recognition and classification. ECC mortality fell in most countries, largely due to the widespread use of cholecystectomy.
Background: Discordance in hepatocellular carcinoma (HCC) staging between pre-transplant imaging and explant pathology is associated with an increased risk of recurrence and death. Our aim was to evaluate variables that predicted concordance/discordance in the era of new generation locoregional therapies (LRT) and improved radiologic technology in diagnosis.
Methods: A single-center retrospective study was performed on patients who received a liver transplant for HCC between 2008-2019. Pre- and post-LT variables, including type of LRT, downstaging (DS), transplant time period, and radiologic response to LRT, were analyzed for concordance/discordance. Kaplan-Meier analysis was used to assess post-LT survival.
Results: Of 146 patients transplanted within Milan Criteria (MC), discordance rates (understaged) were 45%. Discordance was associated with ≥ 3 HCC lesions at diagnosis but not newer generation LRT (transarterial radioembolization/ stereotactic body radiation therapy), traditional LRT or combination. No differences in discordance were seen between transplant periods (2008-2013 vs. 2014-2019), but those within MC in the earlier period had higher concordance rates. A trend was observed between DS and discordance.
Conclusion: HCC stage discordance remains common and poorly predictable. Discordance was associated with three or more HCC lesions at the time of diagnosis. Patients within MC transplanted between 2008-2013 was associated with concordance, while a trend was noted between DS and discordance. No other pre- or post- LT variables predicted discordance/ concordance. Discordance was associated with decreased survival.
Anatomical resection (AR) has been reported to achieve better long-term outcomes than non-anatomical resection for the treatment of hepatocellular carcinoma (HCC). The surgical feasibility and oncological significance of laparoscopic AR (LAR), especially “subsegment resection”, “cone unit resection”, and repeat LAR for HCC, remain unproven. We present a 67-year-old patient with alcoholic liver cirrhosis and HCC who underwent full LAR three times, focusing on the technical aspects of the Glissonean approach. Repeating LAR for recurrent HCC could be a safe and feasible procedure. However, HCC recurred in the neighboring segment twice, even though pathological vascular invasion and marginal remnants were not confirmed. We should investigate the oncological significance and advancements in subsegmentectomy and cone unit resection, in the future.
Consumption of natural products such as herbs, spices, plant-derived compounds, and foods is on the rise globally. The use of these substances is widely recognized as an integral part of culture and tradition, with the philosophy being “no benefit is no harm”. The utility of medicinal plants and extracts is under scrutiny, and the scientific community needs to clarify many conceptual gaps. Medicinal plants are rich in bioactive phytochemicals that produce chemopreventive effects at different levels, including cellular, animal, and clinical. The ultimate translational value is often missing, and some studies suggest that botanicals may contain toxic compounds that cause acute or chronic toxicity. In this regard, the liver is the center, and herbal products can show protective effects or induce hepatotoxicity, thereby promoting liver cancer. In this review article, we examine a range of herbal products implicated in hepatocarcinogenesis and extend the discussion to herbal products that may be potentially involved in the prevention and treatment of liver carcinoma.
Fibrolamellar hepatocellular carcinoma (FHCC) is a rare primary malignancy of the liver for which data remain limited. This tumor is more often diagnosed in younger patient populations in the absence of underlying cirrhosis and hepatitis. These lesions can be diagnosed on computed tomography scan or magnetic resonance imaging with common findings including central calcifications, a central stellate scar, and radiating fibrotic bands. Laboratory markers have not proved useful for diagnosis; however, pathologic analysis can be implemented to aid in diagnosis with findings including ample granular eosinophilic cytoplasm, nuclei with open chromatin and prominent macronuclei, hyaline and pale bodies, and dense lamellar fibrosis that divides the cells into cords or trabeculae. FHCC demonstrates aggressive malignant potential with nodal spread. Treatment patterns have remained mainly surgical; however, systemic therapies have been implemented and are under further investigation with clinical trials. Locoregional therapies and radiation therapies have been trialed sparingly. In this focused review, we discuss the most up-to-date perspective on epidemiology, clinical presentation, diagnostic approach, differential diagnosis, treatment regimens, prognosis, and future directions of FHCC.
