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Simple Summary: The only potentially curative treatment of perihilar cholangiocarcinoma (PHC) is complete (R0) resection. This is difficult to achieve and great effort should be made to optimise surgical margins assessment and to thoroughly define their prognostic value. When considering resections for PHC, not only bile duct margins (ductal margins, DM), but also the liver transection plane and the dissection plane in the hepatoduodenal ligament (radial margins, RM) should be examined. Studies concerning PHC resections with comprehensive analyses of the recurrence and survival related to margins status most frequently consider only ductal margins. The importance of also assessing radial margins' prognostic value was recently introduced and deserves to be further studied. To our knowledge, there is currently no evidence of prognostic value of isolated positive RM. Therefore, the aim of this study was to evaluate the incidence and to investigate the effects on the recurrence and survival of positive isolated RM in resected PHC. In resected perihilar cholangiocarcinoma (PHC), positive ductal margin (DM) is associated with poor survival. There is currently little knowledge about the impact of positive radial margin (RM) when DM is negative. The aim of this study was to evaluate the incidence and the role of positive RM. Patients who underwent surgery between 2005 and 2017 where retrospectively reviewed and stratified according to margin positivity: an isolated RM-positive group and DM ± RM group. Of the 75 patients identified; 34 (45.3%) had R1 resection and 17 had positive RM alone. Survival was poorer in patients with R1 resection compared to R0 (p = 0.019). After stratification according to margin positivity; R0 patients showed better survival than DM ± RM-positive patients (p = 0.004; MST 43.9 vs. 23.6 months), but comparable to RM-positive patients (p = 0.361; MST 43.9 vs. 39.5 months). Recurrence was higher in DM ± RM group compared to R0 (p = 0.0017; median disease-free survival (DFS) 15 vs. 30 months); but comparable between RM and R0 group (p = 0.39; DFS 20 vs. 30 months). In univariate and multivariate analysis, DM positivity resulted as a negative prognostic factor both for survival and recurrence. In conclusion, positive RM resections appear to have different recurrence patterns and survival rates than positive DM resections. [ABSTRACT FROM AUTHOR]

Simple Summary: Biliary tract cancer (BTC) is often refractory to conventional therapeutics and is difficult to diagnose in the early stages. In addition, the pathogenesis of BTC is not fully understood, despite recent advances in cancer genome analysis. To address these issues, the development of fine disease models is critical for BTC. Although still limited in number, there are various platforms for genetic models of BTC owing to newly emerging technology. Among these, implantation-based models have recently drawn attention for their convenience, flexibility, and scalability. To highlight the relevance of this approach, we comprehensively summarize the advantages and disadvantages of BTC models developed using diverse approaches. Currently available research data on intra- and extrahepatic cholangiocarcinoma and gallbladder carcinoma are presented in this review. This information will likely help in selecting the optimal models for various applications and develop novel innovative models based on these technologies. Epithelial cells in the biliary system can develop refractory types of cancers, which are often associated with inflammation caused by viruses, parasites, stones, and chemicals. Genomic studies have revealed recurrent genetic changes and deregulated signaling pathways in biliary tract cancer (BTC). The causal roles have been at least partly clarified using various genetically engineered mice. Technical advances in Cre-LoxP technology, together with hydrodynamic tail injection, CRISPR/Cas9 technology, in vivo electroporation, and organoid culture have enabled more precise modeling of BTC. Organoid-based genetic modeling, combined with implantation in mice, has recently drawn attention as a means to accelerate the development of BTC models. Although each model may not perfectly mimic the disease, they can complement one another, or two different approaches can be integrated to establish a novel model. In addition, a comparison of the outcomes among these models with the same genotype provides mechanistic insights into the interplay between genetic alterations and the microenvironment in the pathogenesis of BTCs. Here, we review the current status of genetic models of BTCs in mice to provide information that facilitates the wise selection of models and to inform the future development of ideal disease models. [ABSTRACT FROM AUTHOR]

