Immunotherapy-based combinations have revolutionized the first-line treatment for advanced hepatocellular carcinoma (HCC), improving overall survival (OS). However, these therapies are associated with adverse events (AEs), particularly cardiological complications and major adverse cardiovascular events (MACE), which may adversely affect outcomes. The influence of comorbid conditions such as arterial hypertension (AHT) and type 2 diabetes mellitus (T2DM) on the incidence and prognosis of cardiological AEs in HCC patients remains understudied.

This retrospective study included 109 HCC patients treated with atezolizumab-bevacizumab, tremelimumab-durvalumab, or durvalumab as first-line therapy at two Spanish medical centers from 2017-2023. Patients were stratified by comorbidities, AE incidence, and cardiological risk (CARDIOSOR scale). The primary endpoints were the incidence of treatment-modifying AEs and MACE, and their association with survival.

Among the cohort, 50.5 % experienced AEs of special interest (AESI), with 34 % considered immune-related (irAE). MACE occurred in 7.3 % of patients, including myocarditis (3.7 %). The CARDIOSOR scale identified a higher risk of MACE in patients with AHT, T2DM, or both (OR: 5.07, p = 0.034). Early cardiological AEs were independently associated with worse OS (HR: 3.38, p = 0.04). Patients with both AHT and T2DM exhibited higher rates of MACE (16.7 %) and treatment discontinuation (25.9 %). The CARDIOSOR scale effectively stratified patients into high-risk groups, correlating with increased MACE rates and poor survival outcomes.

Comorbid conditions, particularly AHT and T2DM, amplify the risk of MACE and influence treatment discontinuation. The CARDIOSOR scale is a valuable tool for personalized risk assessment, guiding tailored therapeutic strategies. Integrating cardiovascular risk management into HCC care is crucial for optimizing both oncological and cardiovascular outcomes.

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is a major cause of cancer-related morbidity and mortality. Limited treatment options for advanced stages highlight the need for effective therapies.

This review explores immune checkpoint inhibitors (ICIs), specifically PD-1, PD-L1, and CTLA-4 inhibitors, as emerging treatments for advanced HCC. It discusses data from phase II and III trials evaluating ICI combinations with tyrosine kinase inhibitors (TKIs), anti-angiogenic agents, and locoregional treatments like Transarterial Chemoembolization (TACE). Clinical outcomes, including progression-free survival and response rates, were analyzed alongside the incidence and management of immune-related adverse events (irAEs). A systematic review approach ensured comprehensive, high-quality study inclusion.

ICI-based therapies and their combinations are transforming advanced HCC treatment, offering improved outcomes and potential survival benefits. However, these therapies need optimization in sequencing and selection, particularly considering variations in liver function and disease stage. Effective management of adverse effects is critical to maximize clinical benefits. Further research is required to develop personalized strategies, tailoring treatments to patient-specific factors and enhancing safety and effectiveness in HCC management.

Safety data for patients with hepatocellular carcinoma (HCC) treated with atezolizumab-bevacizumab in the real-world setting remain uncertain. Thus, the aim of this study was to evaluate the incidence of adverse events (AEs) in patients with HCC treated with atezolizumab-bevacizumab in the literature.

In this systematic review and meta-analysis, we searched PubMed for original studies reporting percentages of AEs in patients with HCC receiving atezolizumab-bevacizumab between 2020 to 2023, using the search terms "Atezolizumab/Bevacizumab", "HCC" and "Adverse events". We summarized the incidence of AEs and performed a meta-analysis in order to evaluate the incidence of AEs reported in the literature.

A total of 30 studies (3,867 patients) were included. The analysis revealed heterogeneity in AE reporting, with arterial hypertension, proteinuria, and fatigue being the most frequently reported AEs whereas incidence of bleeding was reported in 66.7% of the studies and rare immune-related AEs were reported in 26.7% of the studies. The meta-analysis revealed pooled incidence rates of 79% for any grade AEs: 56% for grade 1/2 and 30% for grade ≥3. While the pooled rates of hypertension, anorexia, bleeding, pruritus, rash, and thyroid dysfunction were similar to those reported in the IMbrave150 trial, higher rates were observed in the literature for proteinuria, fatigue, ALT and AST elevations and gastrointestinal perforation. For grade ≥3 AEs, the percentages were consistent with the IMbrave150 trial, except for lower incidences of arterial hypertension and thrombosis in the literature. The exposure-adjusted incidence rates for proteinuria (55.7%), hypertension (45.3%) and fatigue (33.6%) were high. Heterogeneity was observed in the analysis of AEs across articles within the same cohorts of patients.