Liver surgery is the first-line treatment for hepatocellular carcinoma (HCC). Minimally invasive liver resection (MILS) has become an attractive option thanks to reduced intraoperative blood losses, shortened length of hospital stay, and similar oncological outcomes when compared to open liver resection. Nonetheless, the safety of MILS is still debated in challenging situations, such as in cirrhotic patients, difficult tumor locations, multiple or large tumors, and repeat resection. The aim of this review is to discuss current indications of laparoscopic liver resection for HCC treatment in the light of its outcomes, focusing on technical aspects of minimally invasive anatomic liver resection and state of the art of MILS in challenging situations.
Aim: The present study evaluated the duration of chemoembolization in patients with hepatocellular carcinoma, analyzing possible factors affecting the procedural time.
Methods: In total, 175 patients who underwent chemoembolization have been prospectively enrolled. The procedural length was considered the time between the insertion and the removal of the angiographic sheath. The features related to the tumor burden and angiographic procedures, which could be related to the procedural time, were recorded.
Results: The chemoembolization time resulted in a mean of 58.1 min. The longer procedural time was associated with a number of nodules treated per patient ≥ 2 (P < 0.001), a number of segments with nodules ≥ 2 (P < 0.001), the presence of more than 1 nodule in the same segment (P < 0.001), the location of the tumor in the left lobe
Conclusion: The factors related to longer procedural time are the number of nodules treated ≥ 2, the number of segments with nodules ≥ 2, the involvement of the left lobe, the tumor burden outside the Milan criteria, and the number of segments treated ≥ 2. All these characteristics, known in the pre-procedural phase, represent useful tools for a correct planning of the angiographic room’s workflow during the pandemic era as well as in the future to reduce downtime and increase productivity.
Chronic hepatitis C virus (HCV) infection is estimated to affect 56.8 million individuals globally and is a major and independent risk factor for the development of hepatocellular carcinoma (HCC). After the introduction of safe and potent direct-acting antivirals (DAAs), capable of curing HCV infection also in patients with advanced liver disease at high risk of HCC, the beneficial effect on a de novo HCC development after viral clearance has been established. However, studies addressing the relationship between DAA-induced eradication and risk of HCC recurrence (i.e., reappearance of HCC treated before starting antivirals) have produced contradictory data, suggesting either an increase or a decrease of HCC recurrence rate, while some report no effect of these treatments. Thus, there seems to be an unclear benefit of viral clearance in patients with a history of HCC curative treatment, where the recurrence rate remains worryingly high. This short review aims to summarize current evidence on the impact of DAAs on HCC recurrence rates, the pathogenic mechanisms and characteristics of HCC recurrence after DAA treatment, the predictors of tumor recurrence, and the impact of DAAs on overall survival.
Aim: Studies of clinical outcomes in chronic hepatitis C (CHC) patients with pretreatment advanced liver fibrosis (F3) after sustained virologic response (SVR) are scarce, and most studies are of small cohorts and retrospective in nature. Our aim was to assess the clinical outcomes following direct acting antiviral (DAA) treatment among hepatitis C F3 patients after SVR.
Methods: This study included 1517 chronic hepatitis C patients with F3 fibrosis receiving DAAs in the out-patient clinics at the Egyptian Liver Research Institute and Hospital (ELRIAH). We included patients 18 years or older with HCV who received DAAs, have F3 by transient elastography, and have no history of hepatocellular carcinoma (HCC). Patients were followed up every six months after end of treatment using ultrasonography and AFP.
Results: Significant improvement of fibrosis occurred with decreases in LSM, FIB-4, APRI, and FIB-6. When changes in LSM were categorized depending on delta LSM, 873 patients (57.5%) showed regression, 454 (29.9%) were stable, and 190 patients (12.5%) showed progression of fibrosis. Overall, 33 cases developed HCC during follow-up with incidence rate of 0.915/100 py (95%CI: 0.64-1.27). Incidence was high with progression of liver fibrosis (6.17/100 py) compared to patients with stable fibrosis (1.09/100 py) and regression of liver fibrosis (0.75/100 py). There were no significant differences as regards fibrosis indicators at baseline (LSM, FIB-4, APRI, and FIB-6) between those who developed HCC and those who did not.