Simple Summary: Skeletal muscle volume has been reported as a prognostic factor for patients with hepatocellular carcinoma receiving sorafenib. In this study, we show that skeletal muscle volume is not only a predictor of overall survival but also of post-progression survival, which represents survival time following confirmation of progressive disease. We may be able to prolong survival by upregulating skeletal muscle volume, especially in hepatocellular carcinoma patients with skeletal muscle depletion. Few studies exist on the relationship between post-progression survival (PPS) and skeletal muscle volume in hepatocellular carcinoma (HCC) patients receiving sorafenib. This study aimed to analyze the effects of muscle volume on clinical outcomes. We retrospectively enrolled 356 HCC patients. Various clinical parameters, including skeletal muscle index, were analyzed as predictors of overall survival (OS), progression-free survival (PFS), and PPS. Patients with high muscle volume showed longer survival or PPS than those with low muscle volume (median survival time: 12.8 vs. 9.5 months, p = 0.005; median PPS: 8.2 vs. 6.3 months, p = 0.015); however, no differences in PFS were found. Multivariate analysis indicated that muscle volume was an independent predictor of PPS and OS. Skeletal muscle volume was a PPS predictor in HCC patients receiving sorafenib. Therefore, survival can be prolonged by the upregulation of skeletal muscle volume, especially in HCC patients with skeletal muscle depletion. [ABSTRACT FROM AUTHOR]

Simple Summary: Irreversible electroporation (IRE) is an effective alternative for the ablation of small hepatocellular carcinoma (HCC) less than 2 cm, which is often poorly visible under unenhanced computed tomography (CT) and/or an ultrasound resulting in the difficulties of complete ablation. In this study, to achieve successful ablation on these small target HCCs with poor invisibility, the combination of transarterial ethiodized oil tumor marking with sequential computed tomography (CT)-guided IRE was performed. After marking, all 11 target-HCCs demonstrated complete visualization in post-marking CT, which were invisible in pre-marking CT. Technically successful ablation was achieved in all sequential IRE procedures. In the follow-up, no residual unablated tumor was observed and the two-year local tumor progression was 27.3%. Thus, ethiodized oil tumor marking with sequential CT-guided IRE is a safe and feasible combination to treat small HCC which was invisible in unenhanced CT. Introduction. To explore the feasibility, safety, and efficiency of ethiodized oil tumor marking combined with irreversible electroporation (IRE) for small hepatocellular carcinomas (HCCs) that were invisible on unenhanced computed tomography (CT). Methods. A retrospective analysis of the institutional database was performed from January 2018 to September 2018. Patients undergoing ethiodized oil tumor marking to improve target-HCC visualization in subsequent CT-guided IRE were retrieved. Target-HCC visualization after marking was assessed, and the signal-to-noise ratios (SNRs) and contrast-to-noise ratios (CNR) were compared between pre-marking and post-marking CT images using the paired t-test. Standard IRE reports, adverse events, therapeutic endpoints, and survival were summarized and assessed. Results. Nine patients with 11 target-HCCs (11.1–18.8 mm) were included. After marking, all target-HCCs demonstrated complete visualization in post-marking CT, which were invisible in pre-marking CT. Quantitatively, the SNR of the target-HCCs significantly increased after marking (11.07 ± 4.23 vs. 3.36 ± 1.79, p = 0.006), as did the CNR (4.32 ± 3.31 vs. 0.43 ± 0.28, p = 0.023). In sequential IRE procedures, the average current was 30.1 ± 5.3 A, and both the delta ampere and percentage were positive with the mean values of 5.8 ± 2.1 A and 23.8 ± 6.3%, respectively. All procedures were technically successful without any adverse events. In the follow-up, no residual unablated tumor (endpoint-1) was observed. The half-year, one-year, and two-year local tumor progression (endpoint-2) rate was 0%, 9.1%, and 27.3%. The two-year overall survival rate was 100%. Conclusions. Ethiodized oil tumor marking enables to demarcate small HCCs that were invisible on unenhanced CT. It potentially allows a safe and complete ablation in subsequent CT-guided IRE. [ABSTRACT FROM AUTHOR]

