Inflammatory Response in the Pathogenesis and Treatment of Hepatocellular Carcinoma: A Double-Edged Weapon.

Hepatocellular carcinoma (HCC) is the most frequent among primary liver tumors (90%) and one of the main causes of cancer-related death. It develops usually in a chronically inflamed environment, ranging from compensatory parenchymal regeneration to fibrosis and cirrhosis: carcinogenesis can potentially happen in each of these stages. Inflammation determined by chronic viral infection (hepatitis B, hepatitis C, and hepatitis delta viruses) represents an important risk factor for HCC etiology through both viral direct damage and immune-related mechanisms. The deregulation of the physiological liver immunological network determined by viral infection can lead to carcinogenesis. The recent introduction of immunotherapy as the gold-standard first-line treatment for HCC highlights the role of the immune system and inflammation as a double-edged weapon in both HCC carcinogenesis and treatment. In this review we highlight how the inflammation is the key for the hepatocarcinogenesis in viral, alcohol and metabolic liver diseases.

A holistic evaluation of patients with chronic Hepatitis D virus (HDV) infection enrolled in the Italian PITER-B and delta cohort.

BACKGROUND AND AIMS: We aimed to characterize the epidemiologic and comorbidities profiles of patients with chronic Hepatitis D (CHD) followed in clinical practice in Italy and explored their interferon (IFN) eligibility. METHODS: This was a cross-sectional study of the PITER cohort consisting of consecutive HBsAg-positive patients from 59 centers over the period 2019-2023. Multivariable analysis was performed by logistic regression model. RESULTS: Of 5492 HBsAg-positive enrolled patients, 4152 (75.6%) were screened for HDV, 422 (10.2%) were anti-HDV positive. Compared with HBsAg mono-infected, anti-HDV positive patients were more often younger, non-Italians, with a history of drug use, had elevated alanine transaminase (ALT), cirrhosis, or hepatocellular carcinoma (HCC). Compared with Italians, anti-HDV positive non-Italians were younger (42.2% age ≤ 40 years vs. 2.1%; P < 0.001), more often females (males 43.0% vs. 68.6%; P < 0.001) with less frequent cirrhosis and HCC. HDV-RNA was detected in 63.2% of anti-HDV-positive patients, who were more likely to have elevated ALT, cirrhosis, and HCC. Extrahepatic comorbidities were present in 47.4% of anti-HDV positive patients and could affect the eligibility of IFN-containing therapies in at least 53.0% of patients in care. CONCLUSIONS: CHD affects young, foreign-born patients and older Italians, of whom two-thirds had cirrhosis or HCC. Comorbidities were frequent in both Italians and non-Italians and impacted eligibility for IFN.

Hepatocellular Carcinoma and the Multifaceted Relationship with Its Microenvironment: Attacking the Hepatocellular Carcinoma Defensive Fortress.

Hepatocellular carcinoma is a malignant tumor that originates from hepatocytes in an inflammatory substrate due to different degrees of liver fibrosis up to cirrhosis. In recent years, there has been growing interest in the role played by the complex interrelationship between hepatocellular carcinoma and its microenvironment, capable of influencing tumourigenesis, neoplastic growth, and its progression or even inhibition. The microenvironment is made up of an intricate network of mesenchymal cells, immune system cells, extracellular matrix, and growth factors, as well as proinflammatory cytokines and translocated bacterial products coming from the intestinal microenvironment via the enterohepatic circulation. The aim of this paper is to review the role of the HCC microenvironment and describe the possible implications in the choice of the most appropriate therapeutic scheme in the prediction of tumor response or resistance to currently applied treatments and in the possible development of future therapeutic perspectives, in order to circumvent resistance and break down the tumor's defensive fort.

Management of Portal Hypertension in Patients with Hepatocellular Carcinoma on Systemic Treatment: Current Evidence and Future Perspectives.