Conclusion: CHC Patients with F3 fibrosis showed a high rate of regression of fibrosis and decreased HCC incidence after achieving SVR following DAAs.
Cholangiocarcinoma (CCA) is a highly lethal malignancy that comprises approximately 15% of all the primary liver tumors and 3% of gastrointestinal cancers. Diagnosis is often done when the disease is already at advanced stages, resulting in poor outcomes. Prevention of risk factors and early diagnosis are the cornerstones for improving survival. Early diagnosis is feasible in the setting of surveillance programs in patients at high risk of CCA such as patients with primary sclerosing cholangitis. Regrettably, surveillance of CCA in this population is hampered by the low diagnostic accuracy of current tumor markers at earlier stages, the difficulties of imaging techniques for the differential diagnosis between benign and malignant biliary strictures, and the need for invasive procedures for diagnostic confirmation. In this review we discuss the rationale for surveillance of CCA in high-risk populations, particularly patients with primary sclerosing cholangitis, the recommended tools for surveillance and diagnostic work-up, and future perspectives.
Nonalcoholic fatty liver disease (NAFLD) is a disease spectrum that spans simple steatosis, fibrosis, and ultimately cirrhosis, and is a leading cause of chronic liver disease globally. The severe variant of NAFLD, non-alcoholic steatohepatitis (NASH), is characterized by triglyceride accumulation within hepatocytes and the subsequent inflammatory pathway activation, ultimately progressing to cirrhosis in 10%-20% of patients. NASH is a known major risk factor for the development of hepatocellular carcinoma (HCC), and there is emerging data demonstrating the impact of NASH on immune subsets and the tumor microenvironment that may influence therapeutic response. This review describes the various ways in which the immune system is altered in patients with NASH. The innate immune system in NASH shows alterations in dendritic and Kupffer cells, impaired cytotoxicity of Natural Killer cells, and an accumulation of neutrophils. Additionally, there is emerging evidence emphasizing the role of the adaptive immune system in the development and progression of NASH, seen in the alteration of B-cells, T-cells, and NKT Cells. Due to the complex interplay of the immune system in NAFLD/NASH and its progression to HCC, many current treatments focus on targeting immune cells for HCC therapy. Recently, immune checkpoint inhibitors such as atezolizumab and bevacizumab have been approved as first-line therapy for unresectable HCC. Although an emerging field of research, further studies and clinical trials are needed to understand the complex interface of NASH, HCC and the immune response.
Liver transplantation is the only potentially curative option for unresectable hepatoblastoma. The introduction of platinum-based chemotherapy drastically improved the survival outcomes of patients with hepatoblastoma. However, the use of neoadjuvant chemotherapy and the optimal number of cycles required in patients listed for liver transplantation, as well as the potential use of adjuvant chemotherapy, remain unclear. Additionally, the shortage of donor liver grafts, along with the lack of clear consensus on the management of metastatic hepatoblastoma, makes the decision on whether to proceed to liver transplantation even more complex and challenging. Technological advances may optimize intraoperative imaging of both the primary tumor and metastatic sites, thus facilitating complete resection. Such improvements, along with the wider use of social media platforms to increase public awareness, could potentially pave the way for more optimal implementation of liver transplantation for the treatment of patients with unresectable hepatoblastoma.
Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy. In the clinic, therapeutic resistance is largely attributed to tumor heterogeneity. Growing evidence indicates that cancer stem cells (CSCs) are the major source of tumor heterogeneity. Hence, uncovering the resistance mechanisms associated with CSC properties is essential for developing effective therapeutics. CSCs resemble embryonic stem cells. Embryonic development-related genes and signaling pathways are usually abnormally active and function as oncofetal drivers in HCC. Multiple strategies have been applied to identify oncofetal drivers. The mechanisms of CSC resistance could also provide reliable biomarkers to predict treatment failure. Precisely targeting these specific CSC properties may be effective in preventing or annihilating therapy resistance. This review provides an overview of drug resistance mechanisms associated with CSC traits and summarize therapeutic strategies against drug resistance.
