Prediction of cardiovascular risk in patients with hepatocellular carcinoma receiving anti-angiogenic drugs: lessons from sorafenib.

Antiangiogenics are associated with an increased risk of major adverse cardiac and cerebrovascular events (MACE). The identification of at-risk subjects is relevant in the case of hepatocellular carcinoma (HCC), for which anti-angiogenic TKIs and bevacizumab are used in first and subsequent lines of therapy, to select alternative drugs for patients with excessive risk. We verified the ability to predict MACE in sorafenib-treated patients of the 2022 European Society of Cardiology (ESC-2022) score for anti-angiogenics and the recently proposed CARDIOSOR score. A retrospective analysis was conducted of prospectively collected data of the ARPES and ITA.LI.CA databases. All patients received sorafenib for unresectable HCC from 2008 to 2018. Baseline information to calculate the ESC-2022 and CARDIOSOR scores and registration of evolutive events (including MACE) were available for all patients. The predictive ability of both scores was verified using competing risk regressions and tests for goodness of fit. This study included 843 patients (median follow-up 11.3 months). Thirty-four (4.0%) patients presented a MACE. The four-tier ESC-2022 classification showed a progressive risk increase for every class (cumulative risk 1.7%, 2.7%, 4.3%, and 15.0% in the low, medium, high, and high-risk tiers, respectively). The dichotomous CARDIOSOR scale identified a high-risk group with a fourfold increased risk of MACE (sHR 4.66, p = 0.010; cumulative risk 3.8% and 16.4%). ESC-2022 showed a better goodness of fit compared to the CARDIOSOR score [C-index 0.671 (0.583-0.758) vs 0.562 (0.501-0.634), p = 0.021], but this gap was eliminated using the linear version of CARDIOSOR. Both the ESC-2022 and CARDIOSOR scores discriminated patients at increased risk for MACE. The use of these scores in clinical practice should be encouraged, since therapeutic measures can mitigate the cardiovascular risk.

Impact of body mass index on the prognosis of unresectable HCC patients receiving first-line Lenvatinib or atezolizumab plus bevacizumab.

INTRODUCTION: Overweight is a negative prognostic factor in the general population in the long term. However, the role of body mass index (BMI) in the short-mid term in advanced tumours is unclear. The present analysis investigates the role of BMI weight classes in a large sample of patients affected by HCC and receiving atezolizumab plus bevacizumab or lenvatinib as first-line treatment. METHODS AND MATERIAL: The cohort included consecutive patients affected by BCLC-c and BCLC-B HCC patients from a multicenter international study group who received atezolizumab plus bevacizumab or lenvatinib as first-line therapy. Population was stratified according to the BMI in under-, over- and normal-weight according to the conventional thresholds. The primary objective of the study was to evaluate the prognostic and predictive impact of BMI in patients affected by advanced or intermediate HCC. Survival curves were estimated using the product-limit method of Kaplan-Meier. The role of stratification factors was analysed with log-rank tests. RESULTS: 1292 consecutive patients with HCC were analysed. 466 (36%) patients were treated with lenvatinib and 826 (64%) patients were treated with atezolizumab plus bevacizumab. In the atezolizumab plus bevacizumab arm, 510 (62%) patients were normal-weight, 52 (6%) underweight and 264 (32%) overweight. At the univariate analysis for OS, underweight patients had significantly shorter OS compared to normal-weight patients, whereas no differences were found between normal-weight versus overweight. Multivariate analysis confirmed that underweight patients had significantly shorter OS compared to normal-weight patients (HR: 1.7; 95% CI: 1.0-2.8; p = .0323). In the lenvatinib arm, 26 patients (5.6%) were categorized as underweight, 256 (54.9%) as normal-weight, and 184 (39.5%) as overweight. At the univariate analysis for OS, no significant differences were found between normal-weight versus underweight and between normal-weight versus overweight, which was confirmed at multivariate analysis. CONCLUSION: Our analysis highlighted a prognostic role of BMI in a cohort of patients with advanced HCC who received atezolizumab plus bevacizumab, while no prognostic role for low BMI was apparent in patients who received lenvatinib.

Intermediate-stage hepatocellular carcinoma: refining substaging or shifting paradigm?

This review explores the evolution of cancer staging, focusing on intermediate hepatocellular carcinoma (HCC), and the challenges faced by physicians. The Barcelona Clinic Liver Cancer (BCLC) staging system, introduced in 1999, was designed to address the limitations associated with providing accurate prognostic information for HCC and allocating specific treatments, to avoid overtreatment. However, criticism has emerged, particularly regarding the intermediate stage of HCC (BCLC-B) and its heterogeneous patient population. To overcome this limitation, various subclassification systems, such as the Bolondi and Kinki criteria, have been proposed. These systems are aimed at refining categorizations within the intermediate stage and have demonstrated varying degrees of success in predicting outcomes through external validation. This study discusses the shift in treatment paradigms, emphasizing the need for a more personalized approach rather than strictly adhering to cancer stages, without dismissing the relevance of staging systems. It assesses the available treatment options for intermediate-stage HCC, highlighting the importance of considering surgical and nonsurgical options alongside transarterial chemoembolization for optimal outcomes. In conclusion, the text advocates for a paradigm shift in staging systems prioritizing treatment suitability over cancer stage. This reflects the evolving landscape of HCC management, where a multidisciplinary approach is crucial for tailoring treatments to individual patients, ultimately aiming to improve overall survival.

Comparative Analysis of Subclassification Systems in Patients with Intermediate-Stage Hepatocellular Carcinoma (Barcelona Clinic Liver Classification B) Receiving Systemic Therapy.

BACKGROUND: Intermediate-stage hepatocellular carcinoma (BCLC B HCC) occurs in a heterogeneous group of patients and can be addressed with a wide spectrum of treatments. Consequently, survival significantly varies among patients. In recent years, several subclassification systems have been proposed to stratify patients' prognosis. We analyzed and compared these systems (Bolondi, Yamakado, Kinki, Wang, Lee, and Kim criteria) in patients undergoing systemic therapy. METHODS: We considered 171 patients with BCLC B HCC treated with sorafenib as first-line systemic therapy in six Italian centers from 2010 to 2021 and retrospectively applied the criteria of six different subclassification systems. RESULTS: Except for the Yamakado criteria, all the subclassification systems showed a statistically significant correlation to overall survival (OS). In the postestimation analysis, the Bolondi criteria (OS of subgroups 22.5, 11.9, and 6.6 mo, respectively; C-index 0.586; AIC 1338; BIC 1344) and the Wang criteria (OS of subgroups 20.6, 11.9, and 7.0, respectively; C-index 0.607; AIC 1337; BIC 1344) presented the best accuracy. Further analyses of these two subclassification systems implemented with the prognostic factor of alpha-fetoprotein (AFP) > 400 ng/mL have shown an increase in accuracy for both systems (C-index 0.599 and 0.624, respectively). CONCLUSIONS: Intermediate-stage subclassification systems maintain their predictive value also in the setting of systemic therapy. The Bolondi and Wang criteria showed the highest accuracy. AFP > 400 ng/mL enhances the performance of these systems.

A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma.

Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known. Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS). Results: In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73-0.86) but not in female (pooled HR 0.85; 95% CI 0.70-1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59-1.04; 1.02, 95% CI 0.80-1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes. Conclusion: Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted. Impact and implications: While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised. Systematic review registration: PROSPERO CRD42023429625.

Characteristics and outcomes of immunotherapy-related liver injury in patients with hepatocellular carcinoma versus other advanced solid tumours.

BACKGROUND & AIMS: Immune-related liver injury (irLI) is commonly observed in patients with cancer treated with immune checkpoint inhibitors (ICIs). We aimed to compare the incidence, clinical characteristics, and outcomes of irLI between patients receiving ICIs for hepatocellular carcinoma (HCC) vs. other solid tumours. METHODS: Two separate cohorts were included: 375 patients with advanced/unresectable HCC, Child-Pugh A class treated with first-line atezolizumab+bevacizumab from the AB-real study, and a non-HCC cohort including 459 patients treated with first-line ICI therapy from the INVIDIa-2 multicentre study. IrLI was defined as a treatment-related increase of aminotransferase levels after exclusion of alternative aetiologies of liver injury. The incidence of irLI was adjusted for the duration of treatment exposure. RESULTS: In patients with HCC, the incidence of any grade irLI was 11.4% over a median treatment exposure of 4.4 months (95% CI 3.7-5.2) vs. 2.6% in the INVIDIa-2 cohort over a median treatment exposure of 12.4 months (95% CI 11.1-14.0). Exposure-adjusted-incidence of any grade irLI was 22.1 per 100-patient-years in patients with HCC and 2.1 per 100-patient-years in patients with other solid tumours (p <0.001), with median time-to-irLI of 1.4 and 4.7 months, respectively. Among patients who developed irLI, systemic corticosteroids were administered in 16.3% of patients with HCC and 75.0% of those without HCC (p <0.001), and irLI resolution was observed in 72.1% and 58.3%, respectively (p = 0.362). In patients with HCC, rates of hepatic decompensation and treatment discontinuation due to irLI were 7%. Grade 1-2 irLI was associated with improved overall survival only in patients with HCC (hazard ratio 0.53, 95% CI 0.29-0.96). CONCLUSIONS: Despite higher incidence and earlier onset, irLI in patients with HCC is characterised by higher rates of remission and lower requirement for corticosteroid therapy (vs. irLI in other solid tumours), low risk of hepatic decompensation and treatment discontinuation, not negatively affecting oncological outcomes. IMPACT AND IMPLICATIONS: Immune-related liver injury (irLI) is common in patients with cancer receiving immune checkpoint inhibitors (ICIs), but whether irLI is more frequent or it is associated with a worse clinical course in patients with hepatocellular carcinoma (HCC), compared to other tumours, is not known. Herein, we compared characteristics and outcomes of irLI in two prospective cohorts including patients treated with ICIs for HCC or for other oncological indications. irLI is significantly more common and it occurs earlier in patients with HCC, also after adjustment for duration of treatment exposure. However, outcomes of patients with HCC who developed irLI are not negatively affected in terms of requirement for corticosteroid therapy, hepatic decompensation, treatment discontinuation and overall survival.

Exploring occupational toxicant exposures in patients with metabolic dysfunction-associated steatotic liver disease: A prospective pilot study.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) has been traditionally associated with insulin resistance and obesity. Recently, pollutants have been shown to contribute to the development of MASLD. Given the global burden of MASLD, understanding whether pollutants are merely associated with steatosis or contribute to its progression to advanced chronic liver disease (ACLD) and hepatocellular carcinoma (HCC) is critical. Workers exposed to occupational toxicants represent an ideal population for assessing the potentially hazardous consequences of professional exposure. Confirming a link between occupational exposure and ACLD/HCC may not only provide further elements in understanding MASLD, but also contribute to preventive strategies for exposed workers. OBJECTIVE: This study aimed to assess the prevalence of self-reported occupational exposure to toxicants in patients with MASLD. METHODS: This hospital-based prospective pilot study included 201 patients with MASLD. Data on workplace toxicant exposure were collected systematically using a structured questionnaire. Subsequently, patients with ACLD and/or HCC (n = 55) were compared to controls (n = 146). Logistic regression analysis and propensity score models were used to investigate the associations between self-reported occupational exposure and ACLD and/or HCC. RESULTS: Patients with ACLD/HCC reported exposure to metals, halogenated refrigerants, pain/resins, and fuel emissions more often than the controls. After controlling for confounders, durations of 21-30 years and >30 years of occupational exposure to toxicants showed odds ratios (ORs) of 2.31 (95 % confidence interval [CI]: 1.09-4.88, p = 0.029) and 4.47 (95 % CI: 2.57-7.78, p<0.001), respectively. CONCLUSIONS: In this pilot study, patients with MASLD complications were more likely to report workplace toxicant exposure. Our results warrant future multicentre confirmatory studies, as implementing prevention policies may reduce the risk of life-threatening diseases among exposed populations.

Direct oral anticoagulants for the treatment of splanchnic vein thrombosis: A state of art.

Splanchnic vein thrombosis (SVT) is a manifestation of venous thromboembolism in an unusual site. Portal, mesenteric, and splenic veins are the most common vessels involved in SVT which occurs mainly in patients with liver cirrhosis, although non-cirrhotic patients could be affected as well. Thrombosis of hepatic veins, also known as Budd-Chiari syndrome, is another manifestation of SVT. Prompt diagnosis and intervention are mandatory in order to increase the recalization rate and reduce the risk of thrombus progression and hypertensive complications. Traditional anticoagulation with heparin and vitamin-K antagonists is the treatment of choice in these cases. However, recent studies have shown promising results on the efficacy and safety of direct oral anticoagulants (DOACs) in this setting. Available results are mainly based on retrospective studies with small sample size, but first clinical trials have been published in the last years. This manuscript aims to provide an updated overview of the current evidence regarding the role of DOACs for SVT in both cirrhotic and non-cirrhotic patients.

Landscape of alcohol-related hepatocellular carcinoma in the last 15 years highlights the need to expand surveillance programs.

Background & Aims: Alcohol abuse and metabolic disorders are leading causes of hepatocellular carcinoma (HCC) worldwide. Alcohol-related aetiology is associated with a worse prognosis compared with viral agents, because of the lower percentage of patients diagnosed with HCC under routine surveillance and a higher burden of comorbidity in alcohol abusers. This study aimed to describe the evolving clinical scenario of alcohol-related HCC over 15 years (2006-2020) in Italy. Methods: Data from the Italian Liver Cancer (ITA.LI.CA) registry were used: 1,391 patients were allocated to three groups based on the year of HCC diagnosis (2006-2010; 2011-2015; 2016-2020). Patient characteristics, HCC treatment, and overall survival were compared among groups. Survival predictors were also investigated. Results: Approximately 80% of alcohol-related HCCs were classified as cases of metabolic dysfunction-associated fatty liver disease. Throughout the quinquennia, <50% of HCCs were detected by surveillance programmes. The tumour burden at diagnosis was slightly reduced but not enough to change the distribution of the ITA.LI.CA cancer stages. Intra-arterial and targeted systemic therapies increased across quinquennia. A modest improvement in survival was observed in the last quinquennia, particularly after 12 months of patient observation. Cancer stage, HCC treatment, and presence of oesophageal varices were independent predictors of survival. Conclusions: In the past 15 years, modest improvements have been obtained in outcomes of alcohol-related HCC, attributed mainly to underuse of surveillance programmes and the consequent low amenability to curative treatments. Metabolic dysfunction-associated fatty liver disease is a widespread condition in alcohol abusers, but its presence did not show a pivotal prognostic role once HCC had developed. Instead, the presence of oesophageal varices, an independent poor prognosticator, should be considered in patient management and refining of prognostic systems. Impact and Implications: Alcohol abuse is a leading and growing cause of hepatocellular carcinoma (HCC) worldwide and is associated with a worse prognosis compared with other aetiologies. We assessed the evolutionary landscape of alcohol-related HCC over 15 years in Italy. A high cumulative prevalence (78%) of metabolic dysfunction-associated fatty liver disease, with signs of metabolic dysfunction, was observed in HCC patients with unhealthy excessive alcohol consumption. The alcohol + metabolic dysfunction-associated fatty liver disease condition tended to progressively increase over time. A modest improvement in survival occurred over the study period, likely because of the persistent underuse of surveillance programmes and, consequently, the lack of improvement in the cancer stage at diagnosis and the patients' eligibility for curative treatments. Alongside the known prognostic factors for HCC (cancer stage and treatment), the presence of oesophageal varices was an independent predictor of poor survival, suggesting that this clinical feature should be carefully considered in patient management and should be included in prognostic systems/scores for HCC to improve their performance.

Sequential therapies after atezolizumab plus bevacizumab or lenvatinib first-line treatments in hepatocellular carcinoma patients.

INTRODUCTION: The aim of this retrospective proof-of-concept study was to compare different second-line treatments for patients with hepatocellular carcinoma and progressive disease (PD) after first-line lenvatinib or atezolizumab plus bevacizumab. MATERIALS AND METHODS: A total of 1381 patients had PD at first-line therapy. 917 patients received lenvatinib as first-line treatment, and 464 patients atezolizumab plus bevacizumab as first-line. RESULTS: 49.6% of PD patients received a second-line therapy without any statistical difference in overall survival (OS) between lenvatinib (20.6months) and atezolizumab plus bevacizumab first-line (15.7months; p = 0.12; hazard ratio [HR]= 0.80). After lenvatinib first-line, there wasn't any statistical difference between second-line therapy subgroups (p = 0.27; sorafenib HR: 1; immunotherapy HR: 0.69; other therapies HR: 0.85). Patients who underwent trans-arterial chemo-embolization (TACE) had a significative longer OS than patients who received sorafenib (24.7 versus 15.8months, p < 0.01; HR=0.64). After atezolizumab plus bevacizumab first-line, there was a statistical difference between second-line therapy subgroups (p < 0.01; sorafenib HR: 1; lenvatinib HR: 0.50; cabozantinib HR: 1.29; other therapies HR: 0.54). Patients who received lenvatinib (17.0months) and those who underwent TACE (15.9months) had a significative longer OS than patients treated with sorafenib (14.2months; respectively, p = 0.01; HR=0.45, and p < 0.05; HR=0.46). CONCLUSION: Approximately half of patients receiving first-line lenvatinib or atezolizumab plus bevacizumab access second-line treatment. Our data suggest that in patients progressed to atezolizumab plus bevacizumab, the systemic therapy able to achieve the longest survival is lenvatinib, while in patients progressed to lenvatinib, the systemic therapy able to achieve the longest survival is immunotherapy.

Presence of Hepatocellular Carcinoma Does Not Affect Course and Response to Anticoagulation of Bland Portal Vein Thrombosis in Cirrhotic Patients.

Background: Malignancies are generally considered a risk factor for deep vein thrombosis and may hamper the recanalisation of thrombosed veins. Aim: We investigate whether the natural course and response to anticoagulant treatment of bland portal vein thrombosis (PVT) in patients with cirrhosis complicated by hepatocellular carcinoma (HCC) differ from those without HCC. Methods: Retrospective study in two hepatology referral centres, in Italy and Romania where patients with a diagnosis of PVT on cirrhosis and follow-up of at least 3 months with repeated imaging were included. Results: A total of 162 patients with PVT and matching inclusion and exclusion criteria were identified: 30 with HCC were compared to 132 without HCC. Etiologies, Child-Pugh Score (7 vs 7) and MELD scores (11 vs 12, p=0.3679) did not differ. Anticoagulation was administered to 43% HCC vs 42% nonHCC. The extension of PVT in the main portal trunk was similar: partial/total involvement was 73.3/6.7% in HCC vs 67.4/6.1% in nonHCC, p=0.760. The remainder had intrahepatic PVT. The recanalization rate was 61.5% and 60.7% in HCC/nonHCC in anticoagulated patients (p=1). Overall PVT recanalisation, including treated and untreated patients, was observed in 30% of HCC vs 37.9% of nonHCC, p=0.530. Major bleeding incidence was almost identical (3.3% vs 3.8%, p=1). Progression of PVT after stopping anticoagulation did not differ (10% vs 15.9%, respectively, HCC/nHCC, p=0.109). Conclusion: The course of bland non-malignant PVT in cirrhosis is not affected by the presence of active HCC. Treatment with anticoagulation in patients with active HCC is safe and as effective as in nonHCC patients, this can potentially allow us to use otherwise contraindicated therapies (ie TACE) if a complete recanalization is achieved with anticoagulation.

Osteosarcopenia in NAFLD/MAFLD: An Underappreciated Clinical Problem in Chronic Liver Disease.

Chronic liver disease (CLD), including non-alcoholic fatty liver disease (NAFLD) and its advanced form, non-alcoholic steatohepatitis (NASH), affects a significant portion of the population worldwide. NAFLD is characterised by fat accumulation in the liver, while NASH is associated with inflammation and liver damage. Osteosarcopenia, which combines muscle and bone mass loss, is an emerging clinical problem in chronic liver disease that is often underappreciated. The reductions in muscle and bone mass share several common pathophysiological pathways; insulin resistance and chronic systemic inflammation are the most crucial predisposing factors and are related to the presence and gravity of NAFLD and to the worsening of the outcome of liver disease. This article explores the relationship between osteosarcopenia and NAFLD/MAFLD, focusing on the diagnosis, prevention and treatment of this condition in patients with CLD.

Effects of COVID-19 Pandemic on Metabolic Status and Psychological Correlates of a Cohort of Italian NAFLD Outpatients.

Non-alcoholic fatty liver disease (NAFLD) is a potentially progressive condition characterized by the presence of fat in more than 5% of hepatocytes, representing the hepatic expression of metabolic syndrome (MetS). A reduction of at least 5-7% in initial body weight improves the metabolic profile underlying NAFLD. The aim of our study was to evaluate the effects of the COVID-19 lockdown on a cohort of non-advanced NAFLD Italian outpatients. We identified 43 patients with 3 available time point visits in our center: first visit (T0) when behavioral indications aimed at controlling MetS were provided, a pre-COVID visit (T1) and a post-COVID visit (T2). During the lockdown, an online compilation of validated psychological tests (SRQ-20, EQ5D, SF-12 and STAI) and a specifically formulated questionnaire for NAFLD was presented to our cohort and completed by 14 consenting patients. Patients who had lost more than 5% of the initial weight at T1 (9 subjects, 21%) maintained the results even at T2, with an overall reduction in BMI and liver stiffness; patients who had not lost the desired weight at T1 (34 subjects, 79%) displayed a further increase in BMI and visceral adiposity at T2. Of interest is that patients in the latter group reported signs of psychological suffering. Our data demonstrated that the setting of good counseling was effective in controlling the metabolic disorder underlying NAFLD in our cohort of outpatients. Given the need for patients to play an active role in the behavioral therapy for NAFLD, we advocate that a multidisciplinary approach be adopted, including a psychological support to obtain the best results over time.

Prognostic Impact of Metastatic Site in Patients Receiving First-Line Sorafenib Therapy for Advanced Hepatocellular Carcinoma.

Extrahepatic spread is a well-known negative prognostic factor in patients with advanced hepatocellular carcinoma (HCC). The prognostic role of different metastatic sites and their response rate to systemic treatment is still being debated. We considered 237 metastatic HCC patients treated with sorafenib as first-line therapy in five different Italian centers from 2010 to 2020. The most common metastatic sites were lymph nodes, lungs, bone and adrenal glands. In survival analysis, the presence of dissemination to lymph nodes (OS 7.1 vs. 10.2 months; p = 0.007) and lungs (OS 5.9 vs. 10.2 months; p < 0.001) were significantly related to worse survival rates compared with all other sites. In the subgroup analysis of patients with only a single metastatic site, this prognostic effect remained statistically significant. Palliative radiation therapy on bone metastases significantly prolonged survival in this cohort of patients (OS 19.4 vs. 6.5 months; p < 0.001). Furthermore, patients with lymph node and lung metastases had worse disease control rates (39.4% and 30.5%, respectively) and shorter radiological progression-free survival (3.4 and 3.1 months, respectively). In conclusion, some sites of an extrahepatic spread of HCC have a prognostic impact on survival in patients treated with sorafenib; in particular, lymph nodes and lung metastases have worse prognosis and treatment response rate.

TKIs in combination with immunotherapy for hepatocellular carcinoma.

INTRODUCTION: The treatment landscape of hepatocellular carcinoma (HCC) has significantly changed over the last 5 years with multiple options in the frontline, second line, and beyond. Tyrosine kinase inhibitors (TKIs) were the first approved systemic treatments for the advanced stage of HCC; however, thanks to the increasing knowledge and characterization of the immunological features of the tumor microenvironment, the systemic treatment of HCC has been further expanded with the immune checkpoint inhibitor (ICI) approach and the following evidence of the higher efficacy obtained with combined treatment with atezolizumab plus bevacizumab over sorafenib. AREAS COVERED: In this review, we look at rationale, efficacy, and safety profiles of current and emerging ICI/TKI combination treatments and discuss the available results from other clinical trials using similar combinatorial therapeutic approaches. EXPERT OPINION: Angiogenesis and immune evasion are the two key pathogenic hallmarks of HCC. While the pioneering regimen of atezolizumab/bevacizumab is consolidating as the first-line treatment of advanced HCC, it will be essential, in the near future, to determine the best second-line treatment options and how to optimize the selection of the most effective therapies. These points still need to be addressed by future studies that are largely warranted to enhance the treatment's effectiveness and ultimately to tackle down HCC lethality.

Association between anatomic variations of extrahepatic and intrahepatic bile ducts: Do look up!

Biliary anatomic variations are usually asymptomatic, but they may cause problems in diagnostic investigations and interventional and surgical procedures, increasing both their technical difficulty and their postoperative complication rates. The aim of the present study was to evaluate the prevalence of anatomic variations in the intrahepatic biliary ducts (IHBD) in relation to demographical and clinical characteristics in a large study population requiring magnetic resonance cholangiopancreatography (MRCP) for various clinical conditions. The possible association between IHBD and extrahepatic biliary ducts (EHBD) variants was then explored. From January 2017 to May 2019, 1004 patients underwent MRCP. Demographical and clinical data were collected. IHBD and EHBD anatomy were recorded and the EHBD anatomy was classified using both qualitative and quantitative classifications. The presence of a type 3 EHBD variant (an abnormal proximal cystic duct [CD] insertion) in both qualitative and quantitative classifications and an intrapancreatic CD were associated with the presence of IHBD variants at univariate analysis (p = 0.008, p = 0.019, and p = 0.001, respectively). The presence of a posterior or medial insertion of the CD into the EHBD was a strong predictive factor of the presence of IHBD variants both at uni- and multivariate analysis (p = 0.002 and p = 0.003 for posterior insertion and p = 0.002 and p = 0.002 for medial insertion, respectively). The presence of gallstones on MRCP resulted in a strong predictor of the presence of an anatomical variant of the IHBD both at uni- and multivariate analysis (p = 0.027 and p = 0.046, respectively). In conclusion, the presence of a type 3 variant of the EHBD, an intrapancreatic CD and, especially, a posterior/medial CD insertion into the EHBD represent predictive factors of the concomitant presence of IHBD variants, thus radiologists must be vigilant when encountering these EHBD configurations and always remember to "look up" at the IHBD. Finally, the presence of an IHBD variant is a strong predictive factor of gallstones.

Role of the Prognostic Nutritional Index in Predicting Survival in Advanced Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab.

INTRODUCTION: The prognostic nutritional index (PNI) is a multiparametric score introduced by Onodera based on the blood levels of lymphocytes and albumin in patients with gastrointestinal neoplasms. Regarding hepatocellular carcinoma (HCC), its prognostic role has been shown in patients treated with sorafenib and lenvatinib. The aim of this real-world study was to investigate the association between clinical outcomes and PNI in patients being treated with atezolizumab plus bevacizumab. METHODS: The overall cohort of this multicentric study included 871 consecutive HCC patients from 5 countries treated with atezolizumab plus bevacizumab in first-line therapy. The PNI was calculated as follows: 10 × serum albumin concentration (g/dL) + 0.005 × peripheral lymphocyte count (number/mm3). RESULTS: Data regarding lymphocyte counts and albumin levels were available for 773 patients; therefore, these patients were included in the final analysis. The cut-off point of the PNI was determined to be 41 by receiver operating characteristic analysis. 268 patients (34.7%) were categorized as the PNI-low group, while the remaining 505 (65.3%) patients as the PNI-high group. At the univariate analysis, high PNI was associated with longer overall survival (OS) (22.5 vs. 10.1 months, HR 0.34, p <0.01) and progression-free survival (PFS) (8.7 vs. 5.8 months, HR 0.63, p <0.01) compared to patients with low PNI. At the multivariate analysis, high versus low PNI resulted as an independent prognostic factor for OS (HR 0.49, p <0.01) and PFS (HR 0.82, p = 0.01). There was no difference in objective response rate between the two groups (high 26.1% vs. low 19.8%, p = 0.09), while disease control rate was significantly higher in the PNI-high group (76.8% vs. 66.4%, p = 0.01). CONCLUSION: PNI is an independent prognostic factor for OS and PFS in HCC patients on first-line treatment with atezolizumab plus bevacizumab.