Simple Summary: This review proposes a comprehensive overview of the main prognostic systems for HCC classified as prognostic scores, staging systems, or combined systems. Prognostic systems for HCC are usually compared in terms of homogeneity, monotonicity of gradients, and discrimination ability. However, despite the great number of published studies comparing HCC prognostic systems, it is rather difficult to identify a system that could be universally accepted as the best prognostic scheme for all HCC patients encountered in clinical practice. In order to give a contribute in this topic, we conducted a study aimed at externally validate the MESH score and the CNLC classification using the ITA.LI.CA database. Prognostic assessment in patients with HCC remains an extremely difficult clinical task due to the complexity of this cancer where tumour characteristics interact with degree of liver dysfunction, patient general health status, and a large span of available treatment options. Several prognostic systems have been proposed in the last three decades, both from the Asian and European/North American countries. Prognostic scores, such as the CLIP score and the recent MESH score, have been generated on a solid statistical basis from real life population data, while staging systems, such as the BCLC scheme and the recent CNLC classification, have been created by experts according to recent HCC prognostic evidences from the literature. A third category includes combined prognostic systems that can be used both as prognostic scores and staging systems. A recent example is the ITA.LI.CA prognostic system including either a prognostic score and a simplified staging system. This review focuses first on an overview of the main prognostic systems for HCC classified according to the above three categories, and, second, on a comprehensive description of the methodology required for a correct comparison between different systems in terms of prognostic performance. In this second section the main studies in the literature comparing different prognostic systems are described in detail. Lastly, a formal comparison between the last prognostic systems proposed for each of the above three categories is performed using a large Italian database including 6882 HCC patients in order to concretely apply the comparison rules previously described. [ABSTRACT FROM AUTHOR]

Simple Summary: Due to the rapid increase of primary liver cancer incidence and the poor prognosis, it is imperative to identify new modifiable factors such as diet and nutrition for the prevention of liver cancer. Diet high in saturated fatty acids (SFA) has been hypothesized to be associated with increased risk of cancers. However, the associations between dietary fatty acids and liver cancer are not consistent. We aimed to examine the association between dietary total fat, its major components, serum cholesterol, and risk of liver cancer combining current evidence from prospective studies. Our meta-analyses provided new evidence on associations between dietary fats, serum cholesterol, and liver cancer risk. Higher intake of dietary SFA was associated with higher risk of liver cancer while higher serum levels of cholesterol and high-density lipoprotein (HDL) were associated with a lower risk of liver cancer with high between-studies variability. Based on our findings, reducing dietary SFA may help to prevent the development of liver cancer. To quantify the associations between dietary fats and their major components, as well as serum levels of cholesterol, and liver cancer risk, we performed a systematic review and meta-analysis of prospective studies. We searched PubMed, Embase, and Web of Science up to October 2020 for prospective studies that reported the risk estimates of dietary fats and serum cholesterol for liver cancer risk. We carried out highest versus lowest intake or level and dose-response analyses. Higher intake of dietary saturated fatty acids (SFA) was associated with a higher liver cancer risk in both category analysis (relative risk [RR]highest vs. lowest intake = 1.34, 95% confidence interval [CI]: 1.06, 1.69) and dose-response analysis (RR1% energy = 1.04, 95%CI: 1.01, 1.07). Higher serum total cholesterol was inversely associated with liver cancer but with large between-studies variability (RR1 mmol/L = 0.72, 95%CI: 0.69, 0.75, I2 = 75.3%). The inverse association was more pronounced for serum high-density lipoprotein (HDL) cholesterol (RR1 mmol/L = 0.42, 95%CI: 0.27, 0.64). Higher intake of dietary SFA was associated with higher risk of liver cancer while higher serum levels of cholesterol and HDL were associated with a lower risk of liver cancer with high between-studies variability. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is among the most common cancer diseases worldwide and has only limited treatment options at advanced disease stages. Activation of the immune system with checkpoint inhibitors has revolutionized cancer medicine and has become important also for HCC treatment. Here, we summarize the current status of immunotherapy options for HCC and highlight how combination with locoregional therapies could improve the outcome of patients. Novel pathways and targets for immunologic drug development are briefly discussed that could help to increase the response rate of these approaches in HCC. Background: Hepatocellular carcinoma (HCC) still represents a human tumor entity with very limited therapeutic options, especially for advanced stages. Here, immune checkpoint modulating drugs alone or in combination with local ablative techniques could open a new and attractive therapeutic "door" to improve outcome and response rate for patients with HCC. Methods: Published data on HCC experimental to pre-(clinical) treatment strategies from standard of care to novel immunomodulatory concepts were summarized and discussed in detail. Results: Overall, our knowledge of the role of immune checkpoints in HCC is dramatically increased in the last years. Experimental and pre-clinical findings could be translated to phase 1 and 2 clinical trials and became standard of care. Local ablative techniques of HCC could improve the effectivity of immune checkpoint inhibitors in situ. Conclusions: This review demonstrates the importance of immunomodulatory treatment strategies of HCC, whereby the "best treatment code" of immune checkpoint drugs, combination with ablative techniques and of timing must be evaluated in coming clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: There is a growing body of literature demonstrating high cancer drug costs relative to the benefits provided to patients treated on a large scale. We examined the cost-effectiveness of atezolizumab–bevacizumab for the first-line treatment of patients with unresectable hepatocellular carcinoma, based on the results of the pivotal phase 3 trial IMbrave 150. Our model was most sensitive to the overall survival hazard ratio and body weight. We found that atezolizumab–bevacizumab was cost-effective if we assumed all patients at the end of the IMbrave 150 trial were cured of hepatocellular carcinoma. Otherwise, atezolizumab–bevacizumab was not cost-effective. We concluded that price reduction, duration of therapy capped to ≤12 months, or dosage of bevacizumab reduced to ≤10 mg/kg would favorably influence cost-effectiveness, even if long-term clinical benefits were modest. The long-term effectiveness of atezolizumab–bevacizumab is a critical factor of its cost-effectiveness. Further studies to optimize the duration and dosage of therapy are warranted. Background: The IMbrave 150 trial revealed that atezolizumab plus bevacizumab (atezo–bev) improves survival in patients with unresectable hepatocellular carcinoma (HCC) (1 year survival rate: 67.2% vs. 54.6%). We assessed the cost-effectiveness of atezo–bev vs. sorafenib as first-line therapy in patients with unresectable HCC from the US payer perspective. Methods: Using data from the IMbrave 150, we developed a Markov model to compare the lifetime cost and efficacy of atezo–bev as first-line systemic therapy in HCC with those of sorafenib. The main outcomes were life-years, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratio (ICER). Results: Atezo–bev demonstrated a gain of 0.44 QALYs, with an additional cost of USD 79,074. The ICER of atezo–bev was USD 179,729 per QALY when compared with sorafenib. The model was most sensitive to the overall survival hazard ratio and body weight. If we assumed that all patients at the end of the IMbrave 150 trial were cured of HCC, atezo–bev was cost-effective (ICER USD 53,854 per QALY). However, if all patients followed the Surveillance, Epidemiology, and End Results data, the ICER of atezo–bev was USD 385,857 per QALY. Reducing the price of atezo–bev by 20% and 29% would satisfy the USD 150,000/QALY and 100,000/QALY willingness-to-pay threshold. Moreover, capping the duration of therapy to ≤12 months or reducing the dosage of bev to ≤10 mg/kg would render atezo–bev cost-effective. Conclusions: The long-term effectiveness of atezo–bev is a critical but uncertain determinant of its cost-effectiveness. Price reduction would favorably influence cost-effectiveness, even if long-term clinical outcomes were modest. Further studies to optimize the duration and dosage of therapy are warranted. [ABSTRACT FROM AUTHOR]