Nonalcoholic fatty liver disease (NAFLD) is the major contributor to the global burden of chronic liver diseases and ranges from simple and reversible steatosis to nonalcoholic steatohepatitis (NASH), which may progress into cirrhosis and hepatocellular carcinoma (HCC). HCC represents the most common liver cancer, and it is a leading cause of death worldwide with an increasing trend for the future. Due to late diagnosis, non-responsiveness to systemic therapy, and high cancer heterogeneity, the treatment of this malignancy is challenging. To date, liver biopsy and ultrasound (US) are the gold standard procedures for HCC diagnosis and surveillance, although they are not suitable for mass screening. Therefore, it is impelling to find new, less invasive diagnostic strategies able to detect HCC at an early stage as well as monitor tumor progression and recurrence. Common and rare inherited variations that boost the switching from NASH to liver cancer may help to predict tumor onset. Furthermore, epigenetic changes which reflect intertumoral heterogeneity occur early in tumorigenesis and are highly stable under pathologic conditions. The severity of hepatic injuries can be detected through the analysis of cell circulating tumor DNAs (ctDNAs), microRNAs (miRNAs), and noncoding RNAs (ncRNAs), which are involved in several pathological processes that feature cancer, including cell growth, survival, and differentiation, thus representing appealing biomarkers for HCC. Therefore, this review discusses the current options for HCC surveillance, focusing on the role of genetic and epigenetic biomarkers as new strategies to refine HCC management.
Over the last decade, we have been facing a new aetiology responsible for the development of HCC - the non-alcoholic fatty liver disease (NAFLD). The prevalence of HCC development in this group is higher than that observed in the general population and in non-cirrhotic subjects with other causes of liver disease. Conventional ultrasound (US) is the first-line tool for HCC surveillance, but, in this population, it has a decreased diagnostic accuracy due to several particular features, including obesity and steatosis. Contrast-enhanced ultrasound (CEUS) appeared as a new branch of US due to its ability to depict the vascular architecture of all types of focal lesions (FLs). Nevertheless, CEUS has several limitations besides those inherited from US, which renders this method unreliable as the first-line HCC diagnostic tool and for HCC staging. Artificial intelligence eliminates operator limitations, which has led to an increased sensitivity and specificity of US. However, this approach is still in its early stages and more data are needed. Consequently, the purpose of the current study is to highlight the strengths and limits of US, along with its alternatives to HCC screening in NAFLD population.
Human immunodeficiency virus (HIV) and hepatitis-B virus (HBV) infections are weighty public health challenges, especially in the African continent. The direct carcinogenic effect of HBV means that it remains a potent cause of early-onset hepatocellular carcinoma (HCC) in Sub-Saharan Africa (SSA), where it causes significant morbidity and mortality. The presence of HIV infection in HBV-infected patients poses a complicating factor, as coinfection has been shown to hasten the progression of liver disease to cirrhosis and HCC, and often resulting in early-age hepatocarcinogenesis with consequent late diagnosis and lower survival. In this review, we discuss this unique conundrum, the epidemiology of HIV-HBV coinfection in SSA, its effect on liver disease and development of HCC, as well as practices and barriers to HCC surveillance in this distinct population. We propose a way forward to curb this considerable health burden focusing on reduction of disease stigma, the need for easy-to-measure biomarkers, and implementation of large prospective studies in this population.
Artificial intelligence (AI) is an innovative discipline in medicine, impacting both hepatology and hepato-pancreato-biliary surgery, ensuring reliable outcomes because of its repeatable and efficient algorithms. A considerable number of studies about the efficiency of AI in the management of hepatocellular carcinoma (HCC) have been published. While its diagnostic role is well recognized, providing large amounts of quantitative radiological HCC features, its use in HCC treatment is still debated. Innovative use of AI may help to select the best approach for each patient as it is able to predict the outcomes after resection and/or other treatments. In this review, we assess the role of AI in selecting the best therapeutic option and predicting long-term risks after surgical or interventional treatments for HCC patients. Further studies are needed to consolidate AI applications.