The management of CSPH in patients undergoing systemic treatment for HCC has emerged as a critical concern due to the absence of reliable diagnostic criteria and uncertainties surrounding therapeutic approaches. This review aims to underscore the primary pathophysiological aspects linking HCC and PH, while also addressing the current and emerging clinical strategies for the management of portal hypertension. A review of studies from January 2003 to June 2023 was conducted using the PubMed database and employing MeSH terms, such as "hepatocellular carcinoma", "immune checkpoint inhibitors", "systemic therapy", "portal hypertension", "variceal bleeding" and "tyrosine kinase inhibitors". Despite promising results of tyrosine kinase inhibitors in animal models for PH and fibrosis, only Sorafenib has demonstrated similar effects in human studies, whereas Lenvatinib appears to promote PH development. The impact of Atezolizumab/Bevacizumab on PH remains uncertain, with an increasing risk of bleeding related to Bevacizumab in patients with prior variceal hemorrhage. Given the absence of specific guidelines, endoscopic surveillance during treatment is advisable, and primary and secondary prophylaxis of variceal bleeding should adhere to the Baveno VII recommendations. Furthermore, in patients with advanced HCC, refinement of diagnostic criteria for CSPH and guidelines for its surveillance are warranted.

Dynamic Contrast-Enhanced Ultrasound in the Prediction of Advanced Hepatocellular Carcinoma Response to Systemic and Locoregional Therapies.

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and the sixth most common malignant tumor in the world, with an incidence of 2-8% per year in patients with hepatic cirrhosis or chronic hepatitis. Despite surveillance schedules, it is sometimes diagnosed at an advanced stage, requiring complex therapeutic efforts with both locoregional and systemic treatments. Traditional radiological tools (computed tomography and magnetic resonance) are used for the post-treatment follow-up of HCC. The first follow-up imaging is performed at 4 weeks after resection or locoregional treatments, or after 3 months from the beginning of systemic therapies, and subsequently every 3 months for the first 2 years. For this reason, these radiological methods do not grant the possibility of an early distinction between good and poor therapeutic response. Contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced ultrasound (DCE-US) have gained the interest of several researchers for their potential role in the early assessment of response to locoregional treatments (chemoembolization) or antiangiogenic therapies in patients with advanced HCC. In fact, DCE-US, through a quantitative analysis performed by specific software, allows the construction of time-intensity curves, providing an evaluation of the parameters related to neoplastic tissue perfusion and its potential changes following therapies. It has the invaluable advantage of being easily repeatable, minimally invasive, and able to grant important evaluations regarding patients' survival, essential for well-timed therapeutic changes in case of unsatisfying response, and eventual further treatment planning.

Ultrasound Evaluation of Sarcopenia in Patients with Hepatocellular Carcinoma: A Faster and Easier Way to Detect Patients at Risk.

The condition of sarcopenia, defined as a progressive loss of musculoskeletal mass and muscular strength, is very common in patients with hepatocellular carcinoma (HCC) and presents a remarkable association with its prognosis. Thus, the early identification of sarcopenic patients represents one of the potential new approaches in the global assessment of HCC, and there is increasing interest regarding the potential therapeutic implications of this condition. The gold standard for the quantification of muscle mass is magnetic resonance imaging (MRI) or computed tomography (CT), but these techniques are not always feasible because of the high-cost equipment needed. A new possibility in sarcopenia identification could be muscle ultrasound examination. The measurement of specific parameters such as the muscle thickness, muscular fascicles length or pennation angle has shown a good correlation with CT or MRI values and a good diagnostic accuracy in the detection of sarcopenia. Recently, these results were also confirmed specifically in patients with chronic liver disease. This review summarizes the role of imaging for the diagnosis of sarcopenia in patients with HCC, focusing on the advantages and disadvantages of the diagnostic techniques currently validated for this aim and the future perspectives for the identification of this condition.

The New Era of Systemic Treatment for Hepatocellular Carcinoma: From the First Line to the Optimal Sequence.

Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and is considered a major global health problem as one of the leading causes of cancer-related death in the world. Due to the increase in life expectancy and the epidemiological growth of specific risk factors, such as metabolic dysfunction-associated steatotic liver disease (MASLD), the incidence of HCC is growing globally, and mortality rates are still high. Moreover, patients frequently present at an intermediate or advanced tumor stage, when curative treatments, such as surgical resection, liver transplantation or ablation are no longer applicable. In these cases, trans-arterial chemoembolization (TACE), trans-arterial radioembolization (TARE), and systemic therapy are the only suitable options to achieve disease control. The multi-kinase inhibitor Sorafenib has been the only systemic treatment available for unresectable advanced HCC for almost a decade, but in the last couple of years new therapeutic options have emerged. Recent advances in understanding the interactions between the tumor and its microenvironment, especially cancer immune escape, led to the advent of immunotherapy. Currently, first-line systemic treatment for HCC is represented by the combination of the immune checkpoint inhibitor (ICI) Atezolizumab plus Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, but many other ICIs have been investigated, such as Nivolumab, Pembrolizumab, Durvalumab and Ipilimumab. However, the problem of second- and third-line therapies, and the correct sequence of treatments remains open and is not addressed in most studies. This explains the urge to find new systemic treatments that can improve the survival and quality of life in patients that can go beyond the first line of treatment. The aim of this paper is to offer a complete overview of the most recent innovations in systemic treatments for unresectable locally advanced and metastatic HCC, including emerging therapies, with a particular focus on treatment sequences. Moreover, we will provide an outlook on possible future approaches to patients who progress beyond first-line therapies.

The Role of Contrast-Enhanced Ultrasound (CEUS) in the Detection of Neoplastic Portal Vein Thrombosis in Patients with Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the principal primary liver cancer and one of the most frequent malignant tumors worldwide in patients with chronic liver disease. When diagnosed at an advanced stage, it is often associated with portal vein tumor thrombosis (PVTT), which heavily affects patients' prognosis. Imaging evaluation is crucial in PVTT detection and staging; computed tomography and magnetic resonance are the principal diagnostic tools. Contrast-enhanced ultrasound (CEUS) is a non-invasive and easily repeatable method that can also be used in patients with impaired renal function. It represents an important means for the identification of PVTT, particularly differentiating neoplastic and non-neoplastic thrombosis through the analysis of ultrasound enhancement characteristics of the thrombosis (arterial hyperenhancement and portal washout), thus allowing more refined disease staging, appropriate treatment planning, and response evaluation, along with prognosis assessment.

Pharmacokinetic considerations for angiogenesis inhibitors used to treat hepatocellular carcinoma: an overview.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the fifth malignancy in terms of frequency and the fourth malignancy in terms of cancer-related death worldwide. Systemic therapy of advanced HCC has probably gone through the greatest wave of change in the last decade, with the introduction of several anti-angiogenic drugs and immune checkpoint inhibitors, able to significantly improve patients' prognosis. AREAS COVERED: In this review, we summarize the pharmacokinetic characteristic of the antiangiogenic drugs currently approved for the treatment of HCC, from oral tyrosine kinase inhibitors (sorafenib, lenvatinib, regorafenib and cabozantinib) to monoclonal antibodies (bevacizumab and ramucirumab), focusing on the main aspects that differ among compounds from the same class, on factors that can exert an influence on pharmacokinetic parameters and the main issues that could limit their clinical use. EXPERT OPINION: Anti-angiogenic drugs have different profiles in terms of bioavailability, metabolism, elimination and interindividual variability in their pharmacokinetics and effectiveness. More studies should be developed to address the intrinsic and extrinsic factors influencing pharmacokinetics parameters to improve the individual therapeutic response and, furthermore, to evaluate the benefit and the harm of systemic therapy for advanced HCC in selected patients with liver impairment.

Contrast-Enhanced Imaging in the Management of Intrahepatic Cholangiocarcinoma: State of Art and Future Perspectives.