Simple Summary: Some patients with hepatocellular carcinoma (HCC) obtain a very long survival, irrespective of any prediction. In this study, we looked for the impact of surveillance in long-term survival of HCC patients. After adjustment for confounders in multivariable logistic regression analysis, diagnosis under surveillance remained an independent predictor of long-term survival. In the surveillance group, observed and lead-time corrected survivals were significantly longer than in patients with casual/symptomatic diagnosis. However, when adjusted for baseline characteristics with inverse probability weights, surveillance and no surveillance groups demonstrated a similar survival, suggesting that the beneficial effect of surveillance is mediated by early stage diagnosis, which allows higher applicability of curative treatments. Surveillance is a major determinant of long-term survival and a wide implementation of surveillance programs should be pursued in order to improve the still poor prognosis of HCC patients. Purpose: We aimed at assessing the impact of surveillance on long-term survival in HCC patients. Methods: From the ITA.LI.CA database, we selected 1028 cases with long (≥5 years, LS group) and 2721 controls with short-term survival (<5 years, SS group). The association between surveillance and LS was adjusted for confounders by multivariable logistic regression analysis. Survival of surveilled patients was presented both as observed and corrected for the lead-time bias, and the comparison of survival between surveillance and no surveillance groups was also performed after balancing the baseline characteristics with inverse probability weights (IPW). Results: LS patients were more frequently diagnosed under surveillance (p < 0.0001), and had more favorable baseline characteristics. Surveillance was an independent predictor of LS (OR = 1.413, 95% CI 1.195–1.671; p < 0.0001). The observed and the lead-time corrected survival of surveilled patients were significantly longer compared to the survival of not surveilled patients (p < 0.0001 and p = 0.0008, respectively). In IPW adjusted populations, no survival differences were demonstrated between the two groups (p = 0.30). Conclusions: Surveillance, increasing early-stage diagnosis and applicability of curative treatments, is a fundamental determinant of long-term survival in HCC patients. A wide implementation of surveillance programs should be pursued in order to improve HCC patients' prognosis. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, efficacy and safety of embolization alone and trans-arterial chemoembolization were compared in 265 patients with intermediate stage hepatocellular carcinoma. Trans-arterial chemoembolization was associated with a significant increase of complete radiological response, but without significant impact on overall response, and survival outcomes after propensity score matching. Both techniques showed similar safety profiles. To this day, embolization alone and trans-arterial chemoembolization are two available options in the treatment of intermediate stage hepatocellular carcinoma. No definitive conclusion could be reached about the role of chemotherapy in adjunction of embolization in the treatment of hepatocellular carcinoma (HCC). We aim to compare radiological response, toxicity and long-term outcomes of patients with hepatocellular carcinoma (HCC) treated by trans-arterial bland embolization (TAE) versus trans-arterial chemoembolization (TACE). We retrospectively included 265 patients with HCC treated by a first session of TACE or TAE in two centers. Clinical and biological features were recorded before the treatment and radiological response was assessed after the first treatment using modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. Correlation between the treatment and overall, progression-free and transplantation-free survival was performed after adjustment using a propensity score matching: 86 patients were treated by bland embolization and 179 patients by TACE, including 44 patients with drug-eluting beads and 135 with lipiodol TACE, 89.8% of patients were male with a median age of 65 years old. Cirrhosis was present in 90.9% of patients with a Child Pugh score A in 84% of cases. After adjustment, no difference in the rate of AE, including liver failure, was observed between the two treatments. TACE was associated with a significant increase in complete radiological response (odds ratio (OR) = 8.5 (95% confidence interval (CI): 2.8–25.4)) but not in the overall response rate (OR = 2.2 (95% CI = 0.8–5.8)). No difference in terms of overall survival (p = 0.3905), progression-free survival (p = 0.4478) and transplantation-free survival (p = 0.9020) was observed between TACE and TAE. TACE was associated with a higher rate of complete radiological response but without any impact on overall radiological response, progression-free survival and overall survival compared to TAE. [ABSTRACT FROM AUTHOR]

Simple Summary: Individual patients with liver cancer have a highly variable clinical course. Hence, there is an urgent need to identify new prognostic markers to determine prognosis and select specific therapies. Expression of two key enzymes in pyrimidine synthesis was analyzed in a large, well-characterized cohort of patients with liver cancer. Dysregulated expression of these enzymes was associated with shorter survival of the patients. A combined score of both markers was found to be a statistically independent prognostic marker. Patients with hepatocellular carcinoma (HCC) have a highly variable clinical course. Therefore, there is an urgent need to identify new prognostic markers to determine prognosis and select specific therapies. Recently, it has been demonstrated that dysregulation of the urea cycle (UC) is a common phenomenon in multiple types of cancer. Upon UC dysregulation, nitrogen is diverted toward the multifunctional enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD), and increases pyrimidine synthesis. In this study, we investigated the role of CAD and carbamoyl-phosphate synthetase 1 (CPS1), a rate-limiting enzyme of the UC highly expressed in hepatocytes, in HCC. We created a tissue microarray to analyze expression of both enzymes by immunohistochemistry in a large and well-characterized overall cohort of 871 HCCs of 561 patients that underwent surgery. CAD was induced in recurrent HCCs, and high expression predicted shorter overall survival. CPS1 was downregulated in HCC and further reduced in recurrent tumors and distant metastases. Additionally, low CPS1 was associated with short overall survival. A combined score of both enzymes was an independent prognostic marker in a multivariate Cox regression model (HR = 1.37, 95% confidence interval 1.06–1.75, p = 0.014). Inhibition of pyrimidine synthesis may represent a novel therapeutic strategy for HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is one of the deadliest cancer. Clinical guidelines for the management of HCC endorse algorithms deriving from clinical variables whose performances to prognosticate HCC is limited. Liquid biopsy is the molecular analysis of tumor by-products released into the bloodstream. It offers minimally-invasive access to circulating analytes like DNA, RNA, exosomes and cells. This technology demonstrated promising results for various applications in cancers, including prognostication. This review aimed to provide a comprehensive overview of the contribution of liquid biopsy in HCC prognostication. The results suggested that liquid biopsy may be a polyvalent and valuable tool to prognosticate HCC. Showing a steadily increasing cancer-related mortality, the epidemiological evolution of hepatocellular carcinoma (HCC) is concerning. Numerous strategies have attempted to prognosticate HCC but their performance is modest; this is partially due to the heterogeneous biology of this cancer. Current clinical guidelines endorse classifications and scores that use clinical variables, such as the Barcelona Clinic Liver Cancer (BCLC) classification. These algorithms are unlikely to fully recapitulate the genomic complexity of HCC. Integrating molecular readouts on a patient-basis, following a precision-medicine perspective, might be an option to refine prognostic systems. The limited access to HCC tissue samples is an important limitation to these approaches but it could be partially circumvented by using liquid biopsy. This concept consists of the molecular analysis of products derived from a solid tumor and released into biological fluids, mostly into the bloodstream. It offers an easy and minimally-invasive access to DNA, RNA, extracellular vesicles and cells that can be analyzed with next-generation sequencing (NGS) technologies. This review aims to investigate the potential contributions of liquid biopsy in HCC prognostication. The results identified prognostic values for each of the components of liquid biopsy, suggesting that this technology may help refine HCC prognostication. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is the most prevalent tumor of the liver and represents the second most common cause of oncological-related deaths worldwide. Despite all progress made in the field, surgical resection or liver transplantation are, at the moment, the only curative therapies available. Liver resection, especially for large, central tumors, are at risk of important bleeding. Significative hemorrhage during HCC resections have been linked to an increased rate of post-operative complications and tumor recurrence. Therefore, hepatic pedicle clamping during surgery has been used in order to reduce the bleeding risks. However, this method induces ischemia/reperfusion injuries, which has also been associated with tumor recurrence. For this reason, we aimed to evaluate if pedicle clamping is indeed associated with tumor recurrence and shorter survival, by performing a systematic review of the literature and meta-analysis. Liver pedicle clamping minimizes surgical bleeding during hepatectomy. However, by inducing ischemia-reperfusion injury to the remnant liver, pedicle clamping may be associated with tumor recurrence in the regenerating liver. Hepatocellular carcinoma (HCC) having a high rate of recurrence, evidences demonstrating an eventual association with pedicle clamping is strongly needed. We did a systematic review of the literature until April 2020, looking at studies reporting the impact of liver pedicle clamping on long-term outcomes in patients undergoing liver resection for HCC. Primary and secondary outcomes were overall survival (OS) and disease-free survival, respectively. Results were obtained by random-effect meta-analysis and expressed as standardized mean difference (SMD). Eleven studies were included, accounting for 8087 patients. Results of seven studies were pooled in a meta-analysis. Findings indicated that, as compared to control patients who did not receive liver pedicle clamping, those who did had a significantly shorter OS (SMD = −0.172, 95%CI: −0.298 to −0.047, p = 0.007, I2 = 76.8%) and higher tumor recurrence rates (odds ratio 1.36 1.01 to 1.83. p = 0.044, I2 = 50.7%). This meta-analysis suggests that liver pedicle clamping may have a deleterious impact on long-term outcomes. An individual patient-data meta-analysis of randomized trials evaluating liver pedicle clamping is urgently needed. [ABSTRACT FROM AUTHOR]

Despite progress in our understanding of the biology of hepatocellular carcinoma (HCC), this tumour remains difficult-to-cure for several reasons, starting from the particular disease environment where it arises—advanced chronic liver disease—to its heterogeneous clinical and biological behaviour. The advent, and good results, of immunotherapy for cancer called for the evaluation of its potential application also in HCC, where there is evidence of intra-hepatic immune response activation. Several studies advanced our knowledge of immune checkpoints expression in HCC, thus suggesting that immune checkpoint blockade may have a strong rationale even in the treatment of HCC. According to this background, initial studies with tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, and nivolumab, a programmed cell death protein 1 (PD-1) antibody, showed promising results, and further studies exploring the effects of other immune checkpoint inhibitors, alone or with other drugs, are currently underway. However, we are still far from the identification of the correct setting, and sequence, where these drugs might be used in clinical practice, and their actual applicability in real-life is unknown. This review focuses on HCC immunobiology and on the potential of immune checkpoint blockade therapy for this tumour, with a critical evaluation of the available trials on immune checkpoint blocking antibodies treatment for HCC. Moreover, it assesses the potential applicability of immune checkpoint inhibitors in the real-life setting, by analysing a large, multicentre cohort of Italian patients with HCC. [ABSTRACT FROM AUTHOR]

Growing interest is recently being focused on the role played by the platelets in favoring hepatocellular cancer (HCC) growth and dissemination. The present review reports in detail both the experimental and clinical evidence published on this topic. Several growth factors and angiogenic molecules specifically secreted by platelets are directly connected with tumor progression and neo-angiogenesis. Among them, we can list the platelet-derived growth factor, the vascular endothelial growth factor, the endothelial growth factor, and serotonin. Platelets are also involved in tumor spread, favoring endothelium permeabilization and tumor cells' extravasation and survival in the bloodstream. From the bench to the clinics, all of these aspects were also investigated in clinical series, showing an evident correlation between platelet count and size of HCC, tumor biological behavior, metastatic spread, and overall survival rates. Moreover, a better understanding of the mechanisms involved in the platelet–tumor axis represents a paramount aspect for optimizing both current tumor treatment and development of new therapeutic strategies against HCC. [ABSTRACT FROM AUTHOR]