Endoscopic Contrast-Enhanced Ultrasound and Fine-Needle Aspiration or Biopsy for the Diagnosis of Pancreatic Solid Lesions: A Systematic Review and Meta-Analysis.

INTRODUCTION: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) are currently recommended for the pathologic diagnosis of pancreatic solid lesions (PSLs). The application of contrast-enhanced endoscopic ultrasound (ECEUS) could aid the endoscopist during an FNA and/or FNB procedure. CEUS is indeed able to better differentiate the pathologic tissue from the surrounding healthy pancreatic parenchyma and to detect necrotic areas and vessels. OBJECTIVES: Our objective was to evaluate if ECEUS could reduce the number of needle passes and side effects and increase the diagnostic efficacy of FNA and/or FNB. METHODS: A comprehensive literature search of clinical studies was performed to explore if ECEUS-FNA or FNB could increase diagnostic accuracy and reduce the number of needle passes and adverse effects compared to standard EUS-FNA or FNB. In accordance with the study protocol, a qualitative and quantitative analysis of the evidence was planned. RESULTS: The proportion of established diagnoses of ECEUS was 90.9% compared to 88.3% of EUS, with no statistically significant difference (p = 0.14). The diagnosis was made through a single step in 70.9% of ECEUS patients and in 65.3% of EUS patients, without statistical significance (p = 0.24). The incidence of adverse reactions was substantially comparable across both groups (p = 0.89). CONCLUSION: ECEUS-FNA and FNB do not appear superior to standard EUS-FNA and FNB for the diagnosis of pancreatic lesions.

Shear-wave elastography to predict hepatocellular carcinoma after hepatitis C virus eradication: A systematic review and meta-analysis.

BACKGROUND: Direct-acting antiviral agents (DAAs) are highly effective treatment for chronic hepatitis C (CHC) with a significant rate of sustained virologic response (SVR). The achievement of SVR is crucial to prevent additional liver damage and slow down fibrosis progression. The assessment of fibrosis degree can be performed with transient elastography, magnetic resonance elastography or shear-wave elastography (SWE). Liver elastography could function as a predictor for hepatocellular carcinoma (HCC) in CHC patients treated with DAAs. AIM: To explore the predictive value of SWE for HCC development after complete clearance of hepatitis C virus (HCV). METHODS: A comprehensive literature search of clinical studies was performed to identify the ability of SWE to predict HCC occurrence after HCV clearance. In accordance with the study protocol, a qualitative and quantitative analysis of the evidence was planned. RESULTS: At baseline and after 12 wk of follow-up, a trend was shown towards greater liver stiffness (LS) in those who go on to develop HCC compared to those who do not [baseline LS standardized mean difference (SMD): 1.15, 95% confidence interval (95%CI): 020-2.50; LS SMD after 12 wk: 0.83, 95%CI: 0.33-1.98]. The absence of a statistically significant difference between the mean LS in those who developed HCC or not may be related to the inability to correct for confounding factors and the absence of raw source data. There was a statistically significant LS SMD at 24 wk of follow-up between patients who developed HCC vs not (0.64; 95%CI: 0.04-1.24). CONCLUSION: SWE could be a promising tool for prediction of HCC occurrence in patients treated with DAAs. Further studies with larger cohorts and standardized timing of elastographic evaluation are needed to confirm these data.

Inflammatory Bowel Diseases and Non-Alcoholic Fatty Liver Disease: Piecing a Complex Puzzle Together.

Inflammatory bowel diseases (IBD), comprising Crohn's disease and ulcerative colitis, are systemic and multifaceted disorders which affect other organs in addition to the gastrointestinal tract in up to 50% of cases. Extraintestinal manifestations may present before or after IBD diagnosis and negatively impact the intestinal disease course and patients' quality of life, often requiring additional diagnostic evaluations or specific treatments. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Current evidence shows an increased prevalence of NAFLD (and its more advanced stages, such as liver fibrosis and steatohepatitis) in IBD patients compared to the general population. Many different IBD-specific etiopathogenetic mechanisms have been hypothesized, including chronic inflammation, malabsorption, previous surgical interventions, changes in fecal microbiota, and drugs. However, the pathophysiological link between these two diseases is still poorly understood. In this review, we aim to provide a comprehensive overview of the potential mechanisms which have been investigated so far and highlight open issues still to be addressed for future studies.