Intrahepatic cholangiocarcinoma (iCCA) represents the second most common liver cancer after hepatocellular carcinoma, accounting for 15% of primary liver neoplasms. Its incidence and mortality rate have been rising during the last years, and total new cases are expected to increase up to 10-fold during the next two or three decades. Considering iCCA's poor prognosis and rapid spread, early diagnosis is still a crucial issue and can be very challenging due to the heterogeneity of tumor presentation at imaging exams and the need to assess a correct differential diagnosis with other liver lesions. Abdominal contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) plays an irreplaceable role in the evaluation of liver masses. iCCA's most typical imaging patterns are well-described, but atypical features are not uncommon at both CT and MRI; on the other hand, contrast-enhanced ultrasound (CEUS) has shown a great diagnostic value, with the interesting advantage of lower costs and no renal toxicity, but there is still no agreement regarding the most accurate contrastographic patterns for iCCA detection. Besides diagnostic accuracy, all these imaging techniques play a pivotal role in the choice of the therapeutic approach and eligibility for surgery, and there is an increasing interest in the specific imaging features which can predict tumor behavior or histologic subtypes. Further prognostic information may also be provided by the extraction of quantitative data through radiomic analysis, creating prognostic multi-parametric models, including clinical and serological parameters. In this review, we aim to summarize the role of contrast-enhanced imaging in the diagnosis and management of iCCA, from the actual issues in the differential diagnosis of liver masses to the newest prognostic implications.

Microvascular Thrombosis and Liver Fibrosis Progression: Mechanisms and Clinical Applications.

Fibrosis is an unavoidable consequence of chronic inflammation. Extracellular matrix deposition by fibroblasts, stimulated by multiple pathways, is the first step in the onset of chronic liver disease, and its propagation promotes liver dysfunction. At the same time, chronic liver disease is characterized by alterations in primary and secondary hemostasis but unlike previously thought, these changes are not associated with an increased risk of bleeding complications. In recent years, the role of coagulation imbalance has been postulated as one of the main mechanisms promoting hepatic fibrogenesis. In this review, we aim to investigate the function of microvascular thrombosis in the progression of liver disease and highlight the molecular and cellular networks linking hemostasis to fibrosis in this context. We analyze the predictive and prognostic role of coagulation products as biomarkers of liver decompensation (ascites, variceal hemorrhage, and hepatic encephalopathy) and liver-related mortality. Finally, we evaluate the current evidence on the application of antiplatelet and anticoagulant therapies for prophylaxis of hepatic decompensation or prevention of the progression of liver fibrosis.

Gut Microbiota and Antibiotic Treatments for the Main Non-Oncologic Hepato-Biliary-Pancreatic Disorders.

The gut microbiota is a pivotal actor in the maintenance of the balance in the complex interconnections of hepato-biliary-pancreatic system. It has both metabolic and immunologic functions, with an influence on the homeostasis of the whole organism and on the pathogenesis of a wide range of diseases, from non-neoplastic ones to tumorigenesis. The continuous bidirectional metabolic communication between gut and hepato-pancreatic district, through bile ducts and portal vein, leads to a continuous interaction with translocated bacteria and their products. Chronic liver disease and pancreatic disorders can lead to reduced intestinal motility, decreased bile acid synthesis and intestinal immune dysfunction, determining a compositional and functional imbalance in gut microbiota (dysbiosis), with potentially harmful consequences on the host's health. The modulation of the gut microbiota by antibiotics represents a pioneering challenge with striking future therapeutic opportunities, even in non-infectious diseases. In this setting, antibiotics are aimed at harmonizing gut microbial function and, sometimes, composition. A more targeted and specific approach should be the goal to pursue in the future, tailoring the treatment according to the type of microbiota modulation to be achieved and using combined strategies.

Dose-response Analysis in Hepatic Tumors Treated with 90Y-TARE According to a Personalized Dosimetric Workflow: Preliminary Results.

BACKGROUND: Transarterial Radioembolization (TARE) is a widespread radiation therapy for unresectable hepatic lesions, but a clear understanding of the dose-response link is still missing. The aim of this preliminary study is to investigate the role of both dosimetric and clinical parameters as classifiers or predictors of response and survival for TARE in hepatic tumors and to present possible response cut-off. METHODS: 20 patients treated with glass or resin microspheres according to a personalized workflow were included. Dosimetric parameters were extracted from personalized absorbed dose maps obtained from the convolution of 90Y PET images with 90Y voxel S-values. RESULTS: D95 ≥ 104 Gy and tumor mean absorbed dose MADt ≥ 229 Gy were found to be optimal cut-off values for complete response, while D30 ≥ 180 Gy and MADt ≥ 117 Gy were selected as cut-off values for at least partial response and predicted better survival. Clinical parameters Alanine Transaminase (ALT) and Model for End-Stage Liver Disease (MELD) didn't show sufficient classification capability for response or survival. CONCUSION: These preliminary results highlight the importance of an accurate dosimetric evaluation and suggest a cautious approach when considering clinical indicators. Dosimetric cut-off values could be a support tool in both planning and post-treatment phases. Larger multi-centric randomized trials, with standardized methods regarding patient selection, response criteria, Regions of Interest definition, dosimetric approach and activity planning are needed to confirm these promising results.

Multiparametric Dynamic Ultrasound Approach for Differential Diagnosis of Primary Liver Tumors.

A correct differentiation between hepatocellular carcinoma (HCC) and intracellular cholangiocarcinoma (ICC) is essential for clinical management and prognostic prediction. However, non-invasive differential diagnosis between HCC and ICC remains highly challenging. Dynamic contrast-enhanced ultrasound (D-CEUS) with standardized software is a valuable tool in the diagnostic approach to focal liver lesions and could improve accuracy in the evaluation of tumor perfusion. Moreover, the measurement of tissue stiffness could add more information concerning tumoral environment. To explore the diagnostic performance of multiparametric ultrasound (MP-US) in differentiating ICC from HCC. Our secondary aim was to develop an US score for distinguishing ICC and HCC. Between January 2021 and September 2022 consecutive patients with histologically confirmed HCC and ICC were enrolled in this prospective monocentric study. A complete US evaluation including B mode, D-CEUS and shear wave elastography (SWE) was performed in all patients and the corresponding features were compared between the tumor entities. For better inter-individual comparability, the blood volume-related D-CEUS parameters were analyzed as a ratio between lesions and surrounding liver parenchyma. Univariate and multivariate regression analysis was performed to select the most useful independent variables for the differential diagnosis between HCC and ICC and to establish an US score for non-invasive diagnosis. Finally, the diagnostic performance of the score was evaluated by receiver operating characteristic (ROC) curve analysis. A total of 82 patients (mean age ± SD, 68 ± 11 years, 55 men) were enrolled, including 44 ICC and 38 HCC. No statistically significant differences in basal US features were found between HCC and ICC. Concerning D-CEUS, blood volume parameters (peak intensity, PE; area under the curve, AUC; and wash-in rate, WiR) showed significantly higher values in the HCC group, but PE was the only independent feature associated with HCC diagnosis at multivariate analysis (p = 0.02). The other two independent predictors of histological diagnosis were liver cirrhosis (p < 0.01) and SWE (p = 0.01). A score based on those variables was highly accurate for the differential diagnosis of primary liver tumors, with an area under the ROC curve of 0.836 and the optimal cut-off values of 0.81 and 0.20 to rule in or rule out ICC respectively. MP-US seems to be a useful tool for non-invasive discrimination between ICC and HCC and could prevent the need for liver biopsy at least in a subgroup of patients.

Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease: The Prognostic Role of Liver Stiffness Measurement.

Nonalcoholic fatty liver disease (NAFLD), which is nowadays the most common etiology of chronic liver disease, is associated with an increased risk of hepatocellular carcinoma (HCC), with or without cirrhosis. Owing to the high prevalence of NAFLD worldwide, it becomes crucial to develop adequate strategies for surveillance of HCC and new prediction models aiming at stratifying NAFLD population for HCC risk. To this purpose, several noninvasive tests (NITs) have been proposed in the several last years, including clinical parameters, serum biomarkers, and imaging techniques. Most of these tools are focused on the assessment of liver fibrosis. Both ultrasound (US) elastography (especially transient elastography) and magnetic resonance (MR) elastography have been evaluated to estimate HCC risk in NAFLD patients. Recently, the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) include these techniques among the recommended NITs for the assessment of liver fibrosis. The aim of this review is to summarize the most recent data on the role of US and MR elastography in HCC risk stratification in patients with NAFLD.

Prognostic Role of Molecular and Imaging Biomarkers for Predicting Advanced Hepatocellular Carcinoma Treatment Efficacy.

Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and the fourth cause of tumor-related death. Imaging biomarkers are based on computed tomography, magnetic resonance, and contrast-enhanced ultrasound, and are widely applied in HCC diagnosis and treatment monitoring. Unfortunately, in the field of molecular biomarkers, alpha-fetoprotein (AFP) is still the only recognized tool for HCC surveillance in both diagnostic and follow-up purposes. Other molecular biomarkers have little roles in clinical practice regarding HCC, mainly for the detection of early-stage HCC, monitoring the response to treatments and analyzing tumor prognosis. In the last decades no important improvements have been achieved in this field and imaging biomarkers maintain the primacy in HCC diagnosis and follow-up. Despite the still inconsistent role of molecular biomarkers in surveillance and early HCC detection, they could play an outstanding role in prognosis estimation and treatment monitoring with a potential reduction in health costs faced by standard radiology. An important challenge resides in identifying sufficiently sensitive and specific biomarkers for advanced HCC for prognostic evaluation and detection of tumor progression, overcoming imaging biomarker sensitivity. The aim of this review is to analyze the current molecular and imaging biomarkers in advanced HCC.

Balloon-Occluded Radiofrequency Ablation as Bridge to TACE in the Treatment of Advanced HCC with Arterioportal Shunt.

BACKGROUND: Transarterial chemoembolization is the most widely used palliative treatment for unresectable hepatocellular carcinoma; however, arterioportal shunt represents a contraindication to this treatment. OBJECTIVE: The study aims to assess the feasibility of balloon-occluded radiofrequency ablation in the transitory resolution of an extensive arterioportal shunt in patients with advanced hepatocellular carcinoma as a bridge to safe and effective transarterial chemoembolization. METHODS: 12 consecutive patients advanced multinodular unilobar unresectable hepatocellular carcinoma with a target lesion larger than 5 cm (mean diameter 7.7 ± 1.4 cm), not suitable to transarterial chemoembolization due to extensive arterioportal shunt, were recruited. Balloon-occluded radiofrequency ablation of the hepatic area surrounding the shunt during occlusion of the artery supplying the shunt was performed, followed by lobar conventional chemoembolization. Intra/periprocedural complications were evaluated. Technical success was defined by the result of radiofrequency ablation in terms of immediate disappearance, reduction, or persistence of the shunt. Local efficacy of chemoembolization was evaluated at 1-month computed tomography according to m-RECIST criteria. RESULTS: Technical success was achieved in all patients. No major complications were observed. 1- month follow-up showed a mean necrotic diameter of 6.3 cm (range: 3.8-8.7 cm), with an acceptable procedural result and persistence of the shunt. An overall response rate was obtained in all patients, with 25% complete response and 75% partial response. CONCLUSION: Balloon-occluded radiofrequency ablation of an arterioportal shunt in patients with advanced hepatocellular carcinoma can temporarily reduce shunting, allowing to perform safe and therapeutically useful chemoembolization, with satisfactory control of tumor growth.

Durvalumab: an investigational agent for unresectable hepatocellular carcinoma.

INTRODUCTION: Programmed death 1 (PD1), programmed death ligand 1 (PD-L1), and cytotoxic T lymphocyte associated protein 4 (CTLA-4) are proteins involved in the modulation of immune response, which are upregulated in hepatocellular carcinoma (HCC) tumor microenvironment (TME). Immune checkpoint inhibitors (ICIs) are a new class of drugs that counteract immunological tolerance to cancer cells. Despite the aggressiveness of HCC and its poor prognosis, only a few tyrosine kinase inhibitors (TKIs) and ICIs have been approved for patients with advanced disease. AREAS COVERED: We analyze the current knowledge on Durvalumab, a human antibody against PD-L1 its pharmacodynamics, and pharmacokinetics. We provide a description of its application in HCC, illustrating clinical trials that have demonstrated the safety and efficacy in this setting, either as monotherapy or in combination with other ICIs or TKIs, or as adjuvant treatment. EXPERT OPINION: Durvalumab is a promising drug that could extend the landscape of approved treatments for HCC. The clinical safety profile of Durvalumab was well manageable and comparable to other ICIs, with a low incidence of severe immune-related adverse events (irAEs). The importance of personalized therapy according to tumor characteristics is emerging, but very little is known about factors that could influence the efficacy of ICIs.