We observed a significant variability in AE reporting for atezolizumab-bevacizumab treatment in HCC in the literature, underscoring the need for standardized reporting practices.

Considering the demonstrated safety of atezolizumab-bevacizumab in randomized-controlled trials, this meta-analysis offers valuable insights into reported occurrences of adverse events. Our study highlights significant heterogeneity among studies, underscoring the need to improve adverse event recording. Understanding the incidence and severity of treatment-related adverse events beyond clinical trials is essential for prompt intervention and may help in preventing treatment discontinuation and complications, potentially leading to better outcomes without significantly compromising quality of life due to adverse events.

To assess the impact of adverse event (AE) severity, caused by targeted therapy, on overall survival (OS) and progression-free survival (PFS) in patients with unresectable hepatocellular carcinoma (HCC), a total of 183 patients with HCC treated with atezolizumab plus bevacizumab (40), lenvatinib (57), sorafenib (79), cabozantinib (3), ramucirumab (3), and regorafenib (1) were included in this study. Age-, AFP-, and ALBI score-adjusted hazard ratios (HRs) of AE grades 1 to 3 versus grade 0 for OS and PFS were calculated using Cox proportional hazards models. The linear trend of the HRs was assessed by calculating the p values for this trend. The most common AEs were appetite loss (AE grade 0/1/2/3 = 97/23/55/12), general fatigue (102/31/44/6), hypertension (120/6/40/17), hand-foot syndrome (HFS) (135/21/24/3), proteinuria (140/13/16/14), and hypothyroidism (148/12/23/0). The adjusted HRs for OS of these AEs were 0.532-1.450-2.361 (p for trend 0.037), 1.057-1.691-3.364 (p for trend 0.004), 1.176-0.686-0.281 (p for trend 0.002), 0.639-0.759-1.820 (p for trend 0.462), 1.030-0.959-0.147 (p for trend 0.011), and 0.697-0.609 (p for trend 0.119), respectively. Those for PFS of the corresponding AEs were 0.592-1.073-2.811 (p for trend 0.255), 1.161-1.282-4.324 (p for trend 0.03), 0.965-0.781-0.655 (p for trend 0.095), 0.737-0.623-2.147 (p for trend 0.153), 1.061-0.832-0.800 (p for trend 0.391), and 1.412-0.560 (p for trend 0.081), respectively. Appetite loss and general fatigue negatively affected clinical outcomes, whereas hypertension, HFS, proteinuria, and hypothyroidism had positive effects.

Although the treatment landscape has rapidly evolved over the last years, hepatocellular carcinoma (HCC) is one of the most lethal cancers. With recent advances, both immunotherapy and tyrosine kinase inhibitors (TKIs)-based chemotherapy constitute the standard treatment for advanced HCC. A systematic search of randomized clinical trials employing TKIs was performed in 17 databases, obtaining 25 studies evaluating the prognosis, tumor response, and presence of adverse events (AEs) related to TKIs in HCC. Overall effect sizes were estimated for the hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI), either extracted or calculated with the Parmar method, employing STATA 16. Heterogeneity was assessed by Chi-square-based Q-test and inconsistency (I2) statistic; source of heterogeneity by meta-regression and subgroup analysis; and publication bias by funnel plot asymmetry and Egger's test. The research protocol was registered in PROSPERO (CRD42023397263). Meta-analysis revealed a correlation between survival and tumor response parameters and TKI treatment vs. placebo, despite detecting high heterogeneity. Combined TKI treatment showed a significantly better objective response rate (ORR) with no heterogeneity, whereas publication bias was only detected with time to progression (TTP). Few gastrointestinal and neurological disorders were associated with TKI treatment vs. placebo or with combined treatment. However, a higher number of serious AEs were related to TKI treatment vs. sorafenib alone. Results show positive clinical benefits from TKI treatment, supporting the approval and maintenance of TKI-based therapy for advanced HCC, while establishing appropriate strategies to maximize efficacy and minimize toxicity.

In the context of patients with hepatocellular carcinoma (HCC) treated with systemic therapy, the correlation between the appearance of adverse events (AEs) and reported efficacy outcomes is well-known and widely investigated. From other pathological settings, we are aware of the prognostic and predictive value of the occurrence of immune-related AEs in patients treated with immune-checkpoint inhibitors.

This retrospective multicenter real-world study aims to investigate the potential prognostic value of AEs in patients with HCC treated with atezolizumab plus bevacizumab in the first-line setting.

The study population consisted of 823 patients from five countries (Italy, Germany, Portugal, Japan, and the Republic of Korea).

Of the patients, 73.3% presented at least one AE during the study period. The most common AEs were proteinuria (29.6%), arterial hypertension (27.2%), and fatigue (26.0%). In all, 17.3% of the AEs were grade (G) 3. One death due to bleeding was reported. The multivariate analysis confirmed the appearance of decreased appetite G < 2 [versus G ≥ 2; hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.13-0.90; p < 0.01] and immunotoxicity G < 2 (versus G ≥ 2; HR: 0.70; 95% CI 0.24-0.99; p = 0.04) as independent prognostic factors for overall survival, and the appearance of decreased appetite G < 2 (versus G ≥ 2; HR: 0.73; 95% CI 0.43-0.95; p = 0.01), diarrhea (yes versus no; HR: 0.57, 95% CI 0.38-0.85; p = 0.01), fatigue (yes versus no; HR: 0.82, 95% CI 0.65-0.95; p < 0.01), arterial hypertension G < 2 (versus G ≥ 2; HR: 0.68, 95% CI 0.52-0.87; p < 0.01), and proteinuria (yes versus no; HR: 0.79, 95% CI 0.64-0.98; p = 0.03) as independent prognostic factors for progression-free survival.

As demonstrated for other therapies, there is also a correlation between the occurrence of AEs and outcomes for patients with HCC for the combination of atezolizumab plus bevacizumab.

Lenvatinib is approved as a first-line treatment for patients with unresectable and/or recurrent hepatocellular carcinoma (HCC). Lenvatinib achieved promising clinical benefits in REFLECT but was associated with clinically significant treatment-emergent hypertension (CSTE-HTN, a grouped term), a common class effect of tyrosine kinase inhibitors. This post hoc analysis assessed the impact of CSTE-HTN on the efficacy and safety of lenvatinib in HCC.

Patients from REFLECT who received lenvatinib (n = 476) were stratified according to CSTE-HTN. Tumors were assessed by mRECIST. Overall survival (OS) and progression-free survival (PFS) were evaluated using landmark analyses at 4 and 8 weeks.

A total of 212 patients in the lenvatinib arm developed CSTE-HTN, and 264 did not. CSTE-HTN first occurred at 3.7 weeks (median); the worst grade CSTE-HTN occurred at 4.1 weeks (median). No patients had life-threatening CSTE-HTN and/or died due to CSTE-HTN. Median OS was numerically longer in patients with versus without CSTE-HTN (at 4 weeks: 16.3 vs. 11.6 months; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.621-1.004; at 8 weeks: 13.5 vs. 11.6 months; HR, 0.87; 95% CI, 0.696-1.089). Median PFS was similar between patients with and without CSTE-HTN (at 4 weeks: 6.6 vs. 6.4 months; HR, 0.887; 95% CI, 0.680-1.157; at 8 weeks: 5.7 vs. 6.4 months; HR, 1.09; 95% CI, 0.84-1.41). Objective response rate was numerically higher in patients with (48.6%) versus without CSTE-HTN (34.5%).

In this retrospective analysis, CSTE-HTN was associated with improved OS but not PFS. CSTE-HTN did not impair the outcomes of patients with HCC treated with lenvatinib when detected early and managed appropriately.

During the last decade, tyrosine kinase inhibitors (TKIs) sorafenib and regorafenib have been standard systemic treatments for advanced hepatocellular carcinoma (HCC). Previous data associated sorafenib with inflammasome activation. However, the role of the inflammasome in sorafenib and regorafenib signaling has not been described in liver cancer patients. For this purpose, we analyzed inflammasome-related transcriptomic changes in a murine HCC model. Our data confirmed inflammasome activation after both TKI treatments, sharing a similar pattern of increased gene expression. According to human database results, transcriptional increase of inflammasome genes is associated with poorer prognosis for male liver cancer patients, suggesting a sex-dependent role for inflammasome activation in HCC therapy. In biopsies of HCC and its surrounding tissue, we detected durable increases in the inflammasome activation pattern after sorafenib or regorafenib treatment in male patients. Further supporting its involvement in sorafenib action, inflammasome inhibition (MCC950) enhanced sorafenib anticancer activity in experimental HCC models, while no direct in vitro effect was observed in HCC cell lines. Moreover, activated human THP-1 macrophages released IL-1β after sorafenib administration, while 3D Hep3B spheres displayed increased tumor growth after IL-1β addition, pointing to the liver microenvironment as a key player in inflammasome action. In summary, our results unveil the inflammasome pathway as an actionable target in sorafenib or regorafenib therapy and associate an inflammasome signature in HCC and surrounding tissue with TKI administration. Therefore, targeting inflammasome activation, principally in male patients, could help to overcome sorafenib or regorafenib resistance and enhance the efficacy of TKI treatments in HCC.

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.

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.

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).

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.

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.

Worldwide, hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death. The remarkable improvements in treating HCC achieved in the last years have increased the complexity of its management. Following the need to have updated guidelines on the multidisciplinary treatment management of HCC, the Italian Scientific Societies involved in the management of this cancer have promoted the drafting of a new dedicated document. This document was drawn up according to the GRADE methodology needed to produce guidelines based on evidence. Here is presented the second part of guidelines, focused on the multidisciplinary tumor board of experts and non-surgical treatments of HCC.

Sorafenib, a kinase inhibitor, is known to cause skin toxicity, which sometimes leads to treatment interruption or drug dose reduction. Erythema multiforme (EM) is one of these dermatologic toxicities induced by sorafenib. We report the case of a 28-year-old male with hepatocellular carcinoma (HCC). Two months after surgery, the patient presented with multiple metastases to the retroperitoneal lymph nodes and lungs. Therefore, systemic therapy with sorafenib was indicated. While receiving the medication, the patient presented signs compatible with EM. The signs occurred on the torso and then spread to the rest of the body. Sorafenib treatment was interrupted the same day when skin lesions appeared and moisturizers with topical steroids and oral antihistamines were prescribed. The skin lesions decreased in size but without significant cutaneous improvement. The patient showed biologically severe liver failure and radiological progression. Because of the severe hepatic failure, initiation of intravenous steroids and establishment of another line of chemotherapy following tumor progression were contraindicated. The decision of the multidisciplinary staff with patient consent was to proceed with the best supportive care. The patient died in ambulatory care 12 days after discharge and local treatment. This report highlights the possibility of developing severe EM while receiving sorafenib. Patients with HCC who have liver resection without liver dysfunction should not be administered sorafenib, or it must be used with caution at very low doses and accompanied by close and regular follow-ups to avoid disease progression and deaths.

Sorafenib is the standard of care in the management of advanced hepatocellular carcinoma (HCC). The purpose of this study was to investigate the characteristics, treatment patterns and outcomes of sorafenib among HCC patients in South Korea.

This population-based retrospective, single-arm, observational study used the Korean National Health Insurance database to identify patients with HCC who received sorafenib between July 1, 2008, and December 31, 2014. A total of 9,923 patients were recruited in this study.

Among 9,923 patients, 6,669 patients (68.2%) received loco-regional therapy prior to sorafenib, and 1,565 patients (15.8%) received combination therapy with concomitant sorafenib; 2,591 patients (26.1%) received rescue therapy after sorafenib, and transarterial chemoembolization was the most common modality applied in 1,498 patients (15.1%). A total of 3,591 patients underwent rescue therapy after sorafenib, and the median overall survival was 14.5 months compared to 4.6 months in 7,332 patients who received supportive care after sorafenib. The mean duration of sorafenib administration in all patients was 105.7 days; 7,023 patients (70.8%) received an initial dose of 600 to 800 mg. The longest survival was shown in patients who received the recommended dose of 800 mg, subsequently reduced to 400 mg (15.0 months). The second longest survival was demonstrated in patients with a starting dose of 800 mg, followed by a dose reduction to 400-600 mg (9.6 months).

Real-life data show that the efficacy of sorafenib seems similar to that observed in clinical trials, suggesting that appropriate subsequent therapy after sorafenib might prolong patient survival.

To investigate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with PD-(L)1 inhibitors and molecular targeted therapies (MTT) for intermediate and advanced HCC that are unsuitable for transarterial chemoembolization (TACE).

We conducted a retrospective analysis of data from patients with TACE-unsuitable HCC who were receiving triple therapy from January 2020 to December 2021 at two medical centers. The primary outcome was overall survival (OS), and the secondary outcomes were progression-free survival (PFS), objective response rates (ORR), disease control rates (DCR), and incidence of adverse events (AEs).

A total of 55 patients were enrolled in the study with median treatment periods of 4 and 6 for HAIC and PD-(L)1 inhibitors, respectively. The median OS and PFS were 15.0 and 10.0 months, respectively, with a median follow-up of 11.0 months (range: 4.0-27.5 months). According to the mRECIST criteria, the optimal ORR was 43.6% (24/55) and the DCR was 61.8% (34/55). The incidence of AEs was 58.2%, with grade 3 and above accounting for 20.0%; elevated AST (18.2%), hyperbilirubinemia (16.4%), and thrombocytopenia (16.4%) were most common. There were no treatment-related fatalities and all AEs were effectively managed. Multifactorial analysis showed that NLR > 3.82 (HR 2.380, 95% CI 1.116-2-5.079, P = 0.025), ECOG 1 (HR 2.906, 95% CI 1.373-6.154, P = 0.005), and extrahepatic metastases (HR 8.373, 95% CI 3.492-20.078, P < 0.001) were associated with the median OS.

Triple therapy with HAIC, PD-(L)1 inhibitors, and MTT was safe and effective for patients with intermediate and advanced HCC for TACE-unsuitability.

Impaired function of organic cation transporter 1 (OCT1) in hepatocellular carcinoma (HCC) has been associated with unsatisfactory response to sorafenib. However, some patients lacking OCT1 at the plasma membrane (PM) of HCC cells still respond to sorafenib, suggesting that another transporter may contribute to take up this drug. The aim of this study was to investigate whether OCT3 could contribute to the uptake of sorafenib and other tyrosine kinase inhibitors (TKIs) and whether OCT3 determination can predict HCC response to sorafenib. Cells overexpressing OCT3 were used to determine the ability of this carrier to transport sorafenib. Immunostaining of OCT3 was performed in HCC samples obtained in the TRANSFER study. Considering the intensity of staining and the number of OCT3-positive cells, tumors were classified as having absent, weak, moderate, or strong OCT3 expression and were also categorized according to the presence or absence of PM staining. Functional in vitro studies revealed that OCT3 is also able to mediate sorafenib uptake. Other TKIs, such as regorafenib, lenvatinib, and cabozantinib can also interact with this transporter. In silico studies suggested that the expression of OCT3 is better preserved in HCC than that of OCT1. In HCC samples, OCT3 was expressed at the PM of cancer cells, and its presence, detected in 26% of tumors, was associated with better outcomes in patients treated with sorafenib. In conclusion, analysis by immunohistochemistry of OCT3 in the PM of tumor cells may help to predict the response of HCC patients to sorafenib and potentially to other TKIs.

Hepatocellular carcinoma (HCC) is a common malignancy and one of the leading causes of cancer-related death. The biological process of HCC is complex, with multiple factors leading to the broken of the balance of inactivation and activation of tumor suppressor genes and oncogenes, the abnormal activation of molecular signaling pathways, the differentiation of HCC cells, and the regulation of angiogenesis. Due to the insidious onset of HCC, at the time of first diagnosis, less than 30% of HCC patients are candidates for radical treatment. Systematic antitumor therapy is the hope for the treatment of patients with middle-advanced HCC. Despite the emergence of new systemic therapies, survival rates for advanced HCC patients remain low. The complex pathogenesis of HCC has inspired researchers to explore a variety of biomolecular targeted therapeutics targeting specific targets. Correct understanding of the molecular mechanism of HCC occurrence is key to seeking effective targeted therapy. Research on biomarkers for HCC treatment is also advancing. Here, we explore the molecular mechanism that are associated with HCC development, summarize targeted therapies for HCC, and discuss potential biomarkers that may drive therapies.

Several breakthroughs in hepatocellular carcinoma (HCC) therapy across tumor stages provide hope to improve its dismal prognosis. Although surgical and local ablative therapies have few significant changes in technique, an improved understanding of tumor biology has facilitated increase numbers of patients who are now eligible to undergo curative-intent procedures. Most notably, acceptable post-transplant outcomes can be achieved in well selected patients whose tumors are downstaged into Milan Criteria. Adjuvant therapy in patients at high risk of recurrence also significantly improves recurrence-free survival after resection or ablation. For patients with liver-localized disease who are not eligible for curative-intent procedures, transarterial chemoembolization (TACE) was historically the treatment modality of choice, regardless of tumor burden; however, there is now increased recognition of patients who are "TACE unsuitable" and may be better treated with systemic therapy. The greatest evolution in HCC treatment options has occurred with systemic therapy, where several new agents are now available in the first- and second-line setting, including immune checkpoint inhibitor combinations. Objective responses are observed in approximately 30% of patients and median survival is approaching 2 years. The availability of immune checkpoint inhibitors has renewed interest in combination therapies for earlier tumor stages, with several phase III trials ongoing. Considering increasing complexities of HCC care, requiring decisions between therapies delivered by different providers, multidisciplinary care is critical and is associated with improved clinical outcomes. In this review, we detail major breakthroughs in HCC therapy, how these breakthroughs can be applied in clinical practice, and remaining areas in need of further research.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The hypervascular nature of the majority of HCCs and the peculiar vascular derangement occurring during liver carcinogenesis underscore the importance of angiogenesis in the development and progression of these tumors. Indeed, several angiogenic molecular pathways have been identified as deregulated in HCC. The hypervascular nature and the peculiar vascularization of HCC, as well as deregulated angiogenic pathways, represent major therapeutic targets. To a large extent, intra-arterial locoregional treatments (transarterial-(chemo)embolization) rely on tumor ischemia caused by embolization of tumor feeding arteries, even though this may represent the "primum movens" of tumor recurrence through the activation of neoangiogenesis. Considering systemic therapies, the currently available tyrosine kinase inhibitors (sorafenib, regorafenib, cabozantinib and lenvatinib) and monoclonal antibodies (ramucirumab and bevacizumab, in combination with the anti-PD-L1, atezolizumab) primarily target, among others, angiogenic pathways. Considering the importance of angiogenesis in the pathogenesis and treatment of liver cancer, in this paper, we aim to review the role of angiogenesis in HCC, addressing the molecular mechanisms, available antiangiogenic therapies and prognostic biomarkers in patients receiving these treatments.

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.

The treatment landscape of advanced hepatocellular carcinoma (HCC) has broadened with immune checkpoint inhibitors (ICIs) setting a novel standard of care. With the increased number of therapies either in first or in further line, disentangling the possible treatment sequences has become much more complex. Yet, all the second-line therapies have been evaluated after sorafenib. After ICIs, offering multikinase inhibitors is a widespread approach, either shifting forward sorafenib or lenvatinib, or choosing among regorafenib or cabozantinib, already approved in the refractory setting. Under specific circumstances, ICIs could be maintained beyond disease progression in patients with proven clinical benefit, as supported by some data emerging from phase III clinical trials with immunotherapy in HCC. Rechallenge with ICIs is an additional attractive alternative, although requiring careful and individual evaluation as efficacy and safety of such a strategy have not been yet clarified. Still, a considerable number of patients displays primary resistance to ICIs and might benefit from antiangiogenics either alone or in addition to ICIs instead. Hopefully, the ongoing clinical trials will enlighten regarding the most effective treatment pathways. The identification of predictive correlates of response to immunotherapy will help treatment allocation at each stage, thus representing an urgent matter to address in HCC research. With programmed death ligand 1 expression, tumor mutational burden, and microsatellite status being inadequate biomarkers in HCC, patient characteristics, drug safety profile, and regulatory approval remain key elements to acknowledge in routine practice. Despite the tissue remaining a preferred source, biomarkers discovery could take advantage of liquid biopsy to overcome the matter of tissue availability and track tumor changes. Lastly, tumor genetic phenotypes, tumor microenvironment features, gut microbiome, and markers of immune response and systemic inflammation are all potential emergent predictors of response to ICIs, pending validation in the clinical setting.

Hepatocellular carcinoma (HCC) is one of the most common and deadly malignancies worldwide. Approximately, 80% of patients are initially diagnosed at intermediate or advanced stages, which means that curative therapies are unable to be performed. In most cases, systemic treatment is ineffective, especially when conventional cytotoxic agents are used. Sorafenib has been the only systemic agent proven to be effective in treating advanced HCC for over a decade. The rapid development of immunotherapy has remarkably revolutionized the management of advanced HCC. Besides, the combination of immunotherapy with molecular targeted agents or locoregional treatments is emerging as an effective tool for enhancing immunity. In the review, an overview of immunotherapy and its combination therapies for HCC is presented.

Since the approval of sorafenib for systemic treatment of advanced hepatocellular carcinoma (HCC), many tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have shown efficacy and tolerability as first-line treatments. On the other hand, these first-line therapies are associated with low objective response and drug resistance. Many drugs have been successfully tested for second-line treatment of advanced HCC. While the rapid proliferation of second-line treatments for advanced HCC brings hope to patients, it also complicates clinical decision-making.

This review aims to facilitate decisions by summarizing the latest guidelines for second-line treatment of HCC in various countries or regions. We then review existing second-line treatment options and discuss challenges that should be addressed in the future. A literature search was conducted in April 2022 of PubMed/Medline, Cochrane library, and abstracts of international cancer meetings.

There is no standard second-line treatment, especially for the case of sequential treatment after atezolizumab plus bevacizumab (atezo+bev) and further studies focused on sequential treatment are warranted in this setting. The design of clinical trials, different etiologies, and complications or quality of life (QoL) are interesting issues in the second-line setting.

Dermatologic adverse events (DAEs) are associated with a better outcome in patients with hepatocellular carcinoma (HCC) irrespective of the therapeutic agent received. The exact mechanisms associated with the development of DAEs are unknown although several studies point to direct toxicity of tyrosine kinase inhibitors (TKIs) to the skin or an immune-mediated reaction triggered by the oncologic treatment. As is the case in other conditions, individual genetic variants may partially explain a higher risk of DAEs.

To evaluate the contribution of several gene variants to the risk of developing DAEs in HCC patients treated with TKIs.

We first analyzed 27 single-nucleotide polymorphisms (SNPs) from 12 genes selected as potential predictors of adverse event (AE) development in HCC patients treated with sorafenib [Barcelona Clinic Liver Cancer 1 (BCLC1) cohort]. Three additional cohorts were analyzed for AGT1 (rs699) and AGT2 (rs4762) polymorphisms-initially identified as predictors of DAEs: BCLC2 (n = 79), Northern Italy (n = 221) and Naples (n = 69) cohorts, respectively. The relation between SNPs and DAEs and death were assessed by univariate and multivariate Cox regression models, and presented with hazard ratios and their 95% confidence intervals (95%CI).

The BCLC1 cohort showed that patients with arterial hypertension (AHT) (HR = 1.61; P value = 0.007) and/or AGT SNPs had an increased risk of DAEs. Thereafter, AGT2 (rs4762) AA genotype was found to be linked to a statistically significant increased probability of DAEs (HR = 5.97; P value = 0.0201, AA vs GG) in the Northern Italy cohort by multivariate analysis adjusted for BCLC stage, ECOG-PS, diabetes and AHT. The value of this genetic marker was externally validated in the cohort combining the BCLC1, BCLC2 and Naples cohorts [HR = 3.12 (95%CI: 1.2-8.14), P value = 0.0199, AGT2 (rs4762) AA vs AG genotype and HR = 2.73 (95%CI: 1.18-6.32) P value = 0.0188, AGT2 (rs4762) AA vs GG genotype]. None of the other gene variants tested were found to be associated with the risk of DAE development.

DAE development in HCC patients receiving TKIs could be explained by the AGT2 (rs4762) gene variant. If validated in other anti-oncogenic treatments, it might be considered a good prognosis marker.

Circulating endothelial progenitor cells (EPC) predict tumor vascularization and disease progression, but limited information is available on their dynamics in hepatocellular carcinoma (HCC) undergoing systemic treatment.

We prospectively analyzed different populations of EPC in 16 patients with advanced HCC receiving sorafenib. Patients were studied before therapy (T0, n = 16) and after two (T2, n = 12) and eight weeks (T8, n = 8), using high-performance flow-cytometry. The tumor response at T8 was categorized as progressive disease (PD) or clinical benefit (CB, all other responses).

At T0, higher levels of CD34⁺CD133⁺KDR⁺ and CD34⁺KDR⁺ were observed in patients with alpha-fetoprotein ≥400 ng/ml or non-viral liver disease, whereas CD34⁺CD133⁺KDR⁺ cells were virtually absent in patients with vascular invasion. CD34⁺KDR⁺ and CD34⁺CD133⁺KDR⁺ were directly correlated with platelet count. Frequencies of all populations of EPC declined in patients receiving sorafenib. Levels of CD34⁺CD133⁺ were higher at T0 in patients with CB compared to patients with PD. In patients belonging to the CB group CD34⁺KDR⁺ cells at T0 were directly correlated to platelet count.

In patients with advanced HCC, EPC are directly correlated with platelet count, suggesting a common activation of selected bone marrow pathways. Levels of a CD34⁺KDR⁺ are higher at baseline in patients responding to sorafenib.

Hydrogen sulfide (H2S) is an endogenous biologically active gas produced in mammalian tissues. It plays a very critical role in many pathophysiological processes in the body. It can be endogenously produced through many enzymes analogous to the cysteine family, while the exogenous source may involve inorganic sulfide salts. H2S has recently been well investigated with regard to the onset of various carcinogenic diseases such as lung, breast, ovaries, colon cancer, and neurodegenerative disorders. H2S is considered an oncogenic gas, and a potential therapeutic target for treating and diagnosing cancers, due to its role in mediating the development of tumorigenesis. Here in this review, an in-detail up-to-date explanation of the potential role of H2S in different malignancies has been reported. The study summarizes the synthesis of H2S, its roles, signaling routes, expressions, and H2S release in various malignancies. Considering the critical importance of this active biological molecule, we believe this review in this esteemed journal will highlight the oncogenic role of H2S in the scientific community.

Background: Predictive biomarkers for advanced hepatocellular carcinoma are lacking. EZH2 drives sorafenib resistance through H3K27me3 and is counteracted by SETD2, which catalyzes H3K36me3. The authors tested the predictive power of circulating H3K27me3 and H3K36me3 in advanced hepatocellular carcinoma patients treated with sorafenib. Methods: A total of 80 plasma samples were tested for histone variants by ELISA. Changes from baseline to best response or progressive disease were correlated with patient survival. Results: A higher EZH2/SETD2 ratio predicted worse prognosis in this setting. H3K27me3 and H3K36me3 decreased from baseline to best response. The H3K27me3/H3K36me3 ratio increased from baseline to progressive disease. Higher ratios at best response were associated with shorter progression-free survival. Conclusion: The authors suggest that circulating H3K27me3/H3K36me3 ratio level acts as a predictive biomarker for sorafenib treatment outcomes in patients with advanced hepatocellular carcinoma.

The number of effective systemic therapies for the treatment of advanced hepatocellular carcinoma (HCC) is rapidly increasing, and the advent of immunotherapy has changed the treatment paradigm for these patients, leading to significantly improved survival outcomes. However, many patients with HCC will continue to receive tyrosine kinase inhibitors, partly because of contraindications to immune checkpoint inhibitors. Currently, the best sequential first- and second-line systemic treatment remains elusive. Maintenance of optimal liver function is crucial, it is likely to impinge on temporary or permanent treatment discontinuation, and should also be considered when defining the treatment sequence. Hepatic decompensation, which does not always coincide with disease progression, is part of this complex dynamically evolving system, and must be promptly recognized and adequately managed to allow the patient to continue in the therapeutic course. The purpose of this review is to highlight and summarize the evidence on the efficacy and safety of systemic agents, with a focus on the impact of underlying cirrhosis, and to suggest new clinical outcomes for randomized controlled trials for advanced HCC to better assess the net health benefit in this specific setting.

Hepatocellular carcinoma (HCC) remains one of the most prevalent and deadliest cancers. The poor outcome associated with HCC is dramatically changing due to the advent of effective systemic therapies. Here we discuss the molecular pathogenesis of HCC, molecular classes and determinants of heterogeneity. In addition, effective single-agent and combination systemic therapies involving immunotherapies as standard of care are analyzed. Finally, we propose a flowchart of sequential therapies, explore mechanisms of resistance and address the need for predictive biomarkers.