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.

From the Colon to the Liver: How Gut Microbiota May Influence Colorectal Cancer Metastatic Potential.

The gut microbiota's influence on human tumorigenesis is a burning topic in medical research. With the new ontological perspective, which considers the human body and its pathophysiological processes as the result of the interaction between its own eukaryotic cells and prokaryotic microorganisms living in different body niches, great interest has arisen in the role of the gut microbiota on carcinogenesis. Indeed, dysbiosis is currently recognized as a cancer-promoting condition, and multiple molecular mechanisms have been described by which the gut microbiota may drive tumor development, especially colorectal cancer (CRC). Metastatic power is undoubtedly one of the most fearsome features of neoplastic tissues. Therefore, understanding the underlying mechanisms is of utmost importance to improve patients' prognosis. The liver is the most frequent target of CRC metastasis, and new evidence reveals that the gut microbiota may yield an effect on CRC diffusion to the liver, thus defining an intriguing new facet of the so-called "gut-liver axis". In this review, we aim to summarize the most recent data about the microbiota's role in promoting or preventing hepatic metastasis from CRC, highlighting some potential future therapeutic targets.

Endoscopic Ultrasound-Guided Locoregional Treatments for Solid Pancreatic Neoplasms.

Solid pancreatic neoplasms are one of the most diagnosed gastrointestinal malignancies thanks to the current and progressive advances in radiologic methods. Endoscopic ultrasound-guided techniques have over time gained a prominent role in the differential diagnosis and characterization of these pancreatic lesions, including pancreatic cancer, neuroendocrine tumors, and metastases. Recently, several endoscopic ultrasound-guided locoregional treatment techniques, which are divided into thermal ablative techniques and non-thermal injection techniques, have been developed and applied in different settings for the treatment of solid pancreatic neoplasms. The most common ablative techniques are radiofrequency, microwave, laser, photodynamic therapy and hybrid techniques such as hybrid cryothermal ablation. The most common injection techniques are ethanol injection, immunotherapy and brachytherapy. In this review, we update evidence about the efficacy and safety of endoscopic ultrasound-guided locoregional treatments for solid pancreatic neoplasms.

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.

The Role of Transabdominal Ultrasound Elastography in Gastrointestinal Non-Liver Diseases: Current Application and Future Prospectives.

Ultrasound imaging is the first-line investigation for patients with abdominal symptoms, as it effectively depicts the gastrointestinal tract and enables the diagnosis of multiple pathological conditions. Among different recent ultrasound technological advancements, elastography enables the evaluation of various tissue characteristics, such as neoplastic transformation or fibroinflammatory status. In recent years, ultrasound elastography has been utilized extensively for the study of liver diseases and in numerous other clinical settings, including gastrointestinal diseases. Current guidelines suggest the use of transabdominal ultrasound elastography to characterize bowel wall lesions, to assess gastrointestinal contractility, to diagnose and grade chronic pancreatitis; however, no specific indications are provided. In the present paper, we summarize the evidence concerning the application of different ultrasound elastography modalities in gastrointestinal non-liver diseases.

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.

Dynamic contrast enhanced ultrasound in gastrointestinal diseases: A current trend or an indispensable tool?

Contrast enhanced ultrasound (CEUS) has been widely implemented in clinical practice because of the enormous quantity of information it provides, along with its low cost, reproducibility, minimal invasiveness, and safety of the second-generation ultrasound contrast agents. To overcome the limitation of CEUS given by the subjective evaluation of the contrast enhancement behaviour, quantitative analysis of contrast kinetics with generation of time-intensity curves has been introduced in recent years. The quantification of perfusion parameters [named as dynamic-CEUS (D-CEUS)] has several applications in gastrointestinal neoplastic and inflammatory disorders. However, the limited availability of large studies and the heterogeneity of the technologies employed have precluded the standardisation of D-CEUS, which potentially represents a valuable tool for clinical practice in management of gastrointestinal diseases. In this article, we reviewed the evidence exploring the application of D-CEUS in gastrointestinal diseases, with a special focus on liver, pancreas, and inflammatory bowel diseases.

Tumorigenesis in Inflammatory Bowel Disease: Microbiota-Environment Interconnections.

Colo-rectal cancer (CRC) is undoubtedly one of the most severe complications of inflammatory bowel diseases (IBD). While sporadic CRC develops from a typical adenoma-carcinoma sequence, IBD-related CRC follows different and less understood pathways and its pathophysiological mechanisms were not completely elucidated. In contrast to chronic inflammation, which is nowadays a well-recognised drive towards neoplastic transformation in IBD, only recently was gut microbiota demonstrated to interfere with both inflammation processes and immune-mediated anticancer surveillance. Moreover, the role of microbiota appears particularly complex and intriguing when also considering its multifaceted interactions with multiple environmental stimuli, notably chronic pathologies such as diabetes and obesity, lifestyle (diet, smoking) and vitamin intake. In this review, we presented a comprehensive overview on current evidence of the influence of gut microbiota on IBD-related CRC, in particular its mutual interconnections with the environment.

Correlation between a New Point-Shear Wave Elastography Device (X+pSWE) with Liver Histology and 2D-SWE (SSI) for Liver Stiffness Quantification in Chronic Liver Disease.

BACKGROUND: The aim of this study was to investigate the feasibility, the correlation with previously validated 2D-SWE by supersonic imagine (SSI), and the accuracy in fibrosis-staging of a novel point shear-wave elastography device (X+pSWE) in patients with chronic liver disease. METHODS: This prospective study included 253 patients with chronic liver diseases, without comorbidities potentially affecting liver stiffness. All patients underwent X+pSWE and 2D-SWE with SSI. Among them 122 patients also underwent liver biopsy and were classified according to histologic fibrosis. Agreement between the equipment was assessed with Pearson coefficient and Bland-Altman analysis, while receiver operator characteristic curve (ROC) analysis with Youden index was used to establish thresholds for fibrosis staging. RESULTS: A very good correlation was found between X+pSWE and 2D-SWE with SSI (r2 = 0.94; p < 0.001), with X+pSWE average liver stiffness values 0.24 kPa lower than those obtained with SSI. AUROC of X+pSWE for the staging of significant fibrosis (F2), severe fibrosis (F3) and cirrhosis (F4) using SSI as a reference standard was 0.96 (95% CI, 0.93-0.99), 0.98 (95% CI, 0.97-1) and 0.99 (95% CI, 0.98-1), respectively. The best cut-off values for diagnosing fibrosis ≥F2, ≥F3 and F4 were, respectively, 6.9, 8.5 and 12 for X+pSWE. According to histologic classification, X+pSWE correctly identified 93 out of 113 patients (82%) for F ≥ 2 and 101 out of 113 patients (89%) for F ≥ 3 using the aforementioned cut-off values. CONCLUSION: X+pSWE is a useful novel non-invasive technique for staging liver fibrosis in patients with chronic liver disease.

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.

Dynamics of liver stiffness predicts complications in patients with HCV related cirrhosis treated with direct-acting antivirals.

BACKGROUND: Direct acting antivirals(DAAs) are effective in reducing inflammatory ant fibrotic markers in patients with chronic hepatitis C virus(HCV) infection and to prevent liver-related complications. Two-dimensional shear wave elastography(2D-SWE) is an effective technique for the assessment of liver fibrosis. AIM: To evaluate changes in liver stiffness(LS) in HCV cirrhotic patients undergoing DAA therapy and to identify non-invasive parameters that predict the occurrence of liver-related events. METHODS: We enrolled 229 patients who received DAAs between January 2015 and October 2018. Ultrasound parameters and laboratory data were assessed before treatment and 24(T1) and 48(T2) weeks after end of treatment. Patients were followed up every 6 months to evaluate the development of HCC and other liver related complications. Multiple Cox regression analysis was used to determine parameters associated with the development of complications. RESULTS: Model for End-stage Liver Disease(MELD) score(HR 1.16; CI 95% 1.01-1.33; p = 0.026) and a change in LS at T2(1-year Delta LS) < 20%(HR 2.98; CI 95% 1.01-8.1; p = 0.03) were independently associated with HCC risk. One-year Delta-LS <20% was independently associated with the development of ascites(HR 5.08; CI 95% 1.03 - 25.14; p = 0.04). CONCLUSIONS: Dynamic changes of 2D-SWE-measured LS after DAA therapy may be a useful tool to identify patients who are at higher risk of liver related complications.

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.

Diagnostic and Prognostic Role of Extracellular Vesicles in Pancreatic Cancer: Current Evidence and Future Perspectives.

Pancreatic cancer is one of the most aggressive tumors, with a dismal prognosis due to poor detection rates at early stages, rapid progression, post-surgical complications, and limited effectiveness of conventional oncologic therapies. There are no consistently reliable biomarkers or imaging modalities to accurately diagnose, classify, and predict the biological behavior of this tumor. Therefore, it is imperative to develop new and improved strategies to detect pancreatic lesions in the early stages of cancerization with greater sensitivity and specificity. Extracellular vesicles, including exosome and microvesicles, are membrane-coated cellular products that are released in the outer environment. All cells produce extracellular vesicles; however, this process is enhanced by inflammation and tumorigenesis. Based on accumulating evidence, extracellular vesicles play a crucial role in pancreatic cancer progression and chemoresistance. Moreover, they may represent potential biomarkers and promising therapy targets. The aim of the present review is to review the current evidence on the role of extracellular vesicles in pancreatic cancer.

Radiomics could predict surgery at 10 years in Crohn's disease.

BACKGROUND: Predicting clinical outcomes represents a major challenge in Crohn's disease (CD). Radiomics provides a method to extract quantitative features from medical images and may successfully predict clinical course. AIMS: The aim of this pilot study is to evaluate the use of radiomics to predict 10-year surgery for CD patients. METHODS: We selected a cohort of CD patients with CT scan enterographies and a 10-year follow up. The R library Moddicom was used to extract radiomic features from each lesion of CD, segmented in the CT scans. A logistic regression model based on selected radiomic features was developed to predict 10-year surgery. The model was evaluated by computing the area under the curve (AUC) of the receiver operating characteristic curve, sensitivity, specificity, positive and negative predictive values (PPV, NPV). RESULTS: We enroled 30 patients, with 44 CT scans and 93 lesions. We extracted 217 radiomic features from each lesion. The developed model was based on two radiomic features and presented an AUC (95% CI) of 0.83 (0.73-0.91) in predicting 10-year surgery. Sensitivity, specificity, PPV, NPV of the radiomic model were equal to 0.72, 0.90, 0.79, 0.86, respectively. CONCLUSION: Radiomics could be a helpful tool to identify patients with high risk for surgery and needing a stricter monitoring.

Extracellular Vesicles: Novel Potential Therapeutic Agents in Inflammatory Bowel Diseases.

Patients affected by inflammatory bowel diseases (IBD) can nowadays benefit from a growing number of pharmacological options. However, in moderate-to-severe cases, the therapeutic response is still far from optimal, and treatment changes and optimizations are often required. Thus, researchers in this field are strongly engaged in studies aiming to identify new potential therapeutic targets. Extracellular vesicles (EVs) are tiny subcellular bodies with a phospholipid bilayer envelope containing bioactive molecules, which are released from different cells and are involved in intercellular communication. Recent pre-clinical data show their emerging role in the pathogenesis and treatment of IBD. In our review, we summarize current evidence about the function of EVs as active therapeutic agents in ulcerative colitis and Crohn's disease, analyzing the properties of EVs derived from different cellular sources and the mechanisms through which they may improve intestinal inflammation